LETTER TO THE EDITOR: Regarding Bettauer 2010 (39:9–23)
D. Rick Lee DVM 1, Stuart M. Zola PhD 2, John L. VandeBerg PhD 3, Thomas J. Rowell DVM 4, Christian Abee DVM 5
Journal of Medical Primatology
Early View (Articles online in advance of print)
Article first published online: 18 AUG 2010
DOI: 10.1111/j.1600-0684.2010.00437.x
Author Information
1 Washington National Primate Research Center, Seattle, WA, USA
2 Yerkes National Primate Research Center, Atlanta, GA, USA
3 Southwest National Primate Research Center, San Antonio, TX, USA
4 New Iberia Research Center, New Iberia, LA, USA
5 Center for Comparative Medicine and Research, Bastrop, TX, USA
Publication History
Article first published online: 18 AUG 2010
The Journal of Medical Primatology recently published a paper entitled ‘Chimpanzees in hepatitis C virus research: 1998–2007’ by R.H. Bettauer (2010, 39:9–23). This paper concluded that there is no ‘sufficient data, or scientific consensus,... [for] the biological relevance of’ the use of chimpanzees as a model for hepatitis C virus (HCV) research. In addition, this article claimed that because chimpanzee studies ‘have not produced a reliable... vaccine’, the chimpanzee model should be abandoned. We, the National Chimpanzee Resource Consortium, have major concerns regarding the validity of this article, and we consider it to be inappropriate for publication in a scientific journal.
It appears that this study was initiated and supported by The Humane Society of the United States (HSUS), an organization that openly advocates an ‘end to the use of animals in biomedical research’ [1]. As stated by the author, the purpose of this article ‘was to ascertain the extent of chimpanzee use... and any related health and welfare issues.’ It is our view that this article does not objectively evaluate the effectiveness of the chimpanzee model in hepatitis C research. The article appears to contain numerous unsubstantiated conclusions that support the HSUS agenda of banning the use of chimpanzees in biomedical research.
It is our position that the chimpanzee is the only scientifically validated model for in vivo studies of hepatitis C infection [2], and it is essential for the evaluation of antiviral and vaccine efficacy, as well as safety. Research with chimpanzees over many years was critical to the development of the hepatitis B vaccine (licensed in 1982) and the hepatitis A vaccine (licensed in 1992). We consider the argument that the chimpanzee model for hepatitis C research should be abandoned because a hepatitis C vaccine has not yet been developed is as absurd as the same argument regarding hepatitis A and B would have been in 1980. It took 47 years to develop the polio vaccine. Hepatitis C virus was discovered in 1989, only 21 years ago, and great progress has been made in developing an understanding of HCV biology and virus–host interactions from research with chimpanzees, as we move toward developing an effective vaccine.
The author argues that because HCV infections were not found in wild chimpanzees, ‘humans and chimpanzees may respond to HCV exposure differently.’ However, HCV is transmitted almost exclusively by transfusion (prior to testing the blood supply) and intravenous injection with contaminated needles. Not finding HCV in wild chimpanzees has nothing to do with response to exposure, as the animals are never exposed. Very few animal models mimic the human disease exactly.
The author states that ‘small study sizes [in HCV research] lack statistical power and therefore affect our ability to draw broader conclusions.’ Many citations refute that conclusion. For example, in one study two chimpanzees were infected with HIV and infused 60 minutes later with a monoclonal antibody that blocks the HIV receptor on CD34 cells [3]. The chimpanzees did not become infected, although the single control animal did become infected. The monoclonal antibody has since been humanized and is expected to enter clinical trials this year. The results speak for themselves. Therefore, no statistical analyses were needed.
The author states that ‘studies that involve human patients...included large numbers of subjects, which avoids the problem of small sample sizes found in chimpanzees studies.’ The implied conclusion seems to be that we should use humans instead of chimpanzees. However, the kinds of experiments that can be conducted with chimpanzees cannot be conducted with human subjects (e.g., the HIV experiment mentioned earlier).
The author states that ‘there is currently not sufficient data or scientific consensus to establish the biological relevance of the chimpanzee model for HCV.’ As evidence that is contrary to the author’s statement, we refer the readers to the recent publication in Science of results from chimpanzees that establish great promise for a microRNA-silencing drug (SPC3649) for treating hepatitis C patients [4].
The author makes several references to the ‘lack of information on anesthesia and analgesia’ in the articles she surveyed. The implication appears to be that studies upon chimpanzees are carried out without regard to anesthesia and/or analgesia. Initiation of any research study with chimpanzees requires that the study be approved by an Institutional Animal Care and Use Committee and that the study conform to guidelines set forth by the Animal Welfare Act (as amended) and the Guide for the Care and Use of Laboratory Animals [5, 6]. These regulations require the use of anesthesia and analgesia, and the implication that HCV studies were conducted with chimpanzees were without anesthesia and analgesia is in our view unwarranted.
We are concerned that the Journal of Medical Primatology, a reputable scientific journal whose mission is to disseminate knowledge regarding primates as models to study, prevent, and/or treat human diseases, has published this article as we contend that it lacks objectivity critical to research work and is influenced by the animal rights lobby.
Respectfully submitted by the National Chimpanzee Resource Consortium
References
1 The Humane Society of the United States. [Internet]. Recent hepatitis C study challenges chimpanzee use. Press Release December 15, 2009. Available at: http://www.humanesociety.org/news/press_releases/2009/12/hepatitis_c_research_using_chimps_121509.html
Accessed date: 02/05/10.
2 Amako Y, Tsukiyama-Kohara K, Katsume A, Hirata Y, Sekiguchi S, Tobita Y, Hayashi Y, Hishima T, Funata N, Yonekawa H, Kohara M: Pathogenesis of hepatitis C virus infection in Tupaia belangeri. J Virol 2010; 84:303–311.
3 Wang CY, Sawyer LS, Murthy KK, Fang X, Walfield AM, Ye J, Wang JJ, Chen PD, Li ML, Salas MT, Shen M, Gauduin MC, Boyle RW, Koup RA, Montefiori DC, Mascola JR, Koff WC, Hanson CV: Postexposure immunoprophylaxis of primary isolates by an antibody to HIV receptor complex. Proc Natl Acad Sci USA 1999; 96:10367–10372.
4 Lanford RE, Hildebrandt-Eriksen ES, Petri A, Persson R, Lindow M, Munk ME, Kauppinen S, Ørum H: Therapeutic silencing of microRNA-122 in primates with chronic hepatitis C virus infection. Science 2010; 327:198–201.
5 Institute for Laboratory Animal Research. Guide for the Care and Use of Laboratory Animals. Washington (DC): National Academies Press, 1996.
