Chapter 3 -“Treating diseases” and “treating fate”

“Treating diseases” and “treating fate”

Paida and Lajin are effective in relieving or curing joint pains, acute or chronic, especially in the lower back, hips, legs, knees and shoulders. With persistent practice, one can make significant improvements in such chronic diseases as hypertension, heart diseases, diabetes, kidney disorders, liver problems and insomnia; normally significant improvements are gained in seven days’ intensive practice (as have been repeatedly proven in our workshops worldwide), and one’s condition can be expected to return to normal in a month.

Some may wonder if Paida and Lajin can cure all diseases, including cancer. The answer is: they can cure an extremely wide variety of diseases; however, this does not mean that it can thoroughly cure just anyone. No treatment in this world carries that promise. A person’s life (and its quality) is in his/her own hands, and the key lies in his/her thinking. That is why doctors often say, “we treat diseases, but not fate”. For people who disbelieve or sneer at the self-healing methods that we promote, and for those who practice them only when terminally ill, it is just “fate”.

Nonetheless, people’s lives can be transformed by changing their thinking and perceptions. Those who can conscientiously practice Paida and Lajin first have their perceptions changed. Confidence, determination, patience, doubt, fear and contradiction are manifestations of the state and changes of the heart or the mind. Efficacy differs from one to another, as people’s hearts or states of mind are different. Fluctuations in one’s condition and factors like Paida and Lajin intensity and duration are all related to the heart or the mind. Therefore, when diseases are being treated, it is primarily the heart or the mind that is receiving the treatment. Taking charge of your health by self healing your diseases, is taking your fate into your own hands. And this is why we advocate “My Health, I Manage!” 

Websites: 
www.paidalajin.com; 
www.paidalajin.com/en/home; 
http://www.paidalajin.net 

E-mail: 
paidalajin@gmail.com; 
hongchixiao@gmail.com

Note: Paida and Lajin are self-healing methods, they are not methods of medical treatment. 

My Health, I Manage!
E-Tao Paida & Lajin Self-Healing 

Chapter 3 -“Anti-virus software” and the meridian system

“Anti-virus software” and the meridian system (“杀毒软件”与经络系统)

“Can Lajin cure tinnitus?” “Can it cure headaches?” “Diabetes?” “What about hypertension?” All these questions have one thing in common — they are asked in terms of “disease names”. Yet what I want to emphasize is that people should first ignore the “disease names”. When you are trying only to suppress symptoms, problems will arise. For instance, “hypertensive” patients try all they can merely to reduce blood pressure to standard levels; and “diabetic” patients try every possible means just to lower blood sugar levels. (“拉筋能治耳鸣吗？”“拉筋能治头痛吗？”“糖尿病？”“高血压呢？”这些问题都有一个共同点，都是以“病名”来问的。但我想强调的是，大家首先要忽略“病名”，当你一味地抑制症状时，问题就来了，比如“高血压”患者想尽一切办法只是为了把血压降到标准水平；“糖尿病”患者想尽一切办法只是为了降低血糖。)

People should realize that according to Chinese medicine, all diseases are complex diseases, i.e. diseases are all interrelated. Do not look at a “disease” as an isolated phenomenon; instead, treat related diseases altogether. I call it “carpet bombing”. And, whether there are diseases or not, just drop the bombs first, as there could be various potential diseases lurking in your body that you might not even be aware of. Diseases that are detectable by modern medicine are just tip of the iceberg, there are many more yet to be detected. Often times, medication against one disease leads to onset of other diseases. However, what frequently happens with Paida and Lajin is that: when one disease is targeted, other diseases are cured as well. I encountered this when I cured some gynaecological disorders by chance while treating people with other diseases. I have thus become a “gynaecological expert” without realizing it. It is indeed quite amusing. (人们应该认识到，中医认为，一切疾病都是复合病，也就是疾病都是相互关联的。不要把一种“病”当作一个孤立的现象，而要把相关的疾病一起治，我把这叫做“地毯式轰炸”。不管有病没病，先扔炸弹，你的身体里可能还潜伏着各种你不知道的潜在疾病。现代医学能发现的疾病只是冰山一角，还有更多的疾病没有被发现。很多时候，治好了一种病，其他的病也跟着来了。然而，拍打拉筋经常发生的是，治好了一种病，其他的病也跟着好了。我就遇到过这种情况，我在给别人看病时，偶然治好了妇科病，就此不知不觉地成了“妇科专家”，说起来，还挺有意思。)

The human body has an innate “self-healing system” that cannot be seen or touched; it is known in Chinese medicine as the meridian system (system of energy channels). In Western medicine, it might be described as the “nervous system” or the “urinary system”. Chinese medicine holds that “where ‘Qi’ flows smoothly, there will be natural blood flow”, and the actual work of driving blood flow is done by “Qi”. Furthermore, “Qi” is not visible to the naked eye, but cutting-edge scientific instruments can now detect the existence of “Qi”. I have a physicist friend named Zhang Changlin, whose book Invisible Rainbow elaborates on scientific proof of the existence of “Qi”. (人体具有与生俱来的看不见、摸不着的“自愈系统”，中医称之为经络系统，西医称之为“神经系统”或“泌尿系统”。中医认为“气行则血行”，而真正推动血行的是“气”。另外，“气”虽然肉眼看不见，但先进的科学仪器可以探测到“气”的存在。我有一个物理学家朋友，张长林，他的《看不见的彩虹》一书详细阐述了“气”存在的科学依据。)

When practicing Paida and Lajin, we are actually activating the “anti-virus software” in our body, i.e. the self-healing power. Once activated, it scans the entire body to cleanse all stagnant or blocked meridians. That is why one feels such sensations as soreness, numbness, swelling, pain, itchiness, cold, heat, etc. during the process. One feels pain where meridians are blocked. Where there is a minor obstruction (like a narrowed water pipe), when the “anti-virus software” is activated through Paida and/or Lajin, “Qi” will move faster and you will feel some numbing and swelling sensations; sometimes, all the sensations of soreness, numbness, swelling, and itchiness will sweep over you; sometimes, you will feel a warm sensation after the meridians are cleared; sometimes, you can even feel the cold being expelled from your body. (我们拍打拉筋的时候，其实就是启动了身体的“杀毒软件”，也就是自愈能力，它启动之后会扫描全身，把淤堵的经络都清理掉，所以才会有酸、麻、肿、痛、痒、冷、热等感觉。经络不通的地方就会有疼痛的感觉。如果有一点堵塞（比如水管变窄），拍打拉筋启动“杀毒软件”之后，“气”就会运行得更快，会有麻、肿的感觉；有时候酸、麻、肿、痒的感觉全都来了；有时候经络打通了，会有温热的感觉；有时候甚至能感觉到寒气从身体里排出来。)

People are accustomed to treating a disease as an isolated phenomenon, and are prone to being misled by the disease name; they only want to get rid of the disease without being otherwise bothered. Unfortunately, this is not the way to treat diseases.
Then, what should be done? Remember the analogy of “anti-virus software” I just mentioned? (人们习惯于把疾病当成一个孤立的现象，容易被疾病的名称误导，只想摆脱疾病，而不去理会其他事情。不幸的是，这并不是治疗疾病的方法。那么，该怎么办呢？还记得我刚才提到的“杀毒软件”的比喻吗？)

