Some Interesting Connections

If it's on your mind and it has to do with multiple sclerosis in any way, post it here.

Re: Some Interesting Connections

Postby lyndacarol » Thu Sep 05, 2013 7:16 pm

I had not heard this idea of "enzyme inhibitors" until reading the following:

"Most nuts come from the seeds or dried fruits of trees and have an outer shell that protects them from rotting as they lie on the ground waiting to germinate. This shell also protects their healthy fats from spoiling. After being picked, most nuts are processed by drying, and they appear in the store as raw nuts. But unlike most raw foods, which are quite good for you, raw unsprouted nuts have several drawbacks.

The wisdom of Nature has implanted nuts with enzyme inhibitors so they can wait until conditions are right for growth before they germinate. These inhibitors act as preservative for the nut, making sure it can stay viable for a long time. As spring rain comes and the ground becomes soaked, the nut sits in the water and slowly begins to lose its inhibitor, allowing for germination to finally take place.

If nuts are picked, dried and placed on your grocer’s shelf in their raw state, this enzyme inhibitor is still intact. This is why nuts have a reputation as being difficult to digest. The inhibitor actually inhibits digestion when nuts are eaten without undergoing the process nature intended. Not only that, but unsoaked or unsprouted raw nuts actually neutralize the enzymes your body uses to control inflammation and aid in digestion. Eating unsoaked raw nuts is extremely hard on the digestive system and calls for the pancreas to produce huge amounts of digestive enzymes to counteract the inhibitor.

When such a large amount of pancreatic enzymes are needed to digest unsoaked nuts, those enzymes are not available to perform their regular maintenance of the body. A continuous diet of unsoaked raw nuts is so taxing to the pancreas that it can actually swell with distress. Since a happy pancreas keeps you happy, this is not something your want to have happen. This is why most nutritionists and raw foodists suggest eating only very small amounts of unsprouted nuts."

http://alignlife.com/articles/healthyha ... 3zPKl.dpuf
My hypothesis: excess insulin (hyperinsulinemia) plays a major role in MS, as developed in my initial post: http://www.thisisms.com/forum/general-discussion-f1/topic1878.html "Insulin – Could This Be the Key?"
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Re: Some Interesting Connections

Postby PointsNorth » Thu Sep 05, 2013 9:36 pm

@moose Thx for ferreting stuff out :smile:
Albany 2010. Brooklyn 2011
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Re: Some Interesting Connections

Postby Annesse » Fri Sep 06, 2013 7:50 am

Thank you lyndacarol~that is really good info. Most people with MS would probably think nuts would be a healthy food choice, but if they are not properly soaked, they would just further deplete your body of enzymes. I think this information also highlights how important an understanding of the disease process is. Dietary and lifestyle choices can now be made that will have a real impact on the disease process.


ENDOMETRIOSIS, NITRIC OXIDE, VEGF, AND MS

Angiogenesis has long been a recognized feature of endometriosis. Endometriosis is defined as the growth of endometrial tissue outside the uterine cavity. This excess growth pattern can lead to diverse symptoms, such as pelvic pain, infertility, and heavy bleeding.

In the following study from the National Institute of Child Health and Human Development (NICHD), George Washington University and the Endometriosis Association researchers found that women with endometriosis had higher rates of autoimmune disorders, such as MS. The researchers stated their findings suggested a strong association between endometriosis and these disorders.



High rates of autoimmune and endocrine disorders, fibromyalgia, chronic fatigue syndrome and atopic diseases among women with endometriosis: a survey analysis.

Sinaii N, Cleary SD, Ballweg ML, Nieman LK, Stratton P. 2002. Human Reproduction Vol.17, No.10 pp. 2715–2724.

“…Compared with published rates in the general USA female population, women with endometriosis had higher rates of… multiple sclerosis (0.5 versus 0.07%, P < 0.0001)…”




The following studies confirm the involvement of excess nitric oxide and VEGF in endometriosis.

Nitric oxide synthesis is increased in the endometrial tissue of women with endometriosis.
Wu MY, Chao KH, Yang JH, Lee TH, Yang YS, Ho HN. 2003. Hum Reprod 18(12):2688-74.


“Greater amounts of NO and NOS are present in the endometrial tissues of women with endometriosis.”




In the following study published in the Journal of Reproductive Medicine the researchers stated that increased peritoneal fluid (a naturally produced fluid made in the abdominal cavity that lubricates the surface of the tissue that lines the abdominal wall and pelvic cavity) levels of nitric oxide are a common alternation in endometriosis and endometriosis-associated infertility.


Increased nitric oxide in peritoneal fluid from women with idiopathic infertility and endometriosis.
Dong M, Shi Y, Cheng Q, Hao M. 2001. J Repro Med 46(10):887-91.

“To verify whether nitric oxide in peritoneal fluid is associated with endometriosis and infertility…An increased peritoneal level of nitric oxide is a common alteration in endometriosis, endometriosis-associated infertility and idiopathic infertility and may be associated with the pathogenesis of these diseases.”


In the following study the researchers concluded that elevated levels of VEGF may be critical in the pathogenesis of endometriosis.


Vascular endothelial growth factor (VEGF) concentrations are elevated in peritoneal fluid of women with endometriosis.
McLaren J, Prentice A, Charnock-Jones DS, Smith SK. 1996. Hum Reprod. 11(1):220-3.

“Active endometriosis is characterized by hypervascularization both within and surrounding the implant; therefore the presence of angio¬genic factors in the peritoneal environment would be of great importance. Vascular endothelial growth factor (VEGF) is a potent angiogenic factor involved in both physiological and pathological angiogenesis. We sought to determine if VEGF was present in the peritoneal fluid of women with and without endometriosis, and to establish if differences exist between these groups. VEGF was present in all patients sampled. The fluid from patients with endometriosis contained significantly greater amounts of VEGF than controls…We suggest that elevated levels of VEGF in the peritoneal fluid of patients with endometriosis may be critical in the pathogenesis of endometriosis.”
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Re: Some Interesting Connections

Postby Annesse » Sat Sep 07, 2013 7:28 am

INCREASED RISK OF CANCER

At this point, a logical conclusion would be that there may be a correlation to the angiogenesis found in endometriosis and MS, due to the improper regulation of VEGF by nitric oxide, and cancer. In fact, women with endometriosis and MS are at a higher risk of developing certain cancers, such as breast cancer and lymphoma, as the following studies demonstrate.


