CN1997731A - Methods of using ammonia oxidizing bacteria - Google Patents

Abstract

A use of ammonia oxidizing bacteria in the manufacture of a medicament and a method for treating a subject who has developed or is at risk of developing at least one of hypertension, hypertrophic organ degeneration, Raynaud's phenomena, fibrotic organ degeneration, allergies, autoimmune sensitization, end stage renal disease, obesity, diabetes type 1, osteoporosis, impotence, hair loss, cancer, aging, autism, and an autism spectrum symptom comprising positioning ammonia oxidizing bacteria close proximity of a surface of the subject, of nitric oxide and nitric oxide precursors using ammonia oxidizing bacteria.

Description

Use the method for ammonia oxidizing bacteria

Technical field

The invention relates to a composition that contains the ammonia oxidizing bacteria that when being used for the patient surface, can increase nitrogen protoxide and precursor generation thereof, with the patient is used ammonia oxidizing bacteria particularly nitrogen protoxide to delay senility, treat and prevent hypertension, loose sexual organ sex change (hypertrophic organ degneneration), Raynaud's phenomenon, fibering organ sex change (fibrotic organ degneneration), transformation reactions, autoimmunity allergy, end stage kidney disease, obesity, type i diabetes, impotence, osteoporosis [disease], aging, autism, autistic disorder, alopecia, the method for tumour.

Background technology

Live in industrialized country people's health is had many benefits.Developed country cause of the death trend is chronic degenerative disease, and as aging, heart trouble, renal failure, alzheimer disease, liver injury and tumour, and the underlying cause of death of under-developed country trend is acute as infection, hunger and war.As if yet the people that the live in under-developed country people more of the same age than developed country have better healthy state.They have the loose index of lower health, lower blood pressure, lower type i diabetes sickness rate, less renal failure, popular name for, attitude reaction, body immunological disease and alzheimer disease.This difference even between the city and urban residents of same country is significantly same between the rich and poor.Between the casting skin ethnic group, most this difference is particularly evident.Birth and growing up in under-developed country, the adult who migrates developed country migrates than their birth and grows up has better healthy state the child of developed country.

Many chronic diseases of developed country all have obvious relation with obesity.Obesity in fact makes every kind of chronic disease increase the weight of, and is not that each fat people can get these diseases certainly, neither each to get these sick people all be fat people.Some diseases is cancer for example, the cause of disease of none " significantly " as if, and as if they be at random mostly.In the time of in early days people with this disease owing to " evil soul " or " having enraged God ".Now " conventional wisdom " think the reason of all these degenerative diseases be people move not enough, seen too many TV, eaten the refining food that contains excess fat, sugar part, salt too much, contacted many chemical substances.Although the modern lays particular stress on thin, more than these things be considered to take place.Change a people's diet, one day only 100 calories just will make people increase in a year (or losing) about 10 pounds.Rural area in under-developed country, this is seemingly impossible because in fact have no talent to eat up in one day and exceed 100 caloric foods.If any, obesity also can be more general in under-developed country, because except refrigerator, the best method that stores leftover is eaten up exactly, with the form storage of fat.Same, to such an extent as to each wants the people that loses weight will too weak they diet can not be reduced 100 calories of every days.

The degenerative disease of industrialized country more increases the weight of because of obesity, becomes dead reason.Many similar diseases are feature with fibrosis organ hypertrophy, comprise myocarditis expansion, congestive heart failure, end stage kidney disease, systemic sclerosis, liver cirrhosis.Appear to totally different disease and spent a large amount of funds in order to have prevented to treat these, yet it is more and more that those have been damaged healthy fat people by obesity.The method of prevention degenerative disease has huge healthy meaning.

Diabetes have two kinds, all show as the blood sugar concentration of remarkable rising.The pancreas islet of type i diabetes patient excreting insulin is destroyed, and body has lost the function of excreting insulin.Unless give Regular Insulin, otherwise blood sugar will be elevated to ill level.Type ii diabetes body " Regular Insulin resistance ", i.e. blood sugar increasing, pancreas islet strengthens excreting insulin, but can not regulate the utilization of body to glucose.In general type ii diabetes causes type i diabetes, but both also can take place simultaneously.Although mortality ratio is very high, and the diabetes of mortality ratio and two types all have relation, and people are to this cause of disease understanding clearly not.

Immunity system sensitization is followed many same diseases, comprises primary biliary cirrhosis, type i diabetes, systemic sclerosis.Asthma and transformation reactions at the Hen of developed country generally in but Hen rareness of under-developed country." hygiology hypothesis " shows that the people when being exposed in early days among " filth ", bacterium or other antigen the child, just can resist disease of immune system later.Yet,, do not find this example though be devoted to investigation

Autism is the disease of overworking and causing sometimes, the still not clear still autism of reason is several years ago showing clearly at life usually, in this section period, fast growth and form and formed many connection again of brain, some sayings think autism betide can not be suitable when connection formation.People such as B.F.Sparks show that the self-closing children's in 3-4 year cranial capacity reaches 10-13%. (the self-closing children's of Sparks et al. brain textural anomaly, neuroscience 20027.23 than common children and late-blooming non-self-closing children's cranial capacity; 59 (2): 184-92.).People such as Dr.E.H.Aylward had once described abnormal brain development, the particularly excessive growth of cranial capacity, and it is relevant with autism that (the Aylwardet al. age learns 2002 to autism person's brain appearance and affecting the nerves of cerebral circulation; 59:175-183 Effect of age on brain volume and head circumference inautism.Neurlogy 2002; 59:175-183).

Nitrogen protoxide (NO) is relevant with many pathologic processes, because The Effect of Nitric Oxide is non-linear, and follow many other pathologic processes, the test more complicated of test nitrogen protoxide influence is especially when the basal level that changes nitric oxide level is not easy.People such as Ragnar Henningsson show nitric oxide level (the Henningsson et al.chronic blockade ofNosynthase paradoxically increases islet NOproduction andmodulates islate hormone release that can increase specific site with L-NAME inhibition NOS, Am J Physiol EndocrinolMetab279:E95-E107,2000).

People such as Thayne L. Sweeten report that the level that autism patient's nitrogen protoxide is produced increases (Sweeten et al., High nitric oxide production in autisticdisorder:a possible role for interferon-γ, Biological PsychiatryVolume 55, Issue 4, february 2004, pages434-437).People such as Sadik Sogut also report higher (the Sogut et al. of nitric oxide production level among the autism patient, Changes in nitric oxide levels and antioxidant enzyme activities mayhave a role in the pathophysiological mechanisms involoved inautism, Clinica Chimica Acta 331 (2003) 111-117).The blood plasma nitrite and the nitrate levels that raise are also observed (Giovannoni.et.al Raised serum nitrate and nitrite levels inpatients with mutiple sclerosis, Journal of the Neurological Science142 (1997) 77-81) in multiple sclerosis patient by people such as G.Giovannonia.

An investigator Lennart Gustafsson prompting autism may be owing to the not enough low NO that causes of the synthetic level of oxynitride causes.Theoretical and the nearest neuroanatomy of nerve net finds that the synthetic level deficiency of oxynitride will cause autism (In palladeV, Howlett RJ, Jain L, editors, Lecture notes in artificial intelligence, Volume 2774, partII.New York:Springer-Verlag, P1109-14.).The synthetic level of Gustafsson prompting oxynitride is not enough, and to produce between evolution period micro-tubular structure unusual, and this also can be produced by low serotonin level.(Comment on " disruption in the inhibitory architecture of the cell minicolumns " Implications for autism, Neuroscientist 10 (3): 189-191, January 8,2004), he points out autism to treat by the composite reactive that increases oxynitride in the brain, how not to do but provide.He has noticed that oxynitride is explained and can observedly in the disease seem that different symptoms gives proper explanations to comprising that in the autism disease epilepsy, sport injury, sleeping problems, attack, anti-injury reduce.

Osteoporosis is the factor that the senile fracture is increased the weight of.The generation number of low-wound fracture increases in elderly population, do you this not explained (P.Kannus et.al.Perspective:Why is the age-standardize incidence of low-trauma fractures risingin many elderly populations? Journal of bond and mineral researchvol.17, No.8,2002).

Summary of the invention

One embodiment of the invention relate to a kind of treatment and suffer from hypertension, loose sexual organ sex change, Raynaud's phenomenon, the sex change of fibering organ, transformation reactions, autoimmunization system sensitizationization, end stage kidney disease, obesity, type i diabetes, impotence, tumour, osteoporosis, aging, self-closing, self-closing class symptom (an autism spectrum symptom), alopecia, at least a disease or have ill dangerous look patient's method.Method comprises to be determined a patient to use ammonia oxidizing bacteria in patient skin surface.Ammonia oxidizing bacteria can be a kind of or its composition that is selected from nitrous acid zygosaccharomyces, Nitrosococcus, nitrous acid spirillum, nitrosocystis, nitrosolobus, the nitrous acid Vibrio.

Thereby another embodiment of the invention relates to a kind of method that increases growth of animal from animal surface removal autotrophy ammonia oxidizing bacteria.

The another one embodiment, ammonia oxidizing bacteria is used for preparation provides nitric oxide production medicine to the patient, here said medicine is applicable to described patient's body surface, as described in the specification sheets, said patient suffers from hypertension in fact, loose organ hyperplasia, Raynaud's phenomenon, fibrous tissue generates, transformation reactions, autoimmunization system sensitizationization, end stage kidney disease, fat, type i diabetes, osteoporosis, impotence, alopecia, tumour, old and feeble, self-closing, self-closing class symptom, at least a disease or have the people of ill danger in the disease that causes because of aging.

The accompanying drawing summary

Fig. 1 has shown that individual scalp and whole body use the change curve of ammonia oxidizing bacteria front and back liver enzyme and L-Ala saccharase level.

Fig. 2 has shown in some cities the dependency of mean minimum temperature in the alzheimer disease and the hottest month.

Fig. 3 has shown the quantity of the annual patent directly related with shampoo of the U.S. and has been diagnosed as the patient's that suffered from type i diabetes quantity every year.

Fig. 4 has shown the variation of NO flow with NO ppb in the sweep gas

Fig. 5 has shown that NO over time in the sweep gas.

Fig. 6 shown the NO flow with the variation of NO ppb in the sweep gas and

Fig. 7 has shown scalp NO, and volume scan actuator temperature and volume are over time.

Fig. 8 has shown scalp NO, and volume scan actuator temperature and volume are over time.

Detailed Description Of The Invention

The present invention does not limit to and is applied to the described details of specification and combination that hereinafter describe in detail or the content that accompanying drawing is represented, and the present invention also has other embodiment, can the different mode of many kinds uses and implements. And, for convenience of description, shown in term and the specialized vocabulary used should not be considered to be limitation of the present invention, " comprise ", " comprising ", " having ", " containing ", " about ", and similar these vocabulary, the meaning is to have comprised listed subsequently project and convertible and additional project with it.

The present invention relates to contain the composition of ammonia oxidizing bacteria, to increase the generation of patient near surface NO and NO precursor, and by use the mode of NO to the patient, come delaying senility with the autotrophy ammonia oxidizing bacteria, the preventing hypertension for the treatment of, loose sexual organ sex change, Raynaud's phenomenon, the sex change of fibroid organ, allergy, autoimmunity system allergy, end stage kidney disease, obesity, type i diabetes, osteoporosis, impotence, alopecia, tumour. Here said " patient " is in fact people or vertebrate, said vertebrate including, but not limited to dog, cat, horse, ox, pig (pit), sheep, goat, and, primate such as monkey and mouse. Here said " treatment " refer to prevent or delay beginning and after disease or illness begin, it being delayed or stop of disease or illness, perhaps reduce the symptom of disease, although even these symptoms do not reach the threshold value of clinical disease.

As used in this, the self-closing class disease of noun (Autism Spectrum Disorders) is just as define (DSM IV, Diagnostic and statistical mannual of mental disorders, 4 by common cognition^thEd.Washington, DC:American Psychiatric Association, 1994.) self-closing disease by name, or characteristics are extensive development disorder disease (the Pervasive Development Disorder of serious human communication disorders, PDD), oral or non-oral, social interaction and game, interest is narrow, Asperger syndrome (neurotic performance), doings lack and narrow, the Split disease of scope of interest, and the abnormal development of children has caused serious acquired self-closing disease. The example of self-closing class disease comprises self-closing disease, Asperger syndrome and Heller syndrome. In tradition, self-closing class disease is limited to quite serious insufficiency.

Autism is a kind of serious disease, is characterized in the social interaction serious hindrance.People must possess the Case definition that many and serious defective just are considered to meet autism, and many suffer from the people of autism In the view of other people degree is lower in fact, do not reach the degree of clinical autism or self-closing class disease threshold value.The symptom feature that may reach or not reach the self-closing class disease of diagnosis severity according to the quantity of self-closing phenomenon and/or degree is known as self-closing symptom here.The severity of self-closing symptom also can alleviate by method of the present invention.Main application of the present invention is exactly to alleviate the people that those have self-closing phenomenon, no matter suffer from autism or self-closing class disease the patient or and have a people of autism and the ill danger of self-closing class disease, and the people with ill danger of one or more self-closing class disease phenomenons, alleviate the severity of their self-closing symptom.

According to one embodiment of the invention, the compound of NO, NO precursor and/or release NO is used in patient skin surface with delaying senility, the preventing hypertension of treatment, loose organ hyperplasia, Raynaud's phenomenon, the sex change of fibrosis organ, allergy, autoimmunity allergy, end stage kidney disease, obesity, type i diabetes, osteoporosis, impotence, alopecia, tumour.

According to an aspect of the present invention, we believe the most of chronic diseases and the obesity of developed country, cancer may be because modern shower behavior, the natural result of the body's natural physiological response of having washed a large amount of former ignorant symbiosis autotrophy ammonia oxidizing bacterias during shower off and having caused, corresponding one aspect of the present invention is to use the autotrophy ammonia oxidizing bacteria to treat and to prevent these degenerative diseases to patient skin surface, autism, self-closing class disease, type i diabetes, osteoporosis and obesity.Same, another aspect of the present invention is to treat and prevent these degenerative diseases by not taking a shower.

More particularly, in one embodiment, use the autotrophy ammonia oxidizing bacteria during taking a shower and after taking a shower on skin, it can be metabolized to nitrite with the urea in the sweat and other composition, and finally is metabolized to NO, becomes the natural source of NO.One aspect of the present invention is that NO is discharged in the part of skin or skin surface, diffuse into skin then and to body part so that whole body generation effect.This NO can participate in the eubolism approach and be utilized by health.

Any ammonia oxidizing bacteria can be by used herein.In the first-selected embodiment, ammonia oxidizing bacteria all has characteristics as described, just as learning easily in the background technology: can rapidly ammonia and urea be metabolized to nitrite and other NO precursor; Bioclean; No anaphylactogen; Can not produce compound odorous; Can not produce malodorous compound; Can in human sweat, survive and grow; Can under the high salt concentration environment, survive and grow; Can under the active environment of low water, survive and grow.The example of ammonia oxidizing bacteria includes but not limited to be selected from a kind of or its composition in nitrous acid zygosaccharomyces, Nitrosococcus, nitrous acid spirillum, nitrosocystis, nitrosolobus, the nitrous acid Vibrio.As being that WO03/05380A2 and international publication number are disclosed in two pieces of WO02/13982A1 at international publication number, these two pieces of documents are by being incorporated in this paper in this citation.

The autotrophy ammonia oxidizing bacteria generally is present in soil and the natural water body, and there, they carry out the first step (ammonia oxidation is become nitrite) at nitrifying process.NO is the less product that is produced in the metabolism of autotrophy ammonia oxidizing bacteria with dioxygen oxidation ammonia, and some bacterial strains can utilize nitrite or NO2 as final electron donor, and the output of NO increases in this case.The autotrophy ammonia oxidizing bacteria is an autotrophic organism, can not be grown in and be fit to separate in the media of heterotrophism pathogenic agent, it is the process of nitrite that the metabolisable energy of autotrophy ammonia oxidizing bacteria comes from ammonia oxidation, with NO is the intermediate product of respiratory chain, in fact all carbon come from stabilizing carbon dioxide, they can not utilize carbon source except some small molecules, because they lack certain enzyme system, it is autotrophic bacteria (the Alan b.Hooper of obligate that people such as Alan b.Hooper and A.Krummel point out the autotrophy ammonia oxidizing bacteria, Biochemical Basis of Obligate Autotrophy in Nitrosomonaseuropaea, Journal of Bacteriology, Feb1969, p.776-779; AntjeKrummel et al., Effect of Organic Matter on Growth and CELLYield of Ammonia-Oxidizing Bacteria, Arch Microbiol (1982) 133:50-54.).The complete genome of one (Nitrosomonas europaea) was once checked order by people such as Chain, about 2460 encoding egg white genes (Chain et al.Complete Genome Sequence of the Ammonia-Oxidizing Bacteriumand Obligate Chemolithoautotroph Nitrosomonas europaea.Journalof Bacteriology is arranged, May 2003, p2759-2773.).From genomic observation, clearly these bacteriums can not caused a disease, and they do not have toxin gene or toxinferous conducting band or other known toxicity factor, and they do not have the enzyme that generates and utilize the complex organic compound of finding in animal body.They can not be grown in the media (they all are the heterotrophs of being reported as M Schaechter) that any heterotrophic media for example is used for the bacterial isolate body.(Moselio Schaechter, Gerald Mendoff, David Schlessinger, ed., Mechanisms of Didease, Williams﹠amp; Wilkins, Baltimore, MD, USA, 1989.) they are gram-negative bacterias, excite antibody, the antagonist sensitivity can be killed by the alkyl benzene sulfonic acid derivative of ppm level.They are slowly growth in suitable environment, need 20 hours, and heterotrophic bacterium only needs 20 minutes.

Natural bacteria can be changed the same use of bacterium of character with those by gene recombination technology.The microbial culture technology can be used for separating the bacterial strain with These characteristics.The mixture of pure bacterial strain can be avoided the problem of simple traditional bacterial strain of skin, these problems comprise potential pathogen and have the growth of the bacterium of undesirable quality, but the bacterium that grows on the skin and be similar to the bacterium of growth pp9 in the growth medium of human sweat composition can be effective to the increase of the productive rate of NO.One is cultivated with the useful method of separating this bacterium is the bacterium that grows in the medium of the ammonia mineral salt that contains urea, but does not contain the available organic compound of heterotrophic organism, as sugar and protein.When separating autotrophy ammonia and ammonia oxidizing bacteria, also can in the heterotrophism media, attempt the growth bacterium and not mix different oxygen bacterium is arranged to guarantee the autotrophy bacterial strain.Nitrobacter can be by improving pH and being suppressed by free ammonia.In soil can cause comparing the accumulating of nitrite of strong toxicity with nitrate.Skin contains a large amount of xanthine oxidoreductase enzymes that nitrite is reduced into NO, has suppressed accumulating of nitrite basically.Inhibition bacterium such as Nitrobacter are useful method that strengthens NO release with the concentration of the nitrite of minimizing skin.In other words be exactly to contain the generation that Nitrobacter can increase nitrate.The utilizable nitrite that other bacterium utilizes the organic compound on this nitrate and other the skin to form.

Useful bacterium is the bacterium with human skin sweat composition metabolism becoming NO precursor from this aspect, and this comprises that for example from urea to the nitrite, from urea to nitrate, from urea to ammonia, from the nitrite to nitrate, ammonia is to nitrite.More need the blended culture under the certain situation, this microorganism is used in the neutralization of the taking a shower back of taking a shower usually, also can with different perfumed soaps, the powder that use on the surface, emulsion, aerosol, gelifying agent, ointment is used.One aspect of the present invention is to be applied to health maximum position of perspiring, as, pin, hand, reproductive organ position, underarm region, neck and scalp.The difference at these positions of skin is the active different of water.Xerodermatic many than on the pin of skin on hand, pin is worn socks and shoes usually, and hand is because in the environment around constantly being exposed to.Different bacterial strains is in the different best effect of position performance of health.The mixed culture of all kinds can make the best bacterial strain propagation of those growths and adapt to, and grows into dominant colony at privileged site.Also can change the bacterial strain existence that local microclimate helps want by wearing the clothes.For example being branded as to stimulate hair dense, helps scalp to keep warmer temperature and humidity environment.

Because the skin environmental facies are favourable to dry to the bacterium that adapts to low-humidity environment, for example to have a liking for the salt ammonia oxidizing bacteria be as the described Nitrosococcus of people such as HansPeterKoops (Nitrosococcus mobillis) to moderate.(Arch.Microbiol.107,277-282 (1976)). this bacterium has growth scope widely.For example the suitable pH value of its suitable growth is 7.5, but at pH6.5 is still to keep 33% of maximum growth rate, another is hydrophilic, as the described Nitrosococcus of people such as H.P.Koops (Nitrosococcus halophillus), (Arch.Micorbiol. (1990) 154:244-248) is separated from saturated salt solution in natural salt lake.Nitrosococcus (Nitrosococcus oceanus) (ATCC 1907) but be that hydrophilic suitable salt concn is in other between the two.The NaCL concentration that the three is fit to is respectively 200,700 and 500mM/L.N.oceanus can utilize urea, and the concentration that can tolerate ammonia is up to 1100mM ammonium chloride.Being grown in the suitable environment is the fastest of length, and similar result can be by finishing with more bacterium.Therefore when the only pH value that is fit to the N.Mobillis growth is 7.5, be the nitrite that 6.5 o'clock one personal triple times also can generate as much at pH.Because number of bacteria is very big among the present invention, than huge many of the bacterial number that is produced within after the bathing 24 hours, so, also can not limit utilization to them although the pH value of skin is not suitable for these bacteriums.Because N.halophillus can separate out from saturated salt solution, it should easier existence in relatively wet skin environment.

Some bacteriums directly produce NO.Example such as Armin Remde are described in " Nitromonas europaeca produces oxynitride by the nitroso-group reduction " (Arch.Micorbiol. (1990) 154:187-191).N.europaeca and Nitrosovibrio have been proved to be and can have directly produced oxynitride.Nitrosovibrio is grown in the rock, and Suan generation has caused corrosion there.Poth and Focht increase through pointing out, " separate from nitrite, to produce the dinitrogen molecule by Nitromonas " (Appl Environ Microbiol 52:945-959), nitrite be reduced into available oxynitride be body eliminate from the growing environment as the method for the toxic nitrite of rock surface.

For understand these bacteriums useful one side, it is helpful understanding vasculogenesis.All somatocyte except some are exposed to cell in the outside air, all obtain metabolic oxygen from blood supply.Oxygen is by the blood absorption in the lung, is carried to peripheral tissues by the negative oxygen oxyphorase of erythrocyte, and there and carbon dioxide exchange, carbonic acid gas is transported back then, breathes out from lung.Oxygen must spread from red corpuscle, by tenuigenin, passes endothelium, passes various tissues utilize oxygen up to arrival cell mitochondrial.Human body contains 5 liters of blood, and the volume of microcirculqtory system and the volume of health are Comparatively speaking very little, and oxygen can not betransported efficiently.It is passive pass through the concentration gradient difference from the air diffuser to the red corpuscle in, be diffused into the cell from red corpuscle, again from cell to the Terminal oxidase that consumes oxygen.The oxygen concentration that consumes the oxygen position is minimum in vivo.Oxygen flux is by diffusional resistance and concentration gradient decision.Finishing sufficient oxygen supply offers all peripheral tissues and need carry out sharp control to the size of capillary vessel and position.If space capillaceous increases, finishing same O2 flux just needs the bigger concentration difference and the therefore oxygen concentration of lower Terminal oxidase.Cell between the capillary vessel is many more, and the demand of oxygen will be bigger, if the space between the capillary vessel reduces, the available space of finishing the cell of organ metabolic function also reduces.

One aspect of the present invention is absorbed by outer skin from the NO of autotrophy ammonia oxidizing bacteria is easier, does not change into S-nitrosothiol (S-nitrosothios) owing to skin has oxyphorase.People such as Mstructer are at " oxygen supply of human corium and epidermis comes from the picked-up of skin to atmosphericoxygen " (Journal of Physiology (2002), 53 8.3, pp.984-994) show in that outer skin is accepted all oxygen from outside air.This is obvious, because outer skin obviously lacks red corpuscle freely.Because they are alive, need the nutrition in the blood and be not only oxygen, so have plasma circulation between these layers.The S-nitrosothios that forms is stable, can diffuse through health, the NO source that constitutes reliable NO volume source and transform to commentaries on classics nitre ester (transnitrosate) albumen sulphur.

Another aspect of the present invention, kapillary is thin to be one of insufficient primary performance of NO level.Human body begins growth by a cell, and the vascular system of damage is efficient the recovery from illness in all tissues.It is to be studied the many themes of Hen that the adjusting of vasculogenesis and blood vessel change, and therefore many factors are all understood

People such as F.T.Tarek show loose capillary vessel thin (the Structual Skin CapillaryRarefaction in Essential Hypertension comparatively common in suffering from the crowd of essential hypertension of capillary vessel in other words.Hypertension。1999；33：998-1001.)。People such as Trek have shown that in the crowd with the ill danger of hypertension just can to see kapillary before morbidity thin.The skin kapillary that is on the verge of essential hypertension is thin to have hinted early stage textural anomaly.Hypertension 1999; 34 655-658.The reason thin for kapillary do not have good explanation, but the reduction and the capillary vessel round-robin that will occur capillary density when local blood demand reduces reduce, as suggested in people such as E.Serne." it is impaired by thin the causing of functional and structural capillary that the skin heart in the essential hypertension recovers." (hypertension 2001; 35:238-342).The thin hypertension that how to cause of kapillary is conspicuous.The metabolic demand of tissue does not reduce with capillary densities is consistent, and therefore, the capacity blood flow that flows through sparse capillary bed must remain unchanged.But has reduced at the identical available circulation commissure of flow position, so blood pressure must increase.According to observations such as Greene, the microscopic capillary cell can make elevated blood pressure decline (Microvascular rarefaction and tissue vascularresistance in hypertension.Am.J.physiol.262(Heart?Circ.Physiol.25)：H126-H131，1989.)。People such as Green show that also oxygen increases from the path length that capillary vessel is diffused into apart from kapillary cell farthest, must descend apart from the oxygen concentration of kapillary cell farthest and to keep constant (the Effect OfMicrovascular Rarefaction in Tissue Oxygen Delivery inHypertention Am.J.physiol.262 (Heart Circ.Physiol.31): H1486-H1493,1992) of oxygen flux.They show except bigger anoxia in superincumbent last reference, and the inhomogeneity at aerobic/anoxic position is bigger under the thin condition of kapillary, and the fluctuation between aerobic/anoxic position reduces.

Another aspect of the present invention, it is thin to be not only that concentration of oxygen influences kapillary, and the chemical potential energy of oxygen also can.The chemical potential energy of oxygen is directly proportional with the partial pressure of oxygen, is directly proportional with the concentration of melting in free blood plasma of red corpuscle and the extracellular liquid.The chemical potential energy of oxygen equals the chemical potential energy of equilibrated blood plasma with it in the red corpuscle.Oxygen reaches the remote cell of bullet tubule from the tissue that kapillary diffuses through hemoglobin-free.

Many situations are thin relevant with capillary densities.The hypertension of before once mentioning, the investigator reports that sparse kapillary also sees the childhood with essential hypertension and diabetic population.The complication of diabetes is a hypertension, diabetic nephropathy, diabetic retinopathy, diabetic neuropathy.People such as R.Candido have been found that last two kinds of situations with characteristics be to observe the volume of blood flow that flows to affected area before the symptom to reduce (Haemodynamics in microvascular complication in typeIdiabetes.Diabetes Metab Res Rev 2002; 18:286-304.).The capillary densities that reduces is relevant with obesity, common body weight reduces the increase capillary densities and is described to (The journal of Clinical Endocrinology﹠amp by people such as A Philip in " Effect of Weight Loss on Muscle Fiber type; Fiber size; Capilarity, and Succinate Dehydrogenase Activity in Humans " literary composition; Metabolism Vol.84, No.11.4185-4190,1999).

The investigator shows, in primary Raynaud's phenomenon (PRP), first folds in a garment capillary vessel is than thin (slight) of normal control group, yet the many (M.Bukhari that enrich than the patient who develops into whole body sclerosis (SSc), Increased Nailfold CapillaryDimendions in Primary Raynaud S Phenomenon and SystemicSclerosis.British Journal of Rheumatolohy Vol 24 No35:1127-1131,1996).They find that capillary density drops to 33 (PRP groups) from 35loops/mm2 (normal control group), 17 (SSc groups).Mean distance between control group, PRP group, the SSc group capillary vessel branch road is respectively 18 μ, 18 μ and 30 μ.

Another aspect of the present invention, the mechanism that health is experienced " anoxic " under the normal circumstances has influence on the whole body system that regulates capillary densities.According to this aspect of the present invention, a large amount of anoxic compositions are experienced, and are not because by the reduction of oxygen O2 level, but because the reduction of nitrogen protoxide NO level.The impression of " anoxic " has been disturbed in the reduction of nitrogen protoxide basal level, has also influenced many body functions of regulating by " anoxic ".For example anaemia is generally defined as " oxyphorase deficiency ", the insufficient consequence of oxyphorase is exactly " anoxic ", it is defined as " oxygen deficiency ", and according to one aspect of the present invention, these common definition can not be explained the situation of two aspects that nitrogen protoxide causes.

When resting state, appearance anaemia such as acute is well tolerated, and 2/3rds minimizing of hematocrit is very little to the PvO2 influence of the oxygen venous return of vein.This has hinted it is that oxygen is pressed or the transportation of whole health does not all reduce (Weiskopf etal., Human Cardiovascular and Metabolic Response to Acyte, SevereIsovolemic Anemia, JAMA1998, VOL 279, NO.3,217-221).Hematocrit reduces (from 140 to 70g Hb/L) at 50% o'clock, and mean P vO2 saturation ratio (greater than 32 experimenters) drops to 74% from about 77%.The reduction of oxygen capacity is increased to 85 times tachycardia by vasorelaxation and heart rate from per minute 63 and compensates in the blood, and compensation is effectively and significantly, but mechanism but is not.The anoxic susceptor that typical explanation is " anoxic " has detected " anoxic " and has compensated with vasorelaxation and tachycardic mode then.Yet but detect less than " anoxic ".The slight again reduction (lactic acid is the sign of anaerobic respiration) of lactic acid drops to 0.62mm/l from 0.77 and has hinted a spot of anaerobic respiration and few in the blood " anoxic ".In the reflux veins 3% of PvO2 reduction and people to be in 300 meters of height above sea level (do not see can produce tachycardia from the personal experience) be same level " anoxic ".The oxygen concentration of venous return remains unchanged, and the oxygen depletion page or leaf remains unchanged, the space that does not have oxygen concentration to reduce in vivo.Because oxygen-sensitive waits appearance the compensatory of anaemia can not take place.