6 United States Department of Agriculture: Animal Welfare Act as Amended. 7 USC §2131–2156, 2007.
Source
August 21, 2010
Low alpha-fetoprotein HCC
Brian I. Carr M.D. F.R.C.P., Ph.D. 1,*, Petr Pancoska Ph.D. 2, Robert A. Branch M.D. 2
Article first published online: 25 FEB 2010
DOI: 10.1111/j.1440-1746.2010.06303.x
Journal of Gastroenterology and Hepatology
Accepted Article (Accepted, unedited articles published online for future issues)
Author Information
1 Liver Tumor Program of Kimmel Cancer Center, Thomas Jefferson University, Philadelphia,
2 Center for Clinical Pharmacology, University of Pittsburgh.
* Correspondence: Brian I. Carr M.D., F.R.C.P., Ph.D. Liver Tumor Program, Kimmel Cancer Center, Thomas Jefferson University, Bluemle building, room 519, 233 S.10th Street, Philadelphia, PA 19107 Tel: 215 503 8842 Fax: 215 503 8755 E-mail: brian.carr@jefferson.edu
Keywords: low AFP;HCC;survival;GGTP;tumor size
Abstract
BACKGROUND: A large proportion of HCC patients do not secrete elevated levels of the tumor marker alpha-fetoprotein. There is little published guide to prognostic features of this patient subset. METHODS: We interrogated a large HCC database in which all patients had been followed till death, to examine which features might be prognostically useful. RESULTS: We found 413 biopsy-proven unresectable HCC patients with low serum AFP values. Serum GGTP levels were one of the most significant factors for survival. This dichotomization into low and high GGTP levels separated the patients into distinctive survival ranges. Patients with GGTP levels <110 U/100 ml and small tumors had longest survival >795 days. Patients with GGTP ≥110 U/ml and large tumors with presence of PVT had the shortest survival range of 300-560 days. CONCLUSIONS: Serum levels of the onco-fetal protein GGTP represent a useful prognostic parameter in HCC patients with low AFP levels.
Source
Article first published online: 25 FEB 2010
DOI: 10.1111/j.1440-1746.2010.06303.x
Journal of Gastroenterology and Hepatology
Accepted Article (Accepted, unedited articles published online for future issues)
Author Information
1 Liver Tumor Program of Kimmel Cancer Center, Thomas Jefferson University, Philadelphia,
2 Center for Clinical Pharmacology, University of Pittsburgh.
* Correspondence: Brian I. Carr M.D., F.R.C.P., Ph.D. Liver Tumor Program, Kimmel Cancer Center, Thomas Jefferson University, Bluemle building, room 519, 233 S.10th Street, Philadelphia, PA 19107 Tel: 215 503 8842 Fax: 215 503 8755 E-mail: brian.carr@jefferson.edu
Keywords: low AFP;HCC;survival;GGTP;tumor size
Abstract
BACKGROUND: A large proportion of HCC patients do not secrete elevated levels of the tumor marker alpha-fetoprotein. There is little published guide to prognostic features of this patient subset. METHODS: We interrogated a large HCC database in which all patients had been followed till death, to examine which features might be prognostically useful. RESULTS: We found 413 biopsy-proven unresectable HCC patients with low serum AFP values. Serum GGTP levels were one of the most significant factors for survival. This dichotomization into low and high GGTP levels separated the patients into distinctive survival ranges. Patients with GGTP levels <110 U/100 ml and small tumors had longest survival >795 days. Patients with GGTP ≥110 U/ml and large tumors with presence of PVT had the shortest survival range of 300-560 days. CONCLUSIONS: Serum levels of the onco-fetal protein GGTP represent a useful prognostic parameter in HCC patients with low AFP levels.
Source
Central nervous system dysfunction in primary biliary cirrhosis and its relationship to symptoms
Claire McDonald 1,2, Julia Newton 1, H. Ming Lai 3, Stuart N. Baker 2, David E. Jones 1
Received 15 December 2009; received in revised form 24 May 2010; accepted 26 May 2010. published online 18 August 2010.
Uncorrected Proof
Background & Aims
Primary biliary cirrhosis (PBC) is associated with fatigue, memory impairment, and sleep disturbances. These symptoms suggest the possibility of underlying central nervous system (CNS) dysfunction. During exercise, fatigue develops due to muscular processes (peripheral fatigue) and decreased neurological activation of the muscle (central fatigue). In this study we objectively quantify central and peripheral fatigue in PBC and investigate the integrity of cortical inhibitory and excitatory circuits. Finally we determine the relationship of these indices to the symptoms of PBC.
Methods
16 early-stage PBC patients, 8 post-liver transplant PBC patients, and 12 age-matched controls were studied at the Specialist PBC clinic and neuroscience research unit. In these patients, twitch interpolation was used to measure peripheral and central fatigue. Paired-pulse trans-cranial magnetic stimulation was used to assess intra-cortical inhibition (ICI) and facilitation (ICF).
Results
PBC patients had a significantly lower central activation before fatiguing exercise (mean 86.6.8% (±12.75) vs. 95.2% (±7.4); p<0.05) and a greater response variability than controls. The decline in central activation during exercise and peripheral fatigue were normal. ICI was significantly reduced in PBC patients and daytime somnolence was greater in patients where net inhibition exceeded facilitation. Transplanted and non-transplanted patients had similar central activation, ICI, and ICF.
Conclusions
PBC patients have impaired central activation and abnormal ICI, suggesting CNS abnormalities beyond voluntary control. Transplanted and non-transplanted patients show similar abnormalities raising interesting questions about the mechanisms underpinning these changes and the permanence of neurological dysfunction in PBC. ICI and ICF and the balance between them are related to daytime somnolence (an important symptom in PBC).
Keywords: Muscle, Trans-cranial magnetic stimulation, Twitch interpolation, Cortical inhibition, Liver cirrhosis, Biliary
Abbreviations: TMS, trans-cranial magnetic stimulation, ICI, intra-cortical inhibition, ICF, intra-cortical facilitation, ESS, Epworth Sleepiness Scale, PBC, primary biliary cirrhosis, MVC, maximal voluntary contraction
1 Institute of Cellular Medicine, Newcastle University, UK
2 Institute of Neuroscience, Newcastle University, UK
3 Department of Clinical Neurophysiology, Royal Victoria Infirmary, Newcastle-Upon-Tyne, UK
Corresponding author. Address: Institute of Cellular Medicine, Newcastle University, 4th Floor William Leech Building, The Medical School, Newcastle University, Newcastle, NE2 4HH. Tel.: +44 191 222 5784; fax: +44 191 222 0723.
PII: S0168-8278(10)00699-9
doi:10.1016/j.jhep.2010.05.036
© 2010 Published by Elsevier Inc
Source
Received 15 December 2009; received in revised form 24 May 2010; accepted 26 May 2010. published online 18 August 2010.
Uncorrected Proof
Background & Aims
Primary biliary cirrhosis (PBC) is associated with fatigue, memory impairment, and sleep disturbances. These symptoms suggest the possibility of underlying central nervous system (CNS) dysfunction. During exercise, fatigue develops due to muscular processes (peripheral fatigue) and decreased neurological activation of the muscle (central fatigue). In this study we objectively quantify central and peripheral fatigue in PBC and investigate the integrity of cortical inhibitory and excitatory circuits. Finally we determine the relationship of these indices to the symptoms of PBC.
