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Hepatitis C Autoimmunity and Gluten by Jeffrey Dach MD

2013-05-01T01:18:45Z

Hepatitis C, Autoimmunity and Gluten

by Jeffrey Dach MD

Unethical Advertising for a Disease

Advertisement to draw attention to a disease should raise a red warning flag. A basic rule is that real diseases don't need any advertising, Only phony or fake diseases require advertising, to increase sales and profits for the drug for the new disease. In my opinion, such advertising is unethical, and these Hepatitis C ads (upper left) have raised ethical concerns. (14-16) Upper Left ad courtesy of Roche.

Case Report:

Jill is a 52 year old nurse who contracted Hepatitis C after a needle stick at the hospital ten years ago. She has done well with occasional mild liver enzyme elevations and fluctuations in her platelet count which always seem to resolve on their own.

In the past, Jill's doctors have always offered the usual Hepatitis C treatment with interferon and ribaviron. Because of potential adverse side effects , she has so far declined treatment. Now, Jill's doctors are recommending two new drugs, boceprevir (Victrelis) and telaprevir (Incivek). Jill is asking for advice. What should she do?

Problems with Viral Causation of Hepatitis C

Critics have pointed out viral liver infections with Hepatitis A and B are real diseases in which the virus can be isolated in culture from infected individuals, and animal disease can be produced by injecting the virus into animals. Thirdly, a vaccine against the virus can be produced in the lab. These criteria are called Koch's postulates, used for one hundred years to prove microbial causation of disease. None of these Koch's Postulates are satisfied for Hepatitis C, raising questions about the scientific basis for viral causation.

With hepatitis C, Koch's Postulates have been thrown out the window, changing the diagnosis to a new technique called RNA sequencing with the PCR test (polymerase chain reaction).(17) Modern microbiology has accepted this change, no longer requiring satisfaction of Koch's Postulates. I would question the validity of this, and instead examine the profit motives involved. Huge amounts of money are at stake in the sale of drugs to treat the new disease.

Asymptomatic Hep C - Outcomes are Mild

Left Image Hep C Ad courtesy of Jon Cox

In a 25-year study of the outcomes of hepatitis C virus infection in 738 people, outcomes were relatively mild: After 25 years, most (85%) had no or mild fibrosis, and only 2% had cirrhosis. Nearly one-fifth spontaneously recovered.(2) These mild outcomes would raise questions about the merits of treating asymptomatic individuals with toxic Hep C treatments.(8)

Is Hepatitis C an Auto-Immune Disease?

Many clinical features of Hepatitis C resemble an auto-immune disease, such as the long duration, chronic nature and association with other auto-immune symptoms.

According to Dr Strassburg, "Based on biochemical and clinical features, Hep C is almost indistinguishable from autoimmune hepatitis,"(4)

Viral causation of Hepatitis C is accepted as dogma by modern medicine. Will this be modified or overturned in the future and changed to an autoimmune disease? We will have to wait and see.

Left Image: Hep C ad posted on the side of a bus features an aging rocker. Courtesy of Vertex Pharmaceuticals Inc.

Hep C and the Auto-immune and Gluten Connection

In addition to itself being an auto-immune liver disease similar to auto-immune hepatitis, Hepatitis C is associated with various other auto-immune symptoms such as arthralgias, arthritis, vasculitis and sicca syndrome (Sjogrens). (3,4) This type of association might raise the suspicion that Hep C is an auto-immune disease related to gluten exposure and underlying gluten sensitivity. Both gluten sensitivity and celiac disease are known to be associated with autoimmune disease and liver disease.(5,6,7)

According to Kenneth D Fine MD, "hepatitis C appears to be the most common hepatic disease associated with the development of celiac sprue."(5)

True enough, when one examines the medical literature, Hep C does have a strong association with gluten sensitivity and celiac disease. Surprisingly, conventional drug treatment with interferon may exacerbate the autoimmune features, and activate a previously "Silent Celiac Disease"(6)

What Causes Progression of Hep C ?

Although most Hep C patients have a mild outcome, some will progress to advanced liver disease with 30,000 deaths from cirrhosis and liver failure attributed to Hepatitis C annually. What factors predict progression of disease? We don't know. However, one such factor has been defined as LPS and Leaky Gut. Hepatitis C has been linked to Leaky Gut, LPS translocation, Gluten sensitivity, and Celiac Disease.(9)

According to Dr Sandler, "LPS-induced local and systemic inflammation is associated with cirrhosis and predicts progression to end-stage liver disease in patients with HBV or HCV infection."(9)

LPS is lipo-poly-sachharide coating from gram negative bacteria that enter the liver through the portal circulation. They enter because of "leaky gut". Allesio Fasano's group at the University of Maryland has worked out the mechanism involved in increased gut permeability (leaky gut), The most common cause for a dysfunctional mucosal barrier (leaky gut) is gluten consumption in genetically predisposed individuals.(18)

If all the above is true, one might argue that all Hep C patients should be tested for LPS antibodies (Cyrex array 2), as well as gluten sensitivity with anti-gliadin antibodies (Cyrex or Enterolabs). One might then expect Hep C liver patients to benefit from a strict gluten free diet as in this report of 4 patients with liver failure who recovered on a gluten free diet.(21)

Hep C and Treatment with LDN

Low Dose Naltrexone (LDN) is beneficial for various autoimmune diseases. therefore benefit in Hepatitis C patients might be expected. (Nola Hepper patient case report )

Burt Berkson MD and Triple Antioxidant Therapy

Burt Berkson MD has shared his experience treating Hep C patients with triple anti-oxidant therapy: alpha lipoic acid, selenium and silymarin with excellent recovery in three patients with advanced liver disease .(19,20)

Hebrew University in Jerusalem - Natural Medicine for Hep C

Dr Melhem from the Liver Unit of Hebrew University reported on natural treatment of Hep C in the 2005 issue of Gasteroenterology.(22) Dr. Melman treated 50 chronic Hep C patients with oral and IV antioxidants over 20 weeks with glycyrrhizin, schisandra, silymarin, ascorbic acid, lipoic acid, L-glutathione, and alpha-tocopherol. Four different intravenous preparations, glycyrrhizin, ascorbic acid, L-glutathione, B-complex were given twice weekly for the first 10 weeks, and followed up for an additional 20 weeks. Normalization of liver enzymes occurred in 44% of patients who had elevated pretreatment ALT levels.(22)

Hepatitis C may Benefit from Phlebotomy

Iron accumulation in liver in patients genetic hemochromatosis can cause mild elevations in liver enzymes on lab testing, and lead to more severe hepatic dysfunction and cirrhosis. Could reduction in iron stores be beneficial for Hepatitis C patients? A study from Japan shows that liver enzymes may normalize in Hepatitis C patients after repeated phlebotomies.(23) Others have confirmed that iron depletion may be beneficial,

Conclusion:

Hep C advertising campaigns raise warning flags and serious ethical concerns about the motivations of the drug companies. Lack of virus isolation from infected individuals and animal models, lack of a vaccine, and failure to satisfy Koch's Postulates of causation, raise questions about proof of viral causation. The mild clinical outcomes, and long term, chronic auto-immune nature of the illness suggests causation may be auto-immune, or perhaps another cause which is more complex than a simple viral model.

The mild outcomes in asymptomatic individuals with positive Hep C RNA testing raises a question about the merits of treating asymptomatic individuals with expensive drug regimens which carry adverse side effects,

If Hepatitis C causation is autoimmune, then leaky gut, LPS translocation to the liver through the portal circulation, and underlying gluten sensitivity should all be explored with lab testing. This would include gliadin sub fraction antibody testing, and a strict gluten free diet.

There has been renewed interest in natural treatments for Hepatitis C with oral and IV antioxidants, alpha lipoic acid and Low Dose Naltrexone which may improve clinical status without adverse effects.

Jeffrey Dach MD

Articles with related interest:

Four part series on Gluten and Leaky Gut :
part one
part two
part three
part four

Links and references

1) http://www.myspace.com/georgedhenderson/blog/536199261
Hepatitis C, Gluten, Casein and the Folly of Agriculture
Gluten and Casein as Factors responsible for the Characteristic Diseases of Chronic Hepatitis C

2) http://www.ncbi.nlm.nih.gov/pubmed/22740714
J Infect Dis. 2012 Sep 1;206(5):654-61.
A 25-year study of the clinical and histologic outcomes of hepatitis C virus infection and its modes of transmission in a cohort of initially asymptomatic blood donors.Allison RD, Conry-Cantilena C, Koziol D, Schechterly C, Ness P, Gibble J, Kleiner DE, Ghany MG, Alter HJ.Source Department of Transfusion Medicine, National Institutes of Health, Bethesda, MD, USA.

A total of 738 volunteer blood donors who were positive for anti-hepatitis C virus (HCV) were assessed for risk factors and outcomes for up to 15 years within the study and up to 54 years from the estimated onset of infection.
METHODS:A third-generation recombinant immunoblot assay (RIBA) was performed to distinguish true from false anti-HCV reactivity. Findings of HCV polymerase chain reaction classified subjects as having chronic HCV infection or as having recovered. Liver biopsy specimens were staged by Ishak fibrosis score and graded by histologic activity index.
RESULTS:Of 738 anti-HCV-positive subjects, 469 (64%) had positive RIBA results, 217 (29%) had negative results, and 52 (7%) had indeterminate results. Primary independent risk factors were injection drug use (odds ratio [OR], 35.0; P < .0001), blood transfusion (OR, 9.9; P < .0001), and intranasal cocaine use, including 79 "snorters" who repeatedly denied injection drug use or blood transfusion (OR, 8.5; P < .0001). Classification and regression tree and random forest analyses confirmed these risk factors. A total of 384 RIBA-positive donors (82%) were HCV RNA positive; of these, liver biopsy specimens from 185 (48%) showed no fibrosis in 33%, mild fibrosis in 52%, bridging fibrosis in 12%, and cirrhosis in 2% a mean duration of 25 years after infection. Analysis of 63 repeat biopsy specimens showed that 8% progressed ≥2 Ishak stages over 5 years (mean progression, 0.06 Ishak stages/year).
CONCLUSIONS:Injection drug use and blood transfusion before 1990 are dominant risk factors for HCV acquisition; intranasal cocaine use may be a surreptitious route of parenteral spread. After a mean of 25 years of HCV infection, histologic outcomes were relatively mild: 85% had no or mild fibrosis, and only 2% had cirrhosis. Nearly one-fifth spontaneously recovered.