The anaerobism that other reason causes is different for the influence of heart output in " anoxic " that cause owing to other reason.People such as MARRAY show when the normal red corpuscle of dog is completely oxidized to the red corpuscle replacement of methionine(Met) oxyphorase, " anoxic " compensatory minimum (Circulatory Effects of Blood Viscosity:Comparison ofMethemoglobinemia Journal of Applied Physiology Vol.25, No.5,594-599 November, the cyclical effect of 1968 blood viscosities: the comparison of methemoglobin and anaemia, use physiology periodical 25 volumes 5 phase 594-599 1968.12).When keeping identical hematocrit (43%) and replace methionine(Met) oxyphorase (0,26,47%) fully, cardiac output (CO) descend (178,171,156mg/m/kg), arterial oxygen press (93,87,84mmHg) and vein oxygen press (55,46,38) also to descend.Opposite, wait when holding anaemia (Hct40,30,22) and using blood plasma to induce good many of compensatory phenomenon when acute, CO (155,177,187), PaO2 (87,88,91), and PvO2 (51,47,42), (Hct41 when using dextran solution to induce, 25,15), CO (143,195,243), PaO2 (89,92,93), PvO2 (56,56,51), compensatory situation is also better.

With the part of the test of methionine(Met) oxyphorase test, with the final diluent of dextran dilution oxyphorase is reduced-to 26% and the methionine(Met) oxyphorase still keeps 47%.Compensatoryly also improve, CO (263 mg/m/kg), PaO2 (86 mmHg), PvO2 (41 mmHg) has increased, although oxyphorase reduces, oxygen increases, " anoxic " reduces.The compensatory mechanism of handling " anoxic " may not be since the reduction of oxygen level but because oxygen level does not reduce, in fact, the level of oxygen has increased.

DEEM etc. report that the lung qi exchange efficiency improves when waiting appearance anaemia, the nitrogen protoxide of breathing out increases and hematocrit reduction (rat) (Mechanisms ofImproxement in Pulmonary Gas Exchangeduring IsovolemicHemodilution.J.Physiol.83:240-246, improvement mechanism of the lung qi exchange during the hemodilution such as appearance such as 1997 grades.Physiology is used magazine.83：240-246，1997)。

When reducing when hematocrit because by hydroxyethylamyle (30,23,17,11%) dilution, and the cardiac output increase (0.52,0.60,0.70,0.76L/min), the rising of the nitric oxide level of exhalation (30,34,38,43nl/min).

People such as Calbet etc. show that maximal oxygen uptake (VO2max) reduces at high height above sea level place, does not the VO2max that reduces recover (Why is VO2max AfterAltitude Acclimatization Still Rreduced Despite Normalization ofArterial O2 Content because adapt to?, Am J Physiol Regul Integr Com Physiol 284; R304R316,2003.).People such as Koskolou show that the maximum oxygen capacity reduces when hematocrit reduces, although PaO2 or PvO2 do not change (Cardivascular Responseto Dynamic Exercise With Acute Anemia in Humans.Am.J.Physiol.273 (Heart Cirt.Physiol.42) H1787-H1793,1997).

In above-mentioned last reference, when all data of people such as Koskolou clearly show the limit during 17% reduction, oxyphorase changes (154.4 to 123.3g/L), PaO2 changes (119.2 to 115.1mmHg), PvO2 changes (23.6 to 23.0mmHg), and people such as Koskolou do not explain for the oxygen that can not train muscle to extract the blood transportation.This behavior can cause the competition of the cytopigment of maximum oxygen volume-diminished to suppress to explain with the interaction and the nitrogen protoxide of nitrogen protoxide and oxyphorase.

When horse was used no inhibitor L-NAME, stopwatch revealed the increase of the long-pending VO2 of oxysome and the reduction of " oxygen shortcoming ", but the reduction a little that also shows maximum VCO2.This is in " L-NAME absorbs the influence of behavior period to oxygen in the motion of horse high-density " (J Apply physiol 91:891-896,2001) by people such as Casey.The test group that gives LAME can be observed the VO2 that the inhibition of mitochondrial respiratory is quickened owing to the nitrogen protoxide that reduces, because the VCO2max of kinemic reduction (owing to vasotonia has reduced by 12%) and slight reduction (62.5,61.0L/min).The increase of the maximum oxygen volume that increases with hematocrit in " blood doping " is likely because nitrogen protoxide reduces.These examples have all comprised nitrogen protoxide inhibition and the hematocrit of mitochondrial respiratory have been changed caused inhibition.

The well-known NO that transports from solution of oxyphorase, kinergety is oxyphorase and nitric oxide production first requirement.In stationary stage, NO production speed is stable, produce speed and equal wear rate, the unexpected decline 50% of hematocrit will cause the increase of nitric oxide concentration, to continue to equal wear rate because produce speed, wear rate is that nitrogen protoxide and oxyphorase keep stable first requirement that produces, and is that their generation has been kept stable.To such an extent as in fact the very fast new nitrogen protoxide NO of the reaction between nitrogen protoxide and the oxyphorase has just reached when the mixture of blood and dilution flows through vessel wall.

Therefore to wait observed vasorelaxation in the appearance ischemic may be increase owing to nitric oxide concentration on vessel wall acute.The vasodilation of mediated by nitric oxide causes owing to shear-stress and other factors, observing the nitrogen protoxide metaboilic level does not change, because NO production speed does not change and continues to have equaled wear rate, do not observe the methionine(Met) oxyphorase of " hypoxia " compensatory be readily appreciated that because the methionine(Met) oxyphorase just as oxyphorase in conjunction with nitrogen protoxide, therefore reduce the methionine(Met) oxyphorase that causes not increase of nitric oxide concentration when compensatory when oxyphorase.

Many details of nitrogen protoxide chemistry are not understood widely, part oxygen, and carbonic acid gas, hydrogen sulfide, hydrocyanic acid and nitrogen protoxide all combine with protoheme, and be very important on human physiology.Therefore all activity of proteins that contain protoheme (having a lot) are all influenced by the concentration of above-mentioned all these materials.Sometimes, one or several can be out in the cold, but the unheeded environment of lateral reactivity material must be much accounted of and NO, and CO, combining of the part O2 that H2S, the lasting binding ratio of HCN and great majority enrich is big many; Contain proteinic different protoheme and can not independently feel these parts, they only feel the relative concentration of all parts.

The behavior of NO in the health and NOS enzyme is very complicated.The gene of a similar shape nNOS is the maximum gene of end user's genoid structural changes of promotor " up to now according to ", (Y.Wang et al., Rna Diversity Has Profound Effects in TheTranslationof Neuronal Nitric Oxide Synthase.PNAS October 12,1999, Vol.96.21 12150-12155).Nitrogen protoxide is measured difficulty, low-level activity is arranged, and instability can be reacted, diffusion rapidly, and concentration changes rapidly on time and space.At many positions activity is arranged all, bring into play semiotic function and regulatory function by number of mechanisms in those sites.Its is responsible for loosening adjusting vasotonia by unstriated muscle of cGMP mediation, suppresses combination with oxygen regulating oxygen depletion by the Terminal oxidase competition, the nitrosylation by cysteine residues and induce expression of MMPs mRNA with the arrestin enzyme.Nitrogen protoxide is immunoreactive main component, is come out by the INOS mass production when inflammation takes place.Nitric oxide production length standard be very important to individual cells, this also should be realized.Also should be realized that not to be that all " nitrogen protoxide effects " all mediates by " nitrogen protoxide freely ".S-nitrosothiol can make albumen sulphur be changeed nitre esterification (transnitrosate) not existing under the free nitric oxide production situation.The measurement level of NO technical field does not also allow to measure those and is known as important time, distance and concentration standard.On this complexity and test difficulty level, nitrogen protoxide is how just not curious by the most learned technician's approval of this area with the details of oxyphorase (best appreciated becomes human protein) effect.

It is well-known that nitrogen protoxide plays an important role in many pathways metabolisms.Nitric oxide production basic horizontal plays a role in inhibited reaction, and the reduction of this basic horizontal causes these path double inhibition.People such as ZANZINGER reported once that nitrogen protoxide suppressed basic collaborative and excited reflection attenuation (Inhibition of Basal and Reflex-mediate Sympathetic Activity in The RVLM by Nitric Oxide.AM.J.Physiol.268 (Regulatory Integrative Como.Physiol.37): R958-R962,1995)

A nitric oxide production function is to regulate oxygen-consumption by combine and compete the combination that suppresses oxygen with Terminal oxidase.The inhibition of oxygen-consumption is useful because can not be by better controlled in each plastosome concentration of oxygen of each cell.When oxygen was consumed, oxygen level descended, more nitrogen protoxide combination, and suppressing increases, and the consumption of remaining oxygen is slowed down.Do not have this inhibition, with the immediate plastosome of oxygen source can consume more, those will obtain seldom oxygen or almost not have a long way off.Organize for example cardiac muscular tissue for some, oxygen consumption can be changed by the factor greater than 10 kinds between basic and the peak value metabolic activity.In order to finish this oxygen fluctuation, gradient must increase because space capillaceous can not change along with oxygen consumption.(although capillary vessel regeneration increases, and all is empty).The nitric oxide concentration that reduces removes the speed that restraining effect that nitrogen protoxide produces has increased oxygen depletion by plastosome.

Restraining effect by nitric oxide production Terminal oxidase depends on nitrogen protoxide and concentration of oxygen.Therefore the reduction of maximum oxygen gas volume may be owing to oxygen less for identical nitrogen protoxide during low-gravity hypoxia.To hold anaemia be that the reduction of maximum oxygen gas volume may be owing to will the nitrogen protoxide of identical oxygen increase be caused and waiting.The nitrogen protoxide increase of breathing out during waiting appearance anaemia is to stop in lung because the nitrogen protoxide that produces in nasal cavity in the lung is less.During the appearance anaemia, oxygen is because the increase of nitric oxide level to the conveying minimizing of muscle.Nitric oxide concentration increases, and mitochondrial operating point is displaced to higher oxygen concentration.In fact mitochondrial oxygen concentration has increased owing to nitric oxide production bigger restraining effect during waiting appearance anaemia.Less so reaction oxygen reflection is also less in the high local concentration gradient of oxygen concentration.In fact the hypoxgia problem is less so the anaerobism glyconeogenesis is less Deng the reduction proof plastosome that holds blood lactic acid during the anaemia, and the adverse consequences that nitric oxide level reduces causes the increase of anaerobism glyconeogenesis, and this problem will be discussed in bottom.

Hypobaric hypoxia and etc. can observe the reduction of maximum VO2 during the capacitive anaemia, can see the increase of maximum VO2 when suppressing with L-NAAME, this concentration that has proved oxyphorase in nitric oxide production concentration in plastosome and the blood is destroyed by oxyphorase by NO, is produced and coupling by NOS.

Nitrogen protoxide combines with the protoheme of numerous protein, because intravital most of iron ion is present in the protoheme, much higher in other tissue of the concentration ratio of protoheme in the blood, therefore, nitrogen protoxide and protoheme be combined in the there be the most rapidly, blood is considered to the part that exists of nitric oxide production maximum.Nitric oxide production main source is an endothelium, and there, the eNOS enzyme is continuously expressed.Nitric oxide production source and nitric oxide production location are so approaching, apart from the source with exist the nitric oxide production concentration in zone far away, ground to depend on the source sensitively and have interaction between the ground.Other the source that also has this nitrogen protoxide.People such as Stamleer reported once that blood and blood plasma contained a large amount of S-nitroso-group sulfuration enzymes, S-nitrogen protoxide-albumin (NITRIC OXIDE CIRCULATES IN MAMMALIAN PLASMAPRIMARILY AS AN s-NITROSO ADDUCT OF SERUMALBUMIN.PROC.NATL.ACAD.SCI.USA.VOL.89 most importantly wherein, 764-7677,1992).

Nitrogen protoxide can comprise XOD, cupric ion by many different enzymes, contain the copper that comprises copper zinc dismutase uses up from the S-nitrosothiol nitrosothiols and separates, nitric oxide production many metabolic functions do not need free nitric oxide production liberation, when the halfcystine at protein active position was S-nitrosothiol, activity of proteins was affected.Nitrogen protoxide is defined as changeing nitre esterification (transnitrosation) from the transhipment that a S-nitrosothiol is transported to another, can be by many kinds of enzyme catalysiss, comprise the albumen disulfide isomerase, the logical S-nitrosothiol mediation of nitric oxide production many metabolism, the ventilation when for example mediating anoxic.

In the example of hematocrit decline 50%, the nitric oxide production concentration on the capillary wall will increase, and will be consistent with previous fall off rate, may be double.Nitrogen protoxide is with the passive health that diffuses through, and its main source is the oxyphorase in the blood, and other local concentration also can increase.It should be noted because in NO existence and the oxyphorase, the position that nitric oxide production concentration is minimum is to consume the position, is in the oxyphorase in the blood.When therefore there is the nitrogen protoxide source in hypothesis in peripheral tissues, produced the nitric oxide production concentration gradient opposite naturally with the gradient of oxygen.Although the NOS enzyme can be expressed in a lot of tissues, not appearing in the newspapers yet in this source, (perhaps major part is owing to measure the test difficulty of nitric oxide concentration gradient between capillary vessel.)

One aspect of the present invention is that a composition in this nitrogen protoxide source is low molecular S-nitrosothiol, erythrocyticly produced by the autotrophy ammonia oxidizing bacteria on the exterior skin skin not having.These low-molecular-weight S-nitrosothiol long-term stabilities are free to diffusion and circulation in blood plasma, and different enzymes can discharge nitrogen protoxide in the enzyme site from different S-nitrosothiols.It is the disorder that has caused normal physiological function from the loss that the nitrogen protoxide of the autotrophy ammonia oxidizing bacteria on the skin is originated.Health utilizes S-nitrosothiol to be that it is not need oxygen to exist that S-nitrosothiol is made nitrogen protoxide generating nitric oxide production advantage away from the blood capillary pipe end.Nitric oxide synthetase production nitrogen protoxide is to need oxygen when being.When enough S-nitrosothiols exist, also can generate nitrogen protoxide under the oxygen-free environment.Do not need freely nitrogen protoxide and just play a role when another molecule contacts because nitrogen protoxide has only, as the sulphur of cysteine residues or the iron ion of protoheme, therefore The Effect of Nitric Oxide can be changeed the nitre esterification and be mediated, even does not have free nitrogen protoxide and also be fine when having only S-nitrosothiol and nitrosification enzyme to exist.

According to another preferred embodiment, do not exist under the obvious anoxybiotic situation, the nitric oxide level of rising may be one more more effective than hypoxemia, regulate " anoxic " signal of hematocrit and other " anoxic " mediated factor.Because the adjustment point of " normally " hematocrit records not existing under the obvious anoxia condition, the hematocrit adjustment point of " normally " can be by nitrogen protoxide or oxygen level decision, or more accurate theory, by nitrogen protoxide and oxygen (NO/O ₂) ratio decision, " anoxic " signal does not need and NO/O ₂Linear, nitrogen " anoxic signal " can increase along with the reduction of nitric oxide production increase and oxygen.Each all has effect to " anoxic " signal, but effect might not be the same.

Similar, just often recur and do not exist the blood vessel that takes place under the obvious anoxic RST to reinvent also must be by " anoxic " Signal Regulation under the kindred circumstances.Also reduced by the oxygen traffic capacity of that part of tissue of its service when the blood that flows to vescular bed reduces, this has caused the numerous and jumbled sign of anoxybiotic, and the cell of (experiencing the oxygen diffusion resistance) farthest apart from kapillary at first experiences anoxic.This is observed in vitro tests, dabbling rat heart is injected into the plain fen palladium that has extinguished its fluorescence with oxygen, and the fluorescence of the fluorescence of plain fen palladium and NADH (a kind of plastosome deoxygenation method) is observed (Heterogeneity of the hypoxiastateis determined at capillary level.Am.J.Physiol.264 (Heert Circ.Physiol.33): H294-H301 by people such as INCE under normal oxygen and the dabbling situation of anoxic; 1993)).In the process of normal oxygen condition transition, the higher zone of zone that oxygen level is lower and NADH is complementary in anoxic condition, and the length standard inhomogeneity of the inhomogeneity of these zone length standards and capillary vessel is complementary.This piece works has proved that " anoxic " is a local effect, it is numerous and jumbled on the capillary vessel level, this inhomogeneity is caused by intracapillary space, and " anoxic " that is caused by the blood flow that stops to have identical polymorphism with " anoxic " that the anoxic blood flow by high flow rate causes.Maximum polymorphism is observed during anaerobic restitution.Also should be noted that when not having enough nitrogen protoxides, the activity of the Terminal oxidase of oxygen increases, base is active the increase under given oxygen concentration, and therefore the cell near capillary vessel will consume more oxygen, and oxygen that residue is given the cell far away apart from capillary vessel is with regard to still less.Insufficient nitrogen protoxide will make the degree aggravation of anoxic polymorphism, and will therefore increase the conversion number of times under anoxic and the aerobic state.It is maximum that being created in of super-oxide is accompanied by during anoxybiotic reoxidizes, the mitochondrial respiratory chain decline comprehensively that becomes, and oxygen is trapped electron before can shuttling back and forth in Terminal oxidase.When nitric oxide level reduces, mitochondrial operant level will be transferred to lower oxygen concentration level.Because oxygen is stored in the tissue, this means lower " catching ".Produce more super-oxide, because super-oxide damages nitrogen protoxide with limited diffusion power, many more super-oxide mean few more nitrogen protoxide.The super-oxide that is caused by local anoxic destroys the situation that nitrogen protoxide can aggravate hypoperfusion.

It generally is constant that the oxygen of blood is partly pressed, and is able to good adjusting, and in order to regulate intracapillary space, health must be measured the diffusional resistance of oxygen and generate capillary vessel in the high place of oxygen diffusion resistance, at the low place excision kapillary of diffusional resistance.The oxygen demand of tissue fluctuates along with their Metabolic activity, and the intracapillary space of " normally " must satisfy " normally " metabolic demand (adding some reservations).The simplest approach that mensuration oxygen diffusion resistance is regulated thus is to reduce supply when demand is constant.Rotate when supply is constant, the demand of growth will need the method for a dissipation metabolism heat, and this metabolism heat can be released but not observe.The demand of should be must be greater than supply, and " anoxic " state must be induced, normal in the meantime function must sustain damage (otherwise being not anoxic just).Reduce oxygen concentration or blood flow rate, and keep basic metaboilic level constant, will induce anoxic condition, thereby allow the diffusional resistance of cell decision oxygen.Because metabolic function must be damaged, best opportunity is exactly when the metabolism demand is in minimum level, when body does not move or avoids consumption of calorie, for example in bed.Also caused the stable of maximum duration in minimum metaboilic level inductive anoxic, this minimizes the probability of excess load and anoxybiotic damage.

Erythropoiesis is partly by erythropoietin (EPO) mediation, the red corpuscle survivin mainly by kidney hypobaric hypoxia, etc. hold anaemia, cobalt chloride, de-iron ammonium etc. " anoxic " stimulate generation down.Many anoxybiotic effects mediate by hypoxia inducible factor, and hypoxia inducible factor has activated the transduction of the many genes that comprise erythropoietin EPO gene.The complex behavior of the hypoxia inducible factor when nitrogen protoxide exposes proved by people such as Britta (Accumulation of HIF-1Under the influnce of nitric oxide, blood 2001; 97:1009-1015).

People such as Sandau find low nitric oxide level induced one faster the reaction, and produce more hypoxia inducible factor than high-caliber nitrogen protoxide, can not induce unique nitrogen protoxide contributor of hypoxia inducible factor is the nitrous acid sodium cyanide, and it also discharges prussiate.They have also determined what inducing of hypoxia inducible factor was not by cGMP mediation.People such as KIMURA have shown that vasculogenesis is partly mediated by VEGF, it induces generation (Hypoxia reponse elementof the human vasularendothelial growth factor-1 activity by nitritcoxide by nitrogen protoxide inductive hypoxia inducible factor, blood, 2000; 95:189-197).The transduction that makes the energy-producing enzyme of glycolysis-is corresponding to hypoxia inducible factor.Insufficient nitrogen protoxide has also caused the deficiency of glycolytic ferment.

People such as Frank show, the vasculogenesis of following common wound to recover partly is to be by nitrogen protoxide inductive (Nitric oxidetriggers enhanced induction of vascular endothelial growth factorexpression in cultured keratinocytes (hacat) the and during cutaneswound repair that increases by the VEGF that the VEGF that promotes produces, FASEB J.13,2002-2014 (1999.).

Therefore when anoxic is not followed enough nitrogen protoxides, need the oxygen of the lower level of long period to excite inducing of hypoxia inducible factor and VEGF.In the time of should remembering that nitric oxide level hangs down, mitochondrial oxygen depletion level is accelerated, so oxygen level falls to such an extent that the faster farther time is longer when higher than nitrogen protoxide.

According to another one embodiment of the present invention, capillary cell cause anoxic cause organ cell's acceleration to upgrade may be observedly in chronic generative nature disease to quicken an old and feeble factor.Health is controlled the capillary vessel distance to adapt with the partial oxygen demand by the local blood supply.For this reason, it has induced the state of " anoxic ", and starts vasculogenesis by HIF-1 α and VEGF in the place of needs.In order to guarantee to be unlikely to too near between the capillary vessel, near the signal that does not have " anoxic " that may also exist a hint can cause blood vessel to be eliminated, this finishes by endothelial cell apoptosis.This elimination is by from the shortage mediation (or other endotheliocyte Survival Factor) of the VEGF of " anoxic " cell near.People such as LANG have reported that the derivative of VEGF can mediate the apoptosis of endotheliocyte (VEGFdeprivation-induced apoptosis is a component of programmedcapillary regression, development 126,1407-1415 (1999)).The insufficient VEGF that the low base value nitrogen protoxide that insufficient oxygen is arranged but do not have NO/O2 ratio to start the cell of HIF-1 causes stops new capillary vessel formation and eliminates the capillary vessel that has formed by depriving VEGF.The nitrogen protoxide of therefore low base value may be induced the mean distance between chronic oxygen state and increase capillary vessel in bullet tubule cell mass farthest.The number of the affected cell of possibility seldom may occur in the isolated zone of length range less than intracapillary space at any time.And, once may only influence a cell, this isolated hypoxic cell is difficult to be detected.When this apoptosis or necrosis, its inflammation that causes also is difficult to be detected.Overtime, affected cell can be die, and is eliminated, and the geometry of capillary pipe structure will collapse, and new cell will move to anoxic zones, and more capillary vessel is eliminated, and a lot of cells of a lot of years back organs all are affected.If the cell that the cell fission of existence replacement is die, necrocytosis cycle and cell replace and will repeatedly take place, after many years, the quantity of affected cell can surpass the total amount of organ, perhaps can make a lot of times, the cell per minute splits once, and the cell telomere will shorten, when being short to a certain degree, cell is no longer division just.

According to one embodiment of the present of invention, it is that blood vessel is thin that the cell remote apart from kapillary includes the too few consequence of nitrogen protoxide.Do not have enough nitrogen protoxides, cell can not produce the signal of vasculogenesis, although Chronic hypoxia does not have enough nitrogen protoxides, cell just can not produce the signal of vasculogenesis.But cell needs the dioxygen oxidation phosphorylation to provide energy and other to finish the needed thing of different metabolic functions.The oxygen deficiency, cell function will reduce, should be noted that when not having enough nitrogen protoxides, oxygen gradient (dO2/dx) during owing to the hypoxemia level Terminal oxidase suppress to lack and deepen.Therefore the cell on the NO/O2 thresholding that induction of vascular generates may experience can cause Insufficient bigger anoxic.Some cells can be by the anaerobic glycolysis generate energy.But the energy (ATP) of a unit of the every generation of anaerobic glycolysis is just Duoed the glucose of 19 times of amounts than aerobic glycolysis consumption.Even if small amounts of cells is by the anaerobic glycolysis generate energy, partial glucose can be depleted.Because the effect of the local depletion of the glucose level that anoxic causes will be explained in the back.

Anaerobic glycolysis has effect on the other hand, the generation of NADH or the minimizing of Equivalent.These Equivalents that reduced can not be oxidized because the oxygen deficiency.The approach that they can be utilized by cell is the fat route of synthesis.This may be the source that does not conform to viewed liver fat in the fatty liver of alcohol.Because the metabolism generation of alcohol can cause the reduction Equivalent of fatty liver " excessive " in the liver, cause because the anaerobic glycolysis that the chronic hypoxia anoxic diffusion of the thin generation of capillary vessel causes.

When cell hypoxia, or when in anoxic with when containing oxygen condition and rotating, the generation of super-oxide has just increased.Super-oxide further reduces nitric oxide production level, because nitrogen protoxide and super-oxide be with limited diffusion dynamic response, this will aggravate the caused any effect of low nitrogen protoxide.The capillary vessel that has caused nitrogen protoxide crisis and Raynaud's phenomenon that may come to this shrinks.When capillary vessel thins out, tissue will become very responsive to any anoxybiotic,, the change to any perfusion that causes volume of tissue reduces as cold, becomes responsive.When this happens, the tissue anoxic that will become, super-oxide will produce, and nitrogen protoxide will be destroyed, and capillary vessel will shrink more owing to causing more the anoxybiotic blood vessel to relax to become, and super-oxide is many more, shrinks many more.Nitric oxide level that anoxic is low and adverse consequences.It is the cause of positive regeeration.Terms of settlement is exactly to stop the thin generation of blood vessel in the place that begins most.When nitrogen protoxide was destroyed by super-oxide, peroxynitrite salt had just produced, and a strong oxygenant influences many enzymes during peroxynitrite salt.The enzyme that is affected is called ENOS.People such as Goligorsky had reported, and eNOS is from synthetic NO (the Goligorsky et al. of L-arginine, O2, NADPH and tetrahydrobiopterin; Relation between caveolae and eNOS:everything in proximity and the proximity of everything, Am JPhysiol Renal Physiol 283:F1-F10,2002)

Electronics is transferred to the ENOS dipolymer by calcium from NADPH, the zinc sulfate compound becomes unstable when the ENOS dipolymer is exposed to peroxynitrite salt, ENOS will uncoupling, people such as Zou have shown that it has produced super-oxide rather than NO (Zou etal., Oxidation of the zinc-thiolate complex and uncoupling ifendothelial nitric oxide synthase by peroxynitrite, J.Clin.Invest.109:817-826 (2002)).

Another aspect of the present invention, the damage of peroxynitrite salt may not be the too much reasons of nitrogen protoxide, but the very few reason of nitrogen protoxide.It may be the manually modified result of experimental technique that many nitrogen protoxides that show increase cause the test-results of the damage that increases, the most of nitric oxide production contributor who is used for this test discharges nitrogen protoxide mussily, and the compound that discharges similar NO processed goods mussily can cause that problem is not at all surprising.Similar, many no inhibitors not only suppress NO production, and they also suppress to produce super-oxide by NOS, so the provide protection of nitrogen protoxide enzyme inhibitors on local asphyxia might not prove that damage is caused by nitrogen protoxide.

Although have only a cell hypoxia, the super-oxide that cell peripheral produced will destroy nitrogen protoxide, this cell and contiguous cell can become and lack nitrogen protoxide more, nitrogen protoxide reduces, the signal of hypoxia inducible factor and VEGF will weaken, and the sparse of capillary cell will further develop.

The level that relies on oxygen is fully controlled capillary vessel at interval, and do not reflect in the capillary vessel tissue at interval and will have any problem in the level of those oxygen, for example, the gaseous interchange zone in lung.

Cancer

According to an alternative embodiment of the invention, nitric oxide production existence may stop cell to carry out cell fission under anoxic between anaerobic phase, and at this moment cell is in the bigger danger of DNA misreplication.One of cell function is a cell cycle regulation.How and when this be one and controlling the cell regulatory process of repetition DNA, assembles diplochromosome, division.The regulation and control of cell cycle are very complicated, and are not easy to understand, and still, well-knownly have many points on the path of cell cycle, and the cell cycle can be stopped on these aspects, and division can be prevented from being enhanced until the state that this thing happens.Key protein when the P53 tumor suppressor protein is cell cycle regulating, it has started the time-out and the apoptosis of cell by the cell keyed signal that comprises dna damage, and P53 is undergoing mutation in surpassing cancer patients over half.This is people's reports such as Ashcroft, and (Molecular andcellular biology, May 2000, p.3224-3233) to see " StressSignals Utilize Multiple Pathways To Stabilize p53 ".Anoxic starts the accumulation of p53, when anoxic when Hen is important on cell cycle regulation anoxic can not induce the proteic expression of p53mRNA downstream gene inductor block separately, therefore can not cause catching of cell cycle.People such as Goda once reported cell hypoxia inducible need the hypoxia inducible signal.(HIF-1α)(Hypoxia-inducible?factor-1αis?essential?for?cell?cyclearrest?during?hypoxia)。People such as Britta report that NO is one of main stimulator of HIF-1 α (Britta et al., Accumulation of HIF-1 α under the influenceof nitric oxide, Blood, 15 February 2001, Volume 97, and Number 4).Opposite, NO causes the accumulation of the active P53 transduction of meeting, can cause catching of cell cycle, can cause apoptosis (Wang et al., P53 Activation by Nitric Oxide InvolvesDown-Regulation Of Mdm2, The Journal Of Biological ChemistryVol.277, No.18, Issue Of May 3, Pp.15697-15702,2002).

Hypoxic tumor cell has increased the unstable of gene during cell fission, comprise increase, deletion and the transposition of sudden change, people such as Graeber disclose, the anoxic of tumour selects those opposings to cause anoxybiotic cell (the Graeber et al. of apoptosis, Hypoxia-mediated selection of cells with diminished apoptoticpotential in solid tumours, Nature, 1996 Jan 4; 379 (6560): 88-91).If the p53 gene produces mistake, (being taken place in the cancer of half just as surpassing) this cell (with its daughter cell) so all has main cancer suppressor gene no longer, and this gene can stop cancer to be grown uncontrollablely.All to the anoxic tolerance, anoxic is brought the opposing to chemotherapy and radiation to many tumour cells, and many tumour cells all have the anoxic position.People such as Postovit report, tumour is increased the weight of by anoxic, this increase is released compounds block (the Postovit et al. of NO, Oxygen-mediated Regulation of CellInvasiveness Involvement of A Nitric Oxide Signaling Pathway, TheJournal of Biological Chemistary.Vol.227, No.38, issue ofSeptember 20, pp.35730-35737,2002.).Postovit also points out multiple NOS enzyme to use O2 to produce NO, therefore produces NO and reduce under anoxia condition, and the particularly generation of hypoxia inducible VEGF when needing more NO has reduced because the apoptosis that does not have blood plasma to cause.Numerous somatomedins are arranged in blood, have only some to be determined.People wonders that the increase of Regular Insulin (somatomedin of endogenous cell) in the diabetes B whether is compensatory, reduces because the apoptosis of the vascular system that low NO basic horizontal causes.People such as Marchesi have disclosed the L-arginine and have been used for the susceptibility that diabetes B has increased Regular Insulin, increased blood flow (Marchesi et al., Long-Term Oral L-ArginineAdministration Improves Peripheral and Hepatic Insulin Sensitivityin Type2 Diabetic Patient, Diabetic Care 24:875-880,2001.).This has indicated the basic nitric oxide production level that reduces is the characteristics of diabetes B.People such as Wilderoff further report total incidence probability of cancer, and mammary cancer, liver cancer, kidney, carcinoma of the pancreas, colorectal carcinoma, the cancer of the brain or the like, in being diagnosed as the patient of diabetes, all increased (Wideroff et al., Cancer incidence in a population-based cohort ofpatients hospitallized with diabetes mellitus in denmark, J NatlCancer inst 1997; 89:1360-5.).