Methods
16 early-stage PBC patients, 8 post-liver transplant PBC patients, and 12 age-matched controls were studied at the Specialist PBC clinic and neuroscience research unit. In these patients, twitch interpolation was used to measure peripheral and central fatigue. Paired-pulse trans-cranial magnetic stimulation was used to assess intra-cortical inhibition (ICI) and facilitation (ICF).
Results
PBC patients had a significantly lower central activation before fatiguing exercise (mean 86.6.8% (±12.75) vs. 95.2% (±7.4); p<0.05) and a greater response variability than controls. The decline in central activation during exercise and peripheral fatigue were normal. ICI was significantly reduced in PBC patients and daytime somnolence was greater in patients where net inhibition exceeded facilitation. Transplanted and non-transplanted patients had similar central activation, ICI, and ICF.
Conclusions
PBC patients have impaired central activation and abnormal ICI, suggesting CNS abnormalities beyond voluntary control. Transplanted and non-transplanted patients show similar abnormalities raising interesting questions about the mechanisms underpinning these changes and the permanence of neurological dysfunction in PBC. ICI and ICF and the balance between them are related to daytime somnolence (an important symptom in PBC).
Keywords: Muscle, Trans-cranial magnetic stimulation, Twitch interpolation, Cortical inhibition, Liver cirrhosis, Biliary
Abbreviations: TMS, trans-cranial magnetic stimulation, ICI, intra-cortical inhibition, ICF, intra-cortical facilitation, ESS, Epworth Sleepiness Scale, PBC, primary biliary cirrhosis, MVC, maximal voluntary contraction
1 Institute of Cellular Medicine, Newcastle University, UK
2 Institute of Neuroscience, Newcastle University, UK
3 Department of Clinical Neurophysiology, Royal Victoria Infirmary, Newcastle-Upon-Tyne, UK
Corresponding author. Address: Institute of Cellular Medicine, Newcastle University, 4th Floor William Leech Building, The Medical School, Newcastle University, Newcastle, NE2 4HH. Tel.: +44 191 222 5784; fax: +44 191 222 0723.
PII: S0168-8278(10)00699-9
doi:10.1016/j.jhep.2010.05.036
© 2010 Published by Elsevier Inc
Source
Hepatitis C virus entry and glucocorticosteroids
Samira Fafi-Kremer 1,2,3, François Habersetzer 1,2,4, Thomas F. Baumert 1,2,4
Received 5 July 2010; accepted 8 July 2010. published online 18 August 2010.
Uncorrected Proof
COMMENT ON:
Ciesek S, Steinmann E, Iken M, Ott M, Helfritz FA, Wappler I et al. Glucocorticosteroids increase cell entry by hepatitis C virus. Gastroenterology 2010;138:1875–84.
Background & Aims
Corticosteroids are used as immunosuppressants in patients with autoimmune disorders and transplant recipients. However, these drugs worsen hepatitis C virus (HCV) recurrence after liver transplantation, suggesting that they may directly exacerbate HCV infection.
Methods
The influence of immunosuppressive drugs on HCV replication, assembly, and entry was assessed in Huh-7.5 cells and primary human hepatocytes using cell culture- and patient-derived HCV. Replication was quantified by immunofluorescence, luciferase assays, quantitative reverse-transcriptase polymerase chain reaction, or core enzyme-linked immunosorbent assays. Expression of HCV entry factors was evaluated by cell sorting and immunoblot analyses.
Results
Glucocorticosteroids slightly reduced HCV RNA replication but increased efficiency of HCV entry by up to 10-fold. This was independent of HCV genotype but specific to HCV because vesicular stomatitis virus glycoprotein-dependent infection was not affected by these drugs. The increase in HCV entry was accompanied by up-regulation of messenger RNA and protein levels of occludin and the scavenger receptor class B type I – 2 host cell proteins required for HCV infection; increase of entry by glucocorticosteroids was ablated by RU-486, an inhibitor of glucocorticosteroid signaling. Glucocorticosteroids increased propagation of cell culture-derived HCV approximately 5- to 10-fold in partially differentiated human hepatoma cells and increased infection of primary human hepatocytes by cell culture- and patient-derived HCV.
Conclusions
Glucocorticosteroids specifically increase HCV entry by up-regulating the cell entry factors occludin and scavenger receptor class B type I. Our data suggest that the potential effects of high-dose glucocorticosteroids on HCV infection in vivo may be due to increased HCV dissemination [Reprinted with permission of the publisher].
Abbreviations: CLDN1, claudin-1, HCV, hepatitis C virus, HCVcc, cell culture-derived HCV, HCVpp, HCV pseudoparticles, LDLR, low-density lipoprotein receptor, OCLN, occludin, SR-BI, scavenger receptor class B type I
1 Inserm, U748, Strasbourg, France
2 Université de Strasbourg, Strasbourg, France
3 Laboratoire de Virologie, Hôpitaux Universitaires de Strasbourg, Strasbourg, France
4 Pôle Hépato-digestif, Hôpitaux Universitaires de Strasbourg, Strasbourg, France
Corresponding author. Address: Inserm U748, Université de Strasbourg, 3 rue Koeberlé, F-67000 Strasbourg, France. Tel.: +33 3 68 85 37 03; fax: +33 3 68 85 37 24.
PII: S0168-8278(10)00701-4
doi:10.1016/j.jhep.2010.07.007
© 2010 Published by Elsevier Inc.
Source
Received 5 July 2010; accepted 8 July 2010. published online 18 August 2010.
Uncorrected Proof
COMMENT ON:
Ciesek S, Steinmann E, Iken M, Ott M, Helfritz FA, Wappler I et al. Glucocorticosteroids increase cell entry by hepatitis C virus. Gastroenterology 2010;138:1875–84.
Background & Aims
Corticosteroids are used as immunosuppressants in patients with autoimmune disorders and transplant recipients. However, these drugs worsen hepatitis C virus (HCV) recurrence after liver transplantation, suggesting that they may directly exacerbate HCV infection.
Methods
The influence of immunosuppressive drugs on HCV replication, assembly, and entry was assessed in Huh-7.5 cells and primary human hepatocytes using cell culture- and patient-derived HCV. Replication was quantified by immunofluorescence, luciferase assays, quantitative reverse-transcriptase polymerase chain reaction, or core enzyme-linked immunosorbent assays. Expression of HCV entry factors was evaluated by cell sorting and immunoblot analyses.
Results
Glucocorticosteroids slightly reduced HCV RNA replication but increased efficiency of HCV entry by up to 10-fold. This was independent of HCV genotype but specific to HCV because vesicular stomatitis virus glycoprotein-dependent infection was not affected by these drugs. The increase in HCV entry was accompanied by up-regulation of messenger RNA and protein levels of occludin and the scavenger receptor class B type I – 2 host cell proteins required for HCV infection; increase of entry by glucocorticosteroids was ablated by RU-486, an inhibitor of glucocorticosteroid signaling. Glucocorticosteroids increased propagation of cell culture-derived HCV approximately 5- to 10-fold in partially differentiated human hepatoma cells and increased infection of primary human hepatocytes by cell culture- and patient-derived HCV.