Whenever I am asked if this or that disease can be cured, my answer would be, “Please remember ‘anti-virus’! ‘anti-virus’!” By that, I mean in treatment of diseases, we should target the entire body, as a holistic system. Try to recall which meridian hurts most when doing Lajin, the Urinary Bladder Meridian, right? That’s the one located behind the knees. It runs from head to toe, and is the largest detoxification channel in our body. Cleansing this meridian cures numerous diseases, such as lower back and leg pain, liver problems, kidney disorders, gynaecological disorders, prostate disorders and so on. This is because the Urinary Bladder Meridian is linked to the lower back and legs, and is connected to the Spleen, Liver and Kidney Meridians. Some people can neither straighten the raised leg on the Lajin bench, nor can they have the lowered leg touch the ground. This indicates problems with the Urinary Bladder, Liver, Spleen, and Kidney Meridians. There are three “yin” meridians (the Spleen, Liver, and Kidney Meridians) along the inner side of the legs, and once cleared, diabetes, hypertension, gynaecological and prostate disorders will all be cured. Some people like to slap the Gall Bladder Meridian on the outer side of the legs; actually, it is more crucial to Paida the inner side of the thighs, which will deliver benefits that you may have never expected. (每当有人问我这个病那个病能不能治好的时候，我的回答都是：“请记住‘抗病毒’！‘抗病毒’！”我的意思是治病要从全身着眼，整体着眼。大家回忆一下拉筋的时候最疼的经络是膀胱经，对吧？就是膝盖后面的那个经络，从头到脚，是身体最大的排毒通道。疏通这个经络可以治很多病，比如腰腿痛、肝病、肾病、妇科病、前列腺病等等。因为膀胱经通腰腿，又通脾经、肝经、肾经。有些人在拉筋凳上抬起的腿不能伸直，放下的腿也不能碰到地。 这表明膀胱、肝、脾、肾经有问题。腿部内侧有三条“阴”经（脾、肝、肾经），一旦疏通，糖尿病、高血压、妇科病和前列腺病都会好起来。有些人喜欢拍打腿部外侧的胆经；实际上，拍打大腿内侧更为重要，这将带来你可能从未想过的好处。)

I recently discovered an additional type of disease that can be treated with Lajin. Guess what can be most effectively treated among males, especially in older men? The answer is prostate disorders. A leader with the Department of Retired Officials told me that over 90% of the retired officials have prostate problems. They would travel great distances looking for all sorts of remedies, but the effects were only temporary. However, by practicing Paida and Lajin, the efficacy is almost immediate, and the effective rate is above 90%. (最近我发现一种病可以用拉筋来治疗，你猜什么病对男性，特别是老年男性最有效？答案就是前列腺疾病。一位离退休干部局的领导告诉我，离退休干部90%以上都有前列腺问题，他们不远千里去找各种药，但效果都比较短暂，而拍打拉筋则立竿见影，有效率在90%以上。)

Why does Huang Di Nei Jing place so much emphasis on meridians? Because by cleansing meridians, health problems can be solved once and for all. But how come some people give up on meridian therapies shortly after applying knowledge of the meridian system in treatment of diseases? The answer is that the meridian system is quite complex, and that the number of acupoints along the meridians makes it an even greater challenge. Thus people find it hard to even start. This is the reason why I have chosen Lajin, because in Lajin, once the key principle is grasped, the rest will fall in place. The truest path is the simplest. The Lajin method may appear simple, but it stretches and clears all the meridians. Stretch as much as you can, and the pain will target blockages along the meridians. The moment you activate this “anti-virus software”, it starts to scan your entire body, carrying out diagnosis and treatment at the same time. Self-healing is that simple! (《黄帝内经》为什么重视经络？因为疏通经络，健康问题就能一劳永逸地解决。但为什么有些人在运用经络知识治病后不久就放弃了经络疗法呢？因为经络系统非常复杂，经络上的穴位众多，难度更大，让人难以下手。这也是我选择拉筋的原因，因为拉筋只要掌握了要点，其他的就都水到渠成了。真正的道，其实就是最简单的。拉筋的方法看似简单，但却是把所有的经络都拉通了，你能拉多大，痛就痛在经络上的堵塞处。当你启动这个“杀毒软件”的那一刻，它就开始扫描你的全身，一边诊断，一边治疗，自愈就是这么简单！ )

NKCP :

NKCP, a purified filtrate of Bacillus subtilis var. natto culture is a food based extract of “natto”, a Japanese traditional fermented food made from soybean. Purification to remove most of distinctive odor of natto and its vitamin K2 yields an easy-to-eat food that has a wide variety of uses as a functional food. NKCP contains proteolytic enzymes secreted by Bacillus subtilis var. natto (Bacillus subtilis var. natto-produced protein), which balance clotting mechanisms in the blood. 

In vitro and clinical studies have demonstrated that the consistent intake of NKCP over a prolonged period helps to maintain normal circulation. The safety of NKCP has been demonstrated in safety studies. *In vitro (Latin for "within the glass") refers to the technique of performing a given procedure in a controlled environment outside of a living organism.

Patents (Production process for purified filtrate of Bacillus subtilis var. natto culture)
Japan (No.3532503)

NKCP stands for Purified Natto Culture Filtrate. NKCP tablets launched April 2001. Daiwan Health Development Inc. (DHD) began export of NKCP on November 2001.

Development Background

The “People's Health Promotion Campaign for the 21st Century (Healthy Japan 21)” was launched in 2000 by the Ministry of Health, Labour and Welfare. The purposes of this campaign are to reduce premature death, prolong optimal health, and improve the quality of life. Simply put, it focuses on longevity accompanied by optimal health. Cardiovascular and cerebrovascular diseases account for about 30% of causes of death in Japan, about 25% in the world. To lower mortality rates while in the prime of life, it is very important to prevent cardiac and cerebrovascular diseases. 

A patient with cardiovascular disease may evade a fatal cardiovascular event, but eventually their quality and duration of life will be compromised.

Contemporary lifestyles choices are associated with an increased risk of thrombus formation and subsequent ischemic heart disease and cerebrovascular disease. It has recently been demonstrated that the etiology of travel induced thrombosis, also known as “economy class syndrome”, is Deep Vein Thrombosis (DVT), which may result in a pulmonary embolism. DVT may develop as a result of prolonged sitting in cramped quarters related to both air and auto travel. Additionally, common ailments such as stiff shoulder muscles and leg edema may be caused by insufficient peripheral circulation, caused by excess blood viscosity. The key to preventing DVT and insufficient peripheral circulation is to balance coagulation and fibrinolysis, to prevent thrombus formation and to enhance overall cardiovascular health and longevity. NKCP may be a critical component to achieve such balance.

Development

NKCP was developed based on the traditional Japanese food, natto. Natto contains constituents that enhance the fibrinolysis system in favor of clot lysis. Naturally occurring proteolytic enzymes produced by Bacillus subtilis var. natto dissolve clots in a balanced manner, without causing excessive blood thinning. Recent research has shown that other additional constituents from Bacillus subtilis var. natto produce a substance that acts to inhibit blood coagulation, thereby complementing the known fibrinolytic activity to improve blood viscosity. Based on these insights, it is probable that consistent consumption of natto may lower the overall risk of thrombus formation. However, compliance of such a recommendation may be poor, due to natto's potentially objectionable odor and flavor. Additionally, natto consumption may be contraindicated for patients on anti-coagulant therapy due to its high vitamin K2 content. Furthermore, the proteolytic enzyme content may vary greatly in commercially available natto, resulting in inconsistent anti-coagulant activity.

NKCP was therefore developed to provide a raw material for food products which corrects the drawbacks of natto. NKCP is produced by fermenting the bacillus in a liquid medium containing soybean extract and then partially purifying the peptidase. The odor, bacterial body and vitamin K2 content are reduced to a negligible level. NKCP is designed to contain a constant amount of peptidase.

Characteristics of NKCP

•　NKCP is extracted from Bacillus subtilis var. natto and it is free of the undesirable odor and viscous texture of natto.
•　NKCP's purpose is three-fold.
To function as (1) an anticoagulant (2) thrombolytic and (3) decreases blood viscosity.
•　The majority of the vitamin K2 has been eliminated, therefore it is less antagonistic to other drugs such as warfarin.
•　NKCP is standardized to contain specific levels of proteolytic enzymes secreted by Bacillus subtilis var. natto.
•　The principal functional enzyme (protease) is stable at pH 6.0-10.0 and at temperatures 60℃ or below.
•　The safety of NKCP has been confirmed in many animal and human studies.
•　The production process for this purified filtrate of Bacillus subtilis var. natto culture is registered under Patent No. 3532503 in Japan.

Suggested daily dose


125-500mg/day


Mechanism of Action

NKCP is shown to have the following effects:
a. Inhibiting thrombus formation in vitro and in vivo. 
b. Decreasing the viscosity of blood in vitro and in vivo. 
c. Lysing thrombi in vitro and in vivo. 
*In vivo (of processes) performed or taking place in a living organism."fluid transport was measured in vivo"

The coagulation/fibrinolysis system is comprised of a series of complicated reactions designed to maintain the balance between healthy circulation and prevention of excess bleeding. Many factors can influence this system, however, it is not easily disrupted. In the event that the system shifts towards excess thrombus formation, it is challenging to return the system back to balance. Because it is difficult to lyse a formed thrombus, the emphasis should be placed on prevention of thrombus formation rather than on thrombolysis.