The risk of cancer and the role of parity among women with endometriosis.
Melin A, Sparén P , Bergqvist A. 2007. Hum Reprod. 22(11):3021-6. Epub 2007 Sep 13.

“Endometriosis was associated with elevated risks for endocrine tumours…ovarian cancer…renal cancer…thyroid cancer…brain tumours…malignant melanoma…and breast cancer…Women with endometriosis have an increased risk for several malignancies. The increased risks do not seem to be related to parity.” Parity is the number of times a female has given birth.




Cancer risk among patients with multiple sclerosis: a population-based register study.
Nielsen NM, Rostgaard K, Rasmussen S, Koch-Henriksen N, Storm HH, Melbye M, Hjalgrim H. 2006. Int J Cancer.118(4):979-84.


“female MS patients had an increased risk of breast cancer…”



In relation to the following study on Hodgkin’s lymphoma and MS, WebMD stated, “Two diseases that frequently strike young, affluent adults may share similar causes. A new study shows that multiple sclerosis (MS) and Hodgkin’s lymphoma tend to run in families and provides new evidence to support the notion that the two diseases may have a common origin (WebMD, 2004).

Researchers say the diseases share many characteristics, which have prompted many to suspect that they may have a common environmental or physical cause. For example, both emerge in young adulthood, have been associated with socioeconomic affluence, and tend to cluster within families.

The study showed that the risk of Hodgkin's lymphoma was nearly twice as high among close relatives of people with multiple sclerosis. Similarly, the risk of MS was more than doubled in relatives of people with Hodgkin's lymphoma.

The results appear in the May 19 issue of the Journal of the National Cancer Institute.
Researchers say the fact that these two diseases are clustered within families is consistent with the belief that the conditions may share similar risk factors and causes.”


Familial clustering of Hodgkin lymphoma and multiple sclerosis.
Hjalgrim H, Rasmussen S, Rostgaard K, Nielsen NM, Koch-Henriksen N, Munksgaard L, Storm HH, Melbye M. 2004. J Natl Cancer Inst. 96(10):780-4.


“Epidemiologic similarities between Hodgkin lymphoma in young adults (i.e., between 15 and 44 years old) and multiple sclerosis have led to the suggestion that these diseases may have related etiologies…The observed familial clustering of multiple sclerosis and young-adult-onset Hodgkin lymphoma is consistent with the hypothesis that the two conditions share environmental and/or constitutional etiologies.”
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Re: Some Interesting Connections

Postby Annesse » Sat Sep 07, 2013 7:46 am

Continued from previous post...

Are nitric oxide and VEGF linked to cancer also? Studies confirm that this is indeed the case. For instance, in the following study the researchers concluded that nitric oxide and VEGF are involved in breast cancer and that this involvement correlated with “metastasis and poor prognosis.”


Nitric oxide in breast cancer: induction of vascular endothelial growth factor-C and correlation with metastasis and poor prognosis.
Nakamura Y, Yasuoka H, Tsuijmoto M, Yoshidome K, Nakamura M, Kakudo K. 2006. Clin Cancer Res 12(4):1201-7.

“Our data showed a role for NO in stimulating VEGF-C expression in vitro. Formation of its biomarker nitrotyrosine was also correlated with VEGF-C expression and lymph node metastasis.”




In the following study on lymphoma and angiogenesis the researchers stated that high levels of VEGF in blood and tissue are associated with adverse prognosis. In addition, the researchers found that VEGF and VEGF receptors were present in lymphoma cells. The study authors concluded that the role of angiogenesis in malignant lymphoma is evident.



Angiogenesis in malignant lymphoma.

Koster A, Raemaekers JM. 2005. Curr Opin Oncol. 17(6):611-6.

“Angiogenesis plays an important role in the pathophysiology of both solid tumors and hematologic malignancies…High levels of vascular endothelial growth factor in blood and tissue are associated with adverse prognosis. Vascular endothelial growth factor and vascular endothelial growth factor receptors are also present in lymphoma cells. Therapy against vascular endothelial growth factor in animal models is effective and points to both the tumor cell and the host endothelium as targets…The role of angiogenesis in malignant lymphoma is evident…”



In our next study, from Mayo Clinic, researchers found a strong association between blood transfusions, lymphoma, and leukemia. Women who received blood transfusions were almost three times more likely to develop low-grade non-Hodgkin’s lymphoma. The women were also at a higher risk for chronic lymphocytic leukemia.

A lack of nitric oxide to properly regulate VEGF in stored blood would explain why blood transfusions increase the risk of lymphoma and leukemia. “This gas appears to break down almost immediately after red blood cells leave the body, rendering much of the blood stored in blood banks impaired,” stated Dr. Jonathan Stamler, a professor of cardiovascular and pulmonary medicine at Duke University (DukeHealth.org, 2007).

In two separate studies appearing in the Proceedings of the National Academy of Sciences, Duke researchers documented the depletion of nitric oxide in stored blood. “We were surprised at how quickly the blood changes,” stated Dr. Timothy McMahon. We saw clear indications of nitric oxide depletion within the first three hours.”



Blood transfusions and risk of non-Hodgkin’s lymphoma subtypes and chronic lymphocytic leukemia.

Cerhan JR, Wallace RB, Dick F, Kemp J, Parker AS, Zheng W, Sellers TA, Folsom AR. 2001. Cancer Epidemiol Biomarkers Prev. 10(4):361-8.