Conclusions
Glucocorticosteroids specifically increase HCV entry by up-regulating the cell entry factors occludin and scavenger receptor class B type I. Our data suggest that the potential effects of high-dose glucocorticosteroids on HCV infection in vivo may be due to increased HCV dissemination [Reprinted with permission of the publisher].
Abbreviations: CLDN1, claudin-1, HCV, hepatitis C virus, HCVcc, cell culture-derived HCV, HCVpp, HCV pseudoparticles, LDLR, low-density lipoprotein receptor, OCLN, occludin, SR-BI, scavenger receptor class B type I
1 Inserm, U748, Strasbourg, France
2 Université de Strasbourg, Strasbourg, France
3 Laboratoire de Virologie, Hôpitaux Universitaires de Strasbourg, Strasbourg, France
4 Pôle Hépato-digestif, Hôpitaux Universitaires de Strasbourg, Strasbourg, France
Corresponding author. Address: Inserm U748, Université de Strasbourg, 3 rue Koeberlé, F-67000 Strasbourg, France. Tel.: +33 3 68 85 37 03; fax: +33 3 68 85 37 24.
PII: S0168-8278(10)00701-4
doi:10.1016/j.jhep.2010.07.007
© 2010 Published by Elsevier Inc.
Source
The Odd, Yet Dangerous Connection Between Grapefruit Juice and Prescription Drugs
Posted by David Mittleman
August 20, 2010 10:17 AM
If you enjoy a glass of grapefruit juice with your breakfast, you should check to make sure that it doesn't interact with your prescription medications. Unfortunately, many Americans learn this lesson the hard way. Take, for example, Lucas King, a 59-year-old retiree who suffers from heart disease and is on prescription heart medication to treat his condition.
King's heart disease is attributable to many factors: he is obese, inactive, and has a family history of the health condition. In addition, his LDL or "bad" cholesterol level was too high: 225 mg/dL. However, even after following his doctor's advice to get more exercise and change his unhealthy diet, his numbers just wouldn't budge. So, to help King, his doctor prescribed the drug Lipitor, along with continued diet and exercise. Over time, King's doctor raised the dosage to the maximum, which helped him to lose over 36 pounds and bring his LDL cholesterol down to 104.
Feeling much healthier, King decided to travel to his winter home in Florida. Naturally, he took advantage of the grapefruit tree growing in his yard and drank at least 2 glasses of juice each day from the fruit. But just two months after receiving the good news about his health, King was rushed to a Florida emergency room with muscle pain, fever, and fatigue. Subsequently, King was diagnosed with rhabdomyolysis, a severe muscle reaction that can cause death.
While King's diagnosis might seem bizarre and unusual, it is actually more common for individuals who take prescription cholesterol-lowering medications than you might think. Prescription statins can already cause rhabdomyolysis, which is indicated on the warning label and the fact sheet that patients receive with the medication. What most patients don't realize, however, is that grapefruit juice slows the activity of the liver enzyme responsible for metabolizing the drugs. In fact, the Florida Department of Citrus acknowledges that grapefruit juice interacts with some cholesterol-lowering drugs. Thankfully, not all prescription statins interact with the fruit juice, so if you enjoy a glass or two with your morning meal, there are other statins that you could take instead. King did just that: he switched to Pravachol and is doing much better. Read below for a list of prescription drugs that interact with grapefruit juice, including some for other health problems:
Anxiety: Xanax, Buspar, Versed, Halcion
Depression: Luvox, Zoloft
Allergies: Allegra
Abnormal heart rhythm: Cordarone, quinidine
Heart disease/stroke/blood clots: Coumadin
Epilepsy: Tegretol
Cancer: Cyclophosphamide, etoposide, ifosfamide, tamoxifen, vinblastine, vincristine
Cough: Dextromethorphan (found in many over-the-counter cold medicines)
HIV: Agenerase, Crixivan, Viracept, Norvir, Fortovase
Prostate enlargement: Proscar
Heart disease/High blood pressure: Coreg, Cardizem, Plendil, Cardene, Adalat, Procardia, Nimotop, Sular, Covera, Calan, Verelan
Erectile dysfunction: Viagra, Cialis
Asthma/Emphysema: Theophylline
High cholesterol: Lipitor, Lescol, Mevacor, Zocor
Pain: Alfenta, Duragesic, Actiq, Sufenta
Infection: Biaxin, Sporanox, erythromycin, troleandomycin
Most importantly, check with your doctor about specific interactions between grapefruit juice and medication to ensure your health and safety.
Source
August 20, 2010 10:17 AM
If you enjoy a glass of grapefruit juice with your breakfast, you should check to make sure that it doesn't interact with your prescription medications. Unfortunately, many Americans learn this lesson the hard way. Take, for example, Lucas King, a 59-year-old retiree who suffers from heart disease and is on prescription heart medication to treat his condition.
King's heart disease is attributable to many factors: he is obese, inactive, and has a family history of the health condition. In addition, his LDL or "bad" cholesterol level was too high: 225 mg/dL. However, even after following his doctor's advice to get more exercise and change his unhealthy diet, his numbers just wouldn't budge. So, to help King, his doctor prescribed the drug Lipitor, along with continued diet and exercise. Over time, King's doctor raised the dosage to the maximum, which helped him to lose over 36 pounds and bring his LDL cholesterol down to 104.
Feeling much healthier, King decided to travel to his winter home in Florida. Naturally, he took advantage of the grapefruit tree growing in his yard and drank at least 2 glasses of juice each day from the fruit. But just two months after receiving the good news about his health, King was rushed to a Florida emergency room with muscle pain, fever, and fatigue. Subsequently, King was diagnosed with rhabdomyolysis, a severe muscle reaction that can cause death.
While King's diagnosis might seem bizarre and unusual, it is actually more common for individuals who take prescription cholesterol-lowering medications than you might think. Prescription statins can already cause rhabdomyolysis, which is indicated on the warning label and the fact sheet that patients receive with the medication. What most patients don't realize, however, is that grapefruit juice slows the activity of the liver enzyme responsible for metabolizing the drugs. In fact, the Florida Department of Citrus acknowledges that grapefruit juice interacts with some cholesterol-lowering drugs. Thankfully, not all prescription statins interact with the fruit juice, so if you enjoy a glass or two with your morning meal, there are other statins that you could take instead. King did just that: he switched to Pravachol and is doing much better. Read below for a list of prescription drugs that interact with grapefruit juice, including some for other health problems:
Anxiety: Xanax, Buspar, Versed, Halcion
Depression: Luvox, Zoloft
Allergies: Allegra
Abnormal heart rhythm: Cordarone, quinidine
Heart disease/stroke/blood clots: Coumadin
Epilepsy: Tegretol
Cancer: Cyclophosphamide, etoposide, ifosfamide, tamoxifen, vinblastine, vincristine
Cough: Dextromethorphan (found in many over-the-counter cold medicines)
HIV: Agenerase, Crixivan, Viracept, Norvir, Fortovase
Prostate enlargement: Proscar
Heart disease/High blood pressure: Coreg, Cardizem, Plendil, Cardene, Adalat, Procardia, Nimotop, Sular, Covera, Calan, Verelan
Erectile dysfunction: Viagra, Cialis
Asthma/Emphysema: Theophylline
High cholesterol: Lipitor, Lescol, Mevacor, Zocor
Pain: Alfenta, Duragesic, Actiq, Sufenta
Infection: Biaxin, Sporanox, erythromycin, troleandomycin
Most importantly, check with your doctor about specific interactions between grapefruit juice and medication to ensure your health and safety.