3) http://www.ncbi.nlm.nih.gov/pubmed/22155016
Autoimmun Rev. 2012 Jul;11(9):659-63.
Autoantibodies in patients with chronic hepatitis C virus infection: pitfalls for the diagnosis of rheumatic diseases.
Palazzi C, Buskila D, D'Angelo S, D'Amico E, Olivieri I.
Rheumatology Department of Lucania, San Carlo Hospital of Potenza and Madonna delle Grazie Hospital of Matera, Italy.

Abstract Hepatitis C virus infection (HCV) is one of the best mimes in medicine. About 40-70% of patients suffering from this disorder develop at least one extra-hepatic disorder that can have a rheumatic nature (arthralgias, arthritis, vasculitis and sicca syndrome) and must be differentiated from the primitive rheumatic diseases. In addition, HCV infection can also alter the laboratory tests. Several alterations of first line laboratory tests can be usually found in both chronic HCV infection and chronic inflammatory rheumatic disorders. In the present review we analyze the interference of HCV in tests more specifically used in rheumatology: rheumatoid factor and other autoantibodies (ANA, anti-ENA, ANCA, anti-DNA, antiphospholipid, anti-CCP). In patients suffering from HCV infection, the diagnosis of connective tissue diseases (CTD) or rheumatoid arthritis (RA) should be made only when the detected symptoms or laboratory data are not inducible by HCV, otherwise only a diagnosis of "possible CTD" or "possible RA" should be considered.

4) http://www.ncbi.nlm.nih.gov/pubmed/14550873
Autoimmun Rev. 2003 Oct;2(6):322-31.
Autoimmunity and hepatitis C.
Strassburg CP, Vogel A, Manns MP.
Source Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Carl-Neuberg-Str. 1, D-30625 Hannover, Germany.

Abstract Hepatitis C is a widespread chronic liver disease leading to cirrhosis and to the complications of portal hypertension. Based on biochemical and clinical features, it is almost indistinguishable from autoimmune hepatitis, which is characterized by the absence of viral infection, and other causes of chronic liver diseases, and represents a classical autoimmune disease with loss of immunological tolerance of liver tissue. Although the differentiation between both diseases is not difficult due the availability of diagnostic viral markers, it is well recognized that not only are autoantibodies present in autoimmune hepatitis frequently detected in hepatitis C, but also that an array of immune-mediated symptoms and diseases occur in patients with chronic hepatitis C. This has prompted research aimed at identifying a link between hepatitis C and autoimmunity, and autoimmune hepatitis in particular. This review focuses on the general immunological mechanisms linking viral infections with autoimmunity and includes the specific features of hepatitis C- and D-associated autoimmunity. Virus infection remains at the center of molecular and cellular research aimed at identifying the forces driving human autoimmunity and autoimmune diseases.

5)www.nature.com/ajg/journal/v96/n1/abs/ajg200124a.html
The American Journal of Gastroenterology (2001) 96, 138–145;

Celiac sprue: another autoimmune syndrome associated with hepatitis C. Kenneth D Fine MD, Frederick Ogunji PhD, Yasser Saloum MD, Shari Beharry BS, Jeffrey Crippin MD and Jeffrey Weinstein MD

Celiac sprue is being diagnosed with increasing frequency by screening individuals with epidemiologically associated autoimmune syndromes. We sought to test our hypothesis that hepatitis C also may predispose to celiac sprue because it can trigger autoimmune reactions.
METHODS:Two hundred fifty-nine consecutively evaluated patients with chronic hepatitis C infection, 59 with autoimmune liver disease, 137 with other hepatic diseases, 356 with various GI syndromes, and 221 normal volunteers underwent serologic screening for celiac sprue. Patients with antigliadin, antiendomysial, and antitissue transglutaminase antibodies in serum underwent duodenoscopy and biopsy.
RESULTS:There was a statistically significantly higher prevalence of antigliadin antibody in all groups of patients with liver disease compared with GI controls and normal controls. However, only patients with hepatitis C (n = 3; 1.2%) or autoimmune liver disease (n = 2; 3.4%) had antiendomysial/antitissue transglutaminase antibody in serum. One of 221 normal volunteers (0.4%) was antigliadin, antiendomysial, and antitissue transglutaminase positive; this individual also was found to have hepatitis C (previously undiagnosed). Each of these six individuals had mild intestinal symptoms, duodenal histopathology consistent with celiac sprue, and the celiac-associated HLA-DQ2 allele. Five of the six followed a prescribed gluten-free diet and experienced symptomatic improvement.
CONCLUSION:Celiac sprue is epidemiologically associated with chronic hepatitis C infection and with autoimmune liver disease. Because hepatitis C is much more frequently encountered than autoimmune liver disease, hepatitis C appears to be the most common hepatic disease associated with the development of celiac sprue.

6) http://www.ncbi.nlm.nih.gov/pubmed/15492610
J Clin Gastroenterol. 2004 Nov-Dec;38(10):901-5.
Silent celiac disease in chronic hepatitis C: impact of interferon treatment on the disease onset and clinical outcome.
Durante-Mangoni E, Iardino P, Resse M, Cesaro G, Sica A, Farzati B, Ruggiero G, Adinolfi LE.
Divisions of Internal Medicine and Hepatology, Second University of Naples Medical School, Napoli, Italy.

To assess the impact of interferon treatment on celiac disease onset in hepatitis C patients and to clarify its clinical relevance and outcome.
BACKGROUND:Hepatitis C is associated with autoimmunity, which can be exacerbated by interferon treatment. Cases of celiac disease activation during interferon treatment have been reported.
STUDY:Retrospective evaluation of 534 hepatitis C patients with or without symptoms compatible with celiac disease onset during interferon treatment and 225 controls. Anti-transglutaminase antibodies were assayed. HLA-DQA1 and -B1 loci were typed. Upper gastrointestinal endoscopy was applied to confirm the diagnosis in antibody-positive patients.
RESULTS:Anti-transglutaminase antibodies were detected before treatment in 1.3% of hepatitis C patients and in 0.4% of controls (not significant). Eighty-six percent of patients with anti-transglutaminase antibodies showed activation of celiac disease while on interferon. Symptoms ranged from mild to severe, and interferon had to be discontinued in 2 of 7 (29%) patients. Symptoms disappeared in 6 of 7 patients after interferon withdrawal. Onset of symptoms compatible with celiac disease during interferon therapy was significantly associated with the presence of anti-transglutaminase antibodies (OR 53).
CONCLUSIONS:
In hepatitis C patients, the activation of silent celiac disease during interferon treatment is almost universal and should be suspected, but it uncommonly requires interferon treatment discontinuation. Symptoms subside after interferon withdrawal.

7) http://www.ncbi.nlm.nih.gov/pubmed/18231858
Dig Dis Sci. 2008 Aug;53(8):2151-5. doi: 10.1007/s10620-007-0146-1. Epub 2008 Jan 31.
Celiac disease and non-organ-specific autoantibodies in patients with chronic hepatitis C virus infection.
Ruggeri C, La Masa AT, Rudi S, Squadrito G, Di Pasquale G, Maimone S, Caccamo G, Pellegrino S, Raimondo G, Magazzù G. Cystic Fibrosis and Paediatric Gastroenterology Unit, Dipartimento di Scienze Pediatriche Mediche e Chirurgiche, Università di Messina, Messina, Italy.

Considering that celiac disease (CD) is an autoimmune-based entity and the hepatitis C virus is suspected of being able to trigging autoimmune reactions, it has been hypothesized that hepatitis C virus infection might predispose to CD. The aim of this study was to investigate CD-related antibodies in a large series of hepatitis C virus-infected subjects that were also tested for non-organ-specific autoantibodies (NOSA) as indirect marker of autoimmune disorders.
METHODS: Two hundred and forty-four patients with chronic hepatitis C virus infection (HCV-patients) and 121 patients with HCV-negative liver disease (non-HCV-patients) underwent NOSA determination and celiac serology (firstly, anti-tissue transglutaminase antibodies, then the cases which tested positive were subsequently evaluated for the presence of antiendomysial antibodies). Serum samples from 42 of the HCV-patients who underwent interferon-alpha therapy after enrollment were tested for celiac antibodies and NOSA even after stopping treatment. Additionally, sera from 1,230 blood donors were assayed for celiac serology as healthy control population.
RESULTS: Positive anti-endomysial antibodies (AEA) were found in 5/244 (2%) HCV-patients, 1/121 (0.8%) non-HCV-patients and 2/1,230 (0.16%) blood donors, with a significant difference between HCV-patients and blood donors (P = 0.02; Odds ratio 12.8; 95% Confidence Interval 2.4-66). NOSA were found in 51 HCV-patients but only one of them had positive AEA. Eight out of 42 HCV-patients treated with interferon-alpha developed NOSA under therapy and none of them had CD antibodies.
CONCLUSIONS:

AEA occur in 2% of HCV-patients and their presence is independent of other patterns of autoimmunity.