“…Women who reported ever receiving a blood transfusion were at increased risk for all NHLs…In conclusion, prior blood transfusion was associated with NHL and CLL, and the strongest associations were seen for low-grade NHL, particularly follicular and small lymphocytic NHL.”
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Re: Some Interesting Connections

Postby Anonymoose » Sat Sep 07, 2013 8:08 am

Annesse,
Have any MS patients had success with your diet, documented by reduced symptoms, normalization of nutrient and hormone levels, improved MRI's (including grey and white matter atrophy)? The reason I ask is though you can connect a variety of MS characteristics to protease deficiency, these attributes could also be the result of a lot of other causes. The inflammation cascade could be blamed for many, if not all, of them (which i discovered by trying to blame aldosterone and chasing down all if the implications it has relative to MS...waste of time, excess aldosterone in MS is a product of the inflammatory pathway). Things are further complicated by the fact that your proposed diet changes would alter the microbiome which would significantly impact immune response independent of protease activity.

I'm not trying to discredit your idea. You could be right in your assumption. But given the complexity and overlapping impacts of basically everything on everything in the human body, it's difficult to prove a case without documented results of success using a specific approach.

I'd love to hear about experiences pwms have in following your dietary recommendations.
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Re: Some Interesting Connections

Postby Annesse » Sun Sep 08, 2013 7:23 am

Hi Anonymoose~If it is OK I would like to come back to your question. I would like to keep the final information on homocysteine continuous, plus some of the information I am going to post in the next few days applies.




If the link between MS, endometriosis, and cancer is dysregulated nitric oxide and VEGF, due to elevated levels of homocysteine, then we should find increased levels of homocysteine in cancer, just as we have found in MS.

In the following study on homocysteine and metastatic breast cancer researchers discovered that women with metastatic disease had “significantly higher” homocysteine concentrations.


Raised plasma homocysteine levels in women with metastatic breast cancer.
Makris A, Cladd H, Burcombe RJ, Smith JM, Makris M. 2001. Proc Am Soc Clin Oncol. 20: Abstract 179.

“Women with metastatic disease had significantly higher plasma homocysteine concentrations compared to controls…We conclude that hyperhomocysteinaemia is common in women with metastatic breast cancer.”



In the next study the researchers found that elevated homocysteine (Hcy) levels were significantly linked to an increased risk of breast cancer and that the increased cancer risk was observed in both premenopausal and post-menopausal women. In addition, the researchers felt the link was so strong that homocysteine could be considered a metabolic risk factor for breast cancer.

Plasma homocysteine as a metabolic risk factor for breast cancer: findings from a case-control study in Taiwan.
Chou YC, Lee MS, Wu MH, Shih HL, Yang T, Yu CP, Yu JC, Sun CA. 2007. Breast Cancer Res Tr. 101(2):199-205.

“Elevated plasma Hcy levels were significantly linked to increased risk of breast cancer…Moreover, a similar pattern of enhanced breast cancer risk at higher plasma Hcy levels was observed in both pre-menopausal and post-menopausal women. The current study results seem to suggest a possibility that the plasma Hcy levels could be a metabolic risk factor for breast cancer.”



In the following study the researchers stated that plasma homocysteine (Hcy) is a well-known independent risk factor for coronary heart disease, and is also a risk factor for cancer. In addition, the researchers found that homocysteine increased in parallel with the growth of tumor cells. The study authors concluded, “Conceivably, Hcy may be used as a more accurate tumor marker for monitoring cancer patients during treatment, and hyperhomocysteinemia as a risk factor for carcinogenesis.”


Hyperhomocysteinemia is a risk factor for cancer and a new potential tumor marker.

Wu LL, Wu JT. 2002. Clin Chim Acta 322(1-2):21-8.

“Plasma homocysteine (Hcy), a well-known independent risk factor for coronary heart disease, is also a risk factor for cancer. Results from our studies indicate that Hcy could be used as a tumor marker. We found elevated circulating total homocysteine (tHcy) in cancer patients even though they were not treated with anti-folate drugs. In serial specimens from cancer patients undergoing treatment, the change of tHcy coincided with the concentration of tumor markers. The rapid proliferation of tumor cells contributed to the much higher concentrations of circulating tHcy. Both concentrations of tHcy and tumor marker would increase in parallel during the growth of tumor cell, but only the Hcy concentration would decline in response to tumor cell death…Conceivably, tHcy may be used as a more accurate tumor marker for monitoring cancer patients during treatment, and hyperhomocysteinemia as a risk factor for carcinogenesis.”



Of course, angiogenesis is only one component of cancer, but it is an important component. Cancer spreads to other locations in the body by metastasis. In large measure, it is this ability to spread to other tissues and organs that makes cancer a potentially life-threatening disease. According to the National Cancer Institute, angiogenesis is necessary for cancerous tumors to grow and spread. They state: “Before the 1960s, cancer researchers believed that the blood supply reached tumors simply because pre-existing blood vessels dilated. But later experiments showed that angiogenesis--the growth of the new blood vessels--is necessary for cancerous tumors to keep growing and spreading. Without angiogenesis, tumor growth stops” (National Cancer Institute, 2005).

The National Cancer Institute also states that vascular endothelial growth factor (VEGF), along with another protein called basic fibroblast growth factor appear to be the most important for sustaining tumor growth (National Cancer Institute, 2005). The identification of the reason why VEGF is being dysregulated in patients with MS could be an extremely important factor in reducing the possibility of someone with MS succumbing to cancer.
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Re: Some Interesting Connections

Postby Annesse » Mon Sep 09, 2013 7:27 am

One of the drugs used to treat breast cancer is Herceptin®. The National Cancer Institute states, “Herceptin targets cancer cells that “overexpress,” or make too much of a protein called HER-2 or erbB2, which is found on the surface of some cancer cells. Herceptin attaches to the HER-2 positive cancer cells and slows or stops the growth of the cells. Herceptin is used only to treat breast cancers that are HER-2 positive. HER-2 positive cancers overexpress the HER-2 protein or have amplification (too many copies) of the HER-2 gene.”


The HER proteins regulate cell growth and migration. These functions can be amplified in cancer cells. The study entitled “Persistent transactivation of EGFR and ErbB2/ HER2 by protease-activated receptor-1 promotes breast carcinoma cell invasion” states, “In this study, we report that proteolytic activation of PAR1 by thrombin induces persistent transactivation of EGFR and ErbB2/ HER2 in invasive breast cancer carcinoma” (Arora, 2008).