Another aspect of the present invention, the increase of first menses early and height are the signs that low NO causes basal metabolism to increase.In mammary cancer the factor of the ill danger of well-known increase be first menses early, not conceived, not lactation, live in developed regions, live in the city, height is too high.For example people such as Yoo reports that the Chinese correction age sickness rate of living in Los Angeles is per 100000 philtrums, 48.7 people, and the Chinese that live in Shanghai then are 21.2 people, and the Japanese who lives in Los Angeles is 72.2, and the Japanese who lives in Osaka is 21.9.(Epidemiology?of?breast?cancer?in?korea：Occurrence，high-risk?group，and?prevention，J?Korean?Med?Sci?2002；17：1-6.)。Seem that the factor that does not influence mammary cancer comprises that PCN and DDT expose, this has hinted that being exposed in " chemical substance " is not main paathogenic factor.Be that blood vessel hyperplasia and the capillary density increase that is accompanied by conceived and lactation provides provide protection.Be accompanied by the estrogenic increase that first menses early takes place and be considered to reason.Mostly mammary cancer depends on oestrogenic hormon, is not very clear but oestrogenic hormon is this of how to induce the gene unconventionality that causes canceration.Gestation has been induced many somatomedins, and many somatomedins of gestation have the certain protection effect seemingly impossible, but the too early somatomedin of first menses is " reason ".City/rural area, flourishing/influence of undeveloped degree is possible be because AAOB and they influences to basic NO level.Many known protection factors are consistent with higher capillary density, and many known predisposing factors are relevant with the reduction of capillary density.In developed country, the sickness rate of mammary cancer is the twice of under-developed country.This has hinted that the cancer of many developed countries is that the environmental factors that changes by following development causes.

To studies show that of migrating immigrant's mammary cancer morbidity initial with relevant in original residence, relevant after for some time with the area of being moved to.It is on the order of magnitude in 10 years (Commentary the initiation of breast and prostate cancer, Cacinogensis vol 23 no.7 pp.1095-1102,2002.) that but people such as Gover have shown the time constant of this variation.What shown is to use microbiotic to increase ill danger (the Velicer et al.Antibioticuse in relation to the risk of breast cancer JAMA.2004 of mammary cancer; 291:827-835).Use microbiotic by eliminate on the skin or even the AAOB on the newborn tubule amplified the ill danger of mammary cancer.

The adverse consequences that ATP exhausts

Because in fact all metabolic processes all will be utilized ATP, the ATP deficiency will the damaging cells function, and the reduction of ATP can cause apoptosis, if more serious, can cause necrosis.This apoptosis and necrosis occur in those apart from capillary vessel cell farthest, and may next cell.The apoptosis or the necrosis of diffusion are difficult to be observed, but can explain viewed chronic diffusion inflammation in many same degenerative diseases.

The situation that the ATP that any damage that has increased the metabolism load all is considered to be caused by the nitrogen protoxide scarcity exhausts is aggravated.

In all cells, albumen quilt damage and false folding is transduceed into proteolytic enzyme by being connected with ubiquitin, and the proteolytic ferment that is mediated by ATP decomposes there.Under the insufficient situation of ATP, damage will gather a pathology level, just as observed in numerous disease with protein ubiquitin.Alzheimer disease for example, amyloid throw out accumulates in the brain, and is similar, and at Parkinson disease, the LEWY body that the protein of the ubiquitin of damage is formed accumulates in the brain.Similar, the accumulation of the starch deposits of rheumatic arthritis in stomach fat is common, similar, carried out among the patient of dialysis, the accumulation of starch is common, in congestive heart failure, damage, the protein aggregation of ubiquitin is in heart, and it may be the insufficient symptom of ATP that the nitrogen protoxide scarcity is caused that proteinic pathology is assembled.

Another aspect of the present invention, the increase that sodium absorbs may make the metabolism load of kidney increase, and the susceptibility of ischemic injuries increases, and have aggravated the low nitric oxide production development of the thin institute of capillary vessel inductive thus.Fissional increase will cause the increase that suddenlys change and the increase of canceration possibility under anoxic condition.Should be realized that, under chronic low nitrogen protoxide situation, after capillary vessel thins out, always be in the chronic hypoxia stressed condition apart from capillary vessel cell farthest, therefore very responsive to damage, this orders about them and surmounts rim condition and enter to transfer and die or necrosis or mrna instability.Any damage that has increased the metabolism load will increase local anoxic, increases probability dead or sudden change.Main metabolism load is that absorption by sodium causes in kidney.The sodium that increases will increase the metabolism load of kidney and increase the susceptibility of local asphyxia injury, quickens by the low nitric oxide production development of the thin inductive of blood vessel.This possible explanation why high salt diet hypertension and injury of the kidney are worsened.People such as Lieber report in liver, the metabolizable energy of alcohol is replaced other metabolic substd (the Lieber er al. more than 90%, Pharmacology and Metabolism ofAlcohol, inculding Its Metabolic Effection with Other Drugs, Clinics in Dermatology 1999; 17:365-379).The cell that is in stress situation owing to ethanol in liver has been considered to worsen their reactions to anoxic stress.Therefore the hazard factor of many degenerative diseases, the normal patient of vessel density has reasonable endurance to it, but it is complete to worsen the metabolic function of blood vessel open weave.

Same, plastosome consume also can the aggravation nocuity of local asphyxia or anoxia-induced apoptosis.

Another aspect of the present invention can cause the thin and plastosome loss of the kapillary of anoxic or ischemic death to stop necrocytosis can prevent autoimmune disorder by prevention.When cellular exposure during in chronic hypoxia, reactive oxygen species material (ROS) increases, and the damage of cellular metabolism function increases, and finally causes the damage of cell DNA also to increase.The metabolic capacity that reduces is because ROS and ectogenic carcinogen can make the cells injury restorability reduce.After long-time, the damage accumulation will finally cause one of 3 consequences.Disappearance causes canceration thereby cell presses down the cancer base, and cell is dead by necrosis, cell death by apoptosis.When necrocytosis, no matter be necrosis or apoptosis, cell debris all can be removed from that position.Dead cell is by immunocyte, normally dentritic cell is engulfed, behind the dentritic cell cytophagy, become antigene fragment by different proteolytic enzyme digests, these antigens and histocompatibility complex (MHC1 MHC2) with contact, antigen-histocompatibility complex is transferred to cell surface then, there with the T cytosis, then by many different pathway activation T cells.Any cell injury all can discharge the cofactor of stimulating immune system by different approaches.Generally speaking, Huai Si cell can stimulate bigger immune response than apoptotic cells.Therefore dentritic cell is chronic is exposed to that Hen might cause autoimmune disorder in the dead or dead cell.Well-known, chronic inflammatory diseases can increase the sickness rate of cancer.

According to another aspect, the cell that the atrophy of organ degeneration may be thin by blood vessel or injury of mitochondria causes that takes place along with age apoptosis and the loss that causes gradually causes, when necrocytosis, they can bring out inflammation, and cell debris must be engulfed then to be abandoned.When necrotic tissue is engulfed by dentritic cell, the dentritic cell maturation, antigen expressed then, antigen is derived from the immunostimulation factor CD4+CD8+T cell that necrotic tissue and histoincompatiblity mixture are induced generation.A large amount of necrotic tissue (next cell) can well start immune autoimmune disease. and should be realized that a large amount of immunizing compositions has increased the generation of super-oxide, super-oxide will damage nitrogen protoxide and local deteriorated nitrogen protoxide scarcity.

Any capillary vessel is thin with the organ plastosome loss autoimmunity allergy to take place easily all.Only is the reflection that thin expansion of capillary vessel and allergy chance increase by PRP to SSC and autoimmunity development hypersensitive.Same, other autoimmune disorder is also caused by the thin inductive chronic inflammatory diseases of blood vessel.

People such as Bukhari have set forth in primary Raynaud's phenomenon (PRP), first folds in a garment capillary vessel thinner than the normal control (slight), but than abundant (the Bukhari et al. of the patient who suffers from Sjogren's syndrome (SSC), Increase Nailfold CapillaryDimensions in Primary Raynauds Phenomenon and SystemicSclerosis, British Journal of Reumatology Vol 24 No 35:1127-11311996).

They find that capillary density is from 35 ring/millimeters ²(normal control) drops to 33 (Raynaud's phenomenon) to 17 (whole body sclerosis), and the mean distance between the kapillary branch road is to be respectively 18 μ, 18 μ, 30 μ.Even have only a spot of intercapillary cell owing to the anoxic that takes place is at any time damaged, damage also will accumulate, and finally those cells will be downright bad and be engulfed.Owing to there is a so many generation autoimmunity chance hypersensitive, therefore the irritated just problem of time of autoimmunity takes place, if stress cell be removed by apoptosis, the signal that they once existed may not arranged.The degeneration atrophy of the organ that takes place along with the age may be by the thin cell that causes of kapillary apoptosis and the loss cell that causes is caused gradually.

Another aspect of the present invention, low nitrogen protoxide basic horizontal has caused Fibrotic hypertrophy.In case dead cell is eliminated, new cell can not replace easily, because there are not enough oxygen supports.Any one new cell will suffer same destiny.The interval of cell is empty always, in this case, has just produced the organ atrophy, and it is nearer that capillary vessel is drawn, and new cell has been deprived the VEGF of previous generation by dead cell, so capillary vessel is eliminated, and anoxic zone has formed again.This can cause comprehensive atrophy of affected organ.In Fibrotic tissue, abiotic collegen filament have been full of whole space.Because health does not reduce the metabolic demand of the special organ that has problems, it is big that organ is just attempted to become, but a large amount of fibrous matters is arranged.This has just caused the fibrosis hypertrophy, for example the fibrosis hypertrophy of heart, liver and kidney.Some organs such as brain can not become big or dwindle, because neural three-dimensional communication and capacity are very important, can not successive and the brain that becomes asymmetric atrophy at random, and the space is material abrim, and β-starch may become weighting material.It is because of the scrotum that kidney can not become bigger, and therefore the cell of living diminishes, and is replaced by fibrous tissue.If dead cell is eliminated, tissue will atrophy.NO/O2 ratio reduces again, and it is thinner that capillary vessel becomes.This can builder vicious cycle such as the formation of end stage kidney disease, congestive heart failure, myocardial hypertrophy, primary liver cirrhosis, alzheimer disease, the sclerosis of artery congee oxygen, enteritis, loose scar, begins the multistage tissue adhesion that finishes with Sjogren's syndrome and primary Siofren phenomenon with Raynaud's phenomenon, and it is thin wherein can to observe capillary vessel.People such as Ferrini have shown because the reduction of the basic NO level that the chronic inhibition of the NOS that causes with L-NAME causes has caused fibrosis (the Ferrini et al. of heart and kidney, Antifibrotic, Role of Inducible Nitric Oxide Synthase, Nitric Oxide:Biology andChenistry Vol.6 No.3, pp.283-294 (2002)).

Capillary density in the appetite stimulator and plastosome disappearance factor

Another one embodiment of the present invention, the thin and plastosome of capillary vessel has influenced the ability of body regulation and control appetites.It is thin to observe capillary vessel in the brain of old man and animal.The thin decline with the cycling deposition factor that comprises pancreas islet such as growth factor-1 a of capillary vessel is mutually relevant.The neural generation with vasculogenesis worked in coordination with in the Adult Human Brain.Because the equilibrium function of environment in brain regulation and control are many, the increase of brain controlling elements the brain capillary vessel between diffusion length when the blood flow of those materials is not enough, can be interfered.The glucose flux of brain is near normal metabolic demand.Maximum glucose flux is only than the big 50-75% of glucose consumption amount, the glucose transport device by the brain carrier be saturated, be steroidal substances, be what not rely on energy and ion gradient.The major part of appetite regulation and control is regulated by brain, and capillary vessel is thin may to make the competent haemoconcentration of " nutritive substance " the manufacturing compound of nutritive substance (or be equivalent to) be disturbed when deficiency.This may be one of popular fat reason, and the people that can not control appetite may only be between their capillary vessel and trigger the cause of the Path too long between the cell of appetite.Their brain is always telling them to be in hungry state.Because those cells far away apart from kapillary are " hunger ".Be not only because Path too long, also because the cause that nutrition has been consumed by intermediate cell.When cell hypoxia or plastosome deficiency, can not from glucose oxidase, obtain ATP, they obtain ATP from the anaerobic glucose metabolism.The amount of supporting the needed glucose of metabolism by the anaerobic glucose metabolism is than big 19 times by the aerobic glucose metabolism.Therefore cell hypoxia or the insufficient cell consumption of plastosome are equivalent to the glucose amount of 19 non-hypoxic cells.If the some parts hypoxic cell at " glucose recipient cell " with as the capillary vessel of grape glycogen between the time, " glucose recipient cell " will inevitably obtain wrong low identification.Neuron cell only generates ATP by oxidative phosphorylation, and other brain cell for example astroglia cell then can obtain ATP by the anaerobic glucose metabolism.The a spot of astroglia cell approaching with neuron probably makes glucose lose the sort of neurone.The serious hope to sugar and carbohydrate of having tormented many people comes from the special neuron of having been deprived glucose by near anoxic astroglia cell.The blood sugar concentration that raises makes those cells attempt to obtain more glucose, and path saturated during still owing to the glucose transport body is stoped by too many anoxic astroglia cell, and blood sugar rises to such an extent that enough height are impossible.Fat in being associated of chronic degenerative diseases may not be because fat cause they, but can cause that fat material (the thin and plastosome disappearance of capillary vessel) has also caused degenerative disease.KINGWELL has shown that motion can increase nitric oxide production basic horizontal (Kingwell, NitricOxide-Mdiated Metabolic Regulation During Exercise:effect OfTraing in Health and Cardiovascular Disease.FASEBJ14-1685-1696 (2000)) under the normal health situation and among the hypercholesterolemia patient.Motion can be mediated by the nitrogen protoxide that vasculogenesis mediates the advantageous effect on the obesity.Hunger or high fat diet inductive ketoacidosis make liver that fat is generated ketoboidies acetylacetate and β-Qiang Dingsuan.The ketoboidies circulation, place of glucose is utilized in oxidative phosphorylation by neurone.High ketone diet has increased the threshold value of electric sharp inductive epilepsy.High fat diet has surmounted the half a century of growing up as epilepsy therapy.The antiepileptic action of high fat diet is because the neuron energy keeps.The appetite repression of high fat diet may only be because bigger neurone energy keeps.

The inventor uses the autotrophy ammonia oxidizing bacteria to surpass year, has noticed that tangible appetite reduces, and has subtracted about 30 pounds in 1 year, does not only feel tangible discomfort by going on a diet.Skip meal before the inventor and will produce functional defect immediately.He does not eat and but can not produce mentally or the dysfunction on the health meal that can much pause now.

Capillary vessel is sparse/and the plastosome deficiency is as the reason of non insulin dependent diabetes

According to another aspect of the present invention, capillary vessel is sparse/and the plastosome deficiency may be the reason of non insulin dependent diabetes (NIDDM), and the characteristics of non insulin dependent diabetes are exactly that Regular Insulin is produced opposing.Health reduces the susceptibility of Regular Insulin, and insulin level increases.Although carried out many researchs, " reason " is still not clear.In all developed countries, comprise Different Culture has been done observation with different ethnic groups.The people of NIDDM have high blood glucose, high triphosphoric acid glyceryl ester, all are typical obesities, hypertension, typically a large amount of interior fats are arranged.

Be accompanied by other symptom of NIDDP, the inventor believe capillary vessel thin be its reason.40 people are comprised be with or without NIDDP's, fat (BMI29), in the research of thin (BMI24) (ten every kind), people such as Konrad report the man who does not have NIDDM thin under the resting state, the fat man who does not have NIDDM, the thin man that NIDDM is arranged, the fat man's that NIDDM is arranged blood lactic acid level is respectively 1.78,2.26,2.42,2.76 (mM/L) (Konrad et al., A-lipoic and TreamentDecreades Serum Lactate and Pyruvate Concentrations andImproves Glucose Effectiveness in Lean and Obese Patients withType 2 Diabets, Diabetes Care 22:280-287 1999).Lactic acid is the glycometabolic tolerance of anaerobic, and cell can produce ATP by the anaerobic carbohydrate metabolism when oxygen is not enough to by oxidative phosphorylation generation ATP.One of glycometabolic product of anaerobic is exactly a lactic acid, and lactic acid must be got rid of from cell, otherwise the rising of pH value, cell function will be destroyed.By general the measuring of Hen, the amount of increase has hinted the working load in the time of can carrying out maximum oxidation to blood lactic acid in motion study.The glycometabolic increase of anaerobic when the lactate level rising has hinted resting state under the resting state, the anaerobic carbohydrate metabolism is thin with the hair and blood pipe to be consistent.Lactic acid content that what is interesting is thin diabetics is than fat non-diabetic people height.

It is high that the glycolysis-of NIDDM patient's muscle cell/non-NIDDM patient's of oxydase odds ratio ratio is wanted.NIDDM patient's muscular energy is from glycometabolic than coming from the many of oxidative phosphorylation with anaerobic.

With MRI the pH value of muscle and the measurement of phosphoric acid substance have been proved that the people of the type i diabetes of good control has changed the physiology of muscle before the muscle activity and between active period.In people such as Crowether research, the intravital oxidation capacity of diabetic subject reduces, from the anaerobic carbohydrate metabolism, obtain more energy, this difference (Crowther et al. more obvious under resting state, Altered energetic properties is apprent energeticin skeletal muscle of men of with well-controlled insulin-dependent (type 1) diabetes, Am J Physiol Endrocrinol Metab 284:E655-E662,2003).This test is interesting, because it measures intravital lactic acid generation by the change of pH value.They notice that some patients have two kinds of different muscle cells, have different pH values and lactic acid generation in their test.There are 4 non-diabetic people to have 2 among 10 diabeticss.In their research, they have only done on average value, but the cell of different lactic acid productions has hinted the different of the difference of oxidative phosphorylation ability and the O2 supply that therefore causes.

Reduce with the thin maximum VO2 that compares the NIIDM woman with fat control group.The maximum VO2 that has reduced is still obvious when not having cardiovascular syndromes.The NIIDM woman has lower peak work output and higher blood lactic acid level, is not always the case when no matter being rest or when motion.

Glycometabolic increase is consistent with the chronic reduction of the oxygen that is transported to peripheral tissues with the observed on one's body anaerobic of type ii diabetes patient in the I type, and/or it is mitochondrial not enough consistent, the anaerobic carbohydrate metabolism of this increase hour just can be observed when the metabolism demand under resting state, and this has hinted that reduction/mitochondrial deficiency that oxygen transports is chronic.

Capillary vessel is thin/and the plastosome disappearance is as the reason (type i diabetes) of insulin-dependent diabetes mellitus

The characteristics of type i diabetes are exactly that the pancreas islet of uelralante when blood glucose levels increases is by the autoimmunization system destruction.The reduction that ATP disappearance, plastosome disappearance, the glycolytic ferment that is caused by the nitrogen protoxide scarcity of the thin mediation of kapillary expressed can make the plastosome of pancreas reach higher electromotive force, this can produce super-oxide, can cause inducing of uncoupling protein, the reduction of ATP level be can cause, the apoptosis or the necrosis of pancreas islet caused then.Autoimmunity allergy will take place.In case immunity system is super quick to pancreas islet, near them, will produce super-oxide, local lower nitric oxide level is even lower, make that kapillary is thin, plastosome disappearance and glycolytic ferment is not enough worsens.

With autotrophy ammonia oxidizing bacteria treatment hepatitis

Primary biliary cirrhosis is relevant with Raynaud's phenomenon, pruritus, dry syndrome, osteoporosis, portal vein hypertension, neurological disorder, pancreatic insufficiency or the like.Liver is unusual relevant with rheumatosis, and the liver enzyme of rising is the early symptom of the primary liver cirrhosis of " asymptomatic ".

The liver enzyme Hen in the collagenosis patient who suffers from the polyarteritis nodosa that comprises cholehepatocirrhosis liver, autoimmune hepatitis, nodular regenerative hyperplasia, polymyositis, dermatomyositis, systemic sclerosis, mixed connective tissue disease, polyarteritis nodosa that raises is common.

The process of primary biliary cirrhosis is divided into four-stage, first stage is the immunologic injury that causes owing to aforesaid nameless reason of tubule in the liver, being tubule hyperplasia or sheet necrosis then, is fibrous necrosis or bridging necrosis then, is liver cirrhosis then.People such as Benvenvegnu have reported dependency (Benvegu etal., the Evidence for an assiciation between the aetiology of cirrhosisand pattern of hepatocellular carcinoma development.Gut 2001 between liver cirrhosis and the liver cancer; 48:110-115).Many kinds of immune adherence tissue diseases all are accompanied by primary biliary cirrhosis, comprise the sjogren syndromes, scleroderma, CREST symptom (marl, Raynaud's phenomenon, esophagectasia, sclerodactyly or telangiectasis), rheumatic arthritis or thyroid disease.

The selection treatment plan of primary liver cirrhosis is oral Ursodeoxycholic Acid (UDCA).This is a kind of hydrophilic biliary salts, replaces other more toxicity wetting ability biliary salts in the liver circulation kind, and its mechanism is not very clear, effective constituent may from by reducing the biliary metabolism burden that reduces liver of synthesizing.

When though anti-mitochondrial antibody often is present in primary liver cirrhosis, all no longer this has antibody in the PBC patient body of 5-10%, most patient has autoimmune antibody to unstriated muscle or nucleic acid factor, but immunosuppressive therapy is effective not as oral bear oxycholic acid in the development that slows down PBC.This has hinted that autoimmune antibody is not the reason of PBC, but the result of some other reason.

In one embodiment of the invention, use the autotrophy ammonia oxidizing bacteria can make the reduction of liver enzyme to scalp and health.Fig. 1 has shown the liver enzyme of using autotrophy ammonia oxidizing bacteria application front and back, the change curve of transaminase level.After using the autotrophy ammonia oxidizing bacteria, the level of SGPT has dropped to the Schwellenwert over 20 years.People such as Schoen report, oxynitride triggers liver degeneration (Schoen et al., Shear stress-induced nitric OxideRelease triggers the liver regeneration cascade, nitric oxide:biologyand biology and chemistry vol.5, no.5, pp.453-464 (2001)).Therefore be effective on the chronic hepatitis of liver enzyme that is applied in the reduction rising of autotrophy ammonia oxidizing bacteria and rising liver enzyme.As if having only a spot of data but be to use on the time coordinate that hint liver enzyme reduces behind the autotrophy ammonia oxidizing bacteria, drug effect is not to bring into play immediately.The progressively solution that process of Jiang Diing and secular capillary vessel are thin gradually (by the capillary vessel reparation of following the NO level to increase) is corresponding to.

The level that reduces hepatitis can reduce the development of PBC and other hepatopathy, reduces the development of the liver cirrhosis relevant with liver cancer.

Another aspect of the present invention, " anoxic " of regulating capillary density generally takes place in the sleep process.Although from some theory is not certain, the reduction that usually occurs in blood pressure between sleep period and blood flow rate is one of normal " managing household affairs " function of health, make between the capillary vessel and the cell of capillary vessel service between the oxygen diffusion resistance restore.Said as people such as Zoccoli, night, the reduction of blood pressure helped the NO level to increase usually, when suppressing NOS and eliminated the PBF sleep and difference (the Zoccoli et al. when clear-headed with L-NNA, nitric oxide inhibition abolishes sleep-wakedifferences in cerebral circulation, Am J Physiol Heart Circ Physiol280:H2598-H2606,2001).People such as Kapfis have shown that the inhibition of NOS in the rat has caused the inhibition (Kapfis et al., Inhibition of nitric oxidesynthesis inhibits rat sleep.brain research 664 (1994) 189-196) of ortho.People such as Weitzberg report and shout to make the nasal sinus that can produce NO to increase NO (the Weitzberg et al. of nasal cavity by increasing gaseous interchange, Humming Greatly increasesnasal nitric oxide, Am J Respair Crit Care Med Vol 166.pp 144-145,2002).The thin relevant disease of many and capillary vessel is also relevant with the breathing of disorder at night (snore or suffocate).Obesity, aging, cardiovascular disorder, hypertension, rheumatic arthritis, all with sleep during breathing relevant, therefore, the high NO level between sleep period is disadvantageous, night sweat and snoring all are the physiological mechanisms that makes the increase of NO basal level.High NO level has reduced the ratio of NO/O2 between sleep period, has therefore increased " anoxic " signal.

The training philosophy that the hypothesis that intracapillary space is determined between sleep period " is lived in eminence-training at lower " supports that the sportsmen trains at low height above sea level place, in life of high height above sea level place and sleep.Make by the metabolism load of training muscle in the training of low height above sea level place to increase, " anoxic " derived making near maximum metabolism load.Induce anoxic may muscle not had effect by reduction oxygen supply amount at night, because have high-caliber oxygen in the very capable and oxyphorase of their anaerobic respirations.But avoiding making muscle to be in the insufficient anoxic condition of NO level at night is the rarely found reason of muscle cancer why.The organ anoxic of unconscious adjusting can not independently be induced by moving.For example, erythropoietin is that kidney produces under anaerobic state, regulates erythrocytic generation and hematocrit.People such as Ge have shown that erythropoietin is immediately raised nearly 50% (Ge et al. by hypobaric hypoxia at 2800 meters after 6 hours, Determinants oferythropoietin release in reponse to short-term hypobaric hypoxia.JAppl Physiol 92:2361-2367,2002).Usually give EPO disappearance and hemocytes increasing specific volume that kidney dialysis patient EPO causes owing to kidney sick or disappearance with compensation.But near the increase of the hematocrit at normal edge the mortality ratio when low-level.In the random research of people such as Besarab, show 1233 patients, after 29 months, the patient of hematocrit liter 42% causes mortality ratio to increase by 29% than the patient that hematocrit rises 30% (150 death of 183 examples), the cause of disease of two groups of death is similar, the feature of dialysis is also similar, in high hematocrit group higher mortality ratio (Besarab et al. is arranged all, Theeffect of normal as compared with low hematocriy valus in payientwith cardiac disease who are receiving hemodialysis and epoetin, NEngl J Med 1999; 339:584-90).May be the basic horizontal that the hematocrit that raises has increased NO, the NO basic horizontal of reduction have increased mortality ratio.Dead reason is similar, because two groups in fact all have low NO level, is that low NO level has at first caused injury of the kidney, and low hematocrit is bad, low also Hen bad luck of NO level.Do not increase the good method (also not having so far) of low NO basic horizontal, coming the increase of the oxygen capacity of balance blood with the NO concentration that reduces is a very difficult treatment plan.

The alzheimer disease

People such as Torre once reported alzheimer disease be a kind of be the thin vascular disease of microtriche, be accompanied by the nervosa that low perfusion excites and degenerate.This part causes (Review Evidence that Alzhemer ' s Disease Is a MicrovascularDisorder:The Role of Constitutive NitricOxide, Brain ResearchReviews 34 (2000) 119-136) by the NO deficiency.

Alzheimer disease not all people all can get, and it is not single morbidity, in addition a small amount of low perfusion patient also must not, but it is long-term morbidity, sometimes for many years more than.The process of alzheimer disease, firm and dull, be unstable low, irrelevant with the low morbidity of pouring into and fainting.It is sizable different that the neuropathic degree of commitment and decline rate have, and this is the reason that is difficult to commitment diagnosis alzheimer disease.

Observed because low perfusion causes is enough to cause the ischemic level of oxidative damage can cause significant spiritual influence simultaneously in alzheimer disease.It is conspicuous can not causing the ischemic and the anoxic level of oxidative damage, cause psychiatric disorder and the low perfusion level of fainting not by alzheimer patient record, so oxidative damage must be to occur in non-writing time, might occur between sleep period.

Between sleep period, the metaboilic level at each position of health has all reduced, and blood pressure reduces, and blood flow reduces.Blood flow rate by health has reduced, and along with the strain on the vessel wall reduces, the eNO enzyme is reduced, and the NO that the eNO enzyme is produced also reduces.The energy requirement of brain reduces.Though brain is in the period of enlivening but still needs a large amount of blood flows.

Hypothermia can reduce the brain damage between ischemic stage.In the ischemic or hypothermia afterwards reduce brain damage by reducing reperfusion injury.Sleep generally can make body temperature reduce 0.5-0.7 ℃.The reduction a little of body temperature can independently reduce the energy requirement of brain between sleep period, reduces the ischemic thresholding of damage.It is about 14% that 1 ℃ of basal metabolism level of the every rising of body temperature raises, so 0.5-0.7 ℃ the reduction of " normally " is exactly the reduction of the 7-10% of metabolic rate between sleep period.

NO is necessary in the basal body temperature that anoxic causes reduces.People such as Alemida once reported when the NO synthetic enzyme is suppressed by N-nitroso-group L-arginine (L-NNA), the reduction of the basal body temperature that takes place with anoxic is reduced (Almeida et al. greatly, Role ofnitric oxide in hypoxia inhibition of fever, J.Appl Physiol.87 (6): 2186-2190,1999).

It may partly be because they have reduced body temperature that " positive-effect " of report NSAID (non-steroidal anti-inflammatory drug) on alzheimer disease arranged.

The epidemiological study of alzheimer disease is able to excellent research in developed country, but just studies seldom in developing country.Be different and may all be wrong by many reliable with the lasting different diagnostic treatments of many patients, doctor and multiple culture.That is to say according to the anoxic causal event theory between existing sleep period, sickness rate should increase along with the increase of sleep temperature, table 1 and 2 has shown incidence probability (the Guk-Hee suh of the alzheimer disease that Suh and Shah report in comment, Ajit Shah, Review Article:Areview og the epidemiological trasition indementia-cross-national comparisons of the indices related toAlzhemer ' s Disease and vascular dementia, Acta Pyschiatr Scand2001:104:4-11).

Temperature is that the monthly average table look-up from Yahoo's health and fitness site obtains, when the data in the city can not get, usefulness be the data (in the parantheses) in suburb.

Data are divided into two, " developed country " and " developing country ".Beijing comprises two kinds, and 1987 get data is the data of " developing region ", and 1999 is that " developed regions " get data.This division of two groups is to divide on the basis of everyone bath water that is grasped.Relevant crowd is alzheimer disease (AD) risk population, i.e. elderly population.These people lag behind other crowds aspect the new bathing custom probably adapting to.

Table 1 has shown the minimum and maximum value of monthly mean temperature, the dull-witted sum in the sickness rate of alzheimer disease and undeveloped city.Table 2 has shown minimum and maximum monthly mean temperature, the dull-witted sum in the sickness rate of alzheimer disease and flourishing city.