--------------------------------------------------

8) http://www.sciencemag.org/content/285/5424/26.summary
The Scientific Challenge of Hepatitis C Jon Cohen Science 1999 285: 26-30. (in News Focus
for HCV there appears to be no such thing as a typical infection. The severity of the disease varies greatly from person to person and--to the frustration of clinicians and patients--there are few reliable indicators to predict who will do well or badly.
Evidence accumulated over the past few years indicates that the immune systems of 15% to 25% of people infected with HCV will overcome the virus during the initial infection and clear it from the bloodstream. The remaining 75% to 85% will develop a chronic infection.
NIH's Alter and Jay Hoofnagle from the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) reported results from a 7-year study of more than 400 would-be blood donors who had tested positive for HCV and whose infection could, in most cases, be traced to a transfusion or injection. Even though they had been infected for an average of nearly 20 years, only 13% had severe fibrosis and a mere 2% had cirrhosis. These results closely match those from an Irish study published in the 22 April New England Journal of Medicine that charted disease progression over 17 years in 376 women who had received contaminated blood products in the 1970s. And a study by NIDDK's Leonard Seeff looked at 8568 blood samples stored by the U.S. Air Force between 1948 and 1954 and found that 17 tested positive for HCV antibodies; current records revealed that only one of those infected individuals (5.8%) died from liver disease.

LPS Leaky Gut - makes Hep C prognosis Worse
Gluten Connection ?

9) http://www.ncbi.nlm.nih.gov/pubmed/21726511
Gastroenterology. 2011 Oct;141(4):1220-30, 1230.e1-3.
Host response to translocated microbial products predicts outcomes of patients with HBV or HCV infection.
Sandler NG, Koh C, Roque A, Eccleston JL, Siegel RB, Demino M, Kleiner DE, Deeks SG, Liang TJ, Heller T, Douek DC.
Source Human Immunology Section, Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland 20892, USA.

Chronic infection with hepatitis B or C virus (HBV or HCV) is a leading cause of cirrhosis by unknown mechanisms of pathogenesis. Translocation of gut microbial products into the systemic circulation might increase because of increased intestinal permeability, bacterial overgrowth, or impaired clearance of microbial products by Kupffer cells. We investigated whether the extent and progression of liver disease in patients with chronic HBV or HCV infection are associated with microbial translocation and subsequent activation of monocytes.
METHODS:in a retrospective study, we analyzed data from 16 patients with minimal fibrosis, 68 with cirrhosis, and 67 uninfected volunteers. We analyzed plasma levels of soluble CD14 (sCD14), intestinal fatty acid binding protein, and interleukin-6 by enzyme-linked immunosorbent assay, and lipopolysaccharide (LPS) by the limulus amebocyte lysate assay, at presentation and after antiviral treatment.
RESULTS:Compared with uninfected individuals, HCV- and HBV-infected individuals had higher plasma levels of LPS, intestinal fatty acid binding protein (indicating enterocyte death), sCD14 (produced upon LPS activation of monocytes), and interleukin-6. Portal hypertension, indicated by low platelet counts, was associated with enterocyte death (P=.045 at presentation, P<.0001 after therapy). Levels of sCD14 correlated with markers of hepatic inflammation (P=.02 for aspartate aminotransferase, P=.002 for ferritin) and fibrosis (P<.0001 for γ-glutamyl transpeptidase, P=.01 for alkaline phosphatase, P<.0001 for α-fetoprotein). Compared to subjects with minimal fibrosis, subjects with severe fibrosis at presentation had higher plasma levels of sCD14 (P=.01) and more hepatic CD14+ cells (P=.0002); each increased risk for disease progression (P=.0009 and P=.005, respectively).
CONCLUSIONS:LPS-induced local and systemic inflammation is associated with cirrhosis and predicts progression to end-stage liver disease in patients with HBV or HCV infection.

10) http://www.ncbi.nlm.nih.gov/pmc/articles/PMC415836/
J Virol. 2004 June; 78(11): 5867–5874.
Hepatitis C Virus Persistence after Spontaneous or Treatment-Induced Resolution of Hepatitis C
Tram N. Q. Pham,1 Sonya A. MacParland,1 Patricia M. Mulrooney,1 Helen Cooksley,2 Nikolai V. Naoumov,2 and Tomasz I. Michalak1,3,*Molecular Virology and Hepatology Research, Division of Basic Medical Science,

11) https://sites.google.com/site/jccglutenfree/liverdisease2
Liver and Pancreas Disease The Gluten File

LDN for Hep C - autoimmune disorder

12) http://nolahepper.blogspot.com/2010/06/treating-hepatitis-c-with-low-dose.html
NOLA Hepper - Living in New Orleans, Louisiana with Hepatitis C and how taking Low Dose Naltrexone (LDN)to treat it is giving me back my life.

13) http://www.myspace.com/georgedhenderson/blog/536199261
Hepatitis C, Gluten, Casein and the Folly of Agriculture Ron Hoggan, 1997

Gluten and Casein as Factors responsible for the Characteristic Diseases of Chronic Hepatitis C

It so happens that the auto-immune symptoms associated with celiac and gluten sensitivity diseases, including liver and gall-bladder disease, and which usually resolve slowly on a strict gluten and dairy-free diet, are essentially identical to the various syndromes seen in chronic Hep C, especially during or after interferon-alpha treatment.

--------------------------------------

Unethical Advertising

14) http://abcnews.go.com/Health/story?id=117868&page=1#.UXHHzzdaZac
FDA to Examine Hepatitis C Campaign
W A S H I N G T O N, Sept. 14

(ad image of bruised face)

15) http://amarillo.com/stories/111200/tex_healthoff.shtml
Roche Launches New Campaign to Educate Consumers About Hepatitis C
NUTLEY, New Jersey (July 26, 2005) - Roche announced today the launch of a major new campaign to motivate hepatitis C patients who have been diagnosed with the disease to take the critical step of discussing prescription treatment with a liver specialist or hepatitis C-treating physician.

16) http://www.natap.org/2005/HCV/072905_01.htm
Health officials demand changes in hepatitis C ads
Posted: Sunday, November 12, 2000

17) http://www.ncbi.nlm.nih.gov/pmc/articles/PMC172879/

Clin Microbiol Rev. 1996 January; 9(1): 18–33.
Sequence-based identification of microbial pathogens: a reconsideration of Koch's postulates.D N Fredericks and D A Relman Department of Medicine, Stanford University School of Medicine, California 94305, USA. Over 100 years ago, Robert Koch introduced his ideas about how to prove a causal relationship between a microorganism and a disease. Koch's postulates created a scientific standard for causal evidence that established the credibility of microbes as pathogens and led to the development of modern microbiology. In more recent times, Koch's postulates have evolved to accommodate a broader understanding of the host-parasite relationship as well as experimental advances. Techniques such as in situ hybridization, PCR, and representational difference analysis reveal previously uncharacterized, fastidious or uncultivated, microbial pathogens that resist the application of Koch's original postulates, but they also provide new approaches for proving disease causation. In particular, the increasing reliance on sequence-based methods for microbial identification requires a reassessment of the original postulates and the rationale that guided Koch and later revisionists. Recent investigations of Whipple's disease, human ehrlichiosis, hepatitis C, hantavirus pulmonary syndrome, and Kaposi's sarcoma illustrate some of these issues. A set of molecular guidelines for establishing disease causation with sequence-based technology is proposed, and the importance of the scientific concordance of evidence in supporting causal associations is emphasized.

18) http://www.ncbi.nlm.nih.gov/pubmed/22731712
Ann N Y Acad Sci. 2012 Jul;1258:25-33.
Zonulin, regulation of tight junctions, and autoimmune diseases. Fasano A. Mucosal Biology Research Center and Center for Celiac Research, University of Maryland School of Medicine, Baltimore, Maryland, USA.

19) http://www.townsendletter.com/Dec2007/alphalipo1207.htm
Alpha Lipoic Acid and Liver Disease
by Burton M. Berkson, MD, MS, PhD

20) http://www.ncbi.nlm.nih.gov/pubmed/10554539

Med Klin (Munich). 1999 Oct 15;94 Suppl 3:84-9.
A conservative triple antioxidant approach to the treatment of hepatitis C. Combination of alpha lipoic acid (thioctic acid), silymarin, and selenium: three case histories. Berkson BM. Integrative Medical Center of New Mexico, New Mexico State University, Las Cruces, USA.

There has been an increase in the number of adults seeking liver transplantation for hepatitis C in the last few years and the count is going up rapidly. There is no reliable and effective therapy for chronic hepatitis C since interferon and antivirals work no more than 30% of the time, and liver transplant surgery is uncertain and tentative over the long run. This is because, ultimately, residual hepatitis C viremia infects the new liver. Furthermore, liver transplantation can be painful, disabling and extremely costly. TREATMENT PROGRAM:

The author describes a low cost and efficacious treatment program in 3 patients with cirrhosis, portal hypertension and esophageal varices secondary to chronic hepatitis C infection. This effective and conservative regimen combines 3 potent antioxidants (alpha-lipoic acid [thioctic acid], silymarin, and selenium) that possess antiviral, free radical quenching and immune boosting qualities.
CONCLUSION: There are no remarkably effective treatments for chronic hepatitis C in general use. Interferon and antivirals have less than a 30% response rate and because of the residual viremia, a newly transplanted liver usually becomes infected again. The triple antioxidant combination of alpha-lipoic acid, silymarin and selenium was chosen for a conservative treatment of hepatitis C because these substances protect the liver from free radical damage, increase the levels of other fundamental antioxidants, and interfere with viral proliferation. The 3 patients presented in this paper followed the triple antioxidant program and recovered quickly and their laboratory values remarkably improved. Furthermore, liver transplantation was avoided and the patients are back at work, carrying out their normal activities, and feeling healthy. The author offers a more conservative approach to the treatment of hepatitis C, that is exceedingly less expensive. One year of the triple antioxidant therapy described in this paper costs less than $2,000, as compared to mor than $300,000 a year for liver transplant surgery. It appears reasonable, that prior to liver transplant surgery evaluation, or during the transplant evaluation process, the conservative triple antioxidant treatment approach should be considered. If these is a significant betterment in the patient's condition, liver transplant surgery may be avoided.