Source
6 Studies on Hypercoagulation relations to Fatty Liver, Metabolic syndrome, and Increased Cardiovascular Risks
August 21, 2010 posted by Denise Nichols
Hypercoagulation’s relationship to nonalcoholic fatty liver disease, metabolic syndrome, increase risk in Cardiovascular disease, diabetes, cadium toxicity, osteomalacia, anemia, increase risk of thrombosis, cellular thrombosis are discussed in these 6 studies.
Gulf War Veterans have you been diagnosed with Liver problems? You must realize that the liver is important in order to detoxify the body and is damaged by chemicals, heavy metals , and viruses. Gulf War veterans need to not be using alcohol, need to be aware to follow and watch liver function values that the doctors should be monitoring, and also the pharmacist and the gulf war veteran patient should closely monitor other drugs that are prescription that might have adverse effects or side effects related to the liver.
Symptoms of Liver problems include:
1. See if the patient has discoloration of skin. The skin and eyes acquire a yellowish tinge and the urine turns dark yellow. It is called jaundice and this is considered to be the primary sign of liver disease.
2. Track the patient’s diet. Loss of appetite leading to weight loss is indicative of liver dysfunction. The patient may become anemic and have a nauseating feeling.
3. Check for light colored stools as it indicates the beginning of liver disorder. A liver patient may also complain of irritable bowels or irregular bowel movements.
4. Find out if there is distended abdomen. Swelling under the right lower ribs is a common complaint of liver patients. It can put severe pressure on the diaphragm that results in painful breathing.
5. Examine the shape and appearance of the nails. Curved and whitish look of nails also suggests a liver problem.
6. Notice nose bleeding and easy bruises as it shows liver abnormality and deficiency of proteins.
7. Test for polydipsia and polyuria-excessive thirst and frequent urination can occur in case of a liver disease.
8. Frequent headaches, dizziness, spasms, irritability, depression and so on are also indicative of liver problem.
9. Other items to watch for:
--Itchy skin that doesn’t seem to go away
--Dark urine color
--Bloody or tar-colored stool
--Chronic fatigue
Here are the 6 research studies:
1. Clin Liver Dis. 2009 Feb;13(1):109-16.
Hypercoagulation in liver disease.
Northup PG. Division of Gastroenterology and Hepatology, University of Virginia Health System, JPA and Lee Streets, MSB 2142, Charlottesville VA 22908-0708, USA. pgn5qs@virginia.edu
Abstract
The coagulopathy of liver disease is complex and often unpredictable. Despite clear evidence of an increased tendency for bleeding in patients who have cirrhosis, many circumstances also promote local and systemic hypercoagulable states. The consequences of hypercoagulability include the obvious morbidity and mortality of portal vein thrombosis, deep vein thrombosis, and pulmonary embolism, but possibly also include other end-organ syndromes, such as portopulmonary hypertension, hepatorenal syndrome, and spontaneous bacterial peritonitis. A more subtle contribution also could be responsible for progression of early fibrosis to decompensated cirrhosis. Future research is needed to elucidate specific mechanistic pathways that might lead to local hypercoagulation and the clinical interventions that might prevent morbidity and mortality related to hypercoagulation in patients who have cirrhosis.
PMID: 19150315 [PubMed - indexed for MEDLINE]
2. Semin Thromb Hemost. 2009 Apr;35(3):277-87. Epub 2009 May 18.
Nonalcoholic fatty liver disease as a contributor to hypercoagulation and thrombophilia in the metabolic syndrome.
Targher G, Chonchol M, Miele L, Zoppini G, Pichiri I, Muggeo M. Department of Biomedical and Surgical Sciences, University of Verona, Italy. giovanni.targher@univr.it
Comment in:
Semin Thromb Hemost. 2009 Apr;35(3):257-9.
Abstract
Nonalcoholic fatty liver disease (NAFLD), comprising its whole spectrum of conditions ranging from simple steatosis to steatohepatitis (nonalcoholic steatohepatitis; NASH) and cirrhosis, is the most frequent liver disease in developed countries and is now regarded as the liver manifestation of the metabolic syndrome. Several studies indicate that NAFLD, especially in its necro-inflammatory form (NASH), is associated with a systemic proinflammatory/prothrombotic state, independently of shared metabolic risk factors. This suggests that NAFLD/NASH is not simply a marker of the proinflammatory/prothrombotic state in the metabolic syndrome but is actively involved in its pathogenesis, possibly through the systemic release of proinflammatory and procoagulant factors from the steatotic liver (C-reactive protein, plasminogen activator inhibitor-1, interleukin-6, fibrinogen, and other proinflammatory cytokines). The clinical impact of NAFLD on the proinflammatory/prothrombotic risk profile deserves particular attention in view of the implications for screening and surveillance strategies in the growing number of patients with NAFLD.
PMID: 19452403 [PubMed - indexed for MEDLINE]
3. Diabetologia. 2008 Nov;51(11):1947-53. Epub 2008 Sep 2.
Increased risk of cardiovascular disease in non-alcoholic fatty liver disease: causal effect or epiphenomenon?
Targher G, Marra F, Marchesini G.
Department of Biomedical and Surgical Sciences, University of Verona, Ospedale Civile Maggiore, Verona, Italy. giovanni.targher@univr.it
Abstract
Non-alcoholic fatty liver disease (NAFLD), comprising a spectrum of conditions ranging from pure steatosis to steatohepatitis and cirrhosis, has reached epidemic proportions and represents the most common cause of chronic liver disease in the community. The prevalence of NAFLD has been estimated to be between 20% and 30% in the general population, but this value is much higher ( approximately 70-80%) in type 2 diabetic patients, who are also at higher risk of developing advanced fibrosis and cirrhosis. Increasing recognition of the importance of NAFLD and its strong relationship with the metabolic syndrome has stimulated an interest in the possible role of NAFLD in the development of cardiovascular disease (CVD). Several epidemiological studies indicate that NAFLD, especially in its more severe forms, is linked to an increased risk of CVD, independently of underlying cardiometabolic risk factors. This suggests that NAFLD is not merely a marker of CVD, but may also be actively involved in its pathogenesis. The possible molecular mediators linking NAFLD and CVD include the release of pro-atherogenic factors from the liver (C-reactive protein, fibrinogen, plasminogen activator inhibitor-1 and other inflammatory cytokines) as well as the contribution of NAFLD per se to whole-body insulin resistance and atherogenic dyslipidemia, in turn favouring CVD progression. The clinical impact of NAFLD on CVD risk deserves particular attention in view of the implications for screening and surveillance strategies in the growing number of patients with NAFLD.