So, thrombin induces “persistent transactivation of HER2”. Thrombin is an enzyme that presides over the conversion of fibrinogen to fibrin. Transactivation is an increased rate of gene expression. In the following study researchers found that homocysteine potentiates thrombin generation.



Relationships between homocysteine, factor VIIa, and thrombin generation in acute
coronary syndromes.

Al-Obaidi, M.K., H. Philippou, P.J. Stubbs, A. Adami, R. Amersey, M.M. Noble, D.A. Lane. 2000. Circulation 101(4):372-7.


“It has been suggested by clinical, epidemiological, and experimental in vitro studies that homocysteine potentiates thrombin generation…Elevated plasma homocysteine is associated with and may cause elevated Factor VIIa and thrombin generation in patients presenting with ACS. These findings suggest an explanation for the prothrombotic effect of homocysteine in ACS.”


In the following study the researchers found significantly higher levels of thrombin "inhibitors" in EAE and stated, "the physiological importance of excess thrombin in neural tissue is demonstrated by recent experiments which link thrombin with conduction block in the sciatic nerve.”



Autoimmun Rev. 2006 Oct;5(8):528-31. Epub 2006 Mar 21.
Thrombin in inflammatory brain diseases.
Chapman J.


“Inflammatory brain diseases such as multiple sclerosis (MS) include hyperactivation of the coagulation pathway which includes thrombin. In the experimental autoimmune encephalomyelitis (EAE) model we have found significantly higher levels of thrombin inhibitors which include the very early elevation of protease nexin 1. The physiological importance of excess thrombin in neural tissue is demonstrated by recent experiments which link thrombin with conduction block in the sciatic nerve.”
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Re: Some Interesting Connections

Postby Annesse » Mon Sep 09, 2013 7:52 am

Here is some additional information on PAR-1, thrombin and conduction block (failure of impulse transmission at some point along a nerve fiber). So, excess thrombin has implications for breast cancer as well as MS.



Brain. 2008 Apr;131(Pt 4):1113-22. doi: 10.1093/brain/awn005. Epub 2008 Feb 25.
Thrombin receptor PAR-1 on myelin at the node of Ranvier: a new anatomy and physiology of conduction block.
Shavit E, Beilin O, Korczyn AD, Sylantiev C, Aronovich R, Drory VE, Gurwitz D, Horresh I, Bar-Shavit R, Peles E, Chapman J.

"Inflammatory demyelinating diseases of peripheral nerves are associated with altered nerve conduction and with activation of the coagulation pathway. Thrombin mediates many of its effects through protease-activated receptor 1 (PAR-1). We examined the possibility that thrombin may mediate conduction abnormalities through PAR-1 on rat sciatic nerve. PAR-1 was found to be present by both RT-PCR and Western blot analysis of the sciatic nerve. Activation of PAR-1 by a specific peptide agonist caused a 3-fold increase in phosphorylated extracellular signal-regulated kinase (ERK) in the sciatic nerve indicating the existence of functional receptors in the nerve. By confocal immunofluoresence microscopy of the sciatic nerve using anti-PAR-1 antibody and double staining for the paranodal marker contactin-associated protein 1 (Caspr1) or the nodal markers gliomedin and ezrin, the receptor was localized predominantly to myelin microvilli at the node of Ranvier. Thrombin and the PAR-1-specific agonist were applied to exposed rat sciatic nerve and their effects on nerve conduction were measured. Thrombin at concentrations of 100 and 200 U/ml and PAR-1 agonists 150 and 300 muM produced a conduction block within 30 min of application. This effect was maintained for at least 1 h and was reversible by washing. The function of the nodal non-compacted myelin is not well known. The current results implicate this structure and PAR-1 activation in the pathogenesis of conduction block in inflammatory and thrombotic nerve diseases."
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Re: Some Interesting Connections

Postby Annesse » Tue Sep 10, 2013 7:58 am

CELIAC DISEASE, MS, CANCER, AND PROTEASE

Celiac disease (CD) is an autoimmune disease caused by an inability to metabolize gluten, a sticky protein found primarily in wheat, barley, and rye. There is a high correlation of CD with other autoimmune conditions. Autoimmune disorders commonly seen in patients with CD include diabetes, lupus, rheumatoid arthritis, Sjögren’s syndrome, and multiple sclerosis.

Gluten is a protein, so if you lacked protease you would be unable to properly digest gluten, which would explain the association between MS and CD. Proteins that are not properly broken down by protease will elicit an immune response. This is one component of autoimmune disease. We will be discussing this component in MS. An inability to digest proteins will also lead to missing essential amino acids and a lack of vitamin B12. This is the second component of autoimmune disease-the nutritional deficiency component.



If CD patients lack protease, then we should find the same lack of vitamin B12, white matter lesions, high homocysteine, and increased risk of cancer as we have seen in MS.


Studies show that patients with CD are deficient in vitamin B12, which is evidence they are not breaking down animal proteins in addition to gluten. Vitamin B12 is only found attached to dietary animal proteins. The study entitled “Low serum vitamin B12 is common in celiac disease and is not due to autoimmune gastritis” concluded, “Low B12 is common in celiac disease without concurrent pernicious anemia, and may be a presenting manifestation” (Dickey, 2002).



A vitamin B12 deficiency would result in elevated levels of homocysteine. The following study discusses the connections between gluten-sensitive enteropathy (GSE), homocysteine, B12, recurrent miscarriages, and osteoporosis. The authors concluded, “Hyperhomocysteinemia is frequent in newly diagnosed GSE.”

Prevalence of hyperhomocysteinemia in adult gluten-sensitive enteropathy at diagnosis: role of B12, folate, and genetics.
Saibeni, S., A. Lecchi, G. Meucci , M. Cattaneo, L. Tagliabue, E. Rondonotti , S. Formenti , R. De Franchis, M. Vecchi. 2005. Clin Gastroenterol Hepatol. 3(6):574-80.