21) http://www.ncbi.nlm.nih.gov/pubmed/11910339
Gastroenterology. 2002 Apr;122(4):881-8.
Celiac disease in patients with severe liver disease: gluten-free diet may reverse hepatic failure. Kaukinen K, Halme L, Collin P, Färkkilä M, Mäki M, Vehmanen P, Partanen J, Höckerstedt K. Department of Internal Medicine, Tampere University Hospital, Tampere, Finland.

Mild liver abnormalities are common in patients with celiac disease and usually resolve with a gluten-free diet. We investigated the occurrence of celiac disease in patients with severe liver failure.
METHODS: Four patients with untreated celiac disease and severe liver disease are described. Further, the occurrence of celiac disease was studied in 185 adults with previous liver transplantation using serum immunoglobulin A endomysial and tissue transglutaminase antibodies in screening.
RESULTS: Of the 4 patients with severe liver disease and celiac disease, 1 had congenital liver fibrosis, 1 had massive hepatic steatosis, and 2 had progressive hepatitis without apparent origin. Three were even remitted for consideration of liver transplantation. Hepatic dysfunction reversed in all cases when a gluten-free diet was adopted. In the transplantation group, 8 patients (4.3%) had celiac disease. Six cases were detected before the operation: 3 had primary biliary cirrhosis, 1 had autoimmune hepatitis, 1 had primary sclerosing cholangitis, and 1 had congenital liver fibrosis. Only 1 patient had maintained a long-term strict gluten-free diet. Screening found 2 cases of celiac disease, 1 with autoimmune hepatitis and 1 with secondary sclerosing cholangitis.
CONCLUSIONS: The possible presence of celiac disease should be investigated in patients with severe liver disease. Dietary treatment may prevent progression to hepatic failure, even in cases in which liver transplantation is considered.

22) http://www.ncbi.nlm.nih.gov/pubmed/16082287
J Clin Gastroenterol. 2005 Sep;39(8):737-42.
Treatment of chronic hepatitis C virus infection via antioxidants: results of a phase I clinical trial. Melhem A, Stern M, Shibolet O, Israeli E, Ackerman Z, Pappo O, Hemed N, Rowe M, Ohana H, Zabrecky G, Cohen R, Ilan Y.
Source Liver Unit, Department of Medicine, Hebrew University, Hadassah Medical Center, Jerusalem, Israel.

The pathogenesis of chronic hepatitis C virus (HCV) infection is associated with a defective host antiviral immune response and intrahepatic oxidative stress. Oxidative stress and lipid peroxidation play major roles in the fatty liver accumulation (steatosis) that leads to necro-inflammation and necrosis of hepatic cells. Previous trials suggested that antioxidative therapy may have a beneficial effect on patients with chronic HCV infection.
To determine the safety and efficacy of treatment of chronic HCV patients via a combination of antioxidants.

Fifty chronic HCV patients were treated orally on a daily basis for 20 weeks with seven antioxidative oral preparations (glycyrrhizin, schisandra, silymarin, ascorbic acid, lipoic acid, L-glutathione, and alpha-tocopherol), along with four different intravenous preparations (glycyrrhizin, ascorbic acid, L-glutathione, B-complex) twice weekly for the first 10 weeks, and followed up for an additional 20 weeks. Patients were monitored for HCV-RNA levels, liver enzymes, and liver histology. Assessment of quality of life was performed using the SF-36 questionnaire.
RESULTS:In one of the tested parameters (eg, liver enzymes, HCV RNA levels, or liver biopsy score), a combination of antioxidants induced a favorable response in 48% of the patients (24). Normalization of liver enzymes occurred in 44% of patients who had elevated pretreatment ALT levels (15 of 34). ALT levels remained normal throughout follow-up period in 72.7% (8 of 11). A decrease in viral load (one log or more) was observed in 25% of the patients (12). Histologic improvement (2-point reduction in the HAI score) was noted in 36.1% of the patients. The SF-36 score improved in 26 of 45 patients throughout the course of the trial (58% of the patients). Treatment was well tolerated by all patients. No major adverse reactions were noted.
CONCLUSIONS: These data suggest that multi antioxidative treatment in chronic HCV patients is well tolerated and may have a beneficial effect on necro-inflammatory variables. A combination of antiviral and antioxidative therapies may enhance the overall response rate of these patients.

23) http://www.ncbi.nlm.nih.gov/pubmed/16211347
J Gastroenterol. 2005 Sep;40(9):901-6.
Determinants of serum ALT normalization after phlebotomy in patients with chronic hepatitis C infection.
Kawamura Y, Akuta N, Sezaki H, Hosaka T, Someya T, Kobayashi M, Suzuki F, Suzuki Y, Saitoh S, Arase Y, Ikeda K, Kumada H.
Source Department of Gastroenterology, Toranomon Hospital, 2-2-2 Toranomon, Minato-ku, Tokyo 105-8470, Japan.
Abstract BACKGROUNDhlebotomy is performed to reduce excessive iron accumulation in hepatic tissue. We studied serum alanine aminotransferase (ALT) normalization rates and 50% reduction in initial serum ALT (ALT(50%) reduction rate) in patients with hepatitis C viral (HCV) infection and investigated the factors that influenced the response to phlebotomy therapy.
METHODS:We evaluated 23 consecutive patients with HCV infection who underwent phlebotomy. Phlebotomy was performed a few times per week, then a few times per month, and 200-400 ml of blood was removed at each session, depending on the clinical response. During the course of therapy, hemoglobin (Hb), serum ALT, and ferritin levels were assessed monthly.
RESULTS:In patients with Hb of less than 11 g/dl, the ALT(50%) reduction rate was 87.5%. In patients with a serum ferritin level of less than 10 g/dl the ALT(50%) reduction rate was 83.3%. In patients with Hb of less than 11 g/dl, the ALT normalization rate was 50%, and in those with a serum ferritin level of less than 10 g/dl, the ALT normalization rate was 41.7%. Multivariate analysis identified ALT less than 100 IU/l at the start of phlebotomy as an independent factor associated with ALT normalization. Of the 7 patients who showed no response to phlebotomy, 85.7% were obese (body mass index > or =25 kg/m(2)), and 40% showed more than 30% steatosis on liver histology. The cumulative ALT normalization rate in relation to the total volume of blood loss was 43.9% with a blood less or more than 3 l, and thus was optimal above 3 l.
CONCLUSIONS:Although the sample number was relatively small, the results of our study suggest that phlebotomy is effective therapy for HCV patients who are nonobese, show little or no steatosis on liver histology, and have a baseline serum ALT level of less than 100 IU/l.

Jeffrey Dach MD
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Nanotechnolgy Meets Glutathione by Jeffrey Dach MD

2013-05-01T01:11:50Z

Nanotechnolgy Meets Glutathione

by Jeffrey Dach MD

A few years back, my son Benjamin was studying for his pHD in chemistry at Columbia, and we had many conversations about a new molecule called the "Bucky Ball" (also called fullerenes). These are molecular spheres made of carbon atoms named after Buckminster Fuller, the visionary who designed geodesic domes. You probably remember one at the entrance to Epcot at Disney World. This is a large "Bucky Ball". Imagine one of these made with carbon atoms, and now you have nanotechnology. Left Image: Buckminster Fuller with geodesic sphere courtesy of Forbes

Nobel Prize for Fullerenes

"The 1996 Nobel Prize in Chemistry was awarded to Smalley, Curl, Kroto for their discovery of fullerenes, or Buckyballs, spheres of 60 carbon atoms arranged in the shape of a geodesic dome (ie. Epcot Center left image), made famous by architect Richard Buckminster Fuller. The number of carbon atoms can vary. Carbon nanotubes are a byproduct of fullerene research " Quote from Kevin Trow Department of Chemistry Monmouth College.

Above left image: Spaceship Earth Geodesic Dome at night at the entrance to Epcot Disney World.Courtesy of Benjamin D. Esham and wikimedia commons.

Drug Delivery System - Nanotechnology in Medicine

Left image: Geodesic Sphere, courtesy of wikimedia commons.

The invention of the fullerene, or Bucky Ball, opened nanotechnology in medicine, and a rush to find new uses for these little molecular spheres. One potential use is a drug delivery system.(1) A drug molecule can be placed into the center of the fullerene, which serves as a molecular capsule to protect the drug from degradation, and allow delivery to the target tissue or organ. Examples are Gadolinium MRI contrast fullerenes, chemotherapy drug fullerenes, etc.

Glutathione Meets Nanotechnology

A previous article discusses the importance of selenium and seleno-proteins as antioxidants which protect our cells from the damaging by-products of oxidation. An even more important antioxidant is Glutathione, a small molecule manufactured in the body using three amino acids L-cysteine, L-glutamic acid, and glycine. You won't find this at the vitamin store because oral ingestion of glutathione is fruitless. Oral ingestion will not increase blood levels because the little glutathione molecule is oxidized and degraded rapidly. Some other means of delivery is needed. If we could fill the hollow center of carbon nano-tubules or carbon spheres with Glutathione, this might make a good delivery system.

Dan Purser MD and the people at RealGSH.com have done this with their new product, a topical liquid Glutathione spray which delivers Glutathione through the skin into the circulation.

Left image, bottle of Glutathione Topical Spray courtesy of Dan Purser MD and RealGSH.com

Medical Importance of Glutathione

To illustrate the importance of maintaining high intra-cellular glutathione levels, we can take a look at a few animal experiments with the glutathione depleting drug, BSO. This drug blocks production of glutathione, causing very low glutathione levels in the cell, with resulting massive damage to the mitochondria, the little energy producing organelles. This is where Glutathione is needed to quench the destructive by-products of oxidation, mostly the hydrogen peroxide (H2-02). We all know what this is, since we can buy a bottle of Hydrogen Peroxide Antiseptic Solution at the local drug store. Don't drink it. though. It is used topically as an antiseptic for small cuts and abrasions. This is the oxidizing agent that can destroy our mitochondria if we are glutathione depleted.