By inhibiting thrombus formation and decreasing blood viscosity, orally administered NKCP helps maintain balance, shifts blood away from clot formation, and enhances circulation throughout the body.



Scientific Data

1. NKCP Actions

Reduced risk of thrombus formation requires: 1) clot formation prevention 2) maintenance of normal blood viscosity and 3) lysing blood clots (thrombi).
NKCP, derived from Bacillus subtilis var. natto, has been shown to perform these three functions.

2. Supporting Scientific Data

(1) Anticoagulant effect

▶Anticoagulant effect of NKCP in human blood.
▶Anticoagulant effect of NKCP in rat model of thrombosis formation.

(2) Action of preventing increase in blood viscosity.

▶Effect of NKCP on the viscosity of human blood

(3) Thrombolytic effect.

▶Thrombolytic effect of NKCP on artificial thrombi.
▶In vivo thrombolytic effect of oral NKCP in experimental thrombolysis model.
▶Identification of proteases derived from Bacillus subtilis var. natto related to thrombolysis.

3. Clinical Study Results

▶Effect of Bacillus subtilis var. natto-derived protein on the human blood coagulation/fibrinolysis system.

Safety

Single-dose:
LD50＞5,000mg/kg

Repeated-dose:
NOAEL
Males: > 1,325mg/kg body weight/day.

Females: > 1,541mg/kg body weight/day.

Mutagenicity:
Negative (± metabolic activation).

Antigenicity (guinea pigs): Negative for active systemic anaphylactic reaction (ASA) and passive cutaneous anaphylactic reaction (PCA).

Effect on bleeding time (rats):
In rats orally given NKCP, a 0.5mm incision was made in the tail tip after 1 hour to measure bleeding time. NKCP at 300mg/kg did not prolong the bleeding time.

Interaction with warfarin (rats):
NKCP at 250mg/kg was administered into the duodenum by the in situ loop method in rats, in which bleeding time was delayed by treatment with warfarin, and blood collected after 6 hours was measured for coagulation time. The warfarin treatment significantly prolonged the coagulation time in comparison with the control group, but no added delay of coagulation was observed in the warfarin + NKCP treatment group compared with warfarin treatment group.

Long-term administration (humans):
Twenty-three healthy adults were given NKCP at 250mg/day for 12 weeks, and no clinically significant adverse events were observed. There were no statistically significant changes in hematological or biochemistry tests.

Five healthy adults were given NKCP at 750mg/day for 6 consecutive weeks to study and observe changes in laboratory test values (hematological tests, biochemistry tests, and blood coagulation/fibrinolysis parameters) and adverse events. As a result, ELT shortened, t-PA decreased, and thromboplastinogen activity test (TAT) increased but all values were within normal range. In addition, no adverse events were observed, suggesting NKCP safety.

High dose administration(humans):
Eight healthy adults were given NKCP at 1,250mg/day for 7 consecutive days. Observation of clinical signs and laboratory tests were utilized to evaluate NKCP safety. There were no clinically significant adverse events. There were no abnormal changes in hematological or biochemistry tests.

Assays

1. Peptidase Activity (synthetic substrate method)

The sample solution is warmed at 37°C with the synthetic chromogenic substrate S-2251 (H-D-valyl-L-leucyl-L-lysine-p-nitroanilide dihydrochloride) as a substrate and the absorbance at 405nm is determined. The enzyme activity is defined as 1 unit when 1nmol of p-nitroaniline per minute is released.
*An assay is an investigative (analytic) procedure in laboratory medicine, pharmacology, environmental biology and molecular biology for qualitatively assessing or quantitatively measuring the presence, amount, or functional activity of a target entity (the analyte).

2. Bacillus subtilis var. natto-produced Protein

ELISA (enzyme-linked immunosorbent assay) uses rabbit-specific antibodies to the Bacillus subtilis var. natto-produced protein, responsible for the peptidase activity, to measure the amount of antigen reacting with the specific antibodies.

▶Anticoagulant effect of NKCP in human blood

Thirty micro litters of the test substance, NKCP, was added to 3mL of venous blood collected from healthy volunteers who had given informed consent, followed by inversion for mixing. The mixture was warmed at 37°C for 250 seconds and centrifuged, and the supernatant was measured for fibrin monomers (FM) indicative of thrombus formation, using a latex immunity analyzer. The concentration of FM was 160 ± 29.3μg/mL after addition of the control physiological saline and 6.0 ± 1.1μg/mL after addition of heparin sodium (0.5IU/mL). After addition of NKCP at concentrations from 0.005mg/mL to 0.5mg/mL, the concentration of FM decreased dose-dependently, but plateaued at 0.05mg/mL.

The 54th Study Meeting of Rheology 2006;
Department of Legal Medicine, Dokkyo Medical University School of Medicine

▶Anticoagulant effect of NKCP in rat model of thrombosis formation

The anticoagulant effect of NKCP was studied in a rat model of thrombus formation. In this model, platelet aggregation was caused by injuring endothelial cells of the abdominal descending aorta to induce thrombus formation. NKCP was administered into the duodenum 2 hours after producing the thrombus formation model using in situ loop method. Blood was collected from the abdominal aorta 6 hours after administration to determine activated partial thromboplastin time (APTT) and prothrombin time (PT) as indicators of endogenous and exogenous coagulations, respectively. APTT was 33.5 ± 2.4 seconds for the control group (administered physiological saline), 52.0 ± 4.5 seconds for the NKCP 100mg/kg group, and 63.3 ± 2.9 seconds for the NKCP 250mg/kg group. A significant coagulation delay was observed in the NKCP treatment groups as compared to control. PT was 16.7 ± 0.5 seconds for the control group, 20.6 ± 0.9 seconds for the NKCP 100mg/kg group, and 21.3 ± 1.7 seconds for the NKCP 250mg/kg group. As with the APTT, a significant coagulation delay was observed in the NKCP group as compared to control. These results suggest NKCP inhibits thrombus formation.

Research and Development Department, Daiwa Pharmaceutical Co., Ltd., 2001

▶Effect of NKCP on the viscosity of human blood

Eight healthy male adults who had given informed consent were given a single dose of placebo or NKCP at 1,250mg, and blood was collected at various points over 240 minutes to measure changes in blood viscosity. The viscosity of blood was determined by Hitosugi et al.'s method using an oscillating viscometer.
In the NKCP group, there was a significant decrease in blood viscosity at 105 and 180 minutes as compared to baseline. There was a significant decrease in blood viscosity in the NKCP group as compared to placebo at 180 minutes.



Effect of NKCP on the viscosity of human blood:
Department of Legal Medicine, Dokkyo Medical University School of Medicine.

▶Thrombolytic effect of NKCP on artificial thrombi

A small amount of NKCP was added to test tubes containing an artificial thrombus in physiological saline. The thrombus began to lyse within several minutes and was almost completely lysed at 3 hours. To lyse is to cause dissolution or destruction of cells by lysins. Lysis is the disintegration of a cell by rupture of the cell wall or membrane.



Thrombolytic effect of NKCP on artificial thrombi:
J. Pharmacol Sci 2005; 99: 247-251.

▶In vivo thrombolytic effect of oral NKCP in experimental thrombolysis model

The thrombolytic effect of NKCP on rat model was observed in a 14 week study. The NKCP was evaluated in two groups, in a mix of 0.2% and 1% in feed, as compared to a control group. Thrombolysis was evaluated using a He-Ne laser induced thrombosis model in mesenteric microvessels. The size of the artificially produced thrombus was measured from the time of formation to evaluate the thrombolytic effect of NKCP.

Thrombolytic activity clearly increased dose-dependently in the NKCP treatment groups compared with the control group. There was an 82% decrease in thrombus volume in the control group, as compared to 67% decrease in the 0.2% NKCP group, and a 51% decrease (statistically significant) in the 1% NKCP group. The extent of thrombolysis in the 1% group was equivalent to that seen in animals treated with a bolus intravenous infusion of 0.2mg/kg of tissue plasminogen activator (t-PA). Based on the body weight and feed intake of rats used in the study, the dose of NKCP was calculated to be about 160mg/kg/day for the 0.2% NKCP feed and 800mg/kg/day for the 1% NKCP feed.