“Hyperhomocysteinemia, a risk factor for thrombosis, recurrent miscarriages, and osteoporosis, might derive from acquired folate and vitamin B 12 deficiencies…Undiagnosed gluten-sensitive enteropathy (GSE) is associated with vitamin deficiencies, osteoporosis, and recurrent miscarriages. We evaluated the prevalence and the risk factors for hyperhomocysteinemia in patients with newly diagnosed GSE...Results: Hyperhomocysteinemia was more frequent in GSE patients than in control subjects…Multiple regression analysis showed that folate and B12 levels were independently and inversely associated with homocysteine levels...”


Research has shown that even when CD patients follow a careful gluten free diet their homocysteine levels remain high. For instance, in the study entitled “Evidence of poor vitamin status in coeliac patients on a gluten-free diet for 10 years” the researchers stated, “Coeliac patients showed a higher total plasma homocysteine level than the general population, indicative of a poor vitamin status.” The researchers also stated the homocysteine level was a metabolic marker of vitamin deficiency, one of which was vitamin B12. The authors concluded, “This may have clinical implications considering the linkage between vitamin deficiency, elevated total plasma homocysteine levels and cardiovascular disease” (Hallert, 2002).


Low vitamin B12 and high homocysteine would lead to an increased risk of white matter lesions:

In the study entitled “Brain white-matter lesions in celiac disease: a prospective study of 75 diet-treated patients” seventy-five patients with biopsy proven CD were tested for neurologic complications. Ten patients had neurologic findings such as febrile seizures, single generalized seizures, mild ataxia, and muscular hypotonia with retarded motor development. White matter lesions were detected in 15 patients (20%). The study concluded, “Focal white matter lesions in the brain may represent an extraintestinal manifestation of celiac disease” (Kieslich, 2001).



Elevated homocysteine would lead to the same increased risk of cancer as we saw in MS.

Research has found that patients with CD have an increased risk of developing lymphoma and other types of cancer and the level of gluten ingestion didn't appear to make a difference.

In a study conducted at the National Cancer Institute (NIH) in Bethesda, Maryland, and the Karolinska Institute in Sweden, researchers found a more than 5-fold increased risk of non-Hodgkin’s lymphoma in patients with celiac disease. The increased risk of developing lymphoma persisted despite a gluten-free diet. “At this time, we do not know what the actual cause of the link is,” Dr. Ying Gao of the NIH stated. “Prior studies have suggested that celiac disease leads to inflammation and that inflammation drives development of lymphomas.” Dr. Gao concluded, “Taken together, these findings suggest that there might be some underlying mechanisms that lead to both celiac disease and lymphoma” (Gao, 2009).


In the study entitled “Coeliac disease and malignancy” researchers found CD patients were at an increased risk for not only lymphoma, but for other cancers as well (Swinson, 1983). “Patients with coeliac disease also have a greatly increased risk of the development of small-intestinal adenocarcinomas…There were also more oesophageal and pharyngeal squamous carcinomas than expected,” the researchers concluded.



Researchers in Italy have found that patients with CD are more likely to develop thyroid cancer-and the level of gluten ingestion didn’t appear to make a difference (Volta, 2011). “There is a 2.5 fold increased risk of papillary cancer of thyroid for celiac patients. A prompt diagnosis of CD and a strict adherence to a gluten-free diet do not seem to protect from the development of this malignancy,” the researchers concluded.


Homocysteine interferes with nitric oxide and the subsequent regulation of vascular endothelial growth factor (VEGF). In the following study the role of nitric oxide (NO) and VEGF in papillary thyroid cancer (PTC) was discussed. The study concluded, “NO may induce lymph node metastasis via VEGF-D stimulation in PTC.”

Nitric oxide in papillary thyroid carcinoma:induction of vascular endothelial growth factor D and correlation with lymph node metastasis.

Nakamura, Y., H. Yasuoka, H. Zuo, Y. Takamura, A. Miyauchi, M. Nakamura, K. Kakudo. 2006b. J Clin Endocr Metab. 91(4):1582-5.

“Vascular endothelial growth factor-D (VEGF-D) plays an important role in lymph node metastasis via lymphangiogenesis in papillary thyroid carcinoma (PTC…Nitrotyrosine levels were significantly related with VEGF-D immunoreactivity and lymph node metastasis…Our data showed a role for NO in stimulating VEGF-D expression in vitro. The formation of its biomarker, nitrotyrosine, was also correlated with VEGF-D expression in human PTC. NO may induce lymph node metastasis via VEGF-D stimulation in PTC.”


To be continued...
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Re: Some Interesting Connections

Postby PointsNorth » Tue Sep 10, 2013 11:07 am

Annesse,

You ARE barking up the right tree. You are bringing together much of what I have personally experienced.

Crohn's since late 80's
Resection of terminal ileum 1991
MS diagnosis 2003
Struggled w. B12 thereafter
SPMS 2010
1-week symptom relief from CCSVI procedures 2010 and 2011 (suspected B12/homocysteine involvement)
Gluten sensitivity (not Celiac) since 2012
Vitamin deficiencies despite supplementation. Serum levels have been misleading e.g. Vitamin D.

Currently experimenting with cannabis to regulate bowel (some success) and manage spasticity (not so much) I look forward to more direction re:diet etc. !!

Much Thanks, PointsNorth
Albany 2010. Brooklyn 2011
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Re: Some Interesting Connections

Postby Annesse » Tue Sep 10, 2013 6:40 pm

Thank you PointsNorth~

Here is some info on IBD (Crohn's disease and ulcerative colitis), vitamin B12, homocysteine, and garlic from my book. I don't think homocysteine is the real driving factor behind IBD though. I will be posting some additional information on this.

"Elevated homocysteine levels and vitamin B12 deficiencies are common in patients with inflammatory bowel disease (Romagnuolo, 2001; Yakut, 2010). In the following study the researchers concluded there is a high prevalence of elevated homocysteine in ulcerative colitis and Crohn’s disease.

The study also discusses the presence of five endoscopic lesions considered as precancerous and the fact that all of these patients had hyperhomocysteinemia. The researchers concluded: “There is a possible link between colorectal cancer and hyperhomocysteinemia.”