Left Image mitochondria courtesy of MIT Technology Review.

"A significant fraction of the oxygen utilized by mitochondria (about
2-5%) is converted to hydrogen
peroxide . When glutathione levels are greatly decreased, hydro
gen peroxide accumulates, and this leads to extensive mitochondrial
damage. Other antioxidants may be involved in the protection of
mitochondria, but glutathione appears to be the principal functional one. ... Electron microscopy has revealed that mitochondrial damage is an important consequence of glutathione deficiency in many tissues."(6)

Mitochondrial Damage, Dysfunction- Disease and Aging

One might argue that the root cause of most if not all disease and even aging itself is mitochondrial dysfunction. (7,8,9) To name a few, glutathione deficiency has been implicated in neurodegenerative diseases (Parkinson's), cataract formation, macular degeneration, coronary atherosclerosis, diabetes, renal insufficiency and hypertension.(7,8,9)

"A wide range of seemingly unrelated disorders, such as schizophrenia,
bipolar disease, dementia, Alzheimer's disease, epilepsy, migraine headaches, strokes, neuropathic pain, Parkinson's disease, ataxia, transient ischemic attack, cardiomyopathy, coronary artery disease, chronic fatigue syndrome, fibromyalgia, retinitis pigmentosa, diabetes, hepatitis C, and primary biliary cirrhosis have underlying pathophysiological mechanisms in common, namely ROS production, the accumulation of mtDNA damage, resulting in mitochondrial dysfunction".(10) Pieczenik 2007

Conclusion:

The above quote from Dr Pieczenik gives you a brief overview of the major importance of glutathione levels in preventing and treating disease. Along with Vitamin C, Selenium, and Tocotrienol-Vitamin E. Glutathione is our most important anti-oxidant and protector of the mitochondria, and perhaps our most important medicinal weapon in the battle against aging and disease.

Author: Jeffrey Dach MD

Articles with Related Interest:
Mega-Dose">jeffreydach.com/2010/05/05/selenium-reduces-mortality-in-the-icu-by-jeffrey-dach-md.aspx">Mega-Dose Vitamin Therapy in the ICU by Jeffrey Dach MD
Part">jeffreydach.com/2010/05/05/selenium-reduces-mortality-in-the-icu-by-jeffrey-dach-md.aspx">Part Three on Selenium, Your Vitamins Are Killing You

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Links and References:

1) http://www.ncbi.nlm.nih.gov/pubmed/21295087
J Control Release. 2011 May 30;152(1):2-12.
Glutathione-responsive nano-vehicles as a promising platform for targeted intracellular drug and gene delivery. Cheng R, Feng F, Meng F, Deng C, Feijen J, Zhong Z. Source Biomedical Polymers Laboratory, and Jiangsu Key Laboratory of Advanced Functional Polymer Design and Application, College of Chemistry, Chemical Engineering and Materials Science, Soochow University, Suzhou 215123, PR China.
Abstract

The past couple of years have witnessed a tremendous progress in the development of glutathione-responsive nano-vehicles for targeted intracellular drug and gene delivery, as driven by the facts that (i) many therapeutics (e.g. anti-cancer drugs, photosensitizers, and anti-oxidants) and biotherapeutics (e.g. peptide and protein drugs, and siRNA) exert therapeutical effects only inside cells like the cytosol and cell nucleus, and (ii) several intracellular compartments such as cytosol, mitochondria, and cell nucleus contain a high concentration of glutathione (GSH) tripeptides (about 2-10 mM), which is 100 to 1000 times higher than that in the extracellular fluids and circulation (about 2-20 μM). Glutathione has been recognized as an ideal and ubiquitous internal stimulus for rapid destabilization of nano-carriers inside cells to accomplish efficient intracellular drug release. In this paper, we will review recent results on GSH-responsive nano-vehicles in particular micelles, nanoparticles, capsules, polymersomes, nanogels, dendritic and macromolecular drug conjugates, and nano-sized nucleic acid complexes for controlled delivery of anti-cancer drugs (e.g. doxorubicin and paclitaxel), photosensitizers, anti-oxidants, peptides, protein drugs, and nucleic acids (e.g. DNA, siRNA, and antisense oligodeoxynucleotide). The unique disulfide chemistry has enabled novel and versatile designs of multifunctional delivery systems addressing both intracellular and extracellular barriers. We are convinced that GSH-responsive nano-carrier systems have enormous potential in targeted cancer therapy.

2) http://education.mrsec.wisc.edu/Edetc/nanoquest/carbon/
Fullerenes (Buckyballs)

In 1996 Richard Smalley, Robert Curl, and Harold Kroto were awarded the Nobel Prize in chemistry for discovering a new form of carbon - the buckminster fullerene, or buckyball. A buckyball looks like a nanometer-sized soccer ball made from 60 carbon atoms. It was named after Buckminster Fuller, an architect who created geodesic dome structures, like the one in the middle of Disney's Epcot Center.

Disney's Epcot CenterAtomic structure of a buckyball
Carbon Nanotubes The structure of a carbon nanotube is like a sheet of graphite rolled up into a tube. Depending on the direction of hexagons, nanotubes can be classified as either zigzag, armchair or chiral. Different types of nanotubes have different properties. When scientists make nanotubes, they tend to get a mixture of several types. A major challenge in nanoscience today is finding a way to make just one type of nanotube.
Carbon nanotube structures: (a) armchair, (b) zigzag, and (c) chiral (a) armchair, (b) zigzag, (c) chiral

3) http://www.ncbi.nlm.nih.gov/pubmed/20236059
Mini Rev Med Chem. 2010 Jul;10(8):662-77.
Fullerenes: from carbon to nanomedicine. Chawla P, Chawla V, Maheshwari R, Saraf SA, Saraf SK. Source Faculty of Pharmacy, Babu Banarasi Das National Institute of Technology and Management, Lucknow-227105, India.

4) http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2676811/ free full text
http://www.ncbi.nlm.nih.gov/pubmed/18203430
Int J Nanomedicine. 2007;2(4):639-49.
Medicinal applications of fullerenes. Bakry R, Vallant RM, Najam-ul-Haq M, Rainer M, Szabo Z, Huck CW, Bonn GK. Source Institute of Analytical Chemistry and Radiochemistry, Leopold-Franzens University of Innsbruck, Innrain 52a, 6020 Innsbruck, Austria.
Fullerenes have been used as a carrier for gene and drug delivery systems. Furthermore the ability of fullerenes to penetrate through intact skin is widening their application in cellular drug and gene delivery (Ryman-Rasmussen et al 2006). A fullerene-based peptide was synthesized by Rouse et al and its ability to penetrate through flexed and unflexed skin was observed (Rouse et al 2007). For this study porcine skin was used as a model for human skin.

5) http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2789438/
Int J Nanomedicine. 2009; 4: 261–275.
Biomedical applications of functionalized fullerene-based nanomaterials
Ranga Partha and Jodie L Conyers Center for Translational Injury Research, The University of Texas Health Science Center, Houston, TX 77030, USA
Correspondence: Jodie L Conyers, The University of Texas Health Science Center at Houston, Center for Translational Injury Research, Department of Surgery, 6410 Fannin Street, Suite 1100.15, Houston, TX 77030, USA

Deplete Glutahione with BSO - Mitochondrial Damage

6) http://www.grupogales.com/admin_upload/documentos/pagina_medicina/1994-Glutathione-ascorbate.pdf
Cancer Res. 1994 Apr 1;54(7 Suppl):1969s-1975s.
Glutathione, ascorbate, and cellular protection. Meister A.
Source Department of Biochemistry, Cornell University Medical College, New York, New York 10021.

Buthionine sulphoximine (BSO) is an inhibitor of gamma-glutamylcysteine synthetase (gamma-GCS) and, consequently lowers tissue glutathione (GSH) concentrations.

Depletion of glutathione by treatment with buthionine sulfoximine sensitizes cells to the toxic effects of heavy metals (46, 47), nitrogen mustards (48, 49), radiation (1, 2, 5), cisplatin (50), cyclophosphamide (51, 52), morphine (53), compounds that produce oxidative cytolysis (54), and others (55).

Glutathione deficiency leads to oxidative stress in many tissues
(5). Mitochondria! and associated cell damage is found in mice treated
with BSO.

Deficiency of glutathione leads to decreased reduction of dehydroascorbate
to ascorbate in vivo.

Glutathione deficiency in newborn rats and mice leads to for
mation of ocular cataracts (9, 58, 59). Cataracts have also been found
in some patients with inherited glutathione disulfide reductase deficiency.

A significant fraction of the oxygen utilized by mitochondria (about
2-5%) is converted, apparently through Superoxide, to hydrogen
peroxide (73). When glutathione levels are greatly decreased, hydro
gen peroxide accumulates, and this leads to extensive mitochondrial
damage. Other antioxidants may be involved in the protection of
mitochondria, but glutathione appears to be the principal functional
one. Mitochondria do not contain catalase and are therefore largely, if
not entirely, dependent upon glutathione and glutathione peroxidases.

Electron microscopy has revealed that mitochondrial damage is an
important consequence of glutathione deficiency in many tissues.

Although glutathione deficiency is lethal to newborn rats and
guinea pigs, adult mice are able to survive because they can synthesize
ascorbate.