In vivo thrombolytic effect of oral NKCP in experimental thrombolysis model:
Pathophysiol Haemost Thromb 2003; 33: 138-143.

▶Identification of proteases derived from Bacillus subtilis var. natto related to thrombolysis

The thrombolytic effect of NKCP is attributable to a proteolytic enzyme named bacillopeptidase F, produced by Bacillus subtilis var. natto. Bacillopeptidase F is shown to be one of five proteases produced and secreted by Bacillus subtilis var. natto (Table 1).



Identification of proteases derived from Bacillus subtilis natto related to thrombolysis:
1)Journal of Bacteriology 1990; 172: 1019-1023
2)The Journal of Biological Chemistry 1990; 265: 6845-6850
3)Journal of Bacteriology 1990; 172: 1470-1477
4)Experientia 1987; 43: 1110-1111
5)The Journal of Biological Chemistry 2001; 276: 24690-24696
6)Mol Gen Genet 1990 May; 221(3): 486-490

▶Effect of Bacillus subtilis var. natto-derived protein on the human blood coagulation/fibrinolysis system

A total of 23 adults, including patients with metabolic diseases related to thrombosis, were given 250mg NKCP for two consecutive months. Coagulation/fibrinolysis parameters and symptoms were evaluated 1 and 2 months after starting treatment.

Euglobulin lysis time (ELT) significantly decreased from the baseline value at 1 and 2 months, and t-PA significantly increased at 2 months, showing the accelerated fibrinolysis system. However, the measured ELT and t-PA values were within the normal ranges. Fibrinogen degradation products (FDP) significantly decreased 1 month after starting ingestion but returned to the baseline value at 2 months.

Symptoms of shoulder stiffness significantly improved from baseline at 1 and 2 months.



Effect of Bacillus subtilis natto-derived protein on the human blood coagulation/fibrinolysis system:
Journal of the Japanese Society of Biorheology 2004; 18 (1).

Hydration and Health

Can dehydration influence mood?

The brain is mostly made of water - so how does dehydration affect mood, fatigue and concentration?

 

Healthy hydration for cognition and mood state

 

Our brain is made of 75% water. It seems therefore logical that dehydration may have an impact on cognitive functions and mood.

 

Several studies, performed in healthy persons, looked at the effects of induced dehydration on cognitive performance and motor function: fatigue, mood, choice reaction time, short- and long-term memory, attention, arithmetics… It appears that a 2% dehydration is sufficient to impair functions and performances.^1,2 Some studies have suggested that adverse effects may even be present at 1% dehydration.^3,4

 

Young children and adolescents, in particular, may be at risk of impaired cognitive function (concentration, alertness and short-term memory) due to insufficient hydration.^5,6

 

References:

1. Institute of Medicine (IOM). Dietary Reference Intakes for Water, Potassium, Sodium, Chloride, and Sulfate. Washington, DC: National Academies Press,2004.

1. EFSA Panel on Dietetic Products, Nutrition, and Allergies (NDA); Scientific Opinion on Dietary reference values for water. EFSA Journal. 2010; 8:1459-507. doi:10.2903/j.efsa.2010.1459. Available online: www.efsa.europa.eu
2. Gopinathan PM, Pichan G, Sharma VM. Role of dehydration in heat stress-induced variations in mental performance. Arch Env Health. 1998;43:15–7.
3. Lieberman HR. Hydration and Cognition: A Critical Review and Recommendations for Future Research. J Am CollNutr. 2007;26:S555-61.
4. EFSA Panel on Dietetic Products, Nutrition and Allergies (NDA); Scientific Opinion on the substantiation of health claims related to water and maintenance of normal physical and cognitive function (ID 1102, 1209, 1294, 1331), maintenance of normal thermoregulation (ID 1208) and “basic requirement of all living things” (ID 1207) pursuant to Article 13(1) of Regulation (EC) No 1924/2006. EFSA Journal. 2011;9:2075-91. doi:10.2903/j.efsa.2011.2075. Available online: www.efsa.europa.eu/efsajournal
5. D'Anci KE, Constant F, Rosenberg IH. Hydration and cognitive function in children. Nutr Rev. 2006;64:457-64.

Water intake and kidney stones







Kidney stones, also called urolithiasis, are a common pathology affecting about 10% of the population in developed countries at least once in an individual’s lifetime. Recent trends show an increase in stone prevalence.

The role of dietary habits, including fluid intake, has a great implication in stone development.

Hydration: A well recognized role in recurrence prevention

The role of increased fluid intake as a means of preventing recurrence of kidney stones is well recognized today. In fact, it has been used since the time of Hippocrates.

Adequate fluid intake helps to decrease concentrations of substances involved in stone formation thus reducing their saturation degree in urine (a necessary condition for crystallization, and a first step towards stone formation).

Many studies have shown the beneficial effects of improved fluid intake (and consequently urine volume) on stone recurrence prevention.

The strongest scientific evidence certainly comes from a five-year randomized controlled trial conducted amongst patients recruited directly after their first idiopathic calcium stone episode. This study showed that recommending patients to increase fluid intakes to achieve a urine volume superior to 2L per day resulted in reduced kidney stone recurrence compared to a group without specific advice.¹

The European Association of Urology² recommends increasing fluid intake independent of the type of stones to achieve a urine volume of more than 2L a day, on top of other dietary and lifestyle advice.

Recommendations to lower the risk of kidney stones²

 

Is there a role of hydration for first stone prevention?

Several studies suggest that chronic dehydration from different causes such as working in a hot environment or physical exertion increases the risk of stone incidence.^3-7 Data suggests also that stone diseases occur more frequently in geographic areas with a hot climate. In countries such as Saudi Arabia, over 20% of the population develop renal stones whereas the risk of the disease is only 12 to 13% in North America and 5 to 10 % in Europe.⁸ There is also a seasonal variation of stone incidence, with higher rates in summer.^9-10

In addition, some studies show the relationship between fluid intake and stone risk in the healthy population:

• In two large observational studies, total fluid intake was significantly and negatively associated with the risk of renal stones.^11-12
• A three-year intervention controlled trial tested the preventive effect of an educational program on adequate fluid intake in a population living in a hot climate compared to a similar population who did not receive any advice. Results showed that the population with the educational program had a higher urine volume and a lower stone incidence than the population who were not advised on fluid intake.¹³

It has also recently been shown that an additional water intake of 1.3 L could decrease the theoretical risk of crystallization, the first step of stone formation, in the urine of a healthy population as measured by the Tiselius crystallization risk index.¹⁴
Nevertheless, further studies are needed to confirm the role of adequate fluid intake for first stone prevention.

References:

1. Borghi L, Meschi T, Amato F, Briganti A, Novarini A, Giannini A. Urinary volume, water and recurrences in idiopathic calcium nephrolithiasis: a 5-year randomized prospective study. J Urol. 1996;155:839-43.
2. Türk C, Knoll T, Petrik A, Sarica K, Straub M, Seitz C. Guidelines on Urolithiasis, European Association of Urology 2011. 
3. Embon OM, Rose GA, Rosenbaum T. Chronic dehydration stone disease. Br J Urol. 1990;66:357-62.
4. Pin NT, Ling NY, Siang LH. Dehydration from outdoor work and urinary stones in a tropical environment. Occup Med (Lond). 1992;42:30-2.
5. Borghi L, Meschi T, Amato F, Novarini A, Romanelli A, Cigala F. Hot occupation and nephrolithiasis. J Urol. 1993;150:1757-60.
6. Chang MA, Goldfarb DS. Occupational risk for nephrolithiasis and bladder dysfunction in a chauffeur. Urol Res. 2004;32:41-3.
7. Olapade-Olaopa EO, Agunloye A, Ogunlana DI, Owoaje ET, Marinho T. Chronic dehydration and symptomatic upper urinary tract stones in young adults in Ibadan, Nigeria. West Afr J Med. 2004;23:146-50.
8. Ferrari P, Piazza R, Ghidini N, Bisi M, Galizia G, Ferrari G. Lithiasis and riskfactors. UrolInt. 2007;79:8-15.
9. Baker PW, Coyle P, Bais R, Rofe AM. Influence of season, age, and sex on renal stone formation in South Australia. Med J Aust. 1993;159:390-2.
10. Al-Hadramy MS. Seasonal variations of urinary stone colic in Arabia. J Pak Med Assoc. 1997;47:281-4.
11. Taylor EN, Stampfer MJ, Curhan GC. Dietary factors and the risk of incident kidney stones in men: new insights after 14 years of follow-up. J AmSocNephrol. 2004;15:3225-32.
12. Curhan GC, Willett WC, Knight EL, Stampfer MJ. Dietary factors and the risk of incident kidney stones in younger women: Nurses' Health Study II. ArchInternMed. 2004;164:885-91.
13. Frank M, De Vries A. Prevention of urolithiasis. Education to adequate fluid intake in a new town situated in the Judean Desert Mountains. ArchEnvironHealth. 1966;13:625-30.
14. De La Guéronnière V, Le Bellego L., Buendia Jimenez I, Dohein O, Tack I, Daudon M. Increasing water intake by 2 liters reduces crystallization risk indexes in healthy subjects. ArchItalUrolAndrol. 2011;83:43-50.