Undeveloped city	Study dates	The hottest month	Average maximum	Average minimum temperature	The alzheimer disease sickness rate	All dementia sickness rate
Beijing	1987	July	87.4	70.9	0.4	0.8
Shanghai	1990	July	88.9	76.6	3	4.6
Hong Kong	1998	July	92.7	74.5	4	6.1
Taiwan (Taibei)	1998	July	90	77.9	2.3	4
Ibadan (Lagos)	1997	February	91.8	75.4	1.1	1.4
Kerala (Bangalore)	1998	April	93.6	71.2	1.4	3.4
Tokyo	1982	August	87.6	75.2	1.2	4.8
Okinawa	1995	July	88	79	3.1	6.7
Hiroshima	1999	August	87.6	74.5	2.9	7.2
Aichi (Nagoya)	1986	August	90	74.3	2.4	5.8
Wuhan (Wuhu)	1981	July	88.9	76.6	0.1	0.5

Flourishing city	Study dates	The hottest month	Average maximum	Average minimum temperature	The alzheimer disease sickness rate	All dementia sickness rate
Beijing	1999	July	87.4	70.9	4.8	7.8
Boston	1989	July	81.8	65.1	8.7	10.3
Odense	1997	August	69.4	52.2	4.7	7.1
London	1990	July	71.1	52.3	3.1	4.7
Stockholm	1991	July	71.4	56.1	6	11.9
Rotterdam (Amsterdam)	1995	July	85.5	43.7	4.5	6.3

Being considered to very important shower activity is hair washing, washed natural autotrophy ammonia oxidizing bacteria group off with washing composition hair washing skin, and it can produce the nitrogen protoxide that scalp is absorbed.One aspect of the present invention, not washing hair to protect makes the people must not alzheimer disease, and people may present the mixing behavior of different hair washing modes.The developed country that enriches bathing product and bathing usefulness hot water is being arranged, and hair washing is very general, and the number that the hair washing frequency is lower than once a week is seldom really.In under-developed country, also there is the frequency of a considerable amount of people's hair washings enough to remove the autotrophy ammonia oxidizing bacteria.That part of people has represented the great majority of the alzheimer case in undeveloped city.

Data are depicted among Fig. 2, have shown the dependency (temperature when being nighttime sleep) of mean minimum temperature in alzheimer disease sickness rate and the hottest month.Two sets of data form two groups, and the sickness rate that the rising of minimum temperature is relevant to alzheimer disease increases, but slope is different with intercept.The intercept of under-developed country approximately is 70 Fahrenheit degrees.The intercept of flourishing city group not in chart, do not conform to actual because heating can temperature be elevated to the area of " comfortable ".The development of the alzheimer of under-developed area has embodied the seasonality of different sleep temperature, is lower than the minimum temperature of most of people with outdoor irrelevant temperature sleep the time in the developed regions intercept.

According to one aspect of the present invention, an improvement that factor is the shampoo technology of the high incidence of alzheimer disease now.It is early stage that it betides 20th century the seventies, makes that people can often every day, hair washing be sent out even.Before that period, if a people washes hair every day, his hair will " become straw ", is very inaesthetic, is that the development of " hair care " shampoo can be had one's hair wash the people every day.About the chart of the quantity of the United States Patent (USP) of shampoo as shown in Figure 3.20th century, the seventies had a large amount of increases in early days, and is same, approximately after the 10-15, diagnosed the people's of acquisition type diabetes quantity that a large amount of increases has also been arranged.According to one aspect of the present invention, present obesity, diabetes and alzheimer disease popular stems from the development of hair care and hair cleaning agent and their frequent use.

Other side effect relevant with hypertension is also relevant with low nitrogen protoxide basal level.The hypertension medium vessels is reactive to be reduced.Vasodilative reduction is consistent with low nitrogen protoxide basal level.Nitrogen protoxide is a dispersion pattern molecule, can be diffused into the inductor block position from the source, brings into play the signal effect there.When nitric oxide level hanged down, each nitrogen protoxide source must produce more nitrogen protoxide with the nitrogen protoxide signal of generation with specific range certain strength as much.Nitrogen protoxide three-dimensional diffusion, the whole volume of range of scatter must be elevated to the level that can provide appropriate signals at the inductor block position.This can cause the high nitric oxide level between Yuan Heyuan and inductor block.Near the nitric oxide production local side effects that raises the source may be because the too low cause of nitrogen protoxide background level.Exist the evidence that this situation takes place.People such as Hennijngsson report that in rat Langerhans islet NOS enzyme has been increased the NO total amount of inducing generation (Chronic blockade of Nosynthase paradoxically increase islet Noproduction and modulates islet hormone release.Am J Physiol Endocrinol Metab 279:E95-e107,2000) by the iNOS enzyme by the inhibition of L-NAME.Only under condition of limited, work by inducing the NOS enzymic activity to increase NO.The NOS enzyme is activated but when not being supplied enough BH4 or L arginine, so uncoupling generates super-oxide rather than NO, super-oxide can destroy nitrogen protoxide.Attempt to produce the reduction that nitrogen protoxide causes nitric oxide level on the contrary to surpass BH4 or the arginic delivery rate of L.This can cause positive regeeration, low nitrogen protoxide NO level is owing to the stimulation of NOS enzyme becomes worse, the NOS enzyme of uncoupling generates a large amount of super-oxide, cause local oxygen reactive material (ROS) damage, as viewed in atherosclerosis, end stage kidney disease, alzheimer disease and the diabetes.

Osteoporosis

Osteoporosis is the disease that has influenced many old men.The incidence probability of fracture increases when old.The probability of childhood forearm fracture has increased (S.Khosla et al., Incidence of childhood distal foream fractures over 30 years, JAMA.2003 in the past 30 years; 290; 1479-1485).Known nitrogen protoxide can influence bone density, oestrogenic hormon to the beneficial effect of bone density by metabolic influence realizes to NO.People such as S.J.Wimalawansa also report at prevention bone lose the same with oestrogenic hormon of pannonit in " the pannonit therapy is the same with estrin treatment effective " literary composition have effect (Journal of Bone and mineral research Vol.15, NO.11,2000.).The increase of fracture may be the result that the loss of autotrophy ammonia oxidizing bacteria causes the NO loss on the skin when childhood and old age.The recovery of autotrophy ammonia oxidizing bacteria also will reduce osteoporosis on the skin.

Old and feeble

Just study the method that delaying senility develops from ancient times, but achievement seldom.Unique method that prolongs life that is proved to be is the caloric restriction picked-up.Holloszy reports, the erstricted diet picked-up is to 70% of contrast, the life of rat of sitting quietly extended to 1051 days from 858 days, approximately grown 25% (Holloszy, Mortality rate and longevity of food restricted exercising male rats:a reevaluation.J.Appl.Physiol.82 (2): 399-403,1997).Caloric restriction and the contact that prolongs between the life have well been proved, but reason mechanism is unclear.People such as Lopez-Torres report the detection of rat liver cyclophorase and have hinted that thereby the activity of caloric restriction picked-up can reduction compound 1 reduces generation (the Lopez-Torres et al. of H2O2, Influenee of Aging and Long-Term Caloric Restriction on Oxygen Radical Generation and Oxidative DNA Damage in Rat Liver Mitochondria, Free Radical Biology﹠amp; Medicine Vol.32 No.9, pp882-8899,2002).H2O2 is that the disproportionation by super-oxide O2-produces, super-oxide O2-is the main ROS that plastosome was produced between respiratory period, Kushareva and suggestion such as people such as other grades, the main source of super-oxide are the electronics adverse currents of the compound III at the redox Compound I coupling of catalyzing N AD/NADH succsinic acid reduction position.The free-radical theory of the old and feeble hypothesis that proposes by Beckman, promptly along with the cell DNA of age accumulation, the radical damage of antioxidant system and DNA repair system, with be damaged and can not repair when critical system, (Backman just takes place in death thereupon, The FreeRadical Theory of Aging Matures, Physiol.Rev.78:547-581,1998).Recognize that plastosome is the main product survivor of super-oxide, the generation speed and the mitochondrial efficient of super-oxide mainly depend on mitochondrial potential energy.Mitochondrial electromotive force is low more, and the generation efficient of ATP is high more, and the generation of super-oxide is few more.The heat restriction can produce more plastosome so that stronger metabolic efficiency to be arranged by forcing cell, brings into play antidotal provide protection, and its side effect is exactly the generation that reduces super-oxide.

Except radical damage can cause aging, the programmed aging that shortens along with cell fission based on telomere length is arranged also.People such as Vasa prove that nitrogen protoxide can activate telomere, postpone aging (Vasa et al., the Nitric oxide activates telomeraseand delays endothelial cells senscence.circ res.2000 of endotheliocyte; 87:540-542).Low NO basal level suppresses to remove by the pair cell chromo-oxidase increases basal metabolism speed.Increase basal metabolism speed and can increase cell upset and growth velocity, can increase radical damage by chronic hypoxia inductive capillary vessel is thin, also can increase the upset of cell, therefore two kinds of mechanism have all been quickened aging.

Another aspect of the present invention, autotrophy ammonia oxidizing bacteria just influence the age process from pubarche.Interesting observing when an area becomes prosperity in mankind aging's process, menarche also become in advance.This is existed many explanations, still, the best relation that meets data is to be inversely proportional to civilization degree, reports as people such as Thomas.(Thomas et al., Inverse Relationvariability of Ages at Menarche andMenopause.Patterns and Main Determinants.Human Biology April2001, Vol.73, No.2, pp271-290) but it is respectively 12.9 and 12.7 years old that people such as Freedmen report age of menarche the white American in 1974 and girl Black people, (Freedman et al., Relation of Age Menarche to Race, timePeriod, and Anthropometric Dimensions:The Bogalusa Heart Study, Pediatrics 2002; 110 (4)).1994 be respectively 12.1 and 12.5 years old.The decline of age of menarche is relevant with diet, has especially increased fat on the diet.But from 1965 to nineteen ninety-five, 11-18 year child shared proportion of fat on diet drops to 32.7% from 38.7%.In Norway, age of menarche dropped to 13.3 years old of nineteen fifty from 16.9 years old in 1850.Change with the time and be linear.In the U.S., dropped to 13 years old from the first menses of 1910 to nineteen fifty from 14 years old, also be linear dependence, during depressed, do not observe increase, available food has lacked substantially at that time.The hebetic age is actually because when taking a shower due to the loss of autotrophy ammonia oxidizing bacteria, rather than because due to available food increases.First menses becomes early may be owing to the idea that has adopted the westerner " clean just pious " with the relation of civilized degree.Disease is not because of dirt but because pathogenic agent, pathogenic agent can be relevant with dirt also can be uncorrelated, the minimizing of dysentery is not because increased and take a shower but because modern environmental health, is because to the sanitary measure of fatal pathogenic agent, to the prevention of the water that contained the pathogenic agent refuse pollution.

Generally increase along with expanding economy life expectancy, and this increase is brought by multiple factor.The minimizing of hunger, dysentery and other infection reduces infant mortality.Be grown up life expectancy owing to better health-care method raises.But in fact begin to see in some developed countries has reduced old man's life expectancy.In Holland, 85 years old man's life expectancy since 20th century the eighties just begin to have reduced, 1985-1989, the men and women reduced, and reports as people such as Nusselder.(Nusselder?etal.，Lack?of?Improvement?of?Life?Expectancy?at?Advanced?Ages?inthe?Netherlands，International?Journal?of?Epidemiology?2000；29：140-148)。Mental disorder (mainly being alzheimer), cancer, diabetes, chronic obstructive tuberculosis, all situations all can be worsened by the reduction of NO basic horizontal.

Allergy and autoimmune disorder

Another aspect of the present invention, the autotrophy ammonia oxidizing bacteria can produce provide protection to all allergy and autoimmune disorder.Children's irritated sickness rate increases in developed country always to some extent, and asthma is the most general chronic diseases of children.The different of asthma and irritated sickness rate are not clearly explained so far between the different ethnic groups.Data very complicated and also as if the stem of noble dendrobium be contradiction.Autoimmune disorder also Hen is general, the most general may be type i diabetes, the cell of making the Regular Insulin of molecule by pancreas is destroyed by immunity system and causes, habitual abortion is also relevant with autoimmune disorder, and the quantity of autoimmune antibody and the quantity of habitual abortion are proportionate.

Systemic sclerosis, primary biliary cirrhosis, autoimmune hepatitis and dissimilar rheumatism are other examples of autoimmune disorder.

General going up, sickness rate hypersensitive increases along with the increase of wealth, and a rich national sickness rate is higher, and among a nationality, rich crowd's sickness rate is also higher.But people such as Platts-Mills report in the U.S., the African American's of urban residence asthma prevalence is three times of (Platts-mills et al. of suburb children, Asthma and Indoor Exposure to Allergens New England Journal ofMedicine Volume 336:1382-1384 may 8,1997, number 19).

People such as Rasmussen reported once that birth showed lower allergic phenomena (Rasmussen et al. than birth the African offspring of Sweden the Sweden soldier in Africa, Migrationand Atopic Disorder in Swedish Conscripts, pediatr AllergyImmunol 1999:10:209+/-215).This piece paper shown to those " tropical descendant " (those in Africa, the people of Latin America or Asia birth), to birth in Sweden and non-birth in the people of Sweden difference at the irritated sickness rate that draws according to " socioeconomics " (measuring) by the native country research in＞12 years.What is interesting is the (east of those births in " temperate zone ", West Europe and Sweden) people according to " socioeconomics " research difference less, and those mothers are just higher from the irritated rate of people (Middle East, southern Europe) of intermediate zone, but are like this for birth the people of Sweden only.Birth is higher 2.9 times than Swede at the African future generations' of " socioeconomics " " height " of Sweden pathogenesis of asthma probability, can see identical ratio between African American that Gary is lived and suburb (white man) children.Low " socioeconomics " only is reduced to sickness rate 1.1 times of Swedish sickness rate of low " socioeconomics ".Birth has only seldom provide protection to high " socioeconomics " outside Sweden, sickness rate is 2.5 times.Low but " socioeconomics " and birth have but given a large amount of protections outside Sweden, sickness rate only is Swedish 0.56 times.Therefore the different African offspring's in those birthplaces asthma prevalence has 5 times difference.What is interesting is that age of menarche reduces along with the irritated sickness rate of the increase of civilization increases.

In rural area, Bavaria, Germany state, the type of household fuel is relevant with other development hypersensitive with asthma, is found to be provide protection with coal and wood heating (with respect to central-heating).Perhaps lower room temperature can be explained the supersensitivity of dust lower, but the sensitivity of cat, dog and pollen has also been reduced.Keep a cat and family's ratio of dog ratio height in the group of using coal and wood.Use family's " socioeconomics " of coal and wood lower.

What observe such phenomenon suggestion is that increase is exposed to and is considered to have provide protection to cause people's suggestion " hygiology hypothesis " to development hypersensitive afterwards in anaphylactogen and the disease during child.But many experts consistent data of stating in the meeting of hygiology hypothesis remain contradiction, do not show which kind of microorganism or preparation have provide protection.

The application of autotrophy ammonia oxidizing bacteria is considered to the allergy that reverse long-term exists, i.e. inventor's seasonal ragweed fever.Whether the existence of autotrophy ammonia oxidizing bacteria has explained not contradiction of " contradiction " data of reporting in the document.In fact all research can be explained by cause and effect mechanism described herein.Just as those births and the serious reason that increases of the irritated sickness rate of torrid areas people of living in flourishing state 0 family.This has also explained the place that to live in a shower activity why be the function of economic situation, and low economic situation especially has provide protection.Those can not have the hot water from the beginning of the abundant usefulness of having a bath with coal or the wooden German rural people who adds heat-obtaining.Be not the mode that they heat to the house, but provide protection has been played in the shortage of the hot water that is used to take a shower.

The perplexing reason of preparation in " hygiology hypothesis " is that it can not cause any disease.In fact, said preparation can not cause disease (even if in being subjected to the people of immunologic injury), because it is autotrophy ammonia oxidizing bacteria (AAOB).They are not grown in any heterotrophism medium, for example be used for the used medium of bacterial isolate body (all as people such as Scchechter report be heterotroph) (Scchechte et al., Mechanismsof Microbial Disease, Williams﹠amp; Wilkins, Baltimore, MD, USA, 1989).They not in human body found unique reason be that be out of use suitable developing medium and technology studied.They generally are present in all soil, and they are responsible in the nitrifying process the first step with the ammonia oxidation changing into nitrate there.As autotrophic bacteria, they can not lack its desired substance, the place existence of ammonia or urea, O2 or mineral salt.These materials are very abundant on the skin of not washing, and come from the sweat residue, " natural " state and soap of no use frequent have a bath the time, people can not stop the breeding of these bacteriums on outer skin.In fact, these bacteriums are favourable, and according to one aspect of the present invention, they are symbiotic.Many aspects of human physiological activity all will comprise the growth that utilizes these bacteriums and utilize the abundant NO that they produce.

Stoping their separated another one factors is shower activity in developed country.The bath of having enough number of times has become a kind of custom to prevent body odor, and body odour generally just can not produce several days do not have a bath after, savours compound and on outer skin scurf and sweat residue is metabolized to compound odorous by heterotrophic organism and produces.In three days, autotrophic bacteria just can double breeding for 7 times, increases about 100 times than the people who has had bath.Opposite heterotrophic organism can double breeding for 200 times, and reaching than the people who has had bath increases about 100+60-level doubly.The growth of obvious heterotrophic organism is subjected to the restriction of nutrition.0 hypothesis has similar removal effect by having a bath to heterotrophism and autotrophic bacteria, has still also reduced the quantity of autotrophic bacteria by the control heterotrophic organism of having a bath, to the level that does not detect.

In one embodiment of the invention, the AAOB of sufficient amount can be from the body odour that suppresses in essence to be caused by heterotrophic organism on the skin.The inventor uses AAOB to resist not have a bath on his skin to grow up 15 months, also comprise two summers.Almost there is not stink with perspiration.In fact, sweat obtains nutrition and makes autotrophic bacteria produce the approach of the nutrition increase of NO and the growth of inhibition heterotrophic organism by making autotrophic bacteria, can reduce body odour.In winter, because outside air temperature is low, sweat has reduced, and body odour just increases to some extent.But by wear the clothes (wearing woollen sweater), the inventor just can increase basic sweat and basically eliminate again and savour more.Do not itch yet, the phenomenon of dermexanthesis, chafing or beriberi, do not have pin smelly basically.

AAOB produces nitrogen protoxide as intermediate in normal metabolism, as (Pough et al. that the people reported such as Pough, Energy modle and metabolic fluxanalysis for autotrophic nitrifiers biotechnol bioeng 72:416-433,2001).People such as Zart record when NO concentration is 100ppm in air a bacterial strain can obtain suitable growth (highest level of being tested) (Zart et al. in this research, Signinicance of Gaseous NO for Ammonia Oxidation byNitrosomonas Eutropha.Antonie Van Leeuwenhoek 77:49-55,2000).They can tolerate higher level.With other bacterial strain as people such as Schmidt report, not decline when 6-100ppm NH3 consumes.But when 1000ppmNO, reduced by 1/3 (Schmidt et al., Anaerobic Ammonea Oxidation in thePresence of Nitrogen Oxides (NOx) by Two Different Lithotrophs, Applied and Environmental Microbiology, nov 2002, p.5351-5357).

Great majority are aerobic bacterial strains, but some bacterial strains can utilize nitrate and nitrite to increase the generation of NO except O2.The NO of 1000ppm is equivalent to 2 μ M/L in the air in the aqueous solution.The bacterial strain that the inventor uses has produced the NO concentration of 2.2 μ M/L accurately.The metabolism of most of AAOB research is by utilizing AAOB to remove from waste water that ammonia and nitrate excited in the wastewater treatment process.The operation of sewage treatment equipment is unfavorable during the NO of hundreds of ppm, no wonder the physiological activity of these bacteriums also is not studied in this case.

AAOB produces provide protection in irritated and autoimmune disease mechanism is by NO production, mainly is by the inhibition to NK-κ B, has stoped the activation and immunoreactive the inducing of immunocyte.NK-κ B is a kind of transduced element that genetic expression is raised, most this gene and inflammation and immune response comprise that division of cytoplasm, chemokinesis are relevant with different adhesion factor, these different immune factors cause that immunocyte to discharging the position migration, has caused inflammatory reaction.The generation of NO has stoped I κ Ba degraded by stablizing I κ Ba, thereby has shown the strongly inhibited to NK-κ B.

The characteristics of allergy, asthma and autoimmune disorder are that immunity system produces unsuitable, too high reaction to special antigen.At first excite " the first utmost point " the T cell that produces immediately from after uterus or the birth, the T cell transformation becomes the TH2 phenotype then, produces skew and TH1/TH2 then and is polarised to TH2 type (anaphylactogen).

People such as Xu show, the material that use can produce NO can prevent experimental allergic encephalomyelitis (the Xu et al. of rat, SIN-1, a Nitric oxide donor, Ameliorate Experimental Allergic Encepgalomyelitis in Lewis Ratsin The Incipient Phase:The Importance of Time Window.TheJournal of Immunology, 2001,166:5810-5816).In this research, proved and used the material that produces NO can reduce the erosion of scavenger cell, reduced the propagation of blood mononuclear cell, increased the apoptosis of blood mononuclear cell central nervous system.All these results have been considered to reduce the scope and the degree of induction of immunity reaction.

Being exposed to allergen is prerequisite hypersensitive, but proves sickness rate hypersensitive seldom on evidence and to be exposed to anaphylactogen directly related.Be exposed in the anaphylactogen of similar amt not can the gross output looks like the allergy of level.The difference of identical or different anaphylactogen exposes the asthma that also can produce similar level.Level of allergen and subsequently specially in the anaphylactoid comparison of property before East Germany and West Germany are unified, the highest level of anaphylactogen degree of exposure is in East Germany, what specially property anaphylaxis level was the highest is in West Germany.The reduction of anaphylactogen can stop the allergic constitution patient anaphylaxis this by fine proof, but do not have the size of good evidence surface anaphylactogen and the contact between the allergy.For some anaphylactogens are positive reaction effect (dust), but some is side reaction effect (a cat hair).

According to another aspect of the present invention, irritated and autoimmunity inhibition hypersensitive can use AAOB to finish by the part, and AAOB can produce the active NO material on skin.Immunity system is that the detail how to act on is not understood fully.Generally speaking, bacterium, dead or dead cell, exogenous organism and other remains are at first engulfed by antigen presenting cell.These antigen presenting cells mainly refer to dentritic cell (DC).These compositions of having been engulfed are digested smaller segment, these segments are offered the surface of antigen presenting cell with I of histocompatibility complex and II (MHCI MHCII), and jejune DC digests the external source body by proteoplast approach and nucleome approach.In proteoplast approach approach, mainly digested from the cytoplasmic protein of DC, resulting antigen combines with MHCI.External source body digestion in the nucleome approach, resulting antigen combines with MHCII.Be transported to cell surface then with MHC bonded antigen, help cytosis with the T that contacts with antigen presenting cell there.Generally " self " antigen passes through the proteoplast approach, and " foreignness " antigen is processed by the nucleome approach, sometimes intersects, by combining the activity that become with antigen and main histocompatibility complex randomly.These activated T helps cell to cause the activation of other immunocyte then.People such as Gaboury report that nitrogen protoxide suppresses mastocyte (Gaboury et al., Nitri Oxide Inhibits Numerous Feature ofMast Cell-Induced Inflammation, the Circulation.1996 of induction of immunity; 93:318-326).People such as Forsythe show that nitrogen protoxide suppresses S-nitrosylation bonding (the Forsythe et al. of mastocyte by cysteine residues, inhibition of calpain is acomponent of nitric oxide-induced down-regulation of human mastcell adhesion, the iournal of immunology, 2003,170:287-293).It is bonding that S-GSNO (GSNO) is reduced mastocyte strongly.GSNO is the material that AAOB can form on skin.

Autism

Low basic NO level can cause autism, and its mechanism is that the new contact in the brain is not " good formation ", and this odd-shaped contact is the insufficient result of basic nitrogen protoxide.Basis nitrogen protoxide deficiency comes from during nerve connections forms and/or optimizes and lacks competent nitrogen protoxide.Nerve connections forms and/or optimizes and mainly appears between sleep period.

Other symptoms that autism patient shows have shown that also low NO level is a reason, comprises the tone insight of raising, the viscera function disorder, blood flow reduces in the immune system disorder, cell, and brain glucose consumption amount increases, blood plasma lactic acid salt increases, and depends on disorder, and croons.These symptoms all are attributable to low basic NO level.

One stops the method for autism is to improve basic NO level by the symbiosis autotrophy ammonia oxidizing bacteria of not noticing before recovering (AAOB), " wild " symbiosis autotrophy ammonia oxidizing bacteria (under prehistoric condition) existence is obtained urea and is produced nitrogen protoxide in scalp and skin outside from sweat.I have reported the activity of having a bath in modern times in fact than these bacterial proliferation faster speed they are removed, and the nitrogen protoxide that has lost they generations can cause the chronic disease of a lot of modern societies, comprise hypertension, heart trouble, fat, diabetes, and alzheimer's disease (D.Whitlock, NO production onhuman skin from sweat derived urea by commensal AutotrophicAmmonia Oxidizing Bacteria, Poster P208, Presented at:The 3rdInternational Conference on the Biology, Chemistry, and TherapeuicAppllication of Nitric Oxide/The 4th annual Scienticfic meetingof the Nitric Oxide Society of Japan May 24-28,2004.).

Can improve the symptom that some come from autism series disease by improving basic NO level to the outside use of skin AAOB.As other people who achieves success on Science and Technology, I think that I have some also not serious self-closing illness behaviors.Really improved the ability of my creative thinking by the basic NO level of using above-mentioned bacterium to improve me, reduced me simultaneously and ignored the ability of other stimulations that distract attention.

Symbiosis autotrophy ammonia oxidizing bacteria is present in all soil usually, and they have finished the first step of nitrification there, and ammonia oxidation is become the nitro nitrite.As the obligate autotrophy bacterium, they can not be grown at any standard medium that is used for the bacterial isolate body, this soluble why their early stage and people's parasymbiosis, and can not cause a disease.All known pathogenic agent all are non-autotrophys.Many animals all are coated with oneself with mud by the light of nature, and the child also plays in mud by the light of nature.Therefore, the people who lives in " original " torrid areas almost can't be at microbial film that comprises these bacteriums of the outside formation of skin under situation about will perspire for the whole year.Having such continuing between whole evolutionary stage provides the source of available NO, and the physiological system that the human evolution goes out can utilize these NO.Perhaps those are not that to be used to keep the physiological reason of the perspiration of body temperature be exactly in order to produce NO on skin.All Mammalss all have sweat gland and those not to keep the sweat gland of the Mammals (rat, mouse, dog) of body temperature unanimity to concentrate on the foot by perspiration, perhaps are to prevent by non-autotrophy germ and fungi infestation in order to be beneficial to.The activity of having a bath by the modern times removes this NO source and may cause functional disorder.

Axon guidance among CNS and the ANS and cynapse take place:

Brain is unusual complicated and have a contact of a lot of leap numbers inch.Be well known that neurone is movably, and move really that aixs cylinder is extended on length, form contact, bounce back during by wrong direction.Inappropriate contact is removed, and suitable contact is cured.Many contacts in the brain are not " at random ", but the mode " sequencing " that quilt is not understood as yet fully.Various neural factors provide axon growth to bore the chemical signal of beating back with " orientation ".The character that has the pure attraction diffusion that allows several feet length of leap without any chemical substance.The time of diffusion and axon growth can not be weighed with the concentration that can obtain and survey.

So a lot of axon guidances are enforceable, aixs cylinder is from inappropriate brain region compulsory withdrawal like this.When growing tip becomes " close enough ", it can attract diffuse source withdraw by using one.The contact that those cross over several inches shows to have multiple long, and the tropism of short scope that is used for.The quantity of neurocyte has surpassed the quantity of possible close neural factor and close neural factor acceptor.Therefore, many these factors are used by a more than neurocyte." useful range " of a potential parent neural factor depends on its production rate, background concentration, mortality ratio and spread coefficient." ideal " attracts material is a small molecules with high diffusibility, short-life-cycle, low background concentration and low detection restriction.NO possesses these character.Obsessive compound can be can't move fully with static, and some probably are fixed on the cytolemma.The scope of " attraction " of a compound must enough reach the target growing tip, but can not surpass the distance that growing tip is accurately reached by the physiological gradient that depends on diffusion.An enforceable compound can have zero scope and have an effect with only depending on to contact.A growing tip can be repelled in a lot of places in it grows the path, and still, it may only be attracted and form there its final contact by a position.

Balance between the length range that the expanded range of growing tip and Dang Qi can bounce back during by wrong direction can determine the length range of developing brain.Presumablely be that " characteristic length scope " of brain is that a growth aixs cylinder last forces contact and final " correctly " distance between getting in touch.Presumable is that this length range is in an order of magnitude with the scope that attracts diffusion.An aixs cylinder needn't be related to a concrete cell and be come normal functionating.The contact that can infer one " enough near " can allow follow-up Hebbian optimization functional enough until it with " raising " this contact.

People such as H-J Song disclose the ring-type nucleosides and have comprised that cGMP can be with the nerve growth awl from forcing become attraction (H-J Song et al., Conversion of neuronal growthcone responses from repulsion to attraction by cyclic nucleotides.Scinence Vol 281 4 September 1998.).When being stimulated by NO by guanosine acyl enzyme, cGMP produces.Therefore NO can produce a signal with notice growing tip retraction.Some contacts are the earliest perhaps made by " at random ", in case but some suitable aixs cylinders are moved to suitable zone, and they can stimulate the release of NO to be same as the potential action of the aixs cylinder in the migration.By NO, form via cynapse, " weak " is in conjunction with can being become " by force " combination.People such as Jeseph A.Gally have proposed, NO is " second messenger ", it has linked the active neurocyte of local nerve target area and whether has been got in touch (Jeseph A.Gally et al. by enzyme regardless of them, The NO hypothesis:Possible effects of ashort-lived, rapidly diffusible signal in the development andfunction of the nervous system, Proc Natl Acad Sci.USA Vol.87,3547-355 1, and May 1990).

In Embryo Gallus domesticus, many nerve growths and the neural system structure that is connected one of them, can be observed.The approach of getting in touch between the retina of Embryo Gallus domesticus and the visual cortex has experienced significant optimization at growing period.In this optimizing process, nitrogen protoxide is essential the accurate contact in topography.In this optimizing process, NOS is in the target area of brain but not expressed on the retina.Verified optimization (the Hope H.Wu etal. that the system of NOS is suppressed to have stoped this contact of people such as Hope H.Wu, The role of nitric oxide in development of Topographic precisionin the retinotectal projection of chick, J Neurosci.2001,21 (12): 4318-4325.).Yan He has confirmed that nitrogen protoxide has stayed thin residue vestige (Yan He when making aixs cylinder bounce back, Microtubule reconfigurationduring axonal retraction induced by nitric oxide, J Neurosci.2002,22 (14): 5982-5991).This retraction is not followed the depolymerization of microtubule and microfilament.In the presence of Brain Derived Neurotrophic Factor (BDNF), NO has solidified the nerve growth awl.People's solidified nerve growths such as Alan F.Emst awl contacts with the particle that BDNF covers, antagonism NO-inductive retraction (Alan F.Emst et al., Stablization of growingretinal axons by the combined signaling of nitric oxide andbrain-derived neurotrophic factor, J Neurosci.2000,20 (4): 1458-1469.).Other factors, nerve growth factor (NGF) and neurotrophic factor-3 (NT-3) can not stop NO inductive growing tip to subside.People such as Hope H.Wu have proved that the restraining effect of NOS makes with the quantity of side-prominent ganglion cell and have brought up to 1000% of contrast, but has only 10% (the Hope H.Wu et al. of surviving wherein, Involvement of nitric oxide in the elimination of a transientretiontectal projection in development, Science; Sep 9,1994; 265,5178).People such as P.Cammpello-Costa are disclosed to be that blocking-up NOS makes the mistake in the associated process increase, and increased mouse connect the projection of retina top cover by infringement inductive plasticity (P.Cammpello-Costa et al., Acute blockage of nitricoxide synthesis induces disorganization and amplifieslesion-induced plasiticity in the rat retinotectal projection, J.Neurosci.44:371-381,2000).