7) http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2756154/
Biol Chem. 2009 March; 390(3): 191–214.
Glutathione dysregulation and the etiology and progression of human diseases
Nazzareno Ballatori,* Suzanne M. Krance, Sylvia Notenboom, Shujie Shi, Kim Tieu, and Christine L. Hammond Department of Environmental Medicine, University of Rochester School of Medicine, Rochester, NY 14642
*Correspondence to: Ned Ballatori, Ph.D., Department of Environmental Medicine, Box EHSC, University of Rochester School of Medicine, 575 Elmwood Avenue, Rochester, NY 14642,

Overall, growing evidence supports the protective effect of GSH in neurodegenative disorders, and especially in Parkinson’s disease; however, no effective therapies have yet been identified that can enhance GSH levels in affected brain regions.

EYE

In the central region of cataractous lenses, an increase in GSSG leads to an imbalanced GSH/GSSG ratio and extensive nuclear protein modifications, including oxidation, insolubilization, and cross-linking (David et al., 1984), along with a loss of GSH (Calvin et al., 1986). The retina is especially susceptible to oxidative stress because of its high consumption of oxygen and exposure to light. Likewise, GSH is a major antioxidant in the retina, and depletion of GSH has been associated with the etiology of two major retinopathies, age-related macular degeneration and glaucoma. Age-related macular degeneration is a complex multi-factorial disease that affects the central region of the retina. Although the exact etiology is not known, oxidative damage to the retinal pigment epithelium has been implicated in the pathogenesis of this disease (Young et al. 1987, 1988). In patients with exudative age-related macular degeneration, plasma GSH and total thiol content decrease significantly (Coral et al., 2006). Deficiency of GSH synthesis (Sternberg et al., 1993) and GSH recycling (Cohen et al., 1994) in the retinal epithelial cells may be responsible for the decline.

Cardiovascular diseases

The major cardiovascular diseases associated with redox imbalances are hypertension and atherosclerosis. As reviewed by Leopold and Loscalzo (2005), polymorphisms in antioxidant enzymes including glutathione peroxidases and glutathione S-transferases are associated with an increased risk of vascular disease due to increases in reactive oxygen species accumulation (Table 4). In particular, glutathione peroxidase polymorphisms appear to increase the risk of developing coronary heart disease, stroke, and cerebral venous thrombosis and glutathione S-transferase polymorphisms are associated with elevated inflammatory markers and an increased risk of coronary heart disease in smokers (Leopold and Loscalzo, 2005). Thioredoxin and glutaredoxin also play an important role in protection against cardiovascular disease through ameliorating the effects of reactive oxygen species and inflammation (Berndt et al., 2007).

Summary

Changes in GSH levels and/or oxidation state have now been reported in nearly all major human diseases. Although in many cases these changes likely occur as a result of the underlying disease progression, in other cases these changes are closely linked to the onset and/or development of the disease. The growing recognition that GSH is involved in critical cell signaling pathways that are regulated by S-glutathionylation and/or by the thiol redox status, and that GSH may function as a neurotransmitter or neuromodulator, provides considerable new insight into possible links between GSH and disease progression, and raises additional questions that can be addressed experimentally. In addition, the recognition that GSH is intimately involved in so many disease states has generated considerable interest in identifying therapies aimed at modulating GSH levels so as to modulate disease risk or progression. Although such therapies have significant hurdles to overcome, they offer significant promise for many human diseases.

8) http://www.ncbi.nlm.nih.gov/pubmed/22223042
Am J Hypertens. 2012 Jun;25(6):629-35. Cardiovascular and renal manifestations of glutathione depletion induced by buthionine sulfoximine.
Vargas F, Rodríguez-Gómez I, Pérez-Abud R, Vargas Tendero P, Baca Y, Wangensteen R.Departamento de Fisiología, Facultad de Medicina, Granada, Spain.

Oxidative stress contributes to the development of several cardiovascular diseases, including diabetes, renal insufficiency, and arterial hypertension. Animal studies have evidenced the association between higher blood pressure (BP) and increased oxidative stress, and treatment with antioxidants has been shown to reduce BP, while BP reduction due to antihypertensive drugs is associated with reduced oxidative stress. In 2000, it was first reported that oxidative stress and arterial hypertension were produced in normal Sprague-Dawley rats by oral administration of buthionine sulfoximine (BSO), which induces glutathione (GSH) depletion, indicating that oxidative stress may induce hypertension. The contribution of several potential pathogenic factors has been evaluated in the BSO rat model, the prototype of oxidative stress-induced hypertension, including vascular reactivity, endothelium-derived factors, renin-angiotensin system activity, TXA(2)-PGH(2) production, sodium sensitivity, renal dopamine-induced natriuresis, and sympathetic tone. This review summarizes the main factors implicated in the pathogenesis of BSO-induced hypertension and the alterations associated with GSH depletion that are related to renal function or BP control.

9) http://www.ncbi.nlm.nih.gov/pubmed/20228251
FASEB J. 2010 Jul;24(7):2533-45. Depletion of GSH in glial cells induces neurotoxicity: relevance to aging and degenerative neurological diseases. Lee M, Cho T, Jantaratnotai N, Wang YT, McGeer E, McGeer PL.
Source Kinsmen Laboratory of Neurological Research, University of British Columbia, 2255 Wesbrook Mall, Vancouver, BC, Canada V6T 1Z3.
Abstract

Oxidative stress induced by inhibition of glutathione (GSH) biosynthesis with D,L-buthionine-S,R-sulfoximine (BSO) causes human microglia, human astrocytes, THP-1 cells, and U373 cells to secrete materials toxic to human neuroblastoma SH-SY5Y cells and stimulates them to release TNF-alpha, IL-6, and nitrite ions. The effect is correlated with activation of the inflammatory pathways P38 MAP- kinase, Jun-N-terminal kinase, and NF-kappaB. The effect is reduced by adding to the medium GSH or clotrimazole (CTM), an inhibitor of Ca(2+)-influx through TRPM2 channels. It is also produced by inhibiting TRPM2 protein expression in microglia and astrocytes through introduction of its small inhibitory RNA (siRNA). TRPM2 mRNA is expressed by glial cells but not by SH-SY5Y cells. BSO in the culture medium causes an almost 3-fold increase in [Ca(2+)](i) in microglia and astrocytes over a 24-h period, which is reduced to half by the addition of CTM. The data strongly suggest that inhibiting intracellular GSH synthesis induces a neuroinflammatory response in human microglia and astrocytes, which is linked to Ca(2+) influx through TRPM2 channels. It represents a new model for inducing neuroinflammation and suggests that increasing GSH levels in glial cells may confer neuroprotection in neurodegenerative diseases, such as Alzheimer disease, which have a prominent neuroinflammatory component.

10) http://www.nbihealth.com/publications/Mitochondrial_dysfunction.pdf
http://www.sciencedirect.com/science/article/pii/S0014480006001328
http://www.ncbi.nlm.nih.gov/pubmed/17239370
Exp Mol Pathol. 2007 Aug;83(1):84-92. Epub 2007 Jan 18.
Mitochondrial dysfunction and molecular pathways of disease.
Pieczenik SR, Neustadt J.

Since the first mitochondrial dysfunction was described in the 1960s, the medicine has advanced in its understanding the role mitochondria play in health, disease, and aging. A wide range of seemingly unrelated disorders, such as schizophrenia, bipolar disease, dementia, Alzheimer's disease, epilepsy, migraine headaches, strokes, neuropathic pain, Parkinson's disease, ataxia, transient ischemic attack, cardiomyopathy, coronary artery disease, chronic fatigue syndrome, fibromyalgia, retinitis pigmentosa, diabetes, hepatitis C, and primary biliary cirrhosis, have underlying pathophysiological mechanisms in common, namely reactive oxygen species (ROS) production, the accumulation of mitochondrial DNA (mtDNA) damage, resulting in mitochondrial dysfunction. Antioxidant therapies hold promise for improving mitochondrial performance. Physicians seeking systematic treatments for their patients might consider testing urinary organic acids to determine how best to treat them. If in the next 50 years advances in mitochondrial treatments match the immense increase in knowledge about mitochondrial function that has occurred in the last 50 years, mitochondrial diseases and dysfunction will largely be a medical triumph.

---------------------------------

"The 1996 Nobel Prize in Chemistry was awarded to Richard E. Smalley, Robert F. Curl, Jr., and Sir Harold W. Kroto for their work with fullerenes. The discovery of fullerenes (also known as buckyballs) has generated tremendous excitement and opened up a new field of carbon chemistry. Buckyball is the terminology applied to a truncated icosahedron of 60 carbon atoms arranged in the shape of a geodesic dome (ie. Epcot Center upper left image), a structural marvel made famous in the late 1940’s by architect Richard Buckminster Fuller. The number of carbon atoms in these “spherical” structures can vary widely, thereby opening up doors to a multitude of interesting fullerene possibilities. Carbon nanotubes were originally discovered as a byproduct of fullerene research, are attracting much interest in the area of nano-technology." Quote from Kevin Trow Department of Chemistry Monmouth College.

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Donating Blood at the Blood Bank by Jeffrey Dach MD

2013-05-01T00:46:54Z

Donating Blood at the Blood Bank

by Jeffrey Dach MD

Don't Over Do It

George Washington's death in 1799 was attributed to a discredited practice called "blood letting", accepted in the 1700's as treatment for virtually any ailment. One day. George Washington contracted a sore throat, and his doctors removed seven pints of blood (3,750 ml over 9 hours, half of his blood volume). The result was hypovolemic shock and cardiac arrest.(7)

Measuring Hematocrit in 1799

Perhaps the outcome would have been different if Mr. Washington's doctors had measured his blood count (hemoglobin/hematocrit), serum iron and ferritin levels during the blood letting procedure so they would know when to stop, Unfortunately, modern medicine arrived too late to save Mr. Washington from his overzealous doctors.

Is There a Health Benefit to Donating Blood Regularly?