Healthy hydration and obesity

According to WHO,¹⁶ overweight and obesity are now the fifth leading risk for global deaths: in 2008, over 500 million adults were obese.

Living a healthy lifestyle is key component of the fighting against obesity. Promoting physical activity, healthy nutrition and healthy hydration can contribute to maintaining healthy body weight.
Adopting healthy hydration habits is not only a matter of “how much to drink” but also the quality of what we drink is important.
Excessive and regular intake of beverages containing sugar increases the energy intake compared to drinking water. Studies have shown that excessive and regular sugar-sweetened beverages intake can lead to increased body weight.^2-15

Whereas water is calorie free, one glass of sugar-sweetened beverage (250 mL) contains about 100 kcal. Excessive consumption of sugar-sweetened beverages can quickly exceed the World Health Organization recommendation which states that free / added sugar (from all nutrition sources) should not exceed 10% of the total calorie intake.¹

There is increasing evidence that the types of the fluids we drink can have a long-term impact on health, influencing the development of overweight, obesity or metabolic diseases.
Studies have suggested that excessive consumption of sugar-sweetened beverages increases the risk of type 2 diabetes ^16-19 and it has also been shown that in adults, high consumption of sugar-sweetened beverages is associated with the prevalence of metabolic syndrome.^20-22

A sensible advice would be to recommend that the bulk of daily fluid intake should come from plain water.

References:

1. WHO technical report series. Diet, Nutrition and Prevention of Chronic Diseases; Report of a Joint WHO/FAO Expert Consultation; Geneva 2003.
2. Barquera S, Hernandez-Barrera L, Tolentino ML, Espinosa J, Ng SW, Rivera JA, Popkin BM. Energy intake from beverages is increasing among Mexican adolescents and adults. J Nutr. 2008;138:2454-61.
3. Berkey CS, Rockett HR, Field AE, Gillman MW, Colditz GA Sugar-added beverages and adolescent weight change. Obes Res. 2004;12:778-88.
4. Chen L, Appel LJ, Loria C, Lin PH, Champagne CM, Elmer PJ, Ard JD, Mitchell D, Batch BC, Svetkey LP, Caballero B. Reduction in consumption of sugar-sweetened beverages is associated with weight loss: the PREMIER trial. Am J ClinNutr. 2009;89:1299-306.
5. DiMeglio DP, Mattes RD. Liquid versus solid carbohydrate: effects on food intake and body weight. Int J ObesRelatMetabDisord. 2000;24:794-800.
6. Guerrero RT, Paulino YC, Novotny R, Murphy SP. Diet and obesity among Chamorro and Filipino adults on Guam. Asia Pac J ClinNutr.2008;17:216-22.
7. Harnack L,Stang J, Story M. Soft drink consumption among US children and adolescents: nutritional consequences. J Am Diet Assoc.1999;99:436-41.
8. Ludwig DS, Peterson KE, Gortmaker SL. Relation between consumption of sugar-sweetened drinks and childhood obesity: a prospective, observational analysis. Lancet 2001;357:505-8.
9. Malik VS, Schulze MB, Hu FB. Intake of sugar-sweetened beverages and weight gain: a systematic review. Am J ClinNutr. 2006;84:274-88.
10. Mrdjenovic G, Levitsky DA. Nutritional and energetic consequences of sweetened drink consumption in 6- to 13-year-old children. J Pediatr.2003;142:604-10.
11. Raben A, Vasilaras TH, Moller AC, Astrup A. Sucrose compared with artificial sweeteners: different effects on ad libitum food intake and body weight after 10wk of supplementation in overweight subjects. Am J ClinNutr.2002;76:721-9.
12. Tordoff MG, Alleva AM. Effect of drinking soda sweetened with aspartameor high-fructose corn syrup on food intake and body weight. Am J ClinNutr. 1990;51:963-9.
13. Troiano RP, Briefel RR, CarrollMD, Bialostosky K. Energy and fatintakes of children and adolescents in the United States: data from the national health and nutrition examination surveys. Am J ClinNutr2000;72:S1343-53.
14. Van Wymelbeke V, Beridot-Therond ME, de La Gueronniere V, Fantino M. Influence of repeated consumption of beverages containing sucrose or intense sweeteners on food intake. Eur J ClinNutr. 2004;58:154-61
15. Wang YC, Ludwig DS, Sonneville K, Gortmaker SL. Impact of change in sweetened caloric beverage consumption on energy intake among children and adolescents. Arch PediatrAdolesc Med.2009;163:336-43.
16. World Health Organization. Obesity and Overweight. Fact sheet n°311. Available at http://www.who.int/mediacentre/factsheets/fs311/en/index.html. Accessed September 2011.
17. de Koning L, Malik VS, Rimm EB, Willett WC, Hu FB. Sugar-sweetened and artificially sweetened beverage consumption and risk of type 2 diabetes in men. Am J ClinNutr. 2011;93:1321-7.
18. Palmer JR, Boggs DA, Krishnan S, Hu FB, Singer M, Rosenberg L.Sugar-sweetened beverages and incidence of type 2 diabetes mellitus in African American women. Arch Intern Med. 2008;168;1487-92.
19. Schulze MB, Manson JE, Ludwig DS, Colditz GA, Stampfer MJ, Willett WC, Hu FB. Sugar-sweetened beverages, weight gain, and incidence of type 2 diabetes in young and middle-aged women. JAMA. 2004;292:927-34.
20. Yoo S, Nicklas T, Baranowski T, Zakeri IF, Yang SJ, Srinivasan SR, Berenson GS. Comparison of dietary intakes associated with metabolic syndrome risk factors in young adults: the Bogalusa Heart Study. Am J ClinNutr. 2004;80:841-8.
21. Dhingra R, Sullivan L, Jacques PF, Wang TJ, Fox CS, Meigs JB, D'Agostino RB, Gaziano JM, Vasan RS. Soft drink consumption and risk of developing cardiometabolic risk factors and the metabolic syndrome in middle-aged adults in the community. Circulation. 2007;116:480-8.
22. Ventura AK,Loken E, Birch LL. Risk profiles for metabolic syndrome in a nonclinical sample of adolescent girls. Pediatrics. 2006:118:2434-42.

What is peripheral neuropathy?

An estimated 20 million people in the United States have some form of peripheral neuropathy, a condition that develops as a result of damage to the peripheral nervous system — the vast communications network that transmits information between the central nervous system (the brain and spinal cord) and every other part of the body. (Neuropathy means nerve disease or damage.) Symptoms can range from numbness or tingling, to pricking sensations (paresthesia), or muscle weakness. Areas of the body may become abnormally sensitive leading to an exaggeratedly intense or distorted experience of touch (allodynia). In such cases, pain may occur in response to a stimulus that does not normally provoke pain. Severe symptoms may include burning pain (especially at night), muscle wasting, paralysis, or organ or gland dysfunction. Damage to nerves that supply internal organs may impair digestion, sweating, sexual function, and urination. In the most extreme cases, breathing may become difficult, or organ failure may occur.

Peripheral nerves send sensory information back to the brain and spinal cord, such as a message that the feet are cold. Peripheral nerves also carry signals from the brain and spinal cord to the muscles to generate movement. Damage to the peripheral nervous system interferes with these vital connections. Like static on a telephone line, peripheral neuropathy distorts and sometimes interrupts messages between the brain and spinal cord and the rest of the body.