The people is disclosed is for Marriann Sondell etc., axon growth is excited (Marriann Sondell et al. by VEGF, Vascular Endothelial Growth Factor HasNeurotrophic Activity and Stimulates Axonal Outgrowth, EnhancingCell Survival and Schwanm Cell Proliferation in the PeripheralNervous System, The Journal of Neuroscience, July 15,1999,19 (14): 5731-5740.).VEGF transcribes by HIF-1 α and starts, this process has been illustrated by O2 concentration is low and has been excited with high this integrated signal of NO concentration, document (Greg L.Smenza referring to Greg LSemenza, HIF-1 α: mediator of physiologicaland pathophysiologic responses to hypoxia, Invited Review (J.ApplPhysiol 88:1474-1480,2000); And the Accumulation ofHIF-1 α under the influence of nitric oxide of Sandau et al, (Blood.2001; 97:1009-1015)).Be well known that blood flow is very relevant with nervous activity.Can activate the cGMP generation of guanosine acyl enzyme and lax vascular smooth muscle by NO, regulate vasorelaxation.The NO that is produced by neurone can provide the startup signal that VEGF transcribes, and excites vascularization, makes nervous activity and blood supply corresponding simultaneously.Along with " reduction " that brought NO by the hemochrome oxidation, the answer mechanism that exists nature prevents the vascularization of " too much ".The factor that the control cerebral blood vessel forms is restricted to the molecule that the hemato encephalic barrier in the brain can be through, such as NO.People such as Kon are open, and the inhibition of NOS has been hindered the blood vessel blastogenesis in the vascularization.Suppress the blood vessel blastogenesis (Kon et al., Microvascular research65 (2003) 2-8) of NOS line artery in forming with N (G)-nitro-L-arginine methyl esters.People such as Toshiro Matsunaga disclose heart collateral vessel growth needs eNOS and the NO that ischemic causes.The growth that ischemic causes crown collateral vessel depends on vascular endothelial cell growth factor (ECGF) and nitrogen protoxide (Toshiro Matsunage et al., Ischemia-induced coronary collateral growth is dependent onvascular endothelial growth factor and nitric oxide.Circulation2000; 102:3098-3103).Dong Ya Zhu is open, follow the nerve formation of focus brain damage to need nitrogen protoxide, and in lacking the adult mouse body of iNOS gene, fail to occur (Dong Ya Zhu et al.Expression of inducible nitricoxide synthase after focal cerebral ischemia stimulates Neurogenesisin the adult rodent denate gyrus, J.Neurosci.January 1,200323 (1): 223-229).Can infer that the nerve under other situations forms also needs NO.People such as J.D.Robertson have reported, suppress sense of touch and visual cognition (J.David Robertson that nitric oxide synthetase has hindered octopus, et al.Nitric oxide is requiredfor tactile learning in octopus vulgaris, Proc.R.Soc.Lond.B (1994) 256,269-273; With J.David Robertson, et al.Nitric oxide is necessaryfor visual learning in Octopus vulgaris, Proceedings; BiologicalScience, vol 263 No.1377 (Dec.22,1996), 1739-1743).

Many nerve connections in the brain are " good formation ".Can infer, perhaps have a kind of mechanism to come " test " these contacts for reaching this result, " correct " contact be cured and " mistake " get in touch and left out.Presumablely be, the formation of a concrete neuromechanism may relate to the propagation of relevant cell, and aixs cylinder is to the projection of relevant brain target area, being not suitable for the target area repels, get in touch with suitable cell,, be accompanied by removing redundant and wrong cell of getting in touch to breeding the feedback that suppresses.Presumablely be that the length range that these contacts can reach depends on the scope of the distribution inductor that the aixs cylinder of migration is used to lead.If this distribution inductor is NO, any factor that reduces the NO scattered band, all can reduce can be by the scope of the target area, brain position of " good contact ".The brain of growing under low basic NO level conditions is because the reduction of NO useful range will be arranged in small range.

NO is considered to a kind of target area signaling molecule.The character of the uniqueness of NO is, as a very little hydrophobic molecule, compares with other neurotransmitters, and it can spread to farther and can pass liquid film and hemato encephalic barrier.Distance that NO is spreadable and accessible terminal point concentration depend on the environmental concentration of NO.The distribution signal of NO can be added in the environment on the NO concentration, and when total amount has surpassed the action level, the action signal of NO has just occurred.If a signal has produced a certain amount of NO, the scope of this signal just relies the NO in environment.Under the lower situation of environment NO, the amount that makes some target areas reach the required NO of action level will increase.That is to say that under the lower situation of environment NO, the scope of the efficient part that NO signal can reach will reduce, that is, the useful range of this NO signal has been lowered.

The environmental concentration that depends on the scope of activity of NO can be explained some influences of autism.Some autism patients demonstrate the stronger sense of hearing and distinguish sound, " overall signal " sense of hearing is reduced, and/or strengthened " false memory " insight.The ability of this " expert " type is not uncommon.The variation of " scope of activity " distance for the protection aixs cylinder; can strengthen the nerve of " single " task is handled; this enhancing is to provide the local short distance nerve connections density in the zone of this " single " moral function to realize by increase, but this may be just need task be unfavorable is cost with more " complexity " in the comprehensive a plurality of big zones of contact by crossing over long distance.

People such as Dr.E.H.Alward have reported the autism patient, in their limbic brain system, the neuronal cell dimension reduction, density increases, and the complexity of dendron reduces (E.H.Aylward, PhD, et al., MRI volumes of amygdala andhippocampus in non-mentally retarded autistic adolescents andadults, Neurology 1999; 53:2145).

Similarly, people such as M.F.Casanova reported that cell volume in the microcylinder diminishes but number increase (Manuel.F.Casanova, et al., Minicolumnarpathology in autism, Neurology 2002; 58:428-432).D.G.Amaral etal, reported also in the tonsilla that cell volume diminishes but number increases (D.G.Amaral etal., The amygdala and autism:implications from non-human primatestudies, Genes, Brain and Behavior (2003) 2:295-302 Review.).To the fMRI of autism and dislexia disease patient's brain relatively in, find that similarly the white matter target area is excessive.Openly autism patient's spherical target area is excessive for people such as M.R.Herbert, excessive (the M.R.Herbert et al. in dislexia disease patient's top target area, Localization Of White Matter Volume Increase In Autism AndDevelopmental Language Disorder, Ann.Neurol 2004; 55:530-540).Although some autism patient suffers from dislexia disease simultaneously, seldom there is the autism patient to possess high character learning simultaneously.People such as Peter E.Turkeltaub reported a case, boy's study earlier before association speaks of suffering from autism is read, first word that he says is that he once read (Peter E.Turkeltaub, et al., The neuralbasis of hyperlexia reading:an fMRI case study, Neuron, vol 41,11-25, January 8,2004).The outstanding skill that autism patient shows in the test of BLOCK DESIGN for example makes people, for example people such as H.Tgaer-Flusbert has proposed the center weak hypothesis that links up, think that the contact between the brain each several part is inadequate, this insufficient contact is converted into the ability of finishing complete procedure (the H.Tgaer-Flusbert et al that has weakened, Current Directions in Research on Autism, Mental Retardation and Development disabilities Research Reviews7:21-29 (2001)).

NO can with nmda receptor one same-action.The A.Contestbile report, in the feedback control of nervous excitation, too much NO output has suppressed nmda receptor (AntonioContestbile Role of NMDA receptor activity and nitric oxideproduction in brain development, Brain Research Reviews32 (2000) 476-509).New life's blocking-up that people such as M.Virgili have reported nmda receptor in the mouse has caused secular falling tone joint (M.Virgili et al. to nNOS, Neuronalnitric oxide synthase is permanently decreased in the cerebellum ofrats subjected to chronic neonatal blockade of N-methyl-D-aspartate, Neurosci Lett.258 (1988) 1-4.).People such as R.J.Nelson have proved that nNOS lacks and have shown intensive aggressiveness (R.J.Nelson et al. to other mouse with the mouse that the nNOS supressor is handled, Behavioral abnormalities in male micelacking neuronal nitric oxide synthase, Nature 378 (1995) 383-386.).Therefore NO is perhaps to nerve growth, and nerve moves, and cynapse has vital role.Can infer that the upset in the NO metabolism has multiple effect to neurodevelopment.

People such as Klyachko are verified, nitrogen protoxide can, cGMP by ionic channel modifies and improves the hyperpolarization current potential, improve excitability (Klyachko et al., cGMP-mediated facilitation in nerve terminal byenhancement of the spike after hyperpolarization, the Neuron of neurocyte with this, vol 31,1015-1025, September 27,2001).People such as C.Sandie disclose inhibition NOS and have reduced (the Carmen Sandi et al. that is taken aback, Decreased spontaneous motoractivity and startle response in nitric oxide synthase inhibitor-tratedrats, European journal ofpharmacology 277 (1995) 89-97).Simulated childhood hyperkinetic syndrome (ADHD) with spontaneous hypertension rat (SHR) and the high excited rat in Naples (Naples high-excitabilityRat).People such as Raffaele Aspide disclose this two kinds of models, be presented at acute inhibition NOS during scatterbrained degree increase (Raffaele Aspide et al., Non-selective attention and nitric oxidein putative animal models of attention-deficit hyperactivity disorder, Behavioeal Brain Research 95 (1998) 123-133).

M.R.Dzoliic equally also discloses inhibition NOS can suppress sleep (M.R.Dzoljic., Sleep and nitric oxide:effects of 7-nitro indazole, inhibitorof brain nitric oxide synthase, Brain Research 718 (1996) 145-150).G.Zoccoli has reported that a lot of physiological actions were changed when NOS was suppressed between sleep period, comprise that Rapid eye movements and brain circulate in sleep and the difference (G.Zoccoli when clear-headed, et al., Nitric oxide inhibition abolishes sleep-wake differences incerebral circulation, Am.J.Physiol.Heart.Circ.Physiol 280:H2598-2606,2001.).L. people such as Kapas openly the NO donor can promote the non-REM sleep, yet, the time that this raising continues can be longer than the time that NO donor exists, illustrate that this may be a rebound effect (Levente.Kapas et al., Nitricoxide donors SIN-1 and SNAP promote nonrapid-eye-movementsleep in rats, Brain Research Bullitin, vol 41, No 5, pp.293-298,1996.).People such as M.Rosaria report, the NO of central nervous system can promote erection and yawn (Maria Rosaria Melis and Antonio Argiolas, Role ofcentral nitric oxide in the control of penile erection and yawning, Prog Neuro-Psychopharmacol ﹠amp; Biol.Phychiat.1997, vol 21, pp899-922).People such as P.Tani have been reported in very common (the Pekka Tani et al. of insomnia among the grownup who suffers from A Si Burger syndromes, Isommia is a frequent finding inadults with Asperger ' s syndrome, BMC Psychiatry 2003,3:12.).Y.Hoshino has also found sleep disordered (Hoshino Y et al., the Aninvestigation on sleep disturbances in autistic children. FoliaPsychiatr Neurol Jpn.1984 in the autism children; 38 (1): 45-51 (abstract)).People such as K.A.Schreck observe relevant (the Schreck KA of severity of sleep disordered severity and self-closing symptom, et al., Sleep problems as possible predictors ofintensified symptoms of autism, Res Dev Disabil.2004 Jan-Feb; 25 (1): 57-66 (abstract)).

Perhaps, high NO level is necessary to sleeping, and this high NO level is essential for the Neural Optimization that occurs in the sleep procedure equally.Be a desirable period that NO is applied to brain night.Basis metabolism is in its minimum level, therefore, has maximum metabolic reserves to offset the inhibition of NO inductive hypopiesia and NO inductive pair cell chromo-oxidase.So the recipient need not to move the responsibility that brain need not be carried out the control body movement.So the recipient also is the function that unconscious brain need not be carried out the sensorial data of comprehensively importing into.Many secular effects enhancings can appear in surge NO amount during night.A large amount of surge NO may make the aixs cylinder retraction of wrong direction, and also may strengthen the cynapse of new formation.The brain activity that occurs between sleep period can be tempered the cynapse of these new formation so that its impedance matching and optimize various contacts.From whole mechanism of the outside use of brain, for example night, scalp was perspired, and can alleviate the local modulation of brain to basic nitric oxide level.

Further, the high NO level between sleep period may be the part of brain " normally " " household management " function, and may optimize contact under normal conditions, makes short-term memory by permanence and " optimization " brain function.Perhaps, be accompanied by the part of the nervous activity of rapid eye movement sleep (REM sleep) to nerve connections " test ", this test to " determining " which get in touch the needs reservation which need to remove be necessary.High NO level between sleep period may to when sleep effectively " household management " function be necessary.Through finding, be that the movable high NO horizontal component that produces of cerebral nerve of sleep has been born the responsibility that blood pressure is reduced to observing between sleep period.Perspire the night that the adrenal hormone activity brings, and part makes urea be released on the scalp on scalp, will produce NO at this place autotrophy ammonia oxidizing bacteria (AAOB).

S.Ogawa has reported the blood flow in the brain and closely has been accompanied by nervous activity, and this is closely followed is the basis of fMRI research, and the oxyphorase oxidation (improves O in this research ₂Level) relevant (the Seiji Ogawa of change with nervous activity, et al., An approachto probe some neural systems interaction by functional MRI atneural time scale down to milliseconds.PNAS September 26,2000.vol 97 no 19,10661-10665).In the circulation of body surface, blood flow can loosen by the vascular smooth muscle that the activation guanosine acyl enzyme regulated by NO and cGMP regulate to be adjusted.Can infer that the brain vascular system also has similar mechanism.The NO that nervous activity discharges can provide NO with lax vascular smooth muscle.Yet the generation of the variation of oxyphorase oxygenizement also may be to have shown O ₂The raising of variation of consumption (by the inhibition of NO pair cell chromo-oxidase) rather than feed rate (blood flow of regulating by vasorelaxation increases).Because plastosome can be regulated and control by NO, mitochondrial operating point is by O ₂Determine that with the instant concentration of NO any rising of NO all can reduce mitochondrial activity.Above-mentioned two effects of NO probably occur simultaneously.

Equally, measuring N O level is calculated NO/O ₂Ratio can be given O ₂Hb provides a better " O ₂The diffusion intensity " standard of measurement.Can infer a specific site oxygenated haemoglobin (O ₂The source) " O ₂The diffusion intensity " can be measured, vascularization is excited when this value is very little, and capillary vessel reduces when this value is very high.Yet, only measure O ₂Level is not enough, because inadequate dabbling finding out must have pathology O on the pathology ₂Level.Simultaneously, can't distinguish the zone of normal capillary density and the too much zone of those capillary vesseies, because both are O ₂Level all shows as abundance.Measuring N O level then is better measurement.The diffusion of NO is very similar to O ₂O ₂Hb is O ₂The source, equally also represent the reduction of NO, because O ₂Hb limits its motion and has destroyed the NO diffusion.Hang down NO thereby may become the competent " O of hint ₂The diffusion intensity " signal.Found to comprise in numerous disease hypertension and diabetes, low basic NO level causes the minimizing of capillary vessel.Low basic NO in the brain can cause capillary vessel to reduce and hypoperfusion, and the high signal of feature white matter among the fMRI that has been found that, and follows many sacred diseases.The local high NO level that nervous activity brings show this zone by near the growth of nerve fiber bring neural densely distributed, show that also the vascularity of being brought by vascularization is intensive.

People such as Takashi Ohnishi have reported the autism patient and have demonstrated low (the Takashi Ohnishi et al. of volume of blood flow, Abnormal regional cerebral blood flow inchildhood autism, Brain (2000), 123,1838-1844).People such as J.M.Rumsey have reported consumption increase (the Rumsey et al. of autism patient to glucose, Brainmetabolism in autism, Resting cerebral glucose utilization rates asmeasured with position emission tomography.Arch GenPsychiatry, 1985 May; 42 (5): 448-55 (abstract)).D.C.Chugani has reported lactate levels raising (Chugani DC in the autism patient blood plasma, et al., Evidence of altered energy metabolism in autistic children, ProgNeuropsychopharmacol Biol Psychiatry. 1999 May; 23 (4): 635-41).The appearance of these phenomenons may be the result that the brain capillary vessel reduces, and this minimizing has caused blood flow and O ₂The minimizing of supply, the part metabolism of brain load just may have been undertaken by glycolysis-rather than oxidative phosphorylation like this.For producing identical ATP and lactic acid salt, the glucose that glycolysis-consumes is 19 times of oxidative phosphorylation.Although neurocyte does not produce ATP by glycolysis-, other cells in the brain can, i.e. astroglia cell.Capillary vessel reduces both can reduce blood flow, also can improve glucose consumption and improve lactic acid salt to produce.

May be owing to, hindered the high frequency high fidelity of length-specific scope nerve connections and the formation of efficient in the shortage of the NO of the specific critical period that forms.Have been found that the contact decay of chicken visual cortex when suppressing NOS basic NO level is reduced, this equally also may appear at by any means and reduce in the human body of basic NO level.Can this infer that other neurocyte use and the same NO regulation mechanism of visual cortex.Simple neural task can be better carried out in the part contact of high level, but this is a cost comprehensive these simple tasks can't be become an integral body.

Infiltration and crucial contact

The major part of brain all must be the unitary two dimension contact of the standard weave of people's brain cell.The maximum difference of human brain and animal brain does not lie in the unitary structure of standard weave of people's brain cell, but cell quantity that increases greatly in the human brain and enhanced contact.Can infer that the contact between the standard weave unit of those people's brain cells has produced " independently " human characteristic just, language for example, these features make a distinction with animal human.If go to be familiar with the contact between the standard weave unit of these people's brain cells from the angle of a network that connects each other, can characterize contact between this network with length range.G. Grimmett has reported, and the overall contact of network is to the subtle change of part contact very responsive (Geoffrey.Grimmett, Percolation, Springer-Verlag, 1989) near the infiltration threshold.Each unit in the neural network of normal function all can not be with each other unit get in touch.Each unit can not be cut off contact.When the degree variation of contact, it is exactly the infiltration threshold of this network character that degree of contact changes the fastest place, and this place " key " behavior will be found.That is to say that different network character is in this infiltration threshold divergence.For example, the length range that is lower than the maximum contact group of this infiltration threshold slightly is limited, a little higher than this it then be unlimited.Can infer that the neural network that forms brain is higher than the infiltration threshold.Otherwise, will have the zone that can not get in touch in the brain.Brain is not " single " network.It has various neurotransmitters, and perhaps each has all represented a different network.

NO is perhaps as a kind of contact reagent between these different (in a way) separate network.Perhaps, " weak " contact of NO can promote the aixs cylinder migration to form and get in touch by " by force " that the cynapse at " correct point " forms with neural.Some part of brain may be very near apart from break.A degree of contact more a lot of than the break height does not have very strong advantage.Can strengthen the steadiness of this network than the high a lot of relation intensity of break, but will be cost to the susceptibility that changes with this network.Perhaps, autism patient only has a low a little excessively local degree of contact, and this is owing to low basic NO level is brought.Under the infiltration threshold, the function of a network can reduce aspect speed.

The neural network of a stability reduction can make is fainted from fear suddenly easily, and has been found that high convulsions rate is arranged among the autism patient really.What is interesting is, people such as I.T.Demchenko have reported, high pressure supply O2 reduces the NO level in the brain and can cause unexpected convulsions (Ivan.T.Demchenko equally, et al., Hyperbaric O2 reducescerebral blood flow by inactivating nitric oxide.Nitric oxide:Biology and Chemistry vol 4, No.6,597-608 (2000)).The NOS supressor has improved latent period of fainting from fear and has been done just as the L-arginine, but, NO donor S-nitroso-group-N-N-acetylpenicillamine (SNAP) has shortened during this period significantly, this is by N.Bitterman. report (Noemi.Bitterman.et al., L-Arigine-NO pathwayand CNS O2 toxicity, J Appi Physiol 84 (5): 1633-1638,1998).NOS can produce NO, but it also can produce the superoxide that destroys NO.The NOS supressor can block the generation of NO and superoxide simultaneously.When NO and superoxide produced simultaneously, peroxynitrite salt will produce.The Zn-mercaptan salt of peroxynitrite salt in can oxidation NOS complex compound, " dissociated " NOS has caused the formation of superoxide.Therefore, the NOS supressor is that to the effect of convulsant threshold it has blocked the formation of superoxide rather than the retardance that it forms NO.

Can regard human brain as numerous separate to some degree process, such as vision process, auditory processes, human basic reproductive function, language, motorius, ANS, or the like.Presumable is that each different function all may need brain structure separately.Presumable is that the human brain structure may be one and possess the to a certain degree localized network of local contact.Perhaps, the infiltration threshold of a network is a key point.Near the infiltration threshold, the character of this network is with exponential variation, and promptly a very little very little variation can be along with cause great variety with the close of infiltration threshold distance in this network.Can infer that different brain structures may need different degree of contact for realizing the function that requires.Can infer the function for relative as sense process " simply ", the strong sensitivity that " by force " operation comparison changes is more important.The contiguity of this structure is on crucial level of interpenetration.Efficient in the powerful calculating such as creationary function, may need the contiguity of more approaching infiltration threshold.Report has been arranged, " contact " can help autism and A Si Burger disease intelligence of patient and creativeness (Ed.Uta Frith, Elisabeth Hill.Autism:Mindand Brain, Oxford University Press:2003, reviewed Nature 428,1April 2004,470-471).Quote a word " seem autism a little on science and art, achieve success very necessary " (AllanSnyder of attribution Hans Asperger, Autistic genius? Book review:Nature 428,1 April 2004,470-471).Perhaps the autism patient comes from the minimizing of getting in touch in those brain structures in the raising of some thinking field ability and causes more approaching infiltration threshold and the stronger sensitivity to changing.The contact length that reduces is only a bit useful to certain.In case the infiltration threshold reaches, the functional of this network will reduce rapidly.

If the contact that reduces is the problem that exists in the autism patient brain, improves contact and can expect enhancement function.If this contact approaches to permeate the threshold zone, that variation will be exponential, and will be highly non-linear, and improve highly significant.

" seeing " the complete ability that weakens also can extend to other field.Can't discover " ghost ", observe things with " black or white ", these may come from a large amount of driving sources (or fundamental element) comprehensively is the weakening of the ability of integral body.To a certain concrete things obsessive be crazy about may come from brain structure to the part very the similar response of tiny area subside.An integral part of brain target area is made up of the numerous aixs cylinders that connect different zones.Effective connection can minimize approach length and minimize the aixs cylinder target area.Invalid contact can cause enlarging the brain target area and not improve functional.The increase of the big brain volume of autism children that has been found that may be exactly this invalid contact.

The diffusion that people such as N.Schweighofer have reported NO can promote cerebellum study (Nicolas.Schweighofer et al., Diffusion of nitric oxide can facilitatecerebellar learning:A simulation study.PNAS September 12,2000, vol 97, no.19,10661-10665).NO concentration under this modeling effort display simulation situation and scattering nature can improve the correction to mistake.The density that people such as M.F.Casanova have reported autism patient's little microcylinder increases (Manuel.F.Casanovaet al., Minicloumnar pathology in autism.Neurology 2002 to some extent; 58:428-432).Low NO environment can reduce the scope that the NO signal can be taken action, and can provide reasonable dismissal to the increase of little microcylinder density.Excite angiopoietic signal just because of there being one, also exist one certainly and stop neural outgrowth signal.NO can provide this two kinds of signals.High NO level near the source can excite hyperplasia, and owing to the low NO level that has reduced the distant place of NO concentration with diffusion can stop this hyperplasia.The S-nitrosyl salts that people such as Tenneti have reported the intracellular proteolysis enzyme (caspase) of nerve shows the character (Lalitha.Tenneti et al., Suppression neuronal apoptosis by S-nirosylation of caspases.Neuroscience Letters 236 (1997) 139-142) that the inhibition neurocyte withers and forgets.People such as E.Ciani have reported by 0 and have lacked in serum; NO has protected apoptosis (the Elisabetta.Ciani et al. of neuroblastoma cell; Nitric oxide protects neuroblastoma cellsfrom apoptosis induced by serum deprivation throughcAMP-response element-binding progein (CREB) activaton; J BioChem; 277 (51) 49896-49902,2002).People such as C.Nucci have reported NO and played the part of multiple role in lateral geniculate nucleus, from signal transduction to causing and stoping nerve cell apoptosis (C.Nucci et al., Multifaceted roles of nitric oxide in thelateral geniculate nucleus:from visual signal transduction toneuronal apoptosis, Toxicology letters 139 (2003) 163-173).

Early stage in childhood, brain is not the place of unique generation nerve connections.One of reason of baby's incontinence is exactly the nerve control that lacks excretory function.Realized function as voluntary muscle by neural control correctly, the several kind of smooth muscle cells and the visual organ also must be got in touch (ANS) with autonomous nervous system, so just can make function normal.It is exactly owing to lack ANS to multiple Alimentary control that the baby can not digest one of reason of adult's food.Some disorders of digestion of autism patient may just come from and lack ANS to the correct contact between the internal organ.D.Blottner has hinted that nitrogen protoxide is as a courier among the ANS, so very important (Dietre.Blottner of nitrogen energy approach, Nitric oxideand taeget-organ control in the autonomic nervous system:Anatomical distribution spatiotemporal signling, and neuroeffectormaintenance, J Neurosci Res.58:139-151 (1999)).People such as H.Matsuama have reported the release of albumen (VIP) in the vasoactive by NO regulation and control (H.Matsuama et al., Peptidergic and Nitrergic InhibitoryNeurotransmissions In The Hamster Jeiunum:Regulation OfVasoactive Intestinal Peptide Release By Nitric OxideNeuroscience Vol.110, No.4,788,2002).

D.Blottner has also reported nitrogen protoxide has related (Dietre.Blottner in neurovegetative maintenance with in the reaction of the biological nutrition in moulding, Nitric oxideand taeget-organ control in the autonomic nervoussystem:Anatomical distribution spatiotemporal signling, andneuroeffector maintenance, Journalof Neuroscience Research.58:139-151 (1999)).People such as E.Niebergall-Roth have reported pancreas and have discharged digestive ferment partly by ANS control (E.Niebergall-Roth et al., Central andperipheral neural control of pancreatic exocrine secretion, Journal ofphysiology and pharmacology 2001,52.4,523-538).Has H.E.Raybould also reported the release of digestive ferment and has also been controlled (H.E.Raybould.Dose your gut taste from the combination feedback of the sensing cell in the internal organ? Seneory transductionin the gastrointestinal tract, New Physiol.Sci.Vol13, December1998,275-280.).

Can infer, ANS causes the people such as reduction T.Wester of function open to the inappropriate innervation of internal organ meeting, the density of neurocyte has positive remarkable effect to the reduction of NADOH diaphorase (being equivalent to NOS) in the childhood early stage internal organ, and " nitrogen protoxide is the most important transmission medium of the nerve of the non-cholinomimetic energy of the non-suprarenin in the human gastrointestinal tract " (T.Wester et al., Notable post natalalterations in the myenteric plexus of normal human bowel, Gut1999; 44:666-674).

The effect of nitrogen protoxide in depending on

NO has played certain effect in the forming process of the mother and baby of ewe connection and smell identification test and odor detection in 2 hours minute puerperiums.People such as K.M.Kendrick disclose the formation of the inhibition of nNOS having been blocked scent-memorizing, the NO that this retardation can be diffused into olfactory bulb reverses (K.M.Kendrick et al., Formation of olfactory memories mediated bynitric oxide, Nature, 1997Aug 14; 388 (6643): 670-4.).People such as J.N.Ferguson have reported Hou Yecuichansu (Jennifer N.Ferguson et al. essential in the normal social attachment forming process of mouse, Oxytocin in the medialamygdale is essential for social recognition in the mouse, JournalNeuroscience, October 15,2001,21 (20): 8728-8285).G.L. after people such as Williams has reported the heifer epidural anesthesia, discharge minimizing (the G.L. Williams et al. of the minimizing of Hou Yecuichansu prior to the behavior of female tire binding type, Physiological regulationof maternal behavior in heifers:Roles of genital stimulation, intracerebral oxytocin release and ovarian steroid, Biology ofReproduction 65,295-300 (2001)).People such as G.Gimpl have reported activation (the Gerald.Gimpl et al. that the activation of Hou Yecuichansu acceptor has been caused nitricoxide synthase, The oxytocin receptor system:structure, function, and regulation, Physiological reviews vol.81, No.2,629-683, April 2001).People such as S.K.Mani report to the inhibition of nitricoxide synthase oestrogenic hormon (the Shailaja K.Mani et al. that excites of the Progesterone in the lordosis of ovariectomized female mouse in advance, Nitric oxide mediates sexual behavior in female rats, Proc N atl AcadSci, Vol.91,6468-6472, July 1994).

People such as W.D.Ratnasooriya reported inhibition to male mouse NOS reduced sexual intercourse move ahead into, reduced sexual desire, and reduced reproductive performance (W.D.Ratnasooriya etal., Reduction in libido and fertility of male rats by administration ofthe nitric oxide (NO) synthase inhibitor N-nitro-L-arginine methylester, International journal of andrology, 23:187-191 (2000) .).People such as R.R.Ventura have reported nitrogen protoxide has been adjusted Hou Yecuichansu and Hou Yejiayasu in the balance of regulating sodium and water activity (R.R.Ventura et al., Nitrergicmodulation of vasopressin, oxytocin, and artial natriuretic peptidesecretion in response to sodium intake and hypertonic blood volumeexpansion, Brazilian journal of medical and biologicalresearch (2002) 35:1101-1109).Just related to nitrogen protoxide in the important approach in known like this depending on.

Neurological variation in depending on, no matter be that female tire links or both sides' banded that do as one likes is brought, be very strong and the time length very long, showing " good formation " contact.People such as C.O.Okere have reported these contacts (Okere and Kaba can occur in some hrs, Icreased expression of neuronal nitric oxidesynthase mRNA in the accessory olfactory bulb during the formationof olfactory memory in mice, Eur J Nerurosci.2000 Dec; 12 (12): 4552-6.).Aixs cylinder forms the distance that new contact crosses over and perhaps therefore is limited.If should " depending on " nerve connections be to form in the period of a low NO level, these contacts might be limited in a very partial zone, therefore form very strong " depending on ", but it but can not be by the information adjustment from the input in other zones.Perhaps also can cause depending on of malfunction like this,,, and perhaps cause compulsive behavior depending on of dull things to depending on of abuse.