Factors associated with hyperhomocysteinemia in inflammatory bowel disease: prospective study in 81 patients.
Roblin, X., E. Germain, J.M. Phelip, V. Ducros, J. Pofelski, F. Heluwaert, P. Oltean, J.L. Faucheron, B. Bonaz. 2006. Rev Med Interne. 27(2):106-10.

“A high prevalence (52%) of hyperhomocysteinemia is observed in Crohn disease…Five endoscopic lesions considered as precancerous were described; these patients had all had hyperhomocysteinemia…The prevalence of hyperhomocysteinemia is high in UC and in CD. There is a possible link between colorectal cancer and hyperhomocysteinemia…”


Garlic Lowers Homocysteine
Research has shown that garlic can have a profound effect on homocysteine
(Yeh, 2006). Dr. Matthew Budoff, M.D., Professor of Medicine at
UCLA states, “Studies have shown that garlic supplementation can lower
homocysteine levels by up to 35%.” Many of the disease conditions
caused by elevated levels of homocysteine in autoimmune disease such
as migraines, mitral valve prolapse, hypermobility, low magnesium, endometriosis,
and increased risk of cancer could be dramatically reduced
by daily ingestion of garlic.

Garlic can be ingested in a variety of ways. For instance, it can be
added to bone broths to increase their medicinal value, as we have done
in our bone broth recipes. Look for other recipes and opportunities in
your daily cooking to include garlic. Garlic can also be taken in capsule
form. Just be sure it is pure organic whole garlic, not an extract. Garlic tea
is also a very beneficial way to consume garlic.

The following recipe for garlic tea came from a friend’s mother who
is a native of Mexico. Garlic tea is a favorite home remedy in Mexico and
Spain due to its additional healthful properties of being a potent antibacterial
and antiviral. When using garlic tea to fight a bacterial or viral
infection, we find it is especially effective if you start drinking it at the
first sign of illness and continue drinking until you are fully recovered.
You can double the recipe and drink throughout the course of the day.

Ingredients:
• 3–4 cloves organic garlic, smashed with a knife
• 3–4 cups of water
• Raw honey to taste
• Fresh squeezed organic lemon juice to taste

Preparation:
Place smashed cloves of garlic and water in a saucepan and heat to a
gentle simmer. Reduce heat slightly and let steep with the lid on until
the tea has achieved a strong garlic taste. Add honey and lemon to
taste."
Annesse
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Re: Some Interesting Connections

Postby Annesse » Wed Sep 11, 2013 8:39 am

I think the following study is strong evidence that the problem in CD lies with a lack of protease.

In the study celiac patients who were fed a 60-day diet of baked goods made from wheat flour manufactured with sourdough lactobacilli and fungal protease experienced no ill effects.

Clin Gastroenterol Hepatol. 2011 Jan;9(1):24-9. doi: 10.1016/j.cgh.2010.09.025. Epub 2010 Oct 15.
Safety for patients with celiac disease of baked goods made of wheat flour hydrolyzed during food processing.
Greco L, Gobbetti M, Auricchio R, Di Mase R, Landolfo F, Paparo F, Di Cagno R, De Angelis M, Rizzello CG, Cassone A, Terrone G, Timpone L, D'Aniello M, Maglio M, Troncone R, Auricchio S.


"A 60-day diet of baked goods made from hydrolyzed wheat flour, manufactured with sourdough lactobacilli and fungal proteases, was not toxic to patients with CD."



In an additional study from the Netherlands, a team of doctors used a protease derived from Aspergillus niger, a common fungus, to break down whole gluten molecules, as well as the peptides that the immune system is targeting. The lead researcher Dr. Frits Koning stated, “On the basis of our results, there now is a realistic chance that oral supplementation with an enzyme can ensure gluten degradation in the stomach before reaching the small intestine, where it causes problems for people with celiac disease” (Stepniak, 2006). Of course, supplementation would not be necessary if your body had adequate amounts of protease.



Direct evidence of the involvement of the pancreas can also be found in CD. In the study entitled “Is exocrine pancreatic insufficiency in adult coeliac disease a cause of persisting symptoms” researchers concluded, “Low faecal elastase is common in patients with coeliac disease and chronic diarrhoea, suggesting exocrine pancreatic insufficiency” (Leeds, 2007).

Exocrine pancreatic insufficiency is the inability to properly digest food due to a lack of digestive enzymes made by the pancreas. The exocrine pancreas is where DNase I and protease originate. When food isn’t broken down into small enough molecules, it can remain in the small bowel, where it can draw in water and cause diarrhea, one of the primary symptoms of exocrine pancreatic insufficiency.

In an additional study entitled “Pancreatic endocrine and exocrine changes in celiac disease” researchers concluded, “In summary the endocrine and exocrine function of the pancreas may be impaired in celiac disease and their pathogenesis may be closely linked” (Freeman, 2007).



The impairment of the pancreatic “endocrine” function in CD, which is responsible for insulin release, would explain the connection CD has to diabetes. Type I diabetes occurs at a rate of about 0.5% in the general population, but at a rate estimated at 5-10% among celiacs.



Of course, this would also explain the same strong association MS has to type 1 diabetes.

In the following study the researchers concluded that patients with type 1 diabetes are at an enormously increased risk of multiple sclerosis.


Type 1 diabetes and multiple sclerosis: together at last.
Dorman JS, Steenkiste AR, Burke JP, Songini M. 2003. Diabetes Care 10.2337/diacare.26.11.3192 vol. 26 no. 11 3192-3193

“examination of data collected for our Familial Autoimmune and Diabetes (FAD) Study revealed, for the first time, a highly significantly increased prevalence of multiple sclerosis in adults with type 1 diabetes and their first-degree relatives…Thus, we observed a 20-fold increase in the prevalence of multiple sclerosis in our type 1 diabetic women…We therefore conclude that adult women with type 1 diabetes are at an enormously increased risk of multiple sclerosis, and that the answer to questions about the clustering of these disorders is that they are together at last.”
Annesse
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Re: Some Interesting Connections

Postby Annesse » Thu Sep 12, 2013 7:46 am

MS and RA


In the following study published in the Journal of Rheumatology researchers identified an association between MS and rheumatoid arthritis (RA). The researchers stated, “Since a great proportion of our patients developed MS first and subsequently RA, the best explanation for these cases is a predisposition in MS patients to develop another autoimmune disease with common etiologic cofactors.”