Some people actually make a practice of donating blood at the blood bank on a regular basis. Afterwards, one might feel good about doing such a "good deed". You might also wonder if there is a health benefit to donating blood on a regular basis. A study from Finland says there is.

Finland- Donating Blood Every Two Months

In a study done in 1997 in Finland, people who regularly donated blood at the blood bank had an 88% decrease in myocardial infarction.(1) This study from Helsinki Finland included 2,862 males aged 42-60 followed for 9 years. Heart attack rates for blood donors was only 0.7%, compared to 12.5% for non-donors.

Left image : The Kallahti nature conservation area in Helsinki Finland courtesy of wikimedia commons.

Another 1997 study from Kansas City showed a 50% reduction in heart attacks in non-smoking male blood donors.(2)

I was intrigued by this information which I learned from Jonathan V. Wright MD in his April newsletter and again presented during his workshop at the Orlando A4M meeting in April 2013.

Two observations support this idea:

Women have less heart disease than men. Could this be related to their lower iron levels(3), and lower blood count from the regular loss of blood from menses.(2)

Or is cardio-protection a result of higher estrogen levels in women?

Or, is it both factors?

Left Image: soldier in the army donating blood. Image courtesy of wikimedia commons.

Hemochromatosis as a Model

A genetic disease in which iron accumulates in the body, with high serum iron and serum ferritin, is called hemochromatosis. and carriers of the gene are at increased risk for heart attack risk(4). One study showed the risk of heart attack was doubled over 9 years in Hemochromatosis gene carriers. (4) Hemochromatosis is treated with weekly or monthly donations at the blood bank to reduce iron and ferritin levels.

Hemochromatosis in Women

Women hemochromatosis (HH) carriers had a 2.4 times increase in cerebrovascular death compared to non-carriers (5) In addition, women HH gene carriers who were smokers and hypertensive (elevated blood pressure) had a more profound 18.85-fold increased risk of cardiovascular death compared with nonsmokers, nonhypertensives, and noncarriers.(5) See chart below. The highest bar on the right is for hypertensive, smokers who are HH gene carriers.(5)

Why is Donating Blood Beneficial?

The explanation for the beneficial effect of donating blood at the blood bank includes a reduction of iron stores (3). Iron is oxidative, so any reduction of iron reduces oxidative stress in the body.

Secondly, there is a reduction in blood viscosity with younger more flexible red cells generated by the bone marrow to replace the donated blood.(8)

A 2005 study from Yale found that "High-frequency blood donors had evidence of decreased body iron stores, decreased oxidative stress, and enhanced vascular function when compared with low-frequency donors."(6)

Testosterone and Increased Blood Count

Treatment with testosterone may cause erythrocytosis (increased blood count) resulting in increased blood viscosity which if severe, may cause renal insufficiency, and other adverse health consequences. Treatment is a trip to the blood bank to donate blood. It is important not to miss this. So, for you guys out there thinking of skipping your serial blood panel, think again. Testosterone stimulation effects may also be seen with the white count as well, important for patients with CLL chronic lymphocytic leukemia, on Testosterone therapy. The leukemic cells may increase on treatment.(9)

Cautions at the Blood Bank- Avoid Automated Blood Collection, Apheresis, ABC,

Avoid the newer apheresis machines, simply donate whole blood into a bag the old way, without recirculating any fluids back into the vein. The automated machines recirculate anticoagulants, and other unknown chemicals leached from the tubing back into the vein. It is safer to avoid this by donating the old way straight into a collection bag.

Hepatitis C may Benefit from Phlebotomy

A study from Japan shows that liver enzymes may normalize in Hepatitis C patients after repeated phlebotomies.(10)

Conclusion: George Washington's doctors were not completely wrong in their belief in a health benefit from Blood Letting. Unfortunately, in olden days, doctors did not have modern lab equipment to monitor blood count. As a result, they did not know when to stop the blood removal procedure, leading to demise of the patient from excessive blood loss.

Modern Blood Letting at the Blood Bank

Currently, medical studies have renewed interest in the health benefits of regular blood donation. For safety, we carefully monitor hemoglobin, hematocrit, serum iron and ferritin levels. Trips to the blood bank are discontinued when these levels fall into acceptable range.

Author: Jeffrey Dach MD

Links and References:

1) http://www.ncbi.nlm.nih.gov/pubmed/9737556
Am J Epidemiol. 1998 Sep 1;148(5):445-51.
Donation of blood is associated with reduced risk of myocardial infarction. The Kuopio Ischaemic Heart Disease Risk Factor Study. Salonen JT, Tuomainen TP, Salonen R, Lakka TA, Nyyssönen K. Research Institute of Public Health, University of Kuopio, Finland.

Because high body iron stores have been suggested as a risk factor for acute myocardial infarction, donation of blood could theoretically reduce the risk by lowering body iron stores. For this reason, the authors tested the hypothesis that voluntary blood donation is associated with reduced risk of acute myocardial infarction in a prospective epidemiologic follow-up study in men from eastern Finland. The subjects are all participants of the Kuopio Ischaemic Heart Disease Risk Factor Study. A cohort of 2,862 men aged 42-60 years were followed for an average of almost 9 years. One man (0.7%) out of 153 men who had donated blood in 24 months preceding the baseline examination experienced an acute myocardial infarction during 1984 to 1995, whereas 316 men (12.5%) of 2,529 non-blood donors had an acute myocardial infarction (p < 0.0001 for difference between proportions). In a Cox proportional hazards model adjusting for age, examination years and all other predictive coronary disease risk factors, blood donors had a 88% reduced risk (relative hazard = 0.12, 95% confidence interval 0.02-0.86, p = 0.035) of acute myocardial infarction, compared with non-blood donors. These findings suggest that frequent blood loss through voluntary blood donations may be associated with a reduced risk of acute myocardial infarction in middle-aged men.

2) http://www.ncbi.nlm.nih.gov/pmc/articles/PMC484902/
Heart. 1997 August; 78(2): 188–193. Possible association of a reduction in cardiovascular events with blood donation. D. G. Meyers, D. Strickland, P. A. Maloley, J. K. Seburg, J. E. Wilson, and B. F. McManus
Department of Internal Medicine, Kansas University College of Medicine, Kansas City 66160-7378, USA.
BACKGROUND: The iron hypothesis suggests that females are protected from atherosclerosis by having lower iron stores than men, thus limiting oxidation of lipids. OBJECTIVE: To test the iron hypothesis by comparing cardiovascular event rates in whole blood donors compared with nondonors. DESIGN: Prospective cohort with telephone survey follow up. SETTING: The State of Nebraska, USA. PARTICIPANTS: A sample was selected from the Nebraska Diet Heart Survey (NDHS) restricting for age > or = 40 years and absence of clinically apparent vascular diseases at time of enrollment in to NDHS (1985-87). MAIN OUTCOME MEASURES: The occurrence of cardiovascular events (myocardial infarction, angina, stroke), procedures (angioplasty, bypass surgery, claudication, endarterectomy), nitroglycerin use, or death (all cause mortality), and level of blood donation. RESULTS: Participants were 655 blood donors and 3200 non-donors who differed in education, physical activity, diabetes, and frequency of antihypertensive treatment; 889 were lost to follow up. Sixty four donors and 567 non-donors reported cardiovascular events (crude odds ratio = 0.50, 95% confidence interval (CI) 0.38-0.66). The benefit of donation was confined to non-smoking males (adjusted odds ratio 0.67, 95% CI 0.45-0.99). Benefit was limited to current donors (the most recent three years). No additional benefit resulted from donating more than once or twice over three years. CONCLUSION: In support of the iron hypothesis, blood donation in non-smoking men in this cohort was associated with reduced risk of cardiovascular events. A randomised clinical trial is warranted to confirm these findings as the observed personal health benefit of donation has public policy ramifications.

3) http://www.ncbi.nlm.nih.gov/pubmed/9576426
Circulation. 1998 Apr 21;97(15):1461-6.
Association between body iron stores and the risk of acute myocardial infarction in men. Tuomainen TP, Punnonen K, Nyyssönen K, Salonen JT.
Research Institute of Public Health and the Department of Public Health and General Practice, University of Kuopio, Finland.

Epidemiological evidence concerning the role of iron, a lipid peroxidation catalyst, in coronary heart disease (CHD) is inconsistent. We investigated the association of the concentration ratio of serum transferrin receptor to serum ferritin (TfR/ferritin), a state-of-the-art measurement of body iron stores, with the risk of acute myocardial infarction (AMI) in a prospective nested case-control study in men from eastern Finland.

Transferrin receptor assays were carried out for 99 men who had an AMI during an average 6.4 years of follow-up and 98 control men. Both the cases and the controls were nested from the Kuopio Ischemic Heart Disease Risk Factor Study (KIHD) cohort of 1931 men who had no clinical CHD at the baseline study. The controls were matched for age, examination year, and residence. AMIs were registered prospectively. Soluble transferrin receptors were measured by immunoenzymometric assay and ferritin concentration by radioimmunoassay from frozen baseline serum samples. The mean TfR/ferritin ratio was 15.1 (SE, 2.0) among cases and 21.3 (SE, 2.2) among controls (P=.035 for difference). In logistic regression models adjusting for other strongest risk factors for AMI and indicators of inflammation and alcohol intake, men in the lowest and second lowest thirds of the TfR/ferritin ratio had a 2.9-fold (95% CI, 1.3 to 6.6, P=.011) and 2.0-fold (0.9 to 4.2, P=.081) risk of AMI compared with men in the highest third (P=.010 for trend).
CONCLUSIONS: These data show an association between increased body iron stores and excess risk of AMI, confirming previous epidemiological findings.

Hemochromatosis and MI

4) http://www.ncbi.nlm.nih.gov/pubmed/10491370
Circulation. 1999 Sep 21;100(12):1274-9.
Increased risk of acute myocardial infarction in carriers of the hemochromatosis gene Cys282Tyr mutation : a prospective cohort study in men in eastern Finland.Tuomainen TP, Kontula K, Nyyssönen K, Lakka TA, Heliö T, Salonen JT.
Research Institute of Public Health, University of Kuopio, Kuopio, Finland.Background-Homozygosity for a relatively common Cys282Tyr mutation of the human hemochromatosis-associated (HFE) gene was recently found to account for most cases of hereditary hemochromatosis. Because excess iron has been postulated to enhance risk of vascular disease, we studied whether occurrence of this mutation was associated with increased risk of first acute myocardial infarction in healthy middle-aged men in a prospective cohort study. Methods and Results-Study subjects were the 1150 participants in the population-based Kuopio Ischemic Heart Disease Risk Factor Study (KIHD), aged 42, 48, 54, or 60 years at baseline, who had no coronary heart disease at baseline and for whom a DNA sample was available. Information about myocardial infarctions was collected prospectively by use of FINMONICA (FINnish MONItoring of trends and determinants in CArdiovascular disease study) and hospital data. Events were classified by MONICA (MONItoring of trends and determinants in CArdiovascular disease study) diagnostic criteria. The HFE Cys282Tyr mutation was assayed by a solid-phase minisequencing technique. One subject was homozygous and 76 individuals were heterozygous for the HFE Cys282Tyr mutation (6.7%). During a mean follow-up of 9 years, 8 (10.4%) of 77 carriers and 60 (5.6%) of 1073 noncarriers experienced an acute myocardial infarction. In a Cox proportional hazards model allowing for the other strongest risk factors, the carriers had a 2.3-fold (95% CI 1. 1 to 4.8; P=0.03) risk of acute myocardial infarction compared with noncarriers. Conclusions-Male carriers of the common hemochromatosis gene mutation are at 2-fold risk for first acute myocardial infarction compared with noncarriers.

5) http://www.ncbi.nlm.nih.gov/pubmed/10491369
Circulation. 1999 Sep 21;100(12):1268-73.
Heterozygosity for a hereditary hemochromatosis gene is associated with cardiovascular death in women.
Roest M, van der Schouw YT, de Valk B, Marx JJ, Tempelman MJ, de Groot PG, Sixma JJ, Banga JD. SourceJulius Center for Patient Oriented Research, Utrecht University Medical School, The Netherlands.

Background-The genetic background of hereditary hemochromatosis (HH) is homozygosity for a cysteine-to-tyrosine transition at position 282 in the HFE gene. Heterozygosity for HH is associated with moderately increased iron levels and could be a risk factor for cardiovascular death. Methods and Results-We studied the relation between HH heterozygosity and cardiovascular death in a cohort study among 12 239 women 51 to 69 years of age residing in Utrecht, the Netherlands. Women were followed for 16 to 18 years (182 976 follow-up years). The allele prevalence of the HH gene in the reference group was 4.0 (95% CI 2.9 to 5.4). The mortality rate ratios for HH heterozygotes compared with wild types was 1.5 (95% CI 0.9 to 2.5) for myocardial infarction (n=242), 2.4 (95% CI 1.3 to 3. 5) for cerebrovascular disease (n=118), and 1.6 (95% CI 1.1 to 2.4) for total cardiovascular disease (n=530). The population-attributable risks of HH heterozygosity for myocardial infarction and cerebrovascular and total cardiovascular death were 3.3%, 8.8%, and 4.0%, respectively. In addition, we found evidence for effect modification by hypertension and smoking. Conclusions-We found important evidence that inherited variation in iron metabolism is involved in cardiovascular death in postmenopausal women, especially in women already carrying classic risk factors.

6) http://www.ncbi.nlm.nih.gov/pubmed/15961703
Arterioscler Thromb Vasc Biol. 2005 Aug;25(8):1577-83. Epub 2005 Jun 16.Iron stores and vascular function in voluntary blood donors.Zheng H, Cable R, Spencer B, Votto N, Katz SD.
Department of Internal Medicine, Yale University School of Medicine, 135 College St, Suite 301, New Haven, CT 06510,

Iron is a pro-oxidant cofactor that may be linked to atherosclerosis progression. Reduction of body iron stores secondary to blood donation has been hypothesized to reduce coronary risk, but retrospective studies have yielded inconsistent findings. We sought to assess the effects of blood donation frequency on body iron stores and physiological and biochemical biomarkers of vascular function associated with atherosclerosis progression. METHODS AND RESULTS:

Forty high-frequency voluntary blood donors (> or =8 donations in past 2 years) and 42 low-frequency blood donors (1 to 2 donations in past 2 years) aged 50 to 75 years were randomly selected from American Red Cross of Connecticut blood donor records. Flow-mediated dilation in the brachial artery, serum markers of iron stores, vascular inflammation and oxidative stress, and cardiac risk factors were assessed in all subjects. Serum ferritin was significantly decreased in high-frequency blood donors when compared with low-frequency blood donors (median values 17 versus 52 ng/mL; P<0.001), but hematocrit did not differ between groups. Flow-mediated dilation in the brachial artery was significantly greater in high-frequency donors when compared with low-frequency donors in univariate analysis (5.5+/-2.6% versus 3.8+/-1.6%; P=0.0003) and in multivariate analysis adjusting for cardiac risk factors and other potential confounders. Serum biomarkers of vascular inflammation did not differ between groups but 3-nitrotyrosine, a marker of oxidative stress, was decreased in high-frequency donors when compared with low-frequency donors.
CONCLUSIONS: High-frequency blood donors had evidence of decreased body iron stores, decreased oxidative stress, and enhanced vascular function when compared with low-frequency donors. These findings support a potential link between blood donation and reduced cardiovascular risk that warrants further investigation in prospective outcome studies.

7) http://www.thepermanentejournal.org/files/Spring2004/time.pdf
The Asphyxiating and Exsanguinating Death of President George Washington Presented at the Annual Miranda Lecture Series of Kaiser Permanente Bakersfield 2002 By Vibul V Vadakan, MD, FAAP

8) http://www.townsendletter.com/Jan2012/measureblood0112.html
From the Townsend Letter January 2012
Measuring Blood Viscosity to Improve Patient Outcomes
by Pushpa Larsen, ND, and Ralph Holsworth, DO

9) http://www.ncbi.nlm.nih.gov/pubmed/6862037
Fertil Steril. 1983 Jul;40(1):100-4. Effect of testosterone enanthate on hematopoiesis in normal men.Palacios A, Campfield LA, McClure RD, Steiner B, Swerdloff RS. Testosterone enanthate, a commonly used depot form of androgen, was administered to normal men according to several dose schedules. This resulted in significant increments in serum testosterone levels despite the fact that testosterone concentrations remained within the normal population range in almost all instances. Mild but significant increases in white blood cell, red blood cell, hematocrit, and hemoglobin concentrations were noted

10) http://www.ncbi.nlm.nih.gov/pubmed/16211347
J Gastroenterol. 2005 Sep;40(9):901-6.
Determinants of serum ALT normalization after phlebotomy in patients with chronic hepatitis C infection. Kawamura Y, Akuta N, Sezaki H, Hosaka T, Someya T, Kobayashi M, Suzuki F, Suzuki Y, Saitoh S, Arase Y, Ikeda K, Kumada H.
Department of Gastroenterology, Toranomon Hospital, 2-2-2 Toranomon, Minato-ku, Tokyo 105-8470, Japan.

Phlebotomy is performed to reduce excessive iron accumulation in hepatic tissue. We studied serum alanine aminotransferase (ALT) normalization rates and 50% reduction in initial serum ALT (ALT(50%) reduction rate) in patients with hepatitis C viral (HCV) infection and investigated the factors that influenced the response to phlebotomy therapy.
We evaluated 23 consecutive patients with HCV infection who underwent phlebotomy. Phlebotomy was performed a few times per week, then a few times per month, and 200-400 ml of blood was removed at each session, depending on the clinical response. During the course of therapy, hemoglobin (Hb), serum ALT, and ferritin levels were assessed monthly.
RESULTS: In patients with Hb of less than 11 g/dl, the ALT(50%) reduction rate was 87.5%. In patients with a serum ferritin level of less than 10 g/dl the ALT(50%) reduction rate was 83.3%. In patients with Hb of less than 11 g/dl, the ALT normalization rate was 50%, and in those with a serum ferritin level of less than 10 g/dl, the ALT normalization rate was 41.7%. Multivariate analysis identified ALT less than 100 IU/l at the start of phlebotomy as an independent factor associated with ALT normalization. Of the 7 patients who showed no response to phlebotomy, 85.7% were obese (body mass index > or =25 kg/m(2)), and 40% showed more than 30% steatosis on liver histology. The cumulative ALT normalization rate in relation to the total volume of blood loss was 43.9% with a blood less or more than 3 l, and thus was optimal above 3 l.
CONCLUSIONS: Although the sample number was relatively small, the results of our study suggest that phlebotomy is effective therapy for HCV patients who are nonobese, show little or no steatosis on liver histology, and have a baseline serum ALT level of less than 100 IU/l.

Left upper image: A road at the Kallahti nature conservation area in Helsinki, Finland. The Kallahti area contains an esker and land area rising slowly from the sea (a large glacier in the ice age has pressed the earth, which is still slowly rising). The nature conservation area is part of European Natura 2000 nature conservation program. There are 40 nature conservation areas in the City of Helsinki. Suomi: Tie Kallahden luonnonsuojelualueelle Helsingissä courtesy of wikimedia commons.

Links to Images of George Washington Courtesy of Wikimedia commons:
http://upload.wikimedia.org/wikipedia/commons/e/ea/George_Washington_dollar.jpg

http://upload.wikimedia.org/wikipedia/commons/b/b6/Gilbert_Stuart_Williamstown_Portrait_of_George_Washington.jpg

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