" depend on " say so in some sense " being stylized ".The children that attach to them and the spouse of human (with other animals) " being stylized ".Very fast (being several hours in ewe) that these characteristic reactions can occur, shorter than the time that nerve forms, show that the behavior comes from the neuronal cell that has existed, just their contacts in a different manner at that time.

Immune interaction

The vaccine inoculation with the infancy that the outbreak of autism of children shape is wondered very much is relevant.Although EPDMLly studies show that this probability does not change in a large amount of crowds that use or do not use MMR.One of vaccine inoculation and immunity system activatory result discharge cytokine and induce iNOS.Transcribing of iNOS is by NF κ B.The rising of blood plasma nitrate content is relevant with immune stimulation and be one of iNOS inductive result.People such as M.Colasanti have reported NF κ B and have been suppressed by NO, so transcribing by NO of iNOS suppresses (Macro.Colasanti et al.Induction of nitric oxidesynthase mRNA expression suppression by exogenous nitric oxide, J.Bio Chem 270,45,26731-26733,1995).Therefore low basic NO level can bring that iNOS expresses increase with immune activation during the rising (being issued to excessive level) of NO level in higher baseline NO level.Because iNOS is regulated by the mode of a kind of " forward " type, if too much iNOS is produced, the NO level will reach ill level, just as in septic shock.

INOS induces may have effect to nerve signal.High NO in the environment can reduce the amount of the required NO of certain effect of generation, and therefore can increase the scope that these effects can take place.The NO effect of regulating by nNOS and eNOS can occur in the low starting point that NO produces.The feedback inhibition that nNOS and eNOS transcribe can appear at lower nNOS and eNOS probably and express.People such as U.Forstermann have reported with after the bacteria lipopolysaccharide class processing (causing that iNOS expresses), nNOS expresses by falling tone joint (Ulrich.F  rstermann et al., Expression control of the ' constitutive ' isoformaof nitric oxide synthase (NOS I and NOS III), FASEB J.12,773-790 (1998)).After iNOS inductive basis NO raises, before basic NO may reduce to-iNOS level (perhaps lower).NNOS is synthesized in cell paste, on endocytoplasmic reticulum, after this is sent to avtive spot by aixs cylinder.This transport process needs certain hour.The nNOS of the reduction after the immune stimulating of low NO horizontal period transcribes the NO level is further reduced.S.H.Fatemi is verified, before birth, be proved to be the nNOS that has caused in this mouse brain different zones and express medium-term and long-term rising or reduction (Fatemi SH et al. by the mouse of virus infection, Prenatal viral infectioncauses alteration in nNOS expression in developing mouse brains, Neuroreport.2000 May 15; 11 (7): 1493-6 (abstract)).

For the function as transmission medium between the cell of NO, necessary is that NO is by a cell generation and measured in another cell.A cell produces NO and is regulated by the acceptor of this cell interior and this cell surface.Other molecules fast as NO diffusion seldom arranged.The feedback regulation that cell with non--NO transmission medium produces NO may must have a significant time lag, this section in the period generation of NO be not subjected to regulating and can reach an excusing from death reason level.

Yet immunization is not the unique iNOS of causing inductive immunity system activation source between infancy.The child always is being with many infection period, and flu is had a running nose dysentery.Because the metabolic interference of NO can be any other immunostimulating result.Therefore, get the people for susceptible, MMR vaccine inoculation may be maximum " reason ", but under the non-existent situation of MMR, some other immunostimulation, perhaps child's period one of numerous other diseases, all may always cause the metabolic variation of NO.Therefore, in the observation of the autism probability that a large amount of crowds are carried out, the immunity system that the shortage of such variation may come from the self-closing reaction equivalence of multiple other initiation susceptible person of infancy stimulates incident.

If the causal relation chain is arranged between vaccine inoculation and the autism, the approach of a NO adjusting may be the ring that can imagine in this causal relation chain.Yet, be not clear that, be the high level that during immunostimulation, reaches, and/or the low-level autism that excited after the vaccine inoculation.INOS is post-stimulatory low-levelly also might to cause self-closing symptom.Growing is not an one step completed incident, but an ongoing process.Any interference to this process is also underway.Under the situation of the NO that lacks the AAOB generation, it is unstable that basic NO level will become.Low NO causes the increase that iNOS expresses during the immunostimulation, and the minimizing of eNOS and nNOS causes lower basic NO level.Therefore, each immunostimulation may cause basic NO level lower.In " wild " environment, chronic parasitic infection or move on skin is grown AAOB and be applied firm effect can both for basic NO level.Can improve susceptibility the developed regions people to breaking away from parasitic hope to other diseases.Similarly, an AAOB biofilm can improve basic NO level and the NO level is applied firm effect.

People such as Dr.N.A.Halsey have reported and found immune obvious alienation in autism children, feature is (the Neal A.Halsey et al. that increases of the minimizing of Th1 cell and Th2 cell, Meales-Mumps-Rubella Vaccine and AutisticSpectrum Disorder:Report From the New Challenges in ChildhoodImmunizations Conference Convened in Oak Brook, Illinois, June12-13,2000, Pediatrics 2001; 107 (5). URL:http//www.pediatric.org/Cgi/content/full/107/5/e84.).People such as R.C van der Veen disclose the Th1 cell, when producing antigen, the NO that produces has suppressed T cell proliferation (Roel C.van derVeen, et al., Antigen Presentation to Th1 but not to Th2 Cells byMacrophages Results in Nitric Oxide Production and Inhibition of Tcell proliferation:Interferon-γ is essential but insufficient, CellularImmunology 206,125-135 (2000) doi:10.1006/comm.2000.1741, avaiable online at Http:// www.idealibrary.com.).People such as C.S.Benn have reported immune obvious alienation and have been found along with the infancy is increased (Christine.Stabell.Benn et al. by the increasing of number of times of severe infections, Cohort study ofsibling effect, infectious diseases, and risk of atopic dermatitisduring first 18 months of life, BMJ, doi:10.1136/bmi.38069.512245.FE (published 30 April 2004) .).Such one " NO ratchet " caused children's serious immune alienation.

The ATP of cell and energy waste may be results of nitrogen protoxide scarcity (nitropenia)

ATP is the main Conversion of energy material of cell.When ATP is decomposed into ADP+Pi, energy is released, many physiological processs in conjunction with this energy to finish these catabiotic processes.In fact all cell metabolism procedures all need ATP, and if the ATP level too low, just always decline is final dead for cell.Therefore generation and the adjusting of ATP are very important, the mechanism about generation and the adjusting of ATP of existing multiple volume.Yet wherein many all is to be regulated by the process that NO adjusts, when NO is not enough, and perhaps nitrogen protoxide scarcity, a result is exactly very low basic ATP level.Term " nitrogen protoxide scarcity " is used for describing low basic nitrogen protoxide herein.

Since all in fact metabolic processes are all utilized ATP, the ATP deficiency is with regard to all cell functions of entail dangers to.ATP reduces can cause apoptosis, and if serious, can also cause necrosis.This apoptosis and downright bad will start from the thin blood vessel of bullet farthest cell and only on a cell, occur at every turn.Apoptosis and downright bad diffusion are difficult to be found, and this degenerative disorders that can explain that chronic inflammatory diseases is diffused in many same types is found equally.

What need understanding is that requirement to ATP is not a constant, to the requirement of ATP along with the metabolism amount of certain cell with cell function is risen and fallen.Be apparent that lack ATP and just surpassed the problem that just occurs when supplying with in demand, the ATP level is under the control of feedback.A little imbalance (for example nitrogen protoxide scarcity) all can appear in any erroneous calculations to ATP demand and supply in feedback system, or a big imbalance occurs (for example local asphyxia or histanoxia or plastosome suppress) outside feedback system.

The generation of ATP is " strong ".The generation system of ATP can tolerate a certain amount of imbalance and still keep the ATP level at physiological range.Yet the imbalance of certain level can jeopardize ATP and produce, if the ATP deficiency just injures various " household management " function of cell, the effect that this will reduce all cells comprises the generation of ATP.As if which function will begin " reduction " at first, and not know, this depends on each one metabolic special details, local O2 and glucose are supplied with, local metabolic demand, the details that local line's plastochondria density and DNA express.Different mitochondrial protein are expressed in Different Organs, because different metabolic demands may have different ATP and regulate approach.

What need understanding is that requirement to ATP is not a constant, to the requirement of ATP along with the metabolism amount of certain cell with cell function is risen and fallen.Be apparent that lack ATP and just surpassed the problem that just occurs when supplying with in demand, the ATP level is under the control of feedback.A little imbalance (for example nitrogen protoxide scarcity) all can appear in any erroneous calculations to ATP demand and supply in feedback system, or a big imbalance occurs (for example local asphyxia or histanoxia or plastosome suppress) outside feedback system.

Adjusting that generation and ATP produce and consumption and remarkable.Because a lot of approach are non-linear, be bonded, and do not understood fully that their modeling and analysis are very difficult.My target is not to explain all approach exhaustively, and just illustrates some approach of regulating NO and those are saved by falling tone under by the state of nitrogen protoxide scarcity, and those will bring a low ATP production rate.Because relate to ATP loss and nitric oxide production various metabolic processes is non-linear and " bonded ", and they do not occur with a linear mode, on time and the space is not, the description of this paper equally is not arranged to linear model with them yet.Also be not the result that various nitrogen protoxide scarcities are discussed with a kind of succinct describing mode, and how the part among these results aggravate the ATP loss and how the ATP loss aggravates many this situations.

ATP produces and comprises many successive and parallel approach, and wherein each all needs power, so just increase power to increase " non reversibility " exchange.Because ATP produces approach and evolved a very long period, these various approach all are " optimized ".My meaning is herein, and various " inefficiencies " in these approach are distributed in the whole approach usually, minimize whole inefficiency with this.This is meant not " control " approach restriction ATP generation, but " ability " of each step in the metabolic pathway all (substantially) be matched with " ability " of each other step.The ability that exceeds the quata of any one step is all effectively by " waste ", if any source that contributes to this excess capacity be used for those not superfluous steps will be not better.

Very possible is, manyly seems diverse disease, and feature is that ATP loss and final organ failure in fact all " are caused " by the nitrogen protoxide scarcity, is caused by overall basic nitrogen protoxide deficiency.When this occurs in heart, the result expands cardiomyopathy exactly.When this occurs in brain, the result is exactly the high signal infringement of white matter, alzheimer's disease, vascular depression, Parkinson and thunder dimension body dementia.When this occurs in kidney, the result is the nephropathy in latter stage, and when this appears at liver, the result is a primary biliary cirrhosis.When this appears at muscle, the result is fibromyaligia, the complexities of the Gulf War or chronic fatigue syndrome.When this appears at pancreas, first is diabetes B as a result, and then is the chronic inflammatory diseases of pancreas, and then is type 1 diabetes.When this occurs in reticular tissue, the result is a systemic sclerosis.

Because the ATP loss influences each metabolic processes the most at last, I will pay close attention to those known ruined processes in those main degenerative disorders that my conjecture is caused by the nitrogen protoxide scarcity.It is to be noted and exist positive feedback.Jeopardized and danger when beginning to occur in case the ATP of a cell produces, this danger will be quickened and ATP produces and will further be jeopardized.Destroyed when cell " machine ", destructive rate has just quickened.

ATP from oxidative phosphorylation

Mammalian cell all is aerobic.Organic compound (from glucose and lipid acid) transmits by blood flow, possesses to be transported to cell actively, is cleaved into small pieces, sends tricarboxylic acid cycle back to, is oxidized to CO2 and water in plastosome, produces the homologue and the ATP of decrement.For finishing this process, plastosome must be supplied to organism and O2.O2 is sucked by lung, transfers on the oxyphorase in the red blood corpuscle, is transmitted by blood flow, and the capillary vessel from terminal is diffused into the plastosome therein.The diffusion of O2 is the passive diffusion along concentration (actual chemical potential energy) gradient.There is not " initiatively " O2 transmission.The chemical potential energy of O2 in the plastosome (being weighed by dividing potential drop usually) is minimum in the body, because O2 is consumed in plastosome.

Many organs all have a visible metabolism rate.For example, the metabolic rate of heart changes on nearly order of magnitude.Vascular system figure does not almost have anything to change (though existing the increase of new vessel) in this variation.Substantially invariable O2 dividing potential drop and constant transmission region area and a constant diffusion length can will be transported to the unique channel of ten times of mitochondrial O2 raisings in blood, unless be to increase concentration gradient.The way that unique strong this concentration gradient improves is that the O2 level in the plastosome is reduced, because the O2 level in the capillary vessel is substantially invariable, is to be determined by the O2 in the atmosphere.If the O2 level in the plastosome reduces an order of magnitude, and order of magnitude of plastosome O2 consumption raising, concrete O2 consumes (the every Torr O2 of the every Terminal oxidase of the O2 of consumption) just can improve two orders of magnitude.Under basic condition, O2 consumes and suppresses on Terminal oxidase and by nitrogen protoxide (NO).Suppress for reducing NO, must reduce NO.One of approach that reaches this result is to produce super-oxide, and this material can react under the speed of diffusional limitation with NO.Like this, strengthening one of metabolic approach is exactly to produce super-oxide, destroy NO like this, removed the inhibition of pair cell chromo-oxidase, so plastosome consumes O2 at faster speed, the partial O2 level of plastosome has reduced, and increases to mitochondrial O2 concentration gradient from capillary vessel, and more O2 can be diffused in the more great-hearted now plastosome.Therefore, the generation of super-oxide can be counted as improving by the inhibition of removing Terminal oxidase one " feature " of local metabolic speed.If Terminal oxidase suppressed by NO (such as, under the condition of nitrogen protoxide scarcity), apply super-oxide and just can not improve metabolism, only can cause oxidative damage.

In anoxic with all found the active oxygen species generation in the perfusion again, and this is one of reason of the infringement that causes of atrophy and anoxic.1 ROS may be good, if it is by the available O2 of O2 diffusion the raising, but this can only take place under the situation that enough NO exist.

" O2 diffusional resistance " (perhaps other similar diffusional resistance of O2 in proportion to) can be used for weighing the spacing of determining normal capillary vessel and therefore and the diffuse normal resistance of the O2 that sets up.Hypoxia inducible factor, (HIF-1 α) started by anoxic, makes a lot of unlatchings comprise many gene transcriptional starts of the angiogenesis factor of VEGF.People such as Sandau have reported HIF-1 α and have been started (Accumulation of HIF-1 α under the influence of nitric oxide.Blood.2001 by the composite signal of high NO and low O2; 97:1009-1015).

Although health must begin vascularization when vascularity is insufficient, (this can be weighed by the O2 level) also must eliminate capillary vessel when having " too much " vascularity.In such as organs such as hearts, much lower when the O2 consumption is than the peak normally.Because normal capillary vessel spacing determines under " normally " condition perhaps " anoxybiotic " feels not to be only to be caused by " low O2 level ", also part is owing to basic NO level, particularly by high NO level, or especially by the ratio of NO to O2.

The oxyphorase of oxidation (O2Hb) destroys NO under the speed near diffusional limitation.O2Hb is arranged in blood flow and O2 is sent to plastosome.All plastosomes all must come the phosphorus oxide hydrochlorate to obtain O2 within the range of scatter of O2Hb.Because the reduction that O2Hb also brings NO, minimum NO level should be at the O2Hb place.Therefore in the blood vessel outside, vessel wall is the minimum place of NO, and the concentration of NO can be used to weigh a cell has " how far " apart from O2Hb.Therefore the ratio of NO/O2 is that a well definite site needs measuring of more (or still less) O2 exchange capacities.Many physiological responses to " O2 deficiency " all are to regulate by HIF-1 α.HIF-1 α part is adjusted by NO, the level of O2 is increased to the level of HIF-1 α startup when high NO level.

The nitrogen protoxide scarcity has certain effect to the spatial distribution of HIF-1 α, as a function of O2 level.Under a low NO level, low O2 level is that startup HIF-1 α is required.Therefore just as capillary vessel changes (this is that they are done continuously), they gradually spacing become and far be low to moderate capillary vessel farthest of distance that the NO/O2 value is enough to start HIF-1 α until the O2 level.Normal capillary vessel spacing is determined under " normally " condition.Can be tolerated in the O2 level that the basic condition end is low, but under higher metabolism amount, just seemed not enough.

Under a low NO level, low O2 level is that startup HIF-1 α is required.Therefore just as capillary vessel changes (this is that they are done continuously), they gradually spacing become and far be low to moderate capillary vessel farthest of distance that the NO/O2 value is enough to start HIF-1 α until the O2 level.Normal capillary vessel spacing is determined under " normally " condition.Can be tolerated in the O2 level that the basic condition end is low, but under higher metabolism amount, just seemed not enough.

At present also not about the report of NO gradient between capillary vessel, also seldom about the report of O2 gradient.Yet, when unusual situation appears in people, they " unhealthy ".The ability of their aerobic metabolic activity has also reduced.This shows that blood vessel changes certain capillary vessel that reduces to reduce the diffusibility of O2.The time range that oxygen-consuming capacity changes has been distinguished the time range that blood vessel changes.Low NO level can change those to the effective oxygen consumption active of physical qualification level.Under high NO level, the motion of appropriateness can bring significant oxygen-consuming capacity.Under low NO level, need more can bring bigger metabolic anoxybiotic motion.Although the metabolic activity that increases can be induced by the cyclical movement of muscle, the variation of the metabolic demand of some other organ and unlike muscle.

So thin maximum metabolic ability that will reduce of capillary vessel by the tissue of this capillary bed supply.Under basic condition, the maximum capacity that this has reduced is also not obvious, under the condition of nitrogen protoxide scarcity, to a great extent because low NO level, O2 level in the plastosome also reduces, and can solve because the gradient of O2 has increased by thin capillary vessel for reaching O2 diffusion that the basis requires.Yet, under the condition of the metabolism amount that improves, occurred so metabolic ability may be not enough to reach the situation of metabolic demand ATP dilution.

Each organ all possesses different metabolic functions, and different environment has improved metabolic amount.For example, at kidney, main metabolism amount is the absorption again to sodium.The sodium that absorbs in the diet increases the metabolism amount that will improve kidney, if surpassed metabolic ability, will bring ATP dilution and dysfunction.In the distensibility cardiomyopathy, it is very responsive to anoxic and excess load that heart becomes.In fact, in animal, the distensibility cardiomyopathy can be only negative excessively by chronic cardiac, no matter be through-rate or blood pressure, institute causes.This is consistent with the thin inference of the capillary vessel of being regulated by NO.When heart overloads, send into the quantity not sufficient of the O2 of cardiac muscle.Super-oxide is produced to destroy NO, has removed the inhibition to oxyphorase oxidation enzyme, so and the more O2 of concentration that reduced O2 can be diffused into super negative muscle.Temporarily, this has improved metabolic ability (but only limiting to the situation that NO has suppressed oxyphorase oxidation enzyme).Yet chronic low NO causes that blood vessel changes and capillary vessel is thin, and both are features of distensibility cardiomyopathy for the backs.Peroxide breakdown protein, low ATP level has reduced proteoplast proteinic utilization of ubiquitinization (ubiquinated) and super ubiquitinization (hyperubiquinated) protein has been accumulated.

Similarly, in the remaining kidney model of nephropathy in latter stage, excised the part kidney, (destroying) by surgical operation or by toxin, this has aggravated the metabolic load of remainder.Superoxide is produced to reduce NO and to improve O2 to the mitochondrial diffusion of kidney.Chronic bearing excessively caused the progressively thin and progressively kidney depletion of kidney capillary vessel.In acute renal depletion, the patient is dialysed to give one in kidney " rest ", and allow its recovery.In the acute renal failure that rhabdomyolysis (to a kind of muscle injury of blood release myohaemoglobin) causes, the feature of kidney injury is an ischemia injury.Myohaemoglobin utilizes NO, just as oxyphorase, thereby will bring the blood vessel atrophy in the kidney to cause ischemic.Myohaemoglobin can be induced the local nitric oxide scarcity equally and further be caused the ATP dilution.

Reduce metabolic load kidney is recovered if having time, if but NO basal level is very low, the kidney vascular system will still keep atrophy, kidney will be still to metabolism super meet very responsive.

The capillary vessel spacing that increases increases the diffusional resistance of O2, partly by NO the inhibition of oxyphorase oxidation enzyme is offset, and has caused the lower concentration of O2 in the plastosome.The transmittability of glucose also is lowered.O2 is carried by red blood corpuscle, and this is limited by vascular system still.By contrast, glucose is dissolved in the blood plasma, and blood is permeable to the blood vessel external space, can transmit material by multiple glucose and enter cell.Unfortunately, measure very difficulty of EV glucose, and seldom report measuring method in the prior art.Yet it is lower than blood sugar certainly, because glucose consumes in extravascular Fluid body infiltration blood vessel external space process to some extent.Because glucose is consumed, so there is gradient in glucose concn, just as there being the O2 concentration gradient.The transmission of O2 is by diffusion, and the transmission of glucose is equally also by spreading convection current and actively transportation.Can infer, blood vessel is thin will cause lower glucose concn because more cell consumption the glucose that specific capillary vessel is supplied with.Compare with O2 concentration, can improve glucose concn by a bigger concentration gradient is provided.Similar, the concentration of glucose transport material also can be enhanced.The raising of the very possible blood sugar concentration of finding in diabetes B is compensatory, improves from the glucose transport of the tissue of capillary vessel to a hypertelorism.Similarly, increasing that Regular Insulin discharges perhaps is by way of compensation to improve the concentration of glucose transport material.

The main source of ATP is oxidative phosphorylation.Cell can obtain ATP by glycolysis, and the amount that produces the glucose of a unit ATP glycolysis-consumption is 19 times that oxidative phosphorylation consumes.If blood vessel is thin in the supply that has jeopardized O2, cell just must obtain ATP from glycolysis, and glucose consumption will heighten.If the consumption of glucose has surpassed supply, the ATP dilution will always occur.

Appetite partly is metric by grape sample concentration.Presumablely be, this measurement is not very accurate, and the glucose in a large amount of blood vessels is constant, then is not like this in peripheral organization and blood vessel space outerpace.If cell needs glucose, then between thin capillary vessel, regulate glucose, although they may show that the glucose in the most of blood of low glucose concentrations is still competent.When having thin capillary vessel, " normally " blood sugar all can be shown as low, so health just may show hyperglycemia.If capillary vessel is thin in being enough to weaken oxidative phosphorylation,, glycolysis supplies with blood sugar and the insulin level that has improved although may also being not enough to keep ATP.If be in the glucose and/or the horizontal step-down of ATP of a cell in the thin capillary bed, it will send the signal of " I am hungry " and give brain and appetite stimulator.People with thin capillary vessel can continue feed, although the storage of competent body fat, owing to feel that glucose has reached the equilibrated cell not enough.Have been found that in obesity that carbohydrate is thirsted for, the blood sugar that has raise, Regular Insulin resist and the obesity that is difficult to control appetite may be the result of thin capillary vessel.

The plastosome biosynthesizing is to be started by the cGMP from guanosine acyl enzyme, perhaps improves NO under the condition by constant ATP, or reduces ATP under the condition of constant NO.The basic NO level of a reduction will reduce plastosome concentration and will reduce basic ATP concentration.(ml O2/mg protein) that the efficient of oxidative phosphorylation reduces along with this ratio raises.The ATP production rate depends on plastosome potential energy, and the high ATP production rate under high ATP/ADP ratio needs high plastosome potential energy.

The ATP dilution that the symptom of many metabolic syndrome can be brought by the plastosome dilution that the nitrogen protoxide scarcity causes worsens.Along with the plastosome dilution, the ATP that glycolysis-produces increases.Yet,, because glycolysis-only can bring 1/19 ATP, need the glucose in more blood.Glucose by glucose transport material input cell just will reduce, and this process is by insulin-induced.A lot of cells not directly and the blood contact, they are poured into by blood plasma in the blood vessel external space, this place owing to the consumption of glucose of cell and concentration of insulin than low in the blood.Being fit to be produced by oxidative phosphorylation the intracapillary space that transports required glucose of ATP, is not enough for producing same ATP by glycolysis-.Apart from capillary vessel " too far away " even if cell may have under the condition of local insufficient glucose hyperglycemia in main blood vessel.The cell that such ATP lacks will spread out of the signal of " I am hungry ".Although hungry signal like this can force the enough even excess of lipid reserve of the consumption whole organ system of carbohydrate.

Plastosome biosynthesizing/adjusting

The key " engine " that produces ATP is exactly a plastosome.All various kinds of cell organs all have plastosome, and the organ that some single cells are formed also is.Plastosome in the tissue is multiple class, and total amount is near near 20-30% in the cardiac muscle, and to compare percentage composition low slightly with many aerobic muscle.Plastosome is the place that a lot of ROS produce, and mitochondrial many components are very responsive to irreversible infringement, and when the plastosome component became inoperative, they must be replaced.Different cells has different plastosome density, can infer to exist the mechanism of regulating the different densities in the different cells.Can infer comprising eliminating the mechanism of mitochondria number when when too low, increasing mitochondria number and Tai Gao.

People such as Nisoli disclose mitochondrial biosynthesizing; started (Nisoli et al. by solvable guanylate cyclase (sGC) via cGMP by NO; Mitochondrialbiogenesis in mammals:The role of endogenous nitric oxide; Science; 7 February 2003; Vol 299,896-899.).Openly sGC is very responsive to NO and ATP level for people such as Ruiz-Stewart, the starting point that the cGMP that NO starts produces is the part of ATP level, that is to say that under a lower ATP level, sGC is more responsive to NO, vice versa (Ruiz-Stewart et al., Guanylyl cyclaseis an ATP sensor coupling nitric oxide signaling to cell metabolismPNAS January 6,2004, Vol 101, No.1,37-42).Under constant NO level, ATP reduces and will start sGC and produce cGMP.Yet in low basic NO level (nitrogen protoxide scarcity), the ATP level that starts the cGMP generation will be than lower under the high NO level.Therefore the plastosome biosynthesizing will be lowered under the deficient condition of nitrogen protoxide.Lacking under the plastosome condition slightly, each plastosome all will get under the condition in high O2/ substrate upset rate and work.

The ability that the most high-new old metabolic capacity surpasses " during the spare time " metabolism " normally " is necessary.Presumable is that " excessive " mitochondrial generation is come from this difference, promptly than supplying with the more plastosome of the metabolic required plastosome in basis.Presumablely be if that the ATP biosynthetic signal that is plastosome, the plastosome that exists certainly under the base concentration condition suppresses, to prevent producing excessive plastosome under basic ATP concentration.This is suppressed at metabolic ability peak period and is released.NO has served as the role of supressor.NO has suppressed oxyphorase oxidation enzyme.The NO that reduces has quickened metabolism.

People such as Nogueria have reported, usually, the efficient of oxidative phosphorylation raises along with the ratio of (mlO2/mg protein) and reduces (Nogueria et al., Mitochodrialrespiratory chain adjustment to cellular energy demand, J.BiolChem 276,49,46104-46110,2001).Equally, Kadenbach has also reported the ATP production rate and has depended on plastosome potential energy, high ATP production rate under high ATP/ADP ratio needs high plastosome potential energy (Kadenbach, Intrinsic and extrinsicuncoupling of oxidative phosphorylation, Biochimica et BiophysicaActa 1604 (2003) 77-94.).

Plastosome is main ROS producer.Plastosome depends primarily on plastosome potential energy to the manufacturing of ROS, and the raising ROS that high potential energy can be exponential produces.

When mitochondrial density minimizing, each plastosome is more " hardy " work then, works under a high potential energy ground condition, makes more ROS and make ATP under more inefficient.People such as Echtay have reported high plastosome potential energy and high ROS produces, bring (the Echtay et al. that induces to uncoupling protein, Superoxide activatesmitochondrial uncoupling protein 2 from the matrix side, J.BiolChem 277,49,47129-47135,2002).As people such as Sluse report, help to reduce plastosome potential energy like this and reduce ROS producing (Uncoupling proteinsoutside the animal and plant kingdoms:functional and evolutionaryaspects.FEBS Letters 510 (2002) 117-120.).People such as Taniguchi have reported uncoupling protein 2 overexpression under primary bile hardened condition, after successfully using ursodesoxycholic acid (by substituting the synthetic liver metabolic load that reduced of bile) to handle, be lowered (Taniguchi et al., Expression of uncoupling protin-2 inbiliary epithelial cells in primary biliary cirrhosis, Liver 2002:22:451-458.).

Oxyphorase oxidation enzyme is suppressed by NO the consumption of O2.Under basic condition, oxyphorase oxidation enzyme is suppressed by major part, and the consumption of O2 is appeared under the condition of high O2 dividing potential drop.Thereby in the plastosome O2 concentration gradient having been made in the consumption of O2 makes O2 be spread by the trend plastosome.Under the high oxidation phosphorylation level, O2 consumes may be increased～10x, however the not change of the diffusion path length of O2, and the O2 concentration on the vessel wall does not change yet.In order under constant diffusion length, cardiac muscle to be consumed O2 amount increase～10x, the gradient of O2 must increase～and the O2 concentration of 10x and terminal point must be reduced to～and 1/10.Oxyphorase oxidation enzyme obtains by changing NO concentration this changing unit of the avidity of O2.By reducing NO concentration, oxyphorase increases the avidity of O2, and the ATP that plastosome produces increases, though be under the condition that the ROS of the efficient of a reduction and increase produces.The super-oxide that is accompanied by high O2 consumption has reduced the NO level, and allows the high O2 under the low O2 concentration level to consume, and this low O2 concentration level has allowed to the high O2 diffusion of plastosome.Therefore, the generation of super-oxide is to quicken the feature that O2 consumes by consuming NO under high ATP production rate condition.

Cell does not reduce the ATP demand although plastosome density reduces.Under the condition that plastosome density reduces, make same ATP and cause consuming more O2, perhaps the basic metabolic rate of Jia Suing.In a lot of situations, all found the basic metabolic rate of quickening, having comprised: falciform red blood corpuscle anaemia, congestive heart failure, diabetes, liver cirrhosis, Crohn's disease, amyotrophy side direction sclerosis, obesity, end stagerenaldisease, alzheimer's disease and chronic obstructive pulmonary disease.

Although the O2 rate of consumption that improves can be effectively utilized, uncoupling protein is also saved by rising tune in many this situations, shows that the metabolic rate part that improves at least is because inefficient.Known uncoupling protein by the situation that rising tune saves is: obesity and diabetes.

Perhaps improve the situation of ROS and can induce UCP2, this can further reduce the ATP level.Super-oxide has destroyed NO, has further reduced the NO level.Therefore, the nitrogen protoxide scarcity is enough to reduce the plastosome biosynthesizing will cause the ATP dilution, and this will cause more multi-thread plastochondria ROS to produce, and this generation further causes NO to reduce and lower plastosome biosynthesizing.The nitrogen protoxide scarcity will cause the latter stage degenerative disease with the ATP dilution, and ROS produces, and UCP induces, and plastosome reduction and final organ failure are feature.

Like this, the nitrogen protoxide scarcity will cause multipotency more to produce the inefficient plastosome of same ATP, have lower " deposit " metabolic ability, under lower plastosome O2 concentration conditions, and have more super-oxide to produce.