J Rheumatol. 2006 May;33(5):1027-8. Epub 2006 Mar 15.

Association of rheumatoid arthritis with multiple sclerosis: report of 14 cases and discussion of its significance.
Toussirot E, Pertuiset E, Martin A, Melac-Ducamp S, Alcalay M, Grardel B, Seror P, Perdriger A, Wendling D, Mulleman D, Beraneck L, Mariette X; Club Rheumatismes et Inflammation

“…Since a great proportion of our patients developed MS first and subsequently RA, the best explanation for these cases is a predisposition in MS patients to develop another autoimmune disease with common etiologic cofactors…”




As early as the 1940s, Dr. Arnold Renshaw of Manchester, England suspected rheumatoid arthritis might stem from an enzyme deficiency that interferes with protein digestion. He based his suspicions, published in the Annals of Rheumatic Disease in 1947, on the high incidence of intestinal atrophy he observed while conducting thousands of autopsies on patients who had rheumatoid arthritis at the time of death.

Dr. Renshaw understood that the inability to digest proteins would lead not only to nutrient deficiencies, it would also result in incompletely digested protein fragments in the bloodstream, which would trigger an immune response. In the following excerpt from his study, Dr. Renshaw stated, “It has been held that the insidious and slowly developing processes of chronic rheumatism may be due to the continued influx of incompletely digested protein fragments into the blood stream.”


Intestinal extract in rheumatic diseases.
Renshaw, A. 1947. Ann Rheum Dis. 6:1 15-35doi:10.1136/ard.6.1.15

“…As a result of numerous post-mortem examinations, sometimes as many as four or six a day for many years, the frequency with which atrophy of the small intestine occurred and the variations in the appearance of this organ when it was systematically opened and examined throughout its entire length impressed itself upon the writer. The conclusion was reached that rheumatoid arthritis might be a deficiency disease, with perhaps some associated allergic basis, and that the deficiency might arise from an inability to deal adequately with protein digestion and metabolism…

It has been held that the insidious and slowly developing processes of chronic rheumatism may be due to the continued influx of incompletely digested protein fragments into the blood stream, which act as antigens against which the antibody content of the circulating blood is low. The antigen-antibody reaction takes place within the cells with subsequent anaphylactic inflammation, the condition being described as allergic. The theory of protein allergy has the support of many workers in this field, one of whom, Gudzent (1940), was able to produce rheumatic tissue lesions in animals by various types of proteins, and observations on patients indicated that food proteins (animal as well as vegetable) are chiefly responsible. They produce under certain conditions antibody-antigen or allergic reactions, with their cytotoxic effects on the connective tissues, and thus lead to rheumatic tissue lesions…”




Lita Lee, Ph.D., a chemist and enzyme nutritionist, explained the connection to an inability to properly digest proteins and arthritis clearly when she wrote:

“All forms of arthritis involve abnormal calcium metabolism. Ninety-nine percent of the body calcium is (or should be) in the bones and teeth. The other one percent, found in the blood, is just as important because it is essential in the blood clotting mechanism, muscle and nerve function, vitamin D function, and the function of hormones that control calcium metabolism (called parathyroid hormones). Of the one percent of calcium in the blood, half is protein-bound and half is ionized. Both require adequate protein digestion. If you are deficient in protein because you can’t digest it, you cannot carry protein-bound calcium. If you lack optimum acidity from inadequate digestion of protein, you will not have enough ionized calcium. In either case, you are a candidate for arthritis.


The abnormal deposit of calcium is one of the factors involved in arthritis and arthritic inflammation. Soft tissue, any kind of body tissue other than bones and teeth, is a target for depositing calcium. Wherever this happens, pathology occurs: in the joints, around inflamed areas (osteoarthritis), in the arteries (arteriosclerosis), in the kidneys (kidney stones), in the soft lenses of the eyes (cataracts), in the brain (stroke) and so on” (Lee, 2009).
Annesse
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Re: Some Interesting Connections

Postby Annesse » Fri Sep 13, 2013 7:50 am

The inability to properly digest proteins would also lead to the same lack of vitamin B12, high homocysteine, white matter lesions, dysregulated VEGF, and increased risk cancer in RA as we saw in patients with MS.

In the following study researchers found a high incidence of anemia and low vitamin B12 in not only RA patients, but in psoriatic arthritis and lupus as well. The researchers concluded that the incidences of anemia and decreased vitamin B12 levels were high in these three groups of patients.


Anemia, serum vitamin B12, and folic acid in patients with rheumatoid arthritis, psoriatic arthritis, and systemic lupus erythematosus.
Segal, R., Y. Baumoehl, O. Elkayam, D. Levartovsky, I. Litinsky, D. Paran, I. Wigler, B. Habot , A. Leibovitz, B.A. Sela, D. Caspi. 2004. Rheumatol Int. 2004 Jan;24(1):14-9. Epub 2003 Apr 29.

“Although anemia is frequent in inflammatory rheumatic diseases, data regarding vitamin B12 status is scarce. The purpose of this study was to analyze the incidence and nature of B12 and folic acid (FA) deficiencies in a cohort of rheumatic patients with rheumatoid arthritis (RA), psoriatic arthritis (PsA), and systemic lupus erythematosus (SLE)…The incidence of anemia was high: 49%, 46%, and 35%, in RA, SLE, and PsA, respectively. Low levels of serum B12 were also frequent (24%), with almost similar occurrence in the three disease groups…The incidences of anemia and decreased serum B12 levels were high in these three groups of rheumatic patients…”




In the following study the researchers stated that elevated homocysteine levels occur commonly in patients with rheumatoid arthritis.

Abnormal homocysteine metabolism in rheumatoid arthritis.
Roubenoff, R., P. Dellaripa, M.R. Nadeau, L.W. Abad, B.A. Muldoon, J. Selhub, I.H. Rosenberg IH. 1997. Arthritis Rheum. 40(4):718-22.