PMID: 18762907 [PubMed - indexed for MEDLINE]
4. J Thromb Haemost. 2008 Jan;6(1):2-9. Epub 2007 Sep 24.
Hypercoagulation and thrombophilia in liver disease.
Northup PG, Sundaram V, Fallon MB, Reddy KR, Balogun RA, Sanyal AJ, Anstee QM, Hoffman MR, Ikura Y, Caldwell SH; Coagulation in Liver Disease Group. Division of Gastroenterology and Hepatology, University of Virginia Health System, Charlottesville, VA 22908-0708, USA. pgn5qs@virginia.edu
Abstract
A complex balance exists between endogenous procoagulants and the anticoagulant system in liver disease patients. Hypercoagulable events occur in cirrhosis patients despite the well-known bleeding diathesis of liver disease. These events may be clinically evident, such as in portal vein thrombosis or pulmonary embolism, but these conditions may also be a silent contributor to certain disease states, such as portopulmonary hypertension or parenchymal extinction with liver atrophy as well as thrombosis of extracorporeal circuits in dialysis or liver assist devices. Moreover, liver disease-related hypercoagulability may contribute to vascular disease in the increasingly common condition of non-alcoholic fatty liver disease. Despite the incidence of these problems, there are few widely accessible and practical laboratory tests to evaluate the risk of a hypercoagulable event in cirrhosis patients. Furthermore, there is little research on the use of commonly accepted anticoagulants in patients with liver disease. This article is a result of an international symposium on coagulation disorders in liver disease and addresses several areas of specific interest in hypercoagulation in liver disease. Critical areas lacking clinical information are highlighted and future areas of research interest are defined with an aim to foster clinical research in this field.
PMID: 17892532 [PubMed - indexed for MEDLINE]
5. Pathophysiol Haemost Thromb. 2006;35(6):411-6.
The effects of chronic cadmium toxicity on the hemostatic system.
Koçak M, Akçil E. Department of Pathophysiology, Faculty of Medicine, Ankara University, Ankara, Turkey. mkocak@epdk.org.tr
Abstract
Cadmium, a highly toxic heavy metal, is distributed widely in the general environment. The characteristic clinical manifestations of chronic cadmium intoxication include renal proximal tubular dysfunction, osteomalacia and anemia. Accumulating evidence suggests that cadmium toxicity may also affect various organs such as the liver, lung, testis and hematopoietic system. The aim of this study was to determine the effect of chronic cadmium exposure on the anticoagulant system in rats. Fourty-five adult Wistar albino rats were randomly allocated into 2 groups. While the control group was given tap water, the animals in the cadmium group were treated with 15 ppm CdCl(2) for 4 weeks. Blood cadmium concentration, prothrombin time, activated partial thromboplastin time, plasma protein C and antithrombin activity, and platelet count were determined in the rats. Blood cadmium concentrations increased in the experiment group compared to the control group (p < 0.001). Results also show that cadmium exposure shortened prothrombin time (p < 0.05) and activated partial thromboplastin time (p < 0.01) in rats. Protein C (p < 0.001) and antithrombin (p 0.05). In conclusion, when the parameters of the hemolytic system are considered, the decrease in protein C and antithrombin activities and the shortening of prothrombin time and activated partial thromboplastin time suggests the presence of a hypercoagulable state during chronic cadmium intoxication. Therefore, it may be stated that chronic cadmium toxicity sets the stage for hypercoagulation and hence increases the risk of thrombosis.
PMID: 17565233 [PubMed - indexed for MEDLINE]
6. Cell Biochem Funct. 2006 Mar-Apr;24(2):173-92.
Tissue factor upregulation drives a thrombosis-inflammation circuit in relation to cardiovascular complications.
Chu AJ. Surgery Department, Wayne State University, Detroit, MI 48201, USA. ajchu91@hotmail.com
Abstract
The extrinsic coagulation is recognized as an ‘inducible’ signalling cascade resulting from tissue factor (TF) upregulation by exposure to clotting zymogen FVII upon inflammation or tissue injury. Following the substantial initiation, an array of proteolytic activation generates mediating signals (active serine proteases: FVIIa, FXa and FIIa) that lead to hypercoagulation with fibrin overproduction manifesting thrombosis. In addition, TF upregulation plays a central role in driving a thrombosis-inflammation circuit. Coagulant mediators (FVIIa, FXa and FIIa) and endproduct (fibrin) are proinflammatory, eliciting tissue necrosis factor, interleukins, adhesion molecules and many other intracellular signals in different cell types. Such resulting inflammation could ensure ‘fibrin’ thrombosis via feedback upregulation of TF. Alternatively, the resulting inflammation triggers platelet/leukocyte/polymononuclear cell activation thus contributing to ‘cellular’ thrombosis. TF is very vulnerable to upregulation resulting in hypercoagulability and subsequent thrombosis and inflammation, either of which presents cardiovascular risks. The prevention and intervention of TF hypercoagulability are of importance in cardioprotection. Blockade of inflammation reception and its intracellular signalling prevents TF expression from upregulation. Natural (activated protein C, tissue factor pathway inhibitor, or antithrombin III) or pharmacological anticoagulants readily offset the extrinsic hypercoagulation mainly through FVIIa, FXa or FIIa inhibition. Therefore, anticoagulants turn off the thrombosis-inflammation circuit, offering not only antithrombotic but anti-inflammatory significance in the prevention of cardiovascular complications.
PMID: 15617024 [PubMed - indexed for MEDLINE]
————–
- ISAC Panel (Fibrinogen Activity, Prothrombin Fragment 1+2, Thrombin/Antithrombin Complex, PA by Flow)320020 – Hypercoagulation Panel (No Meds) (Antithrombin Activity, Protein C Activity, Protein S Activity, Activated Protein C Resistance, Fibrinogen Activity, Prothrombin Time/INR, Activated Partial Thromboplastin Time, Dilute Russell’s Viper Venom Time Screen, Dilute Russell’s Viper Venom Time Confirm, Lipoprotein (a), Homocysteine, Factor II Mutation, Platelet Activation by Flow) Note: May include PNP, PT Mixing Study, and/or aPTT Mixing Study
Source
Also See: Original Hypercoagulation Study on Gulf War Veterans
Hypercoagulation’s relationship to nonalcoholic fatty liver disease, metabolic syndrome, increase risk in Cardiovascular disease, diabetes, cadium toxicity, osteomalacia, anemia, increase risk of thrombosis, cellular thrombosis are discussed in these 6 studies.
Gulf War Veterans have you been diagnosed with Liver problems? You must realize that the liver is important in order to detoxify the body and is damaged by chemicals, heavy metals , and viruses. Gulf War veterans need to not be using alcohol, need to be aware to follow and watch liver function values that the doctors should be monitoring, and also the pharmacist and the gulf war veteran patient should closely monitor other drugs that are prescription that might have adverse effects or side effects related to the liver.
Symptoms of Liver problems include:
1. See if the patient has discoloration of skin. The skin and eyes acquire a yellowish tinge and the urine turns dark yellow. It is called jaundice and this is considered to be the primary sign of liver disease.
2. Track the patient’s diet. Loss of appetite leading to weight loss is indicative of liver dysfunction. The patient may become anemic and have a nauseating feeling.
3. Check for light colored stools as it indicates the beginning of liver disorder. A liver patient may also complain of irritable bowels or irregular bowel movements.
4. Find out if there is distended abdomen. Swelling under the right lower ribs is a common complaint of liver patients. It can put severe pressure on the diaphragm that results in painful breathing.
5. Examine the shape and appearance of the nails. Curved and whitish look of nails also suggests a liver problem.
6. Notice nose bleeding and easy bruises as it shows liver abnormality and deficiency of proteins.
7. Test for polydipsia and polyuria-excessive thirst and frequent urination can occur in case of a liver disease.
8. Frequent headaches, dizziness, spasms, irritability, depression and so on are also indicative of liver problem.
9. Other items to watch for:
--Itchy skin that doesn’t seem to go away
--Dark urine color
--Bloody or tar-colored stool
--Chronic fatigue
Here are the 6 research studies:
1. Clin Liver Dis. 2009 Feb;13(1):109-16.
Hypercoagulation in liver disease.
Northup PG. Division of Gastroenterology and Hepatology, University of Virginia Health System, JPA and Lee Streets, MSB 2142, Charlottesville VA 22908-0708, USA. pgn5qs@virginia.edu
Abstract
The coagulopathy of liver disease is complex and often unpredictable. Despite clear evidence of an increased tendency for bleeding in patients who have cirrhosis, many circumstances also promote local and systemic hypercoagulable states. The consequences of hypercoagulability include the obvious morbidity and mortality of portal vein thrombosis, deep vein thrombosis, and pulmonary embolism, but possibly also include other end-organ syndromes, such as portopulmonary hypertension, hepatorenal syndrome, and spontaneous bacterial peritonitis. A more subtle contribution also could be responsible for progression of early fibrosis to decompensated cirrhosis. Future research is needed to elucidate specific mechanistic pathways that might lead to local hypercoagulation and the clinical interventions that might prevent morbidity and mortality related to hypercoagulation in patients who have cirrhosis.
PMID: 19150315 [PubMed - indexed for MEDLINE]
2. Semin Thromb Hemost. 2009 Apr;35(3):277-87. Epub 2009 May 18.
Nonalcoholic fatty liver disease as a contributor to hypercoagulation and thrombophilia in the metabolic syndrome.
Targher G, Chonchol M, Miele L, Zoppini G, Pichiri I, Muggeo M. Department of Biomedical and Surgical Sciences, University of Verona, Italy. giovanni.targher@univr.it
Comment in:
Semin Thromb Hemost. 2009 Apr;35(3):257-9.
Abstract
Nonalcoholic fatty liver disease (NAFLD), comprising its whole spectrum of conditions ranging from simple steatosis to steatohepatitis (nonalcoholic steatohepatitis; NASH) and cirrhosis, is the most frequent liver disease in developed countries and is now regarded as the liver manifestation of the metabolic syndrome. Several studies indicate that NAFLD, especially in its necro-inflammatory form (NASH), is associated with a systemic proinflammatory/prothrombotic state, independently of shared metabolic risk factors. This suggests that NAFLD/NASH is not simply a marker of the proinflammatory/prothrombotic state in the metabolic syndrome but is actively involved in its pathogenesis, possibly through the systemic release of proinflammatory and procoagulant factors from the steatotic liver (C-reactive protein, plasminogen activator inhibitor-1, interleukin-6, fibrinogen, and other proinflammatory cytokines). The clinical impact of NAFLD on the proinflammatory/prothrombotic risk profile deserves particular attention in view of the implications for screening and surveillance strategies in the growing number of patients with NAFLD.
PMID: 19452403 [PubMed - indexed for MEDLINE]
3. Diabetologia. 2008 Nov;51(11):1947-53. Epub 2008 Sep 2.
Increased risk of cardiovascular disease in non-alcoholic fatty liver disease: causal effect or epiphenomenon?
Targher G, Marra F, Marchesini G.
Department of Biomedical and Surgical Sciences, University of Verona, Ospedale Civile Maggiore, Verona, Italy. giovanni.targher@univr.it
Abstract
Non-alcoholic fatty liver disease (NAFLD), comprising a spectrum of conditions ranging from pure steatosis to steatohepatitis and cirrhosis, has reached epidemic proportions and represents the most common cause of chronic liver disease in the community. The prevalence of NAFLD has been estimated to be between 20% and 30% in the general population, but this value is much higher ( approximately 70-80%) in type 2 diabetic patients, who are also at higher risk of developing advanced fibrosis and cirrhosis. Increasing recognition of the importance of NAFLD and its strong relationship with the metabolic syndrome has stimulated an interest in the possible role of NAFLD in the development of cardiovascular disease (CVD). Several epidemiological studies indicate that NAFLD, especially in its more severe forms, is linked to an increased risk of CVD, independently of underlying cardiometabolic risk factors. This suggests that NAFLD is not merely a marker of CVD, but may also be actively involved in its pathogenesis. The possible molecular mediators linking NAFLD and CVD include the release of pro-atherogenic factors from the liver (C-reactive protein, fibrinogen, plasminogen activator inhibitor-1 and other inflammatory cytokines) as well as the contribution of NAFLD per se to whole-body insulin resistance and atherogenic dyslipidemia, in turn favouring CVD progression. The clinical impact of NAFLD on CVD risk deserves particular attention in view of the implications for screening and surveillance strategies in the growing number of patients with NAFLD.
PMID: 18762907 [PubMed - indexed for MEDLINE]
4. J Thromb Haemost. 2008 Jan;6(1):2-9. Epub 2007 Sep 24.
Hypercoagulation and thrombophilia in liver disease.
Northup PG, Sundaram V, Fallon MB, Reddy KR, Balogun RA, Sanyal AJ, Anstee QM, Hoffman MR, Ikura Y, Caldwell SH; Coagulation in Liver Disease Group. Division of Gastroenterology and Hepatology, University of Virginia Health System, Charlottesville, VA 22908-0708, USA. pgn5qs@virginia.edu
Abstract
A complex balance exists between endogenous procoagulants and the anticoagulant system in liver disease patients. Hypercoagulable events occur in cirrhosis patients despite the well-known bleeding diathesis of liver disease. These events may be clinically evident, such as in portal vein thrombosis or pulmonary embolism, but these conditions may also be a silent contributor to certain disease states, such as portopulmonary hypertension or parenchymal extinction with liver atrophy as well as thrombosis of extracorporeal circuits in dialysis or liver assist devices. Moreover, liver disease-related hypercoagulability may contribute to vascular disease in the increasingly common condition of non-alcoholic fatty liver disease. Despite the incidence of these problems, there are few widely accessible and practical laboratory tests to evaluate the risk of a hypercoagulable event in cirrhosis patients. Furthermore, there is little research on the use of commonly accepted anticoagulants in patients with liver disease. This article is a result of an international symposium on coagulation disorders in liver disease and addresses several areas of specific interest in hypercoagulation in liver disease. Critical areas lacking clinical information are highlighted and future areas of research interest are defined with an aim to foster clinical research in this field.
PMID: 17892532 [PubMed - indexed for MEDLINE]
5. Pathophysiol Haemost Thromb. 2006;35(6):411-6.
The effects of chronic cadmium toxicity on the hemostatic system.
Koçak M, Akçil E. Department of Pathophysiology, Faculty of Medicine, Ankara University, Ankara, Turkey. mkocak@epdk.org.tr
Abstract
Cadmium, a highly toxic heavy metal, is distributed widely in the general environment. The characteristic clinical manifestations of chronic cadmium intoxication include renal proximal tubular dysfunction, osteomalacia and anemia. Accumulating evidence suggests that cadmium toxicity may also affect various organs such as the liver, lung, testis and hematopoietic system. The aim of this study was to determine the effect of chronic cadmium exposure on the anticoagulant system in rats. Fourty-five adult Wistar albino rats were randomly allocated into 2 groups. While the control group was given tap water, the animals in the cadmium group were treated with 15 ppm CdCl(2) for 4 weeks. Blood cadmium concentration, prothrombin time, activated partial thromboplastin time, plasma protein C and antithrombin activity, and platelet count were determined in the rats. Blood cadmium concentrations increased in the experiment group compared to the control group (p < 0.001). Results also show that cadmium exposure shortened prothrombin time (p < 0.05) and activated partial thromboplastin time (p < 0.01) in rats. Protein C (p < 0.001) and antithrombin (p 0.05). In conclusion, when the parameters of the hemolytic system are considered, the decrease in protein C and antithrombin activities and the shortening of prothrombin time and activated partial thromboplastin time suggests the presence of a hypercoagulable state during chronic cadmium intoxication. Therefore, it may be stated that chronic cadmium toxicity sets the stage for hypercoagulation and hence increases the risk of thrombosis.
PMID: 17565233 [PubMed - indexed for MEDLINE]
6. Cell Biochem Funct. 2006 Mar-Apr;24(2):173-92.
Tissue factor upregulation drives a thrombosis-inflammation circuit in relation to cardiovascular complications.
Chu AJ. Surgery Department, Wayne State University, Detroit, MI 48201, USA. ajchu91@hotmail.com
Abstract
The extrinsic coagulation is recognized as an ‘inducible’ signalling cascade resulting from tissue factor (TF) upregulation by exposure to clotting zymogen FVII upon inflammation or tissue injury. Following the substantial initiation, an array of proteolytic activation generates mediating signals (active serine proteases: FVIIa, FXa and FIIa) that lead to hypercoagulation with fibrin overproduction manifesting thrombosis. In addition, TF upregulation plays a central role in driving a thrombosis-inflammation circuit. Coagulant mediators (FVIIa, FXa and FIIa) and endproduct (fibrin) are proinflammatory, eliciting tissue necrosis factor, interleukins, adhesion molecules and many other intracellular signals in different cell types. Such resulting inflammation could ensure ‘fibrin’ thrombosis via feedback upregulation of TF. Alternatively, the resulting inflammation triggers platelet/leukocyte/polymononuclear cell activation thus contributing to ‘cellular’ thrombosis. TF is very vulnerable to upregulation resulting in hypercoagulability and subsequent thrombosis and inflammation, either of which presents cardiovascular risks. The prevention and intervention of TF hypercoagulability are of importance in cardioprotection. Blockade of inflammation reception and its intracellular signalling prevents TF expression from upregulation. Natural (activated protein C, tissue factor pathway inhibitor, or antithrombin III) or pharmacological anticoagulants readily offset the extrinsic hypercoagulation mainly through FVIIa, FXa or FIIa inhibition. Therefore, anticoagulants turn off the thrombosis-inflammation circuit, offering not only antithrombotic but anti-inflammatory significance in the prevention of cardiovascular complications.
PMID: 15617024 [PubMed - indexed for MEDLINE]
————–
- ISAC Panel (Fibrinogen Activity, Prothrombin Fragment 1+2, Thrombin/Antithrombin Complex, PA by Flow)320020 – Hypercoagulation Panel (No Meds) (Antithrombin Activity, Protein C Activity, Protein S Activity, Activated Protein C Resistance, Fibrinogen Activity, Prothrombin Time/INR, Activated Partial Thromboplastin Time, Dilute Russell’s Viper Venom Time Screen, Dilute Russell’s Viper Venom Time Confirm, Lipoprotein (a), Homocysteine, Factor II Mutation, Platelet Activation by Flow) Note: May include PNP, PT Mixing Study, and/or aPTT Mixing Study
Source
Also See: Original Hypercoagulation Study on Gulf War Veterans
FDA extends review on Acetadote for non-acetaminophen acute liver failure
21. August 2010 00:42
Cumberland Pharmaceuticals Inc. (Nasdaq: CPIX) today announced the U.S. Food and Drug Administration (FDA) has extended its review of the supplemental new drug application (sNDA) for the use of Acetadote® (acetylcysteine) Injection in patients with non-acetaminophen acute liver failure. The review has been extended by three months resulting in a new Prescription Drug User Fee Act (PDUFA) goal date in December 2010.
"We look forward to continued discussion with the FDA regarding this potentially life-saving treatment for patients who have few alternatives," said A.J. Kazimi, Chief Executive Officer of Cumberland Pharmaceuticals.
Acute liver failure is a rare syndrome associated with a high mortality rate and frequent need for liver transplantation. Approximately 50 percent of acute liver failure cases are caused by acetaminophen poisoning. Other causes of acute liver failure not induced by acetaminophen overdose include hepatitis B disease, autoimmune hepatitis, Wilson disease, fatty liver of pregnancy, and HELLP (hemolysis, elevated liver enzymes, low platelets) syndrome. Currently, transplantation of the liver is the only treatment for patients with liver failure not caused by acetaminophen overdose. In March 2010, Cumberland submitted the sNDA to the FDA for the use of Acetadote in patients with non-acetaminophen acute liver failure. The FDA formally accepted the application for review and designated the review classification as Priority in May 2010.
Acetadote was launched by Cumberland in 2004 as the first U.S.-approved injectable drug to treat acetaminophen overdose. In 2006, the FDA approved