Consume O2 at more multi-thread plastochondria and cause under the situation of O2 concentration reduction, O2 gradient diffusive force increases, so the O2 diffusion path length can increase in capillary vessel is thin, this becomes in DCM (dilated cardiomyopathy), hypertension, and diabetes B is all found in the kidney hypertension.

Hypoxia inducible factor HIF-1 α

Many effects of " anoxic " are regulated by hypoxia inducible factor (HIF-1 α), and this factor has activated the many gene transcription that comprise EPO.Complicated activity when people such as Sandau have reported HIF-1 α and are exposed to NO has been proved to be to utilize true NO, the transfectional cell of NO donor and expression iNOS is as NO source (Sandau et al., Accumulation of HIF-1 α under the influence of nitric oxide.Blood.2001; 97:1009-1015.).People such as Sandau find than high level, and low NO level is induced and reacted more rapidly and produce more HIF-1 α.Tested unique one can not to induce the NO donor of HIF-1 α be the sodium Nitroprusside ion, and it also can discharge prussiate.Because HIF-1 α is energy high NO of perception and low O2 equally, under low NO condition, starting HIF-1 α needs lower O2 level.Many approach need HIF-1 α to induce, comprise, the anaerobism glycolysis-, this process can under anaerobic produce ATP and produce lactic acid salt from glucose, glucose is imported the glucose transport person of cell, as the VEGF of an approach of vascularization, and start the erythropoietin that red blood corpuscle generated and improved hematocrit.

People such as Goda have reported HIF-1 α and have also suppressed essential (the Goda et al. of cell cycle by p53, Hypoxia-Inducible Factor 1 α is essential for cellcycle arrest during hypoxia, Molecular and cellular biology, Jan.2003, p359-369.).It is very important suppressing cell cycle under the condition of anoxic pressure, and cell fission just can not occur under the not enough condition of ATP like this.

Therefore the basic NO level that reduces will cause the reduction by the expression of gene of HIF-1 α adjusting, and reduce glucose transport person's level (causing glucose " resistance "), the Epo level (causing anaemia) of reduction.

The assessment that skin absorbs the NO from AAOB

But biology availability and the percutaneous absorbing state of the NO that the purpose of this analysis is assessment AAOB to be produced.Lung and skin are the proximities that is related to oxyphorase as the difference of gaseous interchange place maximum.In lung, the arterial blood basic 90% that the effective O2 of needs measured and left lung is saturated by O2.It is very fast that the Hb of oxidation destroys NO.Non-oxide Hb equally also promptly adheres to NO, and it can not be utilized.With with Hb reacting phase ratio, preserve the vasodilation activity that material has kept NO with albuminous reaction by forming a lot of NO, comprise the S-NO-albumin, NO is absorbed by the aqua region of detesting in the albumin molecule in health, this is by people such as Sampath report (Sampath et al., Anesthetic-like Interactions of Nitric Oxide with Albumin andHemeproteins, A Mechanism For Control Of Protein Function, TheJournal Of Biological Chemistry Vol.276, No.17, Issue of April 27, pp.13635.13643,2001).People such as Nedospasov have also reported equally also to have and have formed the nitroso-group material (December 5 for Nedospasov et al.An autocatalytic mechanism ofprotein nitrosylation, PNAS, 2000, vol.97, no.25,13543-13548).This nitroso-group material is reported to N2O3 by people such as Rafikova and is absorbed (Rafikova et al.Catalysis of S-nitrosothiolsformation by serum albumin:The mechanism and implication invascular control detesting the pool equally, PNAS April 30,2002, vol 99, no.9,5913-5918.).Last piece document proof white cell can be rapidly and truly NO and O2 reacting forming complex, but and stability number minute slowly release true NO then, this NO-O2-albumin complex compound causes with the intravital vasodilation of the vasoconstrictive rat of L-NAME.This complex compound also can cause the mercaptan nitrite acidizing of the molecular weight that multiple material comprises.Block in vitro that mercapto groups has stoped the albuminous formation of S-NO-but formation that can not this NO-O2-albumin nitroso-group complex compound.The S-NO-albumin is also changeed nitre ester (transnitrosates) gsh, is especially containing in the presence of Cu proteinic, for example ceruloplasmin.S-NO-mercaptan also can discharge NO, and uncertain be following which kind of material actually, NO, GSNO, other lower molecular weights S-NO-mercaptan or S-NO-albumin are important active substances, also may they be all.

According to one aspect of the present invention, disclosed the mechanism of mobile NO material from skin to guanosine acyl enzyme (GC), locate it at this and can pass through the S-NO-thiol reactant, comprise the S-NO-albumin, GSNO, or other low molecular weight substances.Use skin to have much as the advantage at the exchange interface of albuminous nitrosylation.The first, this makes NO fully be absorbed into the outer blood plasma of blood vessel and needn't meet with Hb.Do not have under the Hb situation, will grow much the life cycle of NO material.The second, external skin can tolerate more that than lung the NOx. outside surface is dead in fact, continues to be updated.If NO-albumin complex compound systematically is transported to NO in the body in external formation and by these materials, so via the result of treatment of the NO of skin than much higher times of the NO that sucks.The 3rd, since desired active substance is a kind of S-NO-mercaptan, the non--oxydasis by O2 of NO can not destroy NO, and this process is converted into N2O3 with it, and it is a kind of good nitrosation agent.

The autotrophy ammonia oxidizing bacteria may be symbiotic, and the human NO that may can utilize its generation with evolving, can not have any harmful side effect so improve basic NO level with them.According to an aspect of the present invention, a lot of diseases of modern society all are because the NO that the disappearance of this bacterium that the modern activity of having a bath causes is brought lacks.Positive side effect can come from the use of AAOB, and especially in those African recently honorable people, do not evolve out the approach of compensation NO of their earlier generations ancestors loses NO from AAOB with reply during winter.This also may be that the colony from Africa of the why U.S. more is subjected to obesity, diabetes, hypertension, asthma, arteriosclerosis, heart trouble, latter stage nephropathy, precocious puberty is etc. one of reason of the puzzlement of disease.It is known that NO dissociates from the photochemistry of SNO-mercaptan, and the minimizing of high latitude area skin and trichochromes calmness may come from dissociate increasing of demand rather than come from vitamin D metabolism of the photochemistry of the SNO-mercaptan of external skin.What night, scalp was perspired increases, and to dissociate be minimum to the photochemistry of SNO-mercaptan at that time.Hair bleaches with advancing age, perhaps is in order to allow more irradiation thoroughly to be used for photochemistry NO release.Tyrosine oxidase generates melanic enzyme, is a kind of 3-type cupric oxydase, this enzyme catalysis of some amount the formation of SNO-mercaptan.

External skin all required metabolic O2 comes from extraneous air.Therefore red blood corpuscle need not be in those zone circulations, major part, and they are not really yet.Colour of skin major part depends on pigmentation and red blood corpuscle.Do not have Pigmented skin relatively easily to see through, in fact the colour of skin has reacted the circulation of red blood corpuscle at epidermal area.Although the outer skin of living obtains oxygen from air, they obtain other nutritive substances from blood.Blood plasma is that blood does not have erythrocytic part, therefore can supply with other any materials except that O2.Since outer skin need not red blood corpuscle, but still carry out metabolism energetically, blood plasma still circulates and obtains the outer skin of O2 through those from air.Need not at these exactly that NO is converted into the S-NO-albumin in the erythrocytic skin.

The time to live of NO in blood is very short.NO is very fast by the O2Hb oxidation, adheres to Hb very soon, by the albumin complexing, is oxidized to N2O3 and NO2 by non--enzyme reaction, and also forms S-NO-mercaptan.The primary location that people such as Bellamy have reported the NO reaction is a guanosine acyl enzyme (GC), (～(～1 to 10sec) (Bellamy et al. when 100ms) activating slowly when the EC50 value at this place activates soon for about 45nM/L with 20nM/L, Sub-second Kinetics of the Nitric Oxide Receptor, Soluble GuanylylCyclase, in Intact Cerebellar Cells, The Journal Of BiologicalChemistry Vol.276, No.6, Issue of February 9, pp. 4287-4292,2001).Reaching the part of the pharmacology amount of target area in the NO source of prediction given dose, is very difficult.For example, when the NO that sucks is controlled at 80ppm＞90%O2 (16 μ M/min=14 μ M/kg/hr), aortic pressure does not change.Relative therewith, the sodium Nitroprusside ion (SNP) that people such as Cockrill have reported 0.9 μ M/min (0.75 μ M/kg/hr) causes that aortic pressure reduces by 25% (Cockrill et al., Comparison of theEffects of Nitric Oxide, Nitroprusside, and Nifedipine onHemodynamics and Right Ventricular Contractility in PatientsWith Chronic Pulmonary Hypertension ^*CHEST 2001; 119:128-136.).This has shown that when by suction NO administration blood vessel resistance NO concentration is not increased to 20nM/L and activation GC.Therefore, effectively doubly more a lot of than sucking NO when SNP is many times transmitting " NO active substance " and gives GC.

SNP compares with intravenous injection NO with quilt equally, Rassa falls the people and discloses intravenous injection NO, SNP, with the S-NO-gsh, inculcate with pill form with relative " maximum effective dose ", make brachial artery expand 6 μ M respectively, 34nM, and 5nM (Rassafet al., Evidence in vivo transport of bioactive nitric oxide inhuman plasma, J.Clin.Invest.109:1241-1248 (2002)).This proposes intravenous injection NO, and SNP is 1: 176: 1200 with the relative effect of GSNO.In by the temporary transient vasodilation process of above-mentioned processing inductive, significant difference is arranged.It is longer that NO and GSNO handle the effect of handling than SNP.GSNO when transporting to peripheral GC with " NO active substance " approximately than 7 times of SNP " effectively ".Can know by inference, the GSNO of about 0.1 μ M/kg/hr is equivalent to the vasodilation effect of 0.75 μ M/kg/hr SNP.If we suppose that the vasodilation effect of 0.75 μ M/kg/hr SNP and the NO that has produced are in " the same order of magnitude ", the GSNO of 0.1 μ M/kg/hr representative so " effectively NO " raises 50% than basal level.

Copper forms S-NO-mercaptan from NO with the thio-alcohol that comprises (RSH) no matter be Cu2+ or ceruloplasmin (CP) (main cupric serum protein, 0.38g/L in the HAS contains 0.32% copper, comprises 94% serum copper) catalysis.Than free Cu2+ bigger activity is arranged at the CP that is lower than μ M/L concentration, this activation almost doubles under the muriate physiological concentration exists.Many other contain the also forming process of catalysis S-NO-R of Cu enzyme:

People such as Katsuhisa Inoue have proved the forming process of cupric ion and a lot of copper enzyme catalytic cpd S-NO-R, measured the proteinic nitro mercaptan of various cuprics generation activity (Katsuhisa Inoue et al. such as them, Nitrosothiol FormationCatalyzed by Ceruloplasmin Implication For CytoprotectiveMechanism In vivo, The Journal Of Biological Chemistry Vol.274, No.38, Issue of September 17, pp.27069-27075,1999).RS-NO is formed by the gsh (GSH) (20 μ M) that has reduced or N-acetyl-L-cysteine (NAC) (20 μ M) and P-NONOate (10 μ M) reaction, in existence or do not exist under CuSO4 or the proteinic condition of other cuprics.Using CuSO4 or the proteinic concentration of other cuprics is 2.0 μ M.When CuSO4 or the proteinic concentration of each cupric surpass 2 μ M, the amount of RS-NO (GS-NO and NAC-NO) reaches a maintenance level or begins and descends.Data are remarkable 6 standard errors of 4 tests.

Be proved to be approximately high 100 times in the presence of physiological concentration CP from NO and GSH formation GSNO.Even also having reported CP, they under NO nanomolar concentration level, just can produce significant GSNO.

They disclose equally, in cell culture, rat macrophage (RAW264) with disturbed element-γ and lipopolysaccharide-induced iNOS, in Krebs-Ringer-phosphoric acid salt, replenish with CP (2 μ M/L), about 1/3 oxidized NO material generates, (nitrate, nitrate and RSNO) finishes when NAC-NO recovers.This discovery is very remarkable.It has proved when oxyphorase is non-existent, and true NO is more efficient and improved 33% to the RSNO conversion energy.

Copper in the blood plasma is various and increases under infected situation.It is very considerable that people such as Berger have reported in the effluent of burn wound Cu and Zn content, the patient that skin 1/3 is burnt has lost the 20-40% of the normal Cu content of health and 5-10% (the Berger et al. of Zn content in 7 days, Cutaneous copper and ainc losses in burns, Burns, 1992 Oct; 18 (5): 373-80).Cu in the possible burn wound secretory product is converted into S-NO-mercaptan for catalyzing N O.By the way, if on patient's skin, transplant AAOB, comprise urea and Fe, Gu, wound exudate with these AAOB desired substances of Zn, to be converted into NO and nitrite, replenish the NO that local iNOS produces greatly, consume the source (for example O2 and L-arginine) in the metabolic wound of being challenged simultaneously.The a large amount of NO and the nitrite that produce at wound surface AAOB can suppress to infect, and especially anaerobism is microbial, for example can bring tetanus, the clostridium of gas gangrene and food poisoning.The XOD that comprises in the skin wound can improve the NO level by reducing any nitrite that is converted into the NO generation by AAOB.It is the first cause of handling and preserve meat with nitrogen protoxide (nitrite) that inhibition can cause the clostridium of botulism food poisoning.On a textbook of the disease that microorganism causes, the author of this chapter of clostridium, Rubin writes: " in some developing country; neonatal remaining umbilical cord is filled to console this baby with earth or ight soil " (E.Rubin, The Clostridia chapter 11 in Mechanisms ofMicrobial Disease ed.M.Schaechter, G. Medoff, D.Schlessinge, Williams﹠amp; Wilkins, 1989, Baltimore MD.).Rubin propose this process can prevent tetanus infection by add to wound aerobic all, yet in fact anti-tetanus reagent may be nitrogen protoxide, this nitrogen protoxide is by being in AAOB bacterium and ammonia in the ight soil and urea effect generation in the earth.

Skin comprises the Fe of 9.2ppm, and whole blood contains the Fe that comprises 1ppm in the Fe of 500ppm and the blood plasma.Main heme concentration is the oxyphorase in the capillary vessel in the skin, and this is that skin color has reflected dabbling reason.Because the heme content in the skin has only 2% of this content in the blood at most, thus in the expection skin life cycle of NO be in the blood 50 times at least.In fact should the time longer because some ferro elements are not present in the heme, but as not with the iron complex of NO reaction.Skin account for into body weight for humans 18% and comprised albuminous 23% (these data of 70kg man are approximately 65g) in the health.NO and O2Hb reaction form the nitrite and the nitrate of non-activity.NO and thiol reactant form S-NO-mercaptan, carry out non-enzymatic reaction with O2 and form NO2.NO2 is easy to form nitronate with mercaptan.Should therefore can not eliminate or stop NO to form S-NO-mercaptan with the non-enzymatic reaction of O2.Producing the albuminous decisive reaction of S-NO-in the skin is the destruction of O2Hb to NO.Need do not formed the S-NO-albumin by destructive NO like this.In fact, people such as Godber have reported the NO that is converted into nitrite and nitrate can be reduced to NO (Godber et al. by the xanthine oxidoreductase enzyme, Reduction of Nitrite or Nitrate OxideCatalyzed by Xanthine Oxidoreductase, The Jouranl Of BiologicalChemistry.Vol 275, No.11, Issue of March 17, pp.7757-7763,2000).Similarly, nitrite and nitrate can be perspired by skin and is discharged from, and then by AAOB " recirculation ", this process can under anaerobic use nitrite or nitrate to replace O2.

O2 is approximately 3.7E-7ml/m/min/mmHg to the infiltration of keratoderma, is 1.3E-6 at active part.Cuticular thickness is about 10 to 20 microns.The upper epidermis and the papillary layer of living approximately extend to about 250 microns, obtain from air all that O2 supplies with rather than from blood vessel.Along with the seepage force of two kinds of tissues of increase of water content all increases.The stratum corneum of hydration status is not distinguished, so can be expected under the state that scalp perspires higher seepage force is arranged.

The physiological property of O2 and NO is very similar, is included in the distribution in mutually of water and lipid, so NO is similar to O2 to the seepage force of skin, yet the molecular weight of NO is little to have bigger solubleness in water and other liquid.If we suppose that the variation of seepage force changes along with the solubleness in water, NO will be 1.5 times of seepage force of O2 so.If inner NO concentration surpasses 20nM/L, GC will be activated so, and local vascular will expand, and blood flow increases, and will be transferred away by convection current or by the O2Hb oxidation above the NO of 20nM/L.20nM/L is corresponding to the concentration 10ppm in the gas phase.Concentration difference between percutaneous NO and the two-phase, proportional to the thickness of the seepage force of skin and each layer.

Main X factor is that NO need diffuse through to arrive blood plasma is converted into the skin of RSNO at this place thickness.Glutathione content in the stratum corneum of nothing hair mouse is approximately 100pM/ μ g protein, perhaps about 0.3%.Second X factor is the efficient that NO is converted into RSNO.

Outside " microbial film " is easy to adjust in treatment to the resistance of diffusion.Gel quav forms for example KY jelly or the various hair gel diffusion obstacle that can both lose as NO of material from the hair to ambient air.NO level on the skin can not substantially exceed 20nM/L, because this level activates GC and can bring local vessel expansion and exceed the oxidized destruction of part NO.It spreads towards periphery unless stratum corneum NO concentration will raise, or the bacterium that produces it is suppressed.This process takes place primarily to depend on that being easy to controlled outside resists.

Scalp can be modeled as a bio-reactor that produces NO with the sweat that injects.Yet the unique loss mechanism of scalp microbial film is by the diffusion of scalp and the diffusion of air towards periphery.This microbial film can be seen a reactor under dry aerobic condition and moistening anaerobism cycling condition as.NH3 is oxidized to nitrite and accumulates with solid form.Urea is hydrolyzed to ammonia, and the pH value is elevated to 8 from 7.AAOB is very active in this pH scope, and when ammonia is converted into ammonium can not be utilized the time, the pH value is reduced to about 6.Because the active metabolism of low water will be suppressed in dry scalp.In a large amount of the perspiration, the pore fresh sweat of gushing out.People such as Simon have disclosed the pH value, and to be approximately the decomposition of 4 o'clock nitrite very remarkable, AAOB still can be nitrite (Simon et al. with the urea metabotic change, Autotrophic Ammonia Oxidation at Low pHthrough Urea Hydrolysis, Applied And Environmental Microbiology, July 2001, p.2952-2957.).This fresh sweat can decompose the cumulative nitrite, and brings it into the low zone of pH by wicking action, and this is because pH depends on the surface tension (low pH value lower surface tension force is higher) of sweat.The AAOB in the zone that pH is low vivaciously constantly was converted into negatively charged ion (NO2-) with a positively charged ion (NH4+) in ten minutes, and reduced the pH value.Because pore is full of by sweat, will become anaerobicly in this biomembranous bottom, AAOB will utilize nitrite rather than O2.The ratio that people such as Schmidt have reported the NO of NH3 that under anaerobic (with gaseous state NO2 and nitrite) consume and NO2 and generation is 1: 2: 1 (Schmidt et al., Anaerobic AmmoniaOxidation in the Presence of Nitrogen Oxides (NOx) by TwoDifferent Lithotrophs, Applied And Evironmental Microbiology, Nov.2002, p.535 1-5357).Since when nitrogen unique withdraws from approach as NO, so all excessive NH3 and urea all must be converted into NO.Under these conditions, the average N O that perspires from the basis produce be approximately 125 μ M/hr under 0.15 liter of sweat/sky condition and 20mM/ rise NH3=3m M/d 100% conversion=3m M/d=125 μ M/hr.Other people for example people such as Weiner control and suck air and be 1mM NO/hr (Weiner et al., Preliminary asseeement of inhaled nitric oxide foracute vaso-occlusive crisis in pediatric patients with sickle celldisease, JAMA 2003; 289:1136-1142).Skin equally also comprises the xanthine oxidoreductase enzyme, and it can be reduced to NO rapidly and in large quantities with nitrite.

If biomembranous pore is full of sweat, a thick microbial film resists nitric oxide production diffusion and approaches skin.The thickness of skin is limited by the resistance of the diffusion from the capillary vessel to the viable cell, so can not make any thickness as microbial film.

Skin is 3 dimensions, and these bacteriums (part in them is moved) can migrate into the perspire pipe, and they can be supplied to urea and ammonia better at this place, and are absorbed better at the NO of this place.Mammals ground characterizing definition is mammary gland, and it is a perspire passage of having revised.All Mammalss all have sweat gland, although a lot of animal is all lowered the temperature without sweat gland, comprise rodent, dog, and cat.Sweat gland concentrates on foot.

Rely on bacterium from producing the natural physiological mechanism that NO allows to adjust the NO administration from the urea of discharging naturally the sweat.The scalp that adrenal hormone is regulated is perspired and is also occurred for this purpose.

Embodiment

The inventor is present, at (on the scalp of not washing in 33 months) on the skin that he did not wash in 27 months, has the AAOB survival.During this, the hypertension that he suffers from over a long time always significantly reduces, and a very long time he need not to control it with medicine, he has alleviated 30 pounds because appetite reduces, and the discomfort that occurs when fat-reducing is attempted before not occurring, transaminase has been reduced to normal range simultaneously.He almost experiences multiple nocturnal tumescence each evening.Subjective, it is quick and to stronger the restraining oneself of heat that he has experienced higher psychology.He and other people have noticed dreamland more clearly.

Use method of the present invention

According to an aspect of the present invention, the degenerative disorders in many modern times all comes from the shortage of NO, and the AAOB on the external skin can provide those materials by diffusion, uses AAOB to solve long-standing medical conditions on skin.In another embodiment of the present invention, AAOB is applied to acceptor to offset by the modern activity of having a bath, especially by anionic cleaning agents, and the AAOB that removes from external skin.

Exist a lot of different AAOB strains.Yet they are all very similar.They all are autotrophys, so they can not cause infection.To be utilized urea and ammonia by the strain expected, the hydrolysis of urea must not have precedence over and absorbed by bacterium and utilize in the sweat like this.Equally, for growth under low pH value, this bacterium must absorption of N H4+ ion or urea.Selecteed strain should be able to survived in the skin outside, and can stand the condition at this place.The method of the such strain of my employed separation is to collect the mixt bacteria culture from granary soil, and it is cultivated the several months in not containing organic medium, uses it for then on my health, isolates this bacterium again from health again after the several months.This strain of selecting can be survived on the person.

This again isolated bacterial in not containing organic medium, grow this activated bacterial topical application then.Using an advantage that does not contain organic medium is not give non-autotrophic bacteria in order to metabolic substrate material except that the substrate material that is produced by autotrophic bacteria.Use another advantage of such growth medium to be, a large amount of nitrite accumulates in this developing medium, this nitrite suppressed non-autotrophic bacteria equally and at lay up period as a kind of sanitas.When this activated bacterial is employed, the XOD in the skin is reduced to nitrogen protoxide with nitrite, causes " spreading unchecked " of NO.Although the NO of this surge is useful, the long-term NO administration that continues is prior.

The ideal mode provides competent bacterium, wears many clothes then to impel perspiration.Yet a lot of people also can obtain the benefit of AAOB when keeping their present customs of having a bath, and at this moment, can use with its competent substrate cultivating this bacterium that comes out, thereby produce NO with them.A kind of inorganic synthetic nutritive medium near human sweat is optimal.Use is suitable for bacterium near the medium of human sweat and has dwindled adaptation time when using again.Because sweat can evaporate, need to use the developing medium of high ionic strength when being secreted in skin surface.It is the developing medium of human sweat twice that the contriver used about concentration, but also can under other conditions.

The bacterial strain that the inventor uses does not directly utilize urea, does not contain nitrite reductase yet.Under long-time bathless condition, one is not directly utilized the bacterial strain of urea better.Many heterotrophic organisms cause that hydrolysis of urea is an ammonia.The hydrolysis of urea that any bacterioid thus causes under the condition that the AAOB of capacity microbial film exists all can be accompanied by and discharge NO and nitrite immediately, and the both can suppress most of heterotrophic organism.The part degenerative disorders that can be treated by method of the present invention is a feature to discharge ammonia.Latter stage nephropathy, liver cirrhosis is a feature to discharge ammonia all.Another advantage of utilizing the bacterial strain of ammonia is that the urea in the solution is very unstable, can discharge ammonia and pH is raise along with the time decomposition.For the consideration of preserving, the utilization of ammonia is more preferably considered.

When have a bath relatively frequent (every several days are once), had a bath remove before thicker AAOB microbial film do not have the enough time to form.Under such environment, biomembranous activity will depend on has supplied with for how many bacteriums.Under the condition of not having a bath for a long time, this microbial film can form adequate thickness, may need to limit the AAOB activity this moment.

AAOB has simple metabolic demand, NH3 or urea, O2, CO2, and mineral substance.They are high relatively to the demand of trace element, comprise iron, copper and zinc.Some bacterial strains also utilize cobalt, molybdenum, and manganese.They also need sodium, potassium, calcium, magnesium, chlorine, phosphoric acid salt and vitriol.These all compounds all are available in the sweat, its ratio with have nothing different in order to the substratum of cultivating this bacterium.

The effect of AAOB in growth of animal

According to a further embodiment of the invention, domestic animal hypertrophy and volume in the modern industrialization area are excessive, and pubescence, human obesity was all owing to the symbiosis AAOB of normal level is suppressed in advance.According to an aspect of the present invention, shown that growth of animal can be owing to removing of AAOB increases.Herein, term " increase " is used to represent body weight, highly, width, growth rate, and/or feed efficient (taking in the body weight of every pound of food increase), increase.Can in domesticated animal, find interesting parallel lines.Many ton microbiotic inject the food of animal to improve growth rate and feed efficient.Up till now, still not to the suitable explanation of the mechanism of microbiotic stimulating growth.Saying according to McEwen, " mechanism of stimulating growth is not still definitely known " (Scott A.McEwen andPaula J.Fedorka-Cray. (McEwen and Paula J.Fedorka-Cray.Antimicrobial Use and Resistance in Animals, Clinical InfectiousDiseases 2002; 34 (Suppl 3): S93-106.).Someone proposes, and they treat a kind of " subclinical infection ", perhaps by suppressing the bacterium that those have consumed " nutritive substance ", or reduces the nutritive substance that " immunity system " consumes.These mechanism seem it all is incredible." subclinical infection " can solve by treatment, and need not take in microbiotic constantly.It is very amazing that all animal of locality all suffer from the situation of identical " subclinical infection " and each all same amount weightening finish.Similarly, is the immunity system of each animal all caused it to increase weight by suitable speed by excessive stimulation in certain group? the saying that places bacterium to consume nutrient, usually, animal is the food that consumes their aequums ownly.If the per-cent that bacterium consumes increases, this animal can be replenished by more absorptions, yet they do not have.Equally, antibiotic treatment is not eliminated the bacterium of the Digestive tract of those animals fully yet.On the contrary, the number of bacterium is still very many.Equally, much bacterium develops these antibiotic resistances and maintenance high level.

The character of antibiotic increase growth may be to regulate by the autotrophy ammonia oxidizing bacteria (AAOB) that suppresses to be grown on these animal external skin in the food.In the open air, the animal of all perspirations (comprising all Mammalss) all can have the external skin of a large amount of ammonia oxidizing bacterias at them, and the urea in these bacterial metabolism sweat also produces NO and nitrite.Domestic animal is no exception.Use a large amount of microbiotic and make the microbiotic in the animal sweat increase, suppressed any AAOB of external skin.Inhibition to these bacteriums has reduced basic NO level, improves basis metabolism, improves growth rate, improves adult's volume, shortens the time in ripening stage, and improves body weight and body fat.These variations all are found when the human society industrialization.The mankind become greatly, sophisticated morning, become fat.

Understand according to this, the microbiotic in the food is not that the AAOB that suppresses on the external skin is necessary.If recognizing AAOB is the target organism, many aspects of strengthening of the growth of animal that is brought by microbiotic can have been understood so.AAOB has very little genome.Nitrosomonas europaea has only 2,460 protein coding genes.It does not have the gene of metabolic xenobiotic compound.As an autotrophic bacteria, its metabolism is very slow, grows 30 times than the dicycle of heterotrophic organism.Its may be evolved into slowly 30 times by expection, since but it has a very limited genome, and it does not have variation and and then gene with new function that antibiotic resistance for example is provided.The autotrophic bacteria expection antibiotic resistance many (if saying on the whole) slower than heterotrophic bacterium of evolving out.It is gram-negative bacteria that Halling-Srensen has reported AAOB, to the very responsive (Halling-Srensen of a lot of microbiotic, Inhibition ofAgents Growth and Nitrigication of Bacteria in Sewage Sludge byAntibacterial Agents, Arch.Environ.Contam.Toxicol.40,451-460 (2001)).The many microbiotic that are used for animal foodstuff are not absorbed, but are discharged and accumulated in copropel by ight soil.Copropel has comprised competent ammonia and urea, and is comprising abundant AAOB under the condition that does not suppress the compound existence.Under the condition that microbiotic exists in copropel, AAOB can not grow, so can not move into the external skin of domestic animal.Use the domestic animal conduct with microbiotic and the mixed instrument of copropel, and, be a unsatisfactory method its life zone that is used in them.According to the present invention, suppress the compound of AAOB in the animal survival space and can directly be used.

AAOB is very responsive to the compound that suppresses ammonia list (adding) oxygenase.The allyl sulfide compound that comes to this, it is very effective to suppressing ammonia list (adding) oxygenase, and this compound is usually used in testing the biological oxygen demand in the waste water, or BOD.Adding allyl sulfide is in order to suppress AAOB, to consume otherwise AAOB can and improve measured O2 with O2 oxidation ammonia.Nitrification suppresses son and is used for fertilizer utilization equally.Many plants can absorbed nitrogen no matter be ammonia or nitrite.Yet, be amino acid in order to make nitrogen transformation, it is necessary for the form of ammonia.Therefore nitrite must be reduced to ammonia.The energy of this reduction process consumption otherwise can be used to plant is grown up.In some cases, when nitrogenous fertilizer applied with the form of ammonia or urea, the nitrobacteria that suppresses in the soil was supposed to.Usually a lot of compounds all be used as fertilizer, any this compounds, and when the external skin of topical application at farm-animals, it uses all can be also effective to the nitrification of urea in the inhibition sweat.