“…Elevated tHcy levels occur commonly in patients with RA, and may explain some of the increased cardiovascular mortality seen in such patients. Studies of the prevalence and mechanism of hyperhomocysteinemia in RA are warranted.”





In the following study the researchers concluded that the presence of white matter lesions was assoicated with homocysteine in patients with RA.



The role of homocysteine as a significant risk factor for white matter lesions in Japanese women with rheumatoid arthritis.

Futoshi Anana,Takayuki Masakib, Hiroshi Tatsukawac, Shuji Naganoc, Motohiro Oribed, Nobuoki Eshimae, Tetsunori Saikawaf, Hironobu Yoshimatsuba

Plasma total homocysteine (tHcy), which increases with diabetes, has been flagged as a novel predictor for cerebrovascular events. We tested the hypothesis that the presence of WML correlates with tHcy in rheumatoid arthritis patients. Based on brain magnetic resonance imaging findings, 65 rheumatoid arthritis patients were divided into 2 groups: WML-positive group (61 ± 6 years, mean ± SD; n = 25) and WML-negative group (60 ± 7 years, n = 40). The level of metabolic parameters was assessed by total cholesterol, triglycerides, high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, fasting plasma glucose, and homocysteine (tHcy). The duration of rheumatoid arthritis was longer in the WML-positive group than in the WML-negative group (P < .05). Plasma levels of triglyceride was higher whereas high-density lipoprotein cholesterol was lower in the WML-positive group than in the WML-negative group (P < .05 and P < .01, respectively). Fasting plasma glucose (P < .05) and tHcy (<.0001) levels were higher in the WML-positive group than in the WML-negative group. Multivariate logistic analysis revealed that WML was independently predicted by the tHcy (odds ratio, 1.35; 95% confidence interval, 1.12-1.63; P < .0001). Our findings indicate that the presence of WML was associated with the tHcy in Japanese patients with rheumatoid arthritis.




Elevated homocysteine would lead to the same increased risk of cardiovascular disease in RA and association with COPD as we saw in MS.

In a study published in Arthritis and Rheumatism researchers found there was a 50% increased risk of death from ischemic heart disease and stroke in rheumatoid arthritis patients compared to the general population (Avina-Zubieta, 2008).

An additional study published in the Journal of Internal Medicine looked at the risk of ischemic heart disease associated with rheumatoid arthritis and concluded, “The risk of having a heart attack is 60% higher just a year after a patient has been diagnosed with rheumatoid arthritis…” (Wiley-Blackwell, 2010).




A study presented at the EULAR (European League Against Rheumatism) 2011 Annual Congress has confirmed the link between rheumatoid arthritis and COPD. An article discussing this study published in News-Medical stated, “Patients with rheumatoid arthritis are two times more likely to have COPD than healthy controls. The study, of 15,766 patients with RA and 15,340 controls, found that the prevalence of COPD was significantly higher in RA patients than healthy controls. Interestingly, the link was still significant after risk factors common in both RA and COPD patients, such as smoking, obesity and socioeconomic status, were controlled for” (News- Medical, 2011).




RA patients also have a greatly increased risk of developing lymphoma and other types of cancer, due to dysregulated VEGF.

An article from Arthritis Today discusses the link between RA and lymphoma (Flanigan, 2013): “In an investigation, published in Arthritis & Rheumatism, Swedish researchers mined a national registry of nearly 75,000 RA patients and analyzed medical records and case histories of a subset of 378 RA patients who had developed lymphoma between 1964 and 1995 and 378 lymphoma-free patients. They found a dramatic association between lymphoma and disease activity, which is determined by currently swollen or tender joints, increased levels of inflammatory markers and X-ray evidence of erosion in at least one joint.

Compared with patients with low RA activity, those with medium disease activity showed an eight-fold increase in the likelihood of developing lymphoma. For those with high activity, the probability took a staggering 70-fold jump…”





In the following study researchers discussed the connection between RA, angiogenesis, and VEGF. The researchers stated, “the potent pro-angiogenic cytokine vascular endothelial growth factor (VEGF) has been demonstrated to have a central involvement in the angiogenic process in RA.”



The role of the angiogenic molecule VEGF in the pathogenesis of rheumatoid arthritis.
Afuwape, A.O., S. Kiriakidis S, E.M. Paleolog. 2002. Histol Histopathol. 17(3):961-72.

“The expansion of the synovial lining of joints in rheumatoid arthritis (RA), and the subsequent invasion by the pannus of underlying cartilage and bone, necessitates an increase in the vascular supply to the synovium, to cope with the increased requirement for oxygen and nutrients. New blood vessel formation - ‘angiogenesis’ - is now recognised as a key event in the formation and maintenance of the pannus in RA. Although many pro-angiogenic factors have been demonstrated to be expressed in RA synovium, the potent pro-angiogenic cytokine vascular endothelial growth factor (VEGF) has been demonstrated to have a central involvement in the angiogenic process in RA. The additional activity of VEGF as a vascular permeability factor may also increase oedema and hence joint swelling in RA. Several studies, including those from the Kennedy Institute of Rheumatology Division, have shown that targeting angiogenesis in animal models of arthritis ameliorates disease…”




I thought this was interesting, Gilyena (FTY720) works, in part, by inhibiting VEGF-induced vascular permeability.

J Biol Chem. 2003 Nov 21;278(47):47281-90. Epub 2003 Sep 3.
Phosphorylation and action of the immunomodulator FTY720 inhibits vascular endothelial cell growth factor-induced vascular permeability.
Sanchez T, Estrada-Hernandez T, Paik JH, Wu MT, Venkataraman K, Brinkmann V, Claffey K, Hla T.

"...Furthermore, oral FTY720 administration in mice potently blocked VEGF-induced vascular permeability in vivo. These findings suggest that FTY720 or its analogs may find utility in the therapeutic regulation of vascular permeability, an important process in angiogenesis, inflammation, and pathological conditions such as sepsis, hypoxia, and solid tumor growth."
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