Peripheral neuropathies can present in a variety of forms and follow different patterns. Symptoms may be experienced over a period of days, weeks, or years. They can be acute or chronic. In acute neuropathies such as Guillain-Barré syndrome (in which the body’s immune system attacks part of the peripheral nervous system and impairs sending and receiving nerve signals), symptoms appear suddenly, progress rapidly, and resolve slowly as damaged nerves heal. In chronic forms, symptoms begin subtly and progress slowly. Some people may have periods of relief followed by relapse. Others may reach a plateau stage where symptoms stay the same for many months or years. Many chronic neuropathies worsen over time. Although neuropathy may be painful and potentially debilitating, very few forms are fatal.

In diabetic neuropathy, one of the most common forms of peripheral neuropathy, nerve damage occurs in an ascending pattern. The first nerve fibers to malfunction are the ones that travel the furthest from the brain and the spinal cord. Pain and numbness often are felt symmetrically in both feet followed by a gradual progression up both legs. Later, the fingers, hands, and arms may become affected.

How are the peripheral neuropathies classified?

More than 100 types of peripheral neuropathy have been identified, each with its own symptoms and prognosis. In general, peripheral neuropathies are classified according to the type of damage to the nerves. Some forms of neuropathy involve damage to only one nerve and are called mononeuropathies. More frequently however, multiple nerves are affected, called polyneuropathy.

Some peripheral neuropathies are due to damage to the axons (the long, threadlike portion of the nerve cell), while others are due to damage to the myelin sheath, the fatty protein that coats and insulates the axon. Peripheral neuropathies may also be caused by a combination of both axonal damage and demyelination. Electrodiagnostic studies can help healthcare providers determine the type of damage involved.

What are the symptoms of peripheral nerve damage?

Symptoms vary depending on whether motor, sensory, or autonomic nerves are damaged. Motor nerves control voluntary movement of muscles such as those used for walking, grasping things, or talking. Sensory nerves transmit information such as the feeling of a light touch or the pain from a cut. Autonomic nerves control organ activities that are regulated automatically such as breathing, digesting food, and heart and gland functions. Some neuropathies may affect all three types of nerves; others primarily affect one or two types. Doctors may use terms such as predominantly motor neuropathy, predominantly sensory neuropathy, sensory-motor neuropathy, or autonomic neuropathy to describe the types of nerves involved in an individual’s condition.

Motor nerve damage is most commonly associated with muscle weakness. Other symptoms may include painful cramps and fasciculations (uncontrolled muscle twitching visible under the skin), muscle atrophy (severe shrinkage of muscle size), and decreased reflexes.

Sensory nerve damage causes a variety of symptoms because sensory nerves have a broad range of functions. Larger sensory fibers enclosed in myelin register vibration, light touch, and position sense. Damage to large sensory fibers impairs touch, resulting in a general decrease in sensation. Since this is felt most in the hands and feet, people may feel as if they are wearing gloves and stockings even when they are not. This damage to larger sensory fibers may contribute to the loss of reflexes. Loss of position sense often makes people unable to coordinate complex movements like walking or fastening buttons, or to maintain their balance when their eyes are shut.

Smaller sensory fibers without myelin sheaths transmit pain and temperature sensations. Damage to these fibers can interfere with the ability to feel pain or changes in temperature. People may fail to sense that they have been injured from a cut or that a wound is becoming infected. Others may not detect pain that warns of impending heart attack or other acute conditions. Loss of pain sensation is a particularly serious problem for people with diabetes, contributing to the high rate of lower limb amputations among this population.

Neuropathic pain is a common, often difficult to control symptom of sensory nerve damage and can seriously affect emotional well-being and overall quality of life. Often worse at night, neuropathic pain seriously disrupts sleep and adds to the emotional burden of sensory nerve damage. Neuropathic pain can often be associated with an oversensitization of pain receptors in the skin, so that people feel severe pain (allodynia) from stimuli that are normally painless. For example, some may experience pain from bed sheets draped lightly over the body. Over many years, sensory neuropathy may lead to changes in the skin, hair, as well as to joint and bone damage. Unrecognized injuries due to poor sensation contribute to these changes, so it is important for people with neuropathy to inspect numb areas for injury or damage.

Autonomic nerve damage symptoms are diverse since the parasympathetic and sympathetic nerves of the peripheral nervous system control nearly every organ in the body. Common symptoms of autonomic nerve damage include an inability to sweat normally, which may lead to heat intolerance; a loss of bladder control; and an inability to control muscles that expand or contract blood vessels to regulate blood pressure. A drop in blood pressure when a person moves suddenly from a seated to a standing position (a condition known as postural or orthostatic hypotension) may result in dizziness, lightheadedness, or fainting. Irregular heartbeats may also occur.

Gastrointestinal symptoms may accompany autonomic neuropathy. Malfunction of nerves controlling intestinal muscle contractions can lead to diarrhea, constipation, or incontinence. Many people also have problems eating or swallowing if autonomic nerves controlling these functions are affected.

What causes peripheral neuropathy?

Peripheral neuropathy may be either inherited or acquired through disease processes or trauma. In many cases, however, a specific cause cannot be identified. Doctors usually refer to neuropathies with no known cause as idiopathic.

Causes of acquired peripheral neuropathy include:

Physical injury (trauma) is the most common cause of acquired nerve injury.

• Injury or sudden trauma, such as from automobile accidents, falls, sports-related activities, and surgical procedures can cause nerves to be partially or completely severed, crushed, compressed, or stretched, sometimes so forcefully that they are partially or completely detached from the spinal cord. Less severe traumas also can cause serious nerve damage. Broken or dislocated bones can exert damaging pressure on neighboring nerves.

• Repetitive stress frequently leads to entrapment neuropathies, a form of compression injury. Cumulative damage can result from repetitive, awkward, and/or forceful activities that require movement of any group of joints for prolonged periods. The resulting irritation may cause ligaments, tendons, and muscles to become inflamed and swollen, constricting the narrow passageways through which some nerves pass. Ulnar neuropathy and carpal tunnel syndrome are examples of the most common types of neuropathy from trapped or compressed nerves at the elbow or wrist.

Diseases or disorders and their related processes (such as inflammation) can be associated with peripheral neuropathy.

• Metabolic and endocrine disorders impair the body’s ability to transform nutrients into energy and process waste products, and this can lead to nerve damage. Diabetes mellitus, characterized by chronically high blood glucose levels, is a leading cause of peripheral neuropathy in the United States. About 60 percent to 70 percent of people with diabetes have mild to severe forms of nervous system damage that can affect sensory, motor, and autonomic nerves and present with varied symptoms. Some metabolic liver diseases also lead to neuropathies as a result of chemical imbalances. Endocrine disorders that lead to hormonal imbalances can disturb normal metabolic processes and cause neuropathies. For example, an underproduction of thyroid hormones slows metabolism, leading to fluid retention and swollen tissues that can exert pressure on peripheral nerves. Overproduction of growth hormone can lead to acromegaly, a condition characterized by the abnormal enlargement of many parts of the skeleton, including the joints. Nerves running through these affected joints often become entrapped, causing pain.

• Small vessel disease can decrease oxygen supply to the peripheral nerves and lead to serious nerve tissue damage. Diabetes frequently leads to impaired blood flow to nerves. Various forms of vasculitis (blood vessel inflammation) frequently cause vessel walls to harden, thicken, and develop scar tissue, decreasing their diameter and impeding blood flow. Vasculitis is an example of nerve damage called mononeuritis multiplex or multifocal mononeuropathy, in which isolated nerves in two or more areas are damaged.

• Autoimmune diseases, in which the immune system attacks the body’s own tissues, can lead to nerve damage. Sjogren’s syndrome, lupus, and rheumatoid arthritis are among the autoimmune diseases that can be associated with peripheral neuropathy. When the tissue surrounding nerves becomes inflamed, the inflammation can spread directly into nerve fibers. Over time, these chronic autoimmune conditions can destroy joints, organs, and connective tissues, making nerve fibers more vulnerable to compression injuries and entrapment. Chronic conditions may alternate between remission and relapse. Acute inflammatory demyelinating neuropathy, better known as Guillain- Barré syndrome, can damage motor, sensory, and autonomic nerve fibers. Most people recover from this autoimmune syndrome although severe cases can be life threatening. Chronic inflammatory demyelinating polyneuropathy (CIDP) usually damages sensory and motor nerves, leaving autonomic nerves intact. Multifocal motor neuropathy is a form of inflammatory neuropathy that affects motor nerves exclusively. It may be chronic or acute.

• Kidney disorders may cause neuropathies. Kidney dysfunction can lead to abnormally high amounts of toxic substances in the blood that can damage nerve tissue. A majority of indviduals who require dialysis because of kidney failure develop polyneuropathy.

• Cancers can infiltrate nerve fibers or exert damaging compression forces on nerve fibers. Tumors also can arise directly from nerve tissue cells. Paraneoplastic syndromes, a group of rare degenerative disorders that are triggered by a person’s immune system response to a cancerous tumor, also can indirectly cause widespread nerve damage. Toxicity from the chemotherapeutic agents and radiation used to treat cancer also can cause peripheral neuropathy. An estimated 30 to 40 percent of people who undergo chemotherapy develop peripheral neuropathy and it is a leading reason why people with cancer stop chemotherapy early. The severity of chemotherapyinduced peripheral neuropathy (CIPN) varies from person to person. In some cases people may be able to ease their symptoms by lowering their chemotherapy dose or by stopping it temporarily. In others, CIPN may persist long after stopping chemotherapy.

• Neuromas are benign tumors that are caused by an overgrowth of nerve tissue that develops after a penetrating injury that severs nerve fibers. Neuromas are often associated with intense pain and sometimes they engulf neighboring nerves, leading to further damage and even greater pain. Neuroma formation can be one element of a more widespread neuropathic pain condition called complex regional pain syndrome or reflex sympathetic dystrophy syndrome, which can be caused by traumatic injuries or surgical trauma. Widespread polyneuropathy is often associated with neurofibromatosis, a genetic disorder in which multiple benign tumors grow on nerve tissue.

• Infections can cause peripheral neuropathy. Viruses and bacteria that can attack nerve tissues include herpes varicellazoster (shingles), Epstein-Barr virus, West Nile virus, cytomegalovirus, and herpes simplex members of the large family of human herpes viruses. These viruses can severely damage sensory nerves, causing attacks of sharp, lightning-like pain. Postherpetic neuralgia is long-lasting, particularly intense pain that often occurs after an attack of shingles. Lyme disease, diphtheria, and leprosy are bacterial diseases characterized by extensive peripheral nerve damage. Diphtheria and leprosy are rare in the United States, but the incidence of Lyme disease is on the rise. 

 
The tick-borne infection can involve a wide range of neuropathic disorders, including a rapidly developing, painful polyneuropathy, often within a few weeks of being infected. West Nile virus is spread by mosquitoes and is associated with a severe motor neuropathy. The inflammation triggered by infection sometimes results in various forms of inflammatory neuropathies that develop quickly or slowly.

The human immunodeficiency virus (HIV) that causes AIDS is associated with several different forms of neuropathy, depending on the nerves affected and the specific stage of active immunodeficiency disease. A rapidly progressive, painful polyneuropathy affecting the feet and hands can be the first clinically apparent symptom of HIV infection. An estimated 30 percent of people who are HIV positive develop peripheral neuropathy; 20 percent develop distal neuropathic pain.

Exposure to toxins may damage nerves and cause peripheral neuropathy.

• Medication toxicity can be caused by many agents in addition to those for fighting cancer. Other agents that commonly cause peripheral neuropathy as a side effect include those used to fight infection such as antiretroviral agents for treating HIV. In addition, anticonvulsant agents and some heart and blood pressure medications can commonly cause peripheral neuropathy. In most cases, the neuropathy resolves when these medications are discontinued or dosages are adjusted.

• Environmental or industrial toxins such as lead, mercury, and arsenic can cause peripheral neuropathy. In addition, certain insecticides and solvents have also been known to cause neuropathies.
• Heavy alcohol consumption is a common cause of peripheral neuropathy. Damage to the nerves associated with long-term alcohol abuse may not be reversible when a person stops drinking alcohol, however, doing so may provide some symptom relief and prevent further damage. Chronic alcohol abuse also frequently leads to nutritional deficiencies (including B12, thiamine, and folate) that contribute to the development of peripheral neuropathy.

Genetic mutations can either be inherited or arise de novo, meaning they are completely new mutations to an individual and are not passed along by either parent. Some genetic mutations lead to mild neuropathies with symptoms that begin in early adulthood and result in little, if any, significant impairment. More severe hereditary neuropathies often appear in infancy or childhood.

Advances in genetic testing in the last decade have led to significant strides in the ability to identify the genetic causes underlying peripheral neuropathies. For example, several genes have been found to play a role in different types of Charcot-Marie-Tooth, a group of disorders that are among the most common forms of inherited peripheral neuropathies. These neuropathies result from mutations in genes responsible for maintaining the health of the myelin sheath as well as the axons themselves. Key characteristics of Charcot- Marie-Tooth disorders include extreme weakening and wasting of muscles in the lower legs and feet, gait abnormalities, loss of tendon reflexes, and numbness in the lower limbs.

How is peripheral neuropathy diagnosed?

The symptoms of peripheral neuropathy are highly variable. A thorough neurological examination is required to sort out the cause of the symptoms and involves taking an extensive medical history (covering symptoms, work environment, social habits, exposure to toxins, alcohol use, risk of HIV or other infectious diseases, and family history of neurological diseases). In addition, tests are usually performed to identify the cause of the neuropathy as well as the extent and type of nerve damage.

A physical examination and various tests may reveal the presence of a systemic disease causing the nerve damage. Tests of muscle strength, as well as evidence of cramps or fasciculations, indicate motor fiber involvement. Evaluation of the person’s ability to sense vibration, light touch, body position, temperature, and pain reveals any sensory nerve damage and may indicate whether small or large sensory nerve fibers are affected.

Blood tests can detect diabetes, vitamin deficiencies, liver or kidney dysfunction, other metabolic disorders, and signs of abnormal immune system activity. An examination of cerebrospinal fluid that surrounds the brain and spinal cord can reveal abnormal antibodies associated with some immune-mediated neuropathies. More specialized tests may reveal other blood or cardiovascular diseases, connective tissue disorders, or malignancies. Genetic tests are becoming available for a number of the inherited neuropathies.

Based on the results of the neurological exam, physical exam, patient history, and any previous screening or testing, the following additional tests may be ordered to help determine the nature and extent of the neuropathy:

• Nerve conduction velocity (NCV) tests can measure the degree of damage in large nerve fibers, revealing whether symptoms are caused by degeneration of the myelin sheath or the axon. The myelin covering is responsible for the very fast speed of nerve conduction. During this test, a probe electrically stimulates a nerve fiber, which responds by generating its own electrical impulse. An electrode placed further along the nerve’s pathway measures the speed of impulse transmission along the axon. Slow transmission rates and impulse blockage tend to indicate damage to the myelin sheath, while a reduction in the strength of impulses at normal speeds is a sign of axonal degeneration.
• Electromyography (EMG) involves inserting a fine needle into a muscle to record electrical activity when muscles are at rest and when they contract. EMG tests detect abnormal electrical activity in motor neuropathy and can help differentiate between muscle and nerve disorders.

• Magnetic resonance imaging (MRI) can show muscle quality and size, detect fatty replacement of muscle tissue, and can help rule out tumors, herniated discs, or other abnormalities that may be causing the neuropathy.

• Nerve biopsy involves removing and examining a sample of nerve tissue, most often from the lower leg. Although this test can provide valuable information about the degree of nerve damage, it is an invasive procedure that is difficult to perform and may itself cause neuropathic side effects.

• Skin biopsy is a test in which doctors remove a thin skin sample and examine nerve fiber endings. This test offers some unique advantages over NCV tests and nerve biopsy. Unlike NCV, it can reveal damage present in smaller fibers; in contrast to conventional nerve biopsy, skin biopsy is less invasive, has fewer side effects, and is easier to perform.

What treatments are available?

Address underlying conditions

The first step in treating peripheral neuropathy is to address any contributing causes such as infection, toxin exposure, medication-related toxicity, vitamin deficiencies, hormonal deficiencies, autoimmune disorders, or compression that can lead to neuropathy. Peripheral nerves have the ability to regenerate axons, as long as the nerve cell itself has not died, which may lead to functional recovery over time. Correcting an underlying condition often can result in the neuropathy resolving on its own as the nerves recover or regenerate.

The adoption of healthy lifestyle habits such as maintaining optimal weight, avoiding exposure to toxins, exercising, eating a balanced diet, correcting vitamin deficiencies, and limiting or avoiding alcohol consumption can reduce the effects of peripheral neuropathy. Exercise can reduce cramps, improve muscle strength, and prevent muscle wasting. Various dietary strategies can improve gastrointestinal symptoms. Timely treatment of injuries can help prevent permanent damage. Smoking cessation is particularly important because smoking constricts the blood vessels that supply nutrients to the peripheral nerves and can worsen neuropathic symptoms. Self-care skills such as meticulous foot care and careful wound treatment in people with diabetes and others who have an impaired ability to feel pain can alleviate symptoms and improve quality of life. Such changes often create conditions that encourage nerve regeneration.

Systemic diseases frequently require more complex treatments. Strict control of blood glucose levels has been shown to reduce neuropathic symptoms and help people with diabetic neuropathy avoid further nerve damage.

Inflammatory and autoimmune conditions leading to neuropathy can be controlled in several ways. Immunosuppressive drugs such as prednisone, cyclosporine, or azathioprine may be beneficial. Plasmapheresis — a procedure in which blood is removed, cleansed of immune system cells and antibodies, and then returned to the body — can help reduce inflammation or suppress immune system activity. Large intravenously administered doses of immunoglobulins (antibodies that alter the immune system, and agents such as rituximab that target specific inflammatory cells) also can suppress abnormal immune system activity.

Symptom Management

Neuropathic pain, or pain caused by the injury to a nerve or nerves, is often difficult to control. Mild pain may sometimes be alleviated by over-the-counter analgesics such as nonsteroidal anti-inflammatory drugs (NSAIDs). More chronic and discomforting pain may need to be addressed through the care of a physician. Medications that are used for chronic neuropathic pain fall under several classes of drugs: antidepressants, anticonvulsant medications, antiarrythmic medications, and narcotic agents. The antidepressant and anticonvulsant medications modulate pain through their mechanism of action on the peripheral nerves, spinal cord, or brain and tend to be the most effective types of medications to control neuropathic pain. Antidepressant medications include tricyclic antidepressants such as amitriptyline or newer serotonin-norepinephrine reuptake inhibitors such as duloxetine hydrochloride or venlafaxine. Anticonvulsant medications that are frequently used include gabapentin, pregabalin, topiramate, and carbamazepine, although other medications used for treating epilepsy may also be useful. Mexiletine is an anti-arrythmic medication that may be used for treatment of chronic painful neuropathies.

For pain that does not respond to the previously described medications, the addition of narcotic agents may be considered. Because the use of prescription obtained pain relievers that contain opioids can lead to dependence and addiction, their use is recommended only after other means of controlling the pain have failed. One of the newest narcotic medications approved for the treatment of diabetic neuropathy is tapentadol, a drug with both opioid activity and norepinephrine-reuptake inhibition activity of an antidepressant.

Topically administered medications are another option for neuropathic pain. Two agents are topical lidocaine, an anesthetic agent, and capsaicin, a substance found in hot peppers that modifies peripheral pain receptors. Topical agents are generally most appropriate for localized chronic pain such as herpes zoster neuralgia (shingles) pain. Their usefulness for treating diffuse chronic diabetic neuropathy is more limited.

Transcutaneous electrical nerve stimulation (TENS) is a non-invasive intervention used for pain relief in a range of conditions, and a number of studies have described its use for neuropathic pain. The therapy involves attaching electrodes to the skin at the site of pain or near associated nerves and then administering a gentle electrical current. Although data from controlled clinical trials are not available to broadly establish its efficacy for peripheral neuropathies, TENS has been shown in some studies to improve peripheral neuropathy symptoms associated with diabetes.

Other complementary approaches may provide additional support and pain relief. For example, mechanical aids such as hand or foot braces can help reduce pain and physical disability by compensating for muscle weakness or alleviating nerve compression. Orthopedic shoes can improve gait disturbances and help prevent foot injuries in people with a loss of pain sensation. Acupuncture, massage, and herbal medications also are considered in the treatment of neuropathic pain.

Surgical intervention can be considered for some types of neuropathies. Injuries to a single nerve caused by focal compression such as at the carpal tunnel of the wrist, or other entrapment neuropathies, may respond well to surgery that releases the nerve from the tissues compressing it. Some surgical procedures reduce pain by destroying the nerve; this approach is appropriate only for pain caused by a single nerve and when other forms of treatment have failed to provide relief. Peripheral neuropathies that involve more diffuse nerve damage, such as diabetic neuropathy, are not amenable to surgical intervention.

What research is being done?

The mission of the National Institute of Neurological Disorders and Stroke (NINDS) is to seek fundamental knowledge about the brain and nervous system and to use that knowledge to reduce the burden of neurological disease. The NINDS is a component of the National Institutes of Health (NIH), the leading supporter of biomedical research in the world.

NINDS-funded research on neuropathy ranges from clinical studies of the genetics and natural history of hereditary neuropathies to basic science investigations of the biological mechanisms responsible for chronic neuropathic pain. Other efforts are focused on understanding how immune system dysfunction contributes to peripheral nerve damage. Together, these diverse research areas will advance the development of new therapeutic and preventive strategies for peripheral neuropathies.

Specific genetic mutations have been identified for some of the known hereditary neuropathies. NINDS therefore supports studies to identify other genetic defects that may play roles in causing or modifying the course of disease. The Inherited Neuropathies Consortium, focused on Charcot-Marie-Tooth neuropathies, seeks to better characterize the natural history of several different forms and to identify genes that modify clinical features in these disorders. Better knowledge of genetic causes may help identify people who are at high risk for developing peripheral neuropathy before symptoms appear. Understanding the role of genetic mutations may also lead to the development of gene therapies that prevent or reduce cumulative nerve damage. In addition, advances from genetics research inform studies to understand disease mechanisms. For example, scientists are using animal models to study how inflammation and nerve damage result from mutations in the Autoimmune Regulator (AIRE) gene, the cause of chronic inflammatory demyelinating polyneuropathy (CIDP) in some people.

Several NINDS-funded studies aim to determine why nerve axons degenerate in different types of peripheral neuropathies. Rapid communication between the peripheral nervous system and the central nervous system depends on myelination, a process through which special cells called Schwann cells create an insulating sheath around axons. Research has shown that Schwann cells play a critical role in the regeneration of nerve cell axons in the peripheral nervous system. By better understanding myelination and Schwann cell function, researchers hope to find targets for new therapies to treat or prevent nerve damage associated with neuropathy.
One promising area of research focuses on a class of molecules called neurotrophic factors. These substances, produced naturally by the body, protect neurons from injury and enhance their survival. Neurotrophic factors also help maintain normal function in mature nerve cells, and some stimulate axon regeneration. Several NINDS-supported studies seek to learn more about the effects of these powerful chemicals on the peripheral nervous system.

Another area of research aims to better understand inflammatory peripheral neuropathies, such as Guillain-Barre syndrome (GBS), in which the body’s immune system attacks peripheral nerves, damaging myelin and impairing signal conduction along affected nerves. NINDS-funded researchers are investigating the mechanisms by which the body’s immune system stops recognizing peripheral nerves as “self” and starts attacking them. GBS is usually preceded by a microbial infection, some as common as food poisoning or the flu, and researchers hypothesize that antibodies generated by the immune system to fight bacteria also attack nervous system proteins. Studies to test this hypothesis may lead to treatments that prevent these antibodies from damaging nerves. As a different strategy, researchers are studying the blood-nerve barrier in inflammatory nervous system disorders and developing ways to reduce the movement of immune cells from the bloodstream into nerve tissue, which may reduce inflammation, demyelination and nerve injury.

Transcranial magnetic stimulation (TMS), which uses a coil either held above or placed on the scalp that delivers electromagnetic pulses to activate electrical currents in general or specific parts of the brain, has shown some analgesic effect in treating various pain conditions. Current studies are examining the effectiveness of TMS in treating peripheral and chronic neuropathies.

In addition to efforts to treat or prevent underlying nerve damage, other NINDSsupported studies are informing new strategies for relieving neuropathic pain. Researchers are investigating the pathways that carry pain signals to the brain and are working to identify substances that will block this signaling.