Yet, use the security of this compounds also not know to animal.A better way is to use a kind of anionic cleaning agents.It is very responsive to anionic cleaning agents that people such as Brandt have reported AAOB, especially to linear alkylbenzene sulfonate (LAS) 4-(2-dodecyl) Phenylsulfonic acid for example, this compound exhibits goes out Nitrosomonas europaea, N.mobilis, N.multiformis, nitrosification spirillum strain AV divides other 50% inhibition concentration (IC50) to be respectively 5,3,1 and 1mg/L (ppm) (Brandt et al., Toxic Effectsof Linear Alkylbenzene Sulfonate on Metabolic Activity, GrowthRate, and Microcolony Formation of 4 Nitrosomonas andNitrosospira Strains, Applied And Environmental Microbiology, JUNE 2001, Vol.67, No.6, p.2489-2498).Their find when being exposed to low dosage, and the AAOB of test does not develop and resistibility or resistance.The micelle-forming concentration of LAS is 410ppm, and this concentration is far below the IC50 indicator value of chemical action, and let alone the effect of media has been cleaned in conduct.Although can not be confined to some concrete theories, but why sanitising agent has so to AAOB a big toxic possible reason is, as a kind of negatively charged ion, they enter cell by taking in vitriol, phosphoric acid salt and the necessary negatively charged ion transport materials of hydrocarbonate.In case after entering, AAOB does not just possess the metabolic mechanism of removing them,, still it is excreted out no matter be to be non-toxic compound with their metabolism.Heterotrophic organism is easy to adapt to high-caliber LAS and much can utilizes LAS as a carbon source in them.LAS is a common detergents when cleaning many articles for use, comprises dishwashing and clothing, and shampoo is had a few " coarse " usually and made skin feel " shouting pain " because of its but it goes without doing usually.Yet LAS is a kind of material of extensive application, and the ultimate production in the world in 1987 is 1.8 hundred ten thousand tons.By a large amount of being released in the environment, so the AAOB that uses it to disinthibite on the external skin of farm livestock can not expect that it can produce any influence to environment.Under any circumstance, the growth of using LAS to strengthen farm animals will substitute the microbiotic that has been used, and the microbiotic of these uses is owing to the microbiotic resistibility that causes malignant bacteria has been brought very serious problem.Security and the pungency of lot of data about LAS arranged, but a lot of research all not being noticed its concentration far below CMC, may be because these effects are smaller.In fact, detergent solution can be sprayed onto on the animal, does not wash afterwards, perhaps, forces these animals to use the washing bath that contains these materials.The surfactivity sanitising agent approximately is constant on CMC, and concentration approximately is linear under CMC.The side effect of sanitising agent comes from protein denaturation and makes the skin degreasing on the skin.Because sanitising agent is not that to suppress AAOB required, protein denaturation and the level of skin degreasing is not also needed.Guarantee that the long-time method that suppresses dosage is to form an original position low solubility " soap " on the skin.The spray solution of LAS is on animal, and then a kind of divalent salt solutions of for example calcium chloride is gone up in sprinkling.On skin, can occur mixing, will be at the LAS of this place as insoluble relatively calcium LAS soap precipitation.These soap that precipitate will stick on the hair of animal, and with this storage as LAS, in this animal bathing or Sometimes When It Rains can dissolve.The amount of the LAS that precipitates can be adjusted, can obtain the inhibition level of a LAS between per twice processing.The solubility product Ksp of LAS (carbon atom number 12, average MW=343) is 8.4e-12.Calcium contents in the human sweat is 3mM/L.Suppose an approximate assessment, for the ox sweat, under the restriction of the solubleness of Ca (LAS) 2, the concentration of LAS is 18ppm.As long as there are any residual Ca (LAS) 2 soap to be present in ox-hide skin surface, this concentration is enough high concerning suppressing AAOB.When sanitising agent sprayed initial, this initial concentration should be higher.The LAS of other molecular weight has different Ksp ' s.For example, molecular weight is that the Ksp of 339 LAS (carbon atom number 11.4) is 1.8e-11.This means that this concentration is 26ppm.

Other supressors also can be used, but few materials is cheap and optimum and be easy to get as LAS.

Nitrogen protoxide metabolism:

Nitrogen protoxide be by different oxygen bacterium to the nitrate reduction in diet and the saliva, in internal organ, produce.This reduces in two steps, and the first step is reduced to nitrite by nitrate reductase, is reduced to nitrogen protoxide by nitrite reductase then.Milk has comprised abundant xanthine oxidoreductase enzyme, this enzyme can catalysis revert to NO from nitrate and nitrite, this is by people (Ben L.J.Godber, et al., Reduction of Nitrite to Nitric Oxide Catalyzed by XanthineOxidoreductase such as Ben L.J.Godber, The Journal Of Biological Chemistry, Vol.275, No.11, Issue of March 17, pp.7757-7763,2000).The too much NO of route generation can cause " blue baby " syndrome thus, and this disease is oxidized to methemoglobin by the blood oxyphorase and causes.Methemoglobin is not poisonous, but it can not carry O2, if too much can cause anaemia.People such as T.Ljung disclose the children that suffer from inflammatory bowel has NO to produce in internal organ, wherein rectum NO is approximately than high 100 times (the Tryggve.Ljung et al. of healthy children, Increased rectal nitricoxide in children with active inflammatory bowel disease, JPediatric Gastroenterology and Nutrition, 34:302-306,2002).And excretory NO is unlike the healthy children height, hinted except that bacterium to produce another source of NO (still, because their measuring method is aerobic, so expection may not have detected from the aerobic NO generation of bacterium nitrite reductase.) NO that finds during inflammatory bowel increases may be a adaptation reaction to low basic NO level.

People such as E.Weitzberg have reported to croon and have improved (the Eddie.Weitzberg et al. of the generation of NO in the nasal meatus, Humming greatly increases nasal nitric oxide, Am JResp Crit Medicine Vol166.144-145 (2002)).The O2 that diffuses to activating enzymes has limited the generation of NO.Crooning has increased gaseous interchange, so increased generation and the airborne NO of nasal cavity of NO.Airborne NO is inhaled into, but most of meeting be oxidized to nitrate in lung.Yet still very high in the concentration that produces place NO, wherein some can be spread to supply with and give in the blood of nasal meatus, and these blood row is as in the various holes in the brain.Croon, be found to be some autism patients' classical symptom, can improve the NO level.

Openly chronic inhibition has improved NO total amount (the Ragnar.Henningsson etal. that pancreas islet produces to people such as R.Henningsson unexpectedly to NOS with L-NAME in the mouse body, Chronic blockade of NO synthase paradoxically increase isletNO production and modulates islet hormone release, Am J PhysiolEndocrinol Metab 279:E95-E107,2000).Yet, regulate very complicated to the NO synthetic.In all eubolism products, NO be can suppress respiratory that.Sufficiently high NO level will make respiration stop and causing primary cellular defect.NO is a part that causes the mechanism of outside necrocytosis, so immunocyte possesses the ability that produces the horizontal NO of cytotoxin.The NO of cytotoxin level can not be regulated in the NO source, because should the death of place's cell.Therefore, this adjusting can make a distinction from the NO generation on time or space.NOS with inducibility can distinguish the adjusting that high NO produces from the time.Distinguishing from the space need different (also ignorant at present) trustworthy historical record molecule.

NO result to many receptor activations stress.For example, K.Chanbliss discloses release (the Ken.L.Chanbliss et alEstrogen modulation of endothelial nitric oxide synthase.Endocrinereviews 23 (5): 665-686.) that estrogen receptor can cause NO.P.Forte has proved that the NO metabolism of finding the women is higher, reduced and suffered from and low nitrogen protoxide diseases associated, comprise hypertension and cardiovascular disorder (Pablo Forte et al., Evidence for a difference in nitricoxide biosynthesis between healthy women and men.Hypertension, 1998; 32:730-734).The different risk of trouble autism of masculinity and femininity may be because of the basic NO level that improves in women's body, and this raising is because the NO release of the estrogen regulating that improves.

Nitrogen protoxide and pressure

NO can be by suppressing Terminal oxidase with the O2 competition.This inhibition has the important physical effect, is undertaken by passive diffusion fully owing to transmit O2 to human mitochondrion.If the not adjusting that O2 is consumed, the plastosome nearest apart from the O2 source will consume maximum O2, and the far plastosome of distance will obtain seldom or not have.Suppress with the competition of NO, metabolic load can be distributed to numerous plastosomes.This is very important in the tissue that oxygen-consumption alters a great deal, for example muscle.The oxygen-consumption of cardiac muscle almost changes on an order of magnitude.Because O2 is by passive diffusion transport, and the arrangement in source and acceptance are constantly (to exist the angiogenesis of some increases, but be not on a very big order of magnitude, to change), it is few that the source of O2 (dividing potential drop of O2 in the blood vessel) also changes, when the O2 transmission quantity changes on an order of magnitude, the O2 diffusion power that has improved to provide will be provided the O2 gradient.The concentration of O2 will reduce by an order of magnitude so that more O2 diffuses to this place in the plastosome under high O2 consumption condition.For the transmission quantity that makes O2 improves an order of magnitude, the acceptor concentration of O2 can reduce an order of magnitude under the situation of constant source and arrangement.Concentration reduces an order of magnitude if the O2 consumption improves an order of magnitude, and the activity of enzyme will improve two orders of magnitude so.For improving metabolic ability, the NO level will be lowered.This is the feature that super-oxide produces between anaerobic phase.Super-oxide has destroyed NO, and has removed the inhibition that plastosome is consumed O2, allows plastosome to consume O2 under low O2 concentration conditions.This very low O2 concentration can allow O2 to its place's of being consumed diffusion.Super-oxide is not hoped to produce, because it can destroy protein.Yet the ATP deficiency is worse situation because this moment cell will not have ability stress and with necrosis.

Nitrogen protoxide is regulated and feedback

NO produces in different sites, is diffused into other a plurality of sites then, plays a role by different mechanism at these local NO.Although NO is the gas of a rapid diffusion, and have " weak point " the evolving path, each site can be comprehensively its whole NO signal of being subjected to.The reduction of basis nitric oxide level can reduce the NO ambient level.The useful range of the NO that provides as the second messenger can be provided the NO ambient level that reduces.Ambient level under, temporary transient NO downstream targets can be diluted, so will have the activation concentration that more among a small circle its arrives.This sphere of action that diminishes is important to nerve connections unusually.The aixs cylinder of migration may apart from can obtain they need rely on it and the NO signal that leads enough not closely.These not the aixs cylinder of " enough near " make the density of local contact very high, perhaps this can explain that the enhanced sense of hearing distinguishes sound.

When a NO source is a feedback round-robin part, this source will be conditioned to produce high NO level, and this is with compensate for slower low environment level.The concentration in NO source is spreading the back for can reach adjusted level to the NO sensing substance, may be very high, and may be than taller under high background level.Those cells nearer apart from the NO source than NO sensing substance will be so will be exposed to the NO level that is higher than " normally ".Than NO sensing substance those cells far away, will be exposed under the lower NO level apart from the NO source.

In fact all important metabolic system all are to be subjected to certain type feedback control.Nitrogen protoxide participates in the control of many feedback elements, comprises NO release and the regulation and control of vasodilation subsequently peripheral blood vessel resistance by depending on shearing force.A difficult point of nitrogen protoxide feedback control is exactly its easy diffusion, and the transformation period is short.The NO source must produce the higher NO concentration of its acceptor of specific consumption.High-caliber nitrogen protoxide is virose, and any nitrogen protoxide source all can be subjected to the time, or feedback, or the spatial regulation and control.If basic NO concentration will cause the rise in other source by feedback regulation to the inhibition in some source.Observed autism children has the metabolic high level of NO, also can explain like this, owing to there are not enough NO to be used for correct place, just need fecund to give birth to a little NO and compensates.

For example, to be considered to be because the excess nitric oxide that iNOS produces causes to the hypostension of septic shock to a great extent.INOS is the form of inducing of NOS, and is the example of the control of a kind of " feedforward " type, and is the control of " feedback " type unlike eNOS.Produce very high-caliber nitrogen protoxide at cell, preferably the control by " feedforward " type obtains.In case cell begins to produce high-caliber nitrogen protoxide, the nitrogen protoxide that is produced is just slept and suppress mitochondrial Terminal oxidase in those cell, and this can disturb normal cellular metabolism.

The basic NO production that people such as G.Stefano disclose human granulocyte is periodic, this cycle is several minutes, scope is at 100pM (George.B.Stefano, et al., Cyclic nitric oxide release by human granulocytes andinvertebreate ganglia and immunocyes:nano-technologicalenhancement of amperometric nitric oxide determination, Med SciMonit, 2002; 8 (6): BR199-204).These measurements are to contain 10 ³The 10 μ m places, a drop top of individual cell finish.The mean value of this periodic signal yes many cells.Observe cyclical signal and represent that cell is to produce NO with time dependent speed, the generation of this NO is in-phase.So many cells all keep phase coherence to illustrate and have communication and feedback between these cells.Have some other the numerator mediated cell-cell communication of ventricle, but the life-span of any such molecule all must be than the shorter coherency that just can keep phase place of NO.Explanation to this in box exists exactly to the direct perception of nitric oxide production concentration, and the feedback regulation NO production, though hysteresis is arranged in time.

Basis NO level can not be measured in the site that produces NO and be regulated, and must be higher than basal level because produce the site of NO.NO must measure a long way off, and this signal is transferred to the cell that produces basic NO by a non--NO transport materials.

One " motion " supposed to propose, because nitrogen protoxide is because to stress the producing of body movement, the mankind may be evolved into the NO that the body movement that relies on appropriateness produces, and these appropriate activities are that to adopt shooter's mode of life needed.Therefore " normally " body movement level can produce enough nitrogen protoxides, does not exist evolution pressure to force human body other nitrogen protoxides sources of evolving.Yet the baby is not the hunter with begining to learn the child who walks when prehistoric.Their food is caught and is collected by their caretaker, and these caretakers at that time are more positive than modern caretaker's health.The body movement of child before creeping and walking can be not many than prehistoric age.Yet the nitrogen protoxide source of the unknown that prehistoric age, the mankind were relied on is a symbiosis autotrophy ammonia oxidizing bacteria, and these nitrogen protoxide sources have been removed in frequent shower in the modern way of life.

The autotrophy ammonia oxidizing bacteria is as a NO source

The urea of symbiosis autotrophy ammonia oxidizing bacteria on the especially scalp on the skin from sweat produces physiology NO, and to liken to be more proper explanations of cooling mechanism for perspiration provides one.During adrenergic system is upset, cause the perspiration that suprarenin causes.The perspiration that suprarenin causes is also often to appear at night during feeling the stress.Perhaps, the scalp at night is perspired and can be offered the NO of brain than higher dosage, so and " restarting " NO signal pathway and allow brain to carry out " household management " function that all need high-level NO

It is because they can not cause disease that these bacteriums are not also determined to connect with human body.In fact, they almost can not cause disease (even the people that immunizing power is reduced also is like this).Genomic detection is found that these bacteriums can not cause disease.Be not used in the enzyme of toxin or lysis.They do not have and utilize complex compound, for example find metabolic mechanism in animal tissues.

As autotrophic bacteria, they can not lack their desired material, ammonia or urea, O2, mineral salt, existence Anywhere.Because sweat is residual very abundant, under " field " and the condition of having a bath without soap commonly used, the mankind can not stop these bacteriums on their external skin to these materials on the skin that did not clean.These bacteriums can be benefited and symbiosis, and therefore human physiological a lot of aspects have been evolved into the growth that can utilize these bacteriums and have utilized a large amount of NO that produced by them.

May stop their isolated Another reason may be the shower custom of developed regions.Having a bath has continually become custom with the development that stops body odor.Smell will not appear in the back health of not having a bath at several days usually, and these compounds odorous are that the heterotrophic organism metabolism skin exfoliation thing by the skin outside is produced.In the frequent crowd that has a bath, in 3 days, autotrophic bacteria is can 7 times double, approximately increases by 100 times.Relative is, heterotrophic organism can 200 times double about increases 10e+60 times.The growth of heterotrophic organism is subjected to the restriction of nutritive substance.Suppose that the power that removes by having a bath to autotrophy and heterotrophic organism is akin, autotrophic bacteria will be able to be arrived a very low level by the control heterotrophic organism of having a bath, perhaps to the level that can not detect.

The inventor finds that the AAOB of use sufficient amount on skin has suppressed the body odour that is produced by autotrophic bacteria in fact.The inventor is applied to AAOB on his skin, and does not have a bath more than 2 years so far, comprising 3 summers.The body odour that causes because of perspiration does not really appear.In fact, perspiration has alleviated body odour by nourishing its generation NO of AAOB and reinforcement and nitrite.During winter, because the minimizing that outside temperature is brought is perspired, body odour increases.Yet along with adding clothing, (wearing sweater) contriver can improve the basis perspiration and again body odour be reduced near zero.Can not cause itching, fash, skin infections, the ringworm of the foot infects, and does not have pin smelly.

People such as L Poughon have reported AAOB and have produced media (the Laurent Poughon of nitrogen protoxide as their eubolism, et al., Energy Model andMetabolic Flux Analysis for Autotrophic Nitrifiers.BiotechnolBioeng 72:416-433,2001).People such as D.Zart report has proved that bacterial strain NO concentration in air is that 100ppm is its growth (in this research higher concentration also tested) of optimum (Dirk.Zart.et al., Significance of gaseous NO for ammoniaoxidation by Nitrosomonas eutropha, Antonie van Leeuwenhoek77:49-55,2000).AAOB can stand higher level.I.Schmidt discloses other bacterial strains, (adds CO at Ar at NO from 0 to 600ppm ₂Under the oxygen free condition) the not minimizing of NH3 consumption, but under NO 1000ppm condition, reduced by 1/3 (IngoSchmidt et al., Anaerobic Ammonia Oxidation in the Presence ofNitrogen Oxides (NOx) by Two Difference Lithotrophs, AppliedAnd Environmental Microbiology, Nov.2002, p.5351-5357).Most of AAOB is an anaerobic, but some strains wherein can utilize O2 and nitrate or nitrite, and increases generation NO thus.1000ppm NO is corresponding to 2 μ M/L in the solution in the air.The NO concentration that the bacterial strain that the inventor uses produces is through being measured as 2.2 μ M/L.Much to the research of AAOB at they effects that ammonia and nitrate can be removed in wastewater treatment.The NO of hundreds and thousands of ppm that the wastewater treatment operations aggravation produces is not supposed to, so can not look to the physiological action of these bacteriums under those conditions fully to be studied.

The inventor notices that a lot of features relevant with A Si Burger syndromes all change to some extent since having used these bacteriums.Do " multi-job " and become more difficult.The easier quilt of attention disperses, easy work unlike at ordinary times when attention is dispersed.Yet, accept fresh information and become easily, and those information are easier and informix before gets up.

Subjective, contriver's sleep pattern is subjective to be changed, the increased frequency that he regains consciousness now night.It is sharper that contriver's sense of smell and sense of touch subjectively become, and compressing causes that arthralgic starting point obviously reduces.Although it is these variations are subjective, consistent with the NO level that has raise.Contriver and other people notice that dreamland is clearer after having used these bacteriums to scalp, and the NO that this proof raises is to the effect of normal nerve process.

Experimental example: preliminary study (n is 1):

The AAOB enrichment medium uses NH from from the barnyard soil processing in the inorganic components in anthropomorphic dummy's sweat ₄CL.In series of steps with after developing into high mM nitrate levels (weakening heterotrophic organism with this), this AAOB substratum is applied to an experimenter (about 49 years old male sex now).Lasting cultivation has been adhered to 33 months so far, has accumulated having formed an active A AOB microbial film, only obtains nutrition from natural secretory product in this process.After 5 months, this substratum is applied to this experimenter's whole body.To simulate one in " field " condition, the activity of having a bath is stopped like this.It is shocking, do not develop and body odour, even under the situation of not having a bath in 27 months, even very hot and take exercise after inductive perspires.Although caused the rising of savouring a little because the low perspiration that causes of outside temperature reduces in first winter.Yet, wear sweater and improved basic perspiration and reduced body odour rapidly.

Probably be those NO that produce by AAOB, nitrite, NO ₂(being smelt sometimes) perhaps also has the NO adducts, suppressed those body odours that brought by heterotrophic organism.

The NO that is produced by microbial film is carried out measurement.Scalp closely is covered with the cover of a suitable PTFE film, be bonded in this place and close (hard shade type wind sleeve) by the polyester bond of outside, extraneous air sees through scalp, by a gas meter (OmegaFMA1816), use a NO analyzer (Sievers NOA 280i) sample testing then.Air-flow and NO～1/sec writes down once.NO in NO air-flow and the residual gas is plotted among Fig. 4.Under high gas flow speed, NO concentration reduces, but flow raises.The NO flow is produced by the AAOB film, and diffuse in the air under this cover at this place it respectively simultaneously can be measured and enter that this part can not be measured in the scalp.Yet the NO source can not promptly be changed as outer gas stream, so can infer inner flow by the external diffusional resistance that changes." NO source " is " halting person ", and it is the NO flow of outside concentration when being zero." zero flow " point is measured, and it is the concentration that reached under the outside diffusion situation about being prevented from (restarting the peak value of measuring N O behind the air-flow).

The NO flow brings the accumulation of enough AAOB microbial film to scalp, after the exercise in one period near 1nM/min.After exercise, this fluctuations in discharge very rapid is so there are some spaced points when attempting that it is fitted to straight line.It is very big to measure the NO flow of inferring from these, and～0.3.With same instrument, a proximate experimenter (48 years old male sex) does not have these bacteriums (contrast) to have a very low NO flow (0.03) of measuring.After taking exercise fast, find that NO has a rising, yet this basic NO level of having accepted the people that these bacteriums transplant is significantly higher than and does not accept the NO level that people that this bacterium transplants is excited by violent exercise.

In another campaign, 10 μ MNH ₄CL adds in 5 ml waters, is applied on the scalp.Fig. 5 is the lasting curve of NO concentration in the residual gas.10 μ MNH in this 5 ml water ₄CL is by the pipe under the PTFE cover.Result's NO flow is illustrated among Fig. 6.This NO flow raises rapidly (from 0.3 to 0.8nM/min～1minute), proves that NO comes from NH3 rather than nitrite or nitrate or Mammals nitric oxide synthetase.This rising rapidly, the release that has proved NO approximately is the twice of the NH3 that discharges in the sweat.The specific bacterial strain that is applied to the AAOB of this experiment not directly utilizes urea to have only NH3, and it does not have nitrite reductase.

This PTFE cover is employed, and the measuring N O that continues betwixt is during except sleep.A plethysmograph is by pressure (amount) and temperature (blood flow), in order to the monitoring enlargement.NO measures and the pressure and temperature of plethysmograph writes down once Fig. 7 and 8 per 10 seconds.In the measurement in four successive evenings, there are 11 nocturnal tumescences and 6 NO flows to raise, directly be better than or consistent with the increase of swelling.Show the contact that forces between twice main NO release and the swelling first night of this figure, shown 4 swelling the 4th night.Ignorant be the rising of this NO have because of or only with perspire relevant, this perspiration prior to or be accompanied by swelling.The nocturnal tumescence that increases is noticed it is after using AAOB for the first time by subjectivity, and this continues not have to eliminate approximately to have surpassed 2 years so far always.NO is known very important in physiology erects.As the method for a treatment impotence among the people, be that saliva is coated onto on the penis.The nitrite that contains in the saliva comes from heterotrophic organism on the tongue with the nitrate reduction in the saliva.Skin has comprised the xanthine oxidoreductase enzyme, and it can be reduced to NO with nitrite.Local use NO donor can be treated erection can not.

By the NO that AAOB produces, almost be the twice of the ammonia supplied with, the inhibition of the heterotrophic organism on the skin also has been proved to be.If the evolution time that experience is so long, a such NO substance source also is not included into ordinary person's physiological system, and this will be a startled thing.NO discharges and is found consistent with those known physiological actions of regulating by NO.This may be that a physiology of the perspiration that causes of suprarenin is explained, that is, and and for the microbial film of giving resident AAOB is supplied with nitrite and the NO that discharges rapidly.A large amount of perspirations in numerous disease may be the normal physiological responses to the nitrogen protoxide scarcity.

As the NO supplier, AAOB has resistibility to the immune attack that suppresses inflammation by inhibition NF κ B to a certain extent.Experienced evolution period as a non-pathogenic micro-organism of symbiosis on the skin, immunity system may be evolved and be allowed their existence.Some AAOB are transportable, they are moved into and be implanted in the pore these bacteriums and the mankind all are beneficial to.This will shorten the diffusion length that NO absorbs, and also will reduce the possible transplanting of heterotrophic organism and fungi.Although AAOB is aerobic, they can stand low O2 level, and can breathe energetically under～12Torr O2, this is by people such as Ruiz report (Nitrification with high nitrite accumulation for thetreatment of wastewater with high ammonia concentration.WaterRes.2003 Mar; 37 (6): 1371-7).The minimum O2 level that～12 Torr compare the skin of being measured is also low.Be transplanted to and protect AAOB not to be subjected to illumination in these pores, wash away with casual and have a bath, yet it is that they are insupportable that frequent use negatively charged ion clean-out system and antiseptic-germicide are had a bath.

Hard water and soft water

Live in the area of water hardness big (water that contains calcium ions and magnesium ions), suffer from as apoplexy, the risk of a lot of diseases such as cardiovascular disorder and diabetes is less.Magnesium in the drinking-water and the risk of dying from diabetes even cancer, calcium in the drinking-water and magnesium are found in pertinent literature with the risk of dying from mammary cancer, and (J Toxicol Environ Health is Jun A.2000; 60 (4): 231-41).The health benefit of hard water is generally by the active effect that increases owing to calcium and magnesium intake, or reduced Cd or other heavy metals and reduced toxic action is arranged.Yet, calcium and the magnesium taken in from other diet approach just do not have this effect (Nerbrand C, Agreus L, Lenner RA, Nyberg P, Svardsudd K., The influence ofcalcium and magnesium in drinking water and diet oncardiovascular risk factors in individuals and living in hard and softwater areas with differences in cardiovascular mortality, BMCPublic Health.2003 Jun 18).Drinking not is unique purposes of domestic use of water.In general, domestic use of water is used to drink and have a bath simultaneously.Hard water is difficult to have a bath because divalent ion has formed insoluble soap precipitation, makes soap lose effect as tensio-active agent.Because hard water has precipitated a lot of anion active agents, therefore hard water has reduced toxicity (the Coral Verge of tensio-active agent to a lot of materials, Alfonso Moreno, JoseBravo, Jose L.Berna, Influence of water hardness on thebioavailability and toxicity oflinear alkylbenzene sulfonate (LAS), Chemosphere 44 (2001) 1749-1757).On human skin, it is biomembranous mobile that hard water can fetter AAOB, reduced soap and the clean-out system toxicity to AAOB, can reduce the impulsion of having a bath, especially the impulsion of people's hair washing.

A negative contact between water hardness and the atrophic deaths from heart disease rate is found in Holland, has significant reduction coefficient, from 1958-1962,1965-1970, and 1971-1977 (Zielhuis RL, Haring BJ.Water Hardness and mortalityin the Netherlands, Sci Total Environ.1981 Apr; 18:35-45).What is interesting is that this also almost is the contemporaneously that the use of synthetic detergent increases, the fast development of shampoo technology at that time.As if as if the symbiosis of AAOB is adapted to the bacterial strain of skin can stand saponified fat acid, do not having enrichment on the skin that cleans.Soap can quicken them and surperficial dust moves together, but do not apply concrete toxic action.By contrast, alkyl benzene sulphonate (ABS) all is deleterious to AAOB under the ppm level.

The main place that possible NO produces is at hair, and hair on the scalp and pubes can be to anti-infective at this NO of place and nitrite.Hair can provide a suitable protection ground to AAOB, can reduce by parts of skin loses heat thin and a lot of vascular systems that distribute, like this to quicken the absorption of NO.I guess that AAOB is under positive physiology control.Variation on some health has appearred in this preliminary study.Yet, only under n is 1 situation, not contrast, the NO that being difficult to describe is definitely only increased by local AAOB cause these change, and much these variations are subjective.

The subjective changes in health of finding in preliminary study comprises: appetite reduces and loses weight, the motor impulse that improves, Sensitive disease reduces (hay fever), the serum alanine transaminase level reduces, blood pressure reduces, the faster healing of skin wound, the regeneration rate of alopecia rate/hair loss reduces, and acuity increases and is in a cheerful frame of mind.

Claims (14)

1. a treatment suffers from hypertension, loose sexual organ sex change, Raynaud's phenomenon, the sex change of fibering organ, nasal allergy disease, autoimmunity allergy, latter stage nephropathy, obesity, type i diabetes, osteoporosis, impotence, alopecia, alopecia, cancer, aging, autism, self-closing class symptom, by aging cause blunt, at least a disease or the patient's of ill danger method is arranged, comprising:

Determine to suffer from hypertension, loose sexual organ sex change, Raynaud's phenomenon, the sex change of fibering organ, nasal allergy disease, autoimmunity allergy, latter stage nephropathy, obesity, type i diabetes, osteoporosis, impotence, alopecia, alopecia, cancer, aging, autism, self-closing class symptom, by aging cause blunt, at least a disease or the patient of ill danger is arranged; With

Ammonia oxidizing bacteria is applied near the patient.

2. method as claimed in claim 1, the behavior of wherein placing bacterium comprise placing to be selected from down organizes any bacterium: nitrated Zymomonas mobilis, nitrosification coccus, nitrosification spirillum, nitrosocystis, nitrosification leaf bacterium, nitrosification vibrios, and combination.

3. method as claimed in claim 2, the behavior of wherein placing ammonia oxidizing bacteria comprises:

The ammonia oxidizing bacteria of significant quantity is applied to patient's dignity, makes bacterium, ammonium salt, or any nitrogen protoxide that is metabolized in the urea, any in nitric oxide precursors or its combination lip-deep ammonia.

4. method as claimed in claim 3, the behavior of wherein using bacterium comprise uses the bacterium that is included in the suitable carrier.

5. method as claimed in claim 3, the behavior that wherein bacterium is applied to the surface comprises bacterium is applied to skin, hair, or in its combination.

6. method as claimed in claim 3, the behavior of wherein using bacterium comprise uses pure basically bacterium.

7. method as claimed in claim 3, the behavior of wherein using bacterium comprises:

Bacterium is applied on the article; With

These article are contacted with the patient surface.

8. method as claimed in claim 3, the behavior of wherein using bacterium comprise uses the bacterium mixed with a kind of acid.

9. a method that increases growth of animal comprises:

AAOB is removed from the animal surface.

Ammonia oxidizing bacteria preparation to the patient provide purposes in the nitric oxide production preparation, described preparation be fit to be applied to described patient near, as fully describing in the specification sheets, described patient suffers from hypertension, loose sexual organ sex change, Raynaud's phenomenon, the sex change of fibering organ, nasal allergy disease, autoimmunity allergy, latter stage nephropathy, obesity, type i diabetes, osteoporosis, impotence, alopecia, alopecia, cancer, aging, autism, self-closing class symptom, the health that is caused by aging reduces, at least a disease or ill danger is arranged.

11. as the thorough fare of claim 10, bacterium wherein is selected from down any bacterium of group: nitrated Zymomonas mobilis, nitrosification coccus, nitrosification spirillum, nitrosocystis, nitrosification leaf bacterium, nitrosification vibrios, and combination.

12. as the purposes of claim 11, preparation wherein is fit to

With significant quantity be applied to patient surface so that described bacterium with lip-deep ammonia, ammonium salt, or any nitrogen protoxide that is metabolized in the urea, any in nitric oxide precursors or its combination.

13. as the purposes of claim 12, described preparation is fit to be applied to skin, hair, or in its combination.

14. as the purposes of claim 12, described preparation is suitable for being applied on the article and these article are fit to contact with described patient's surface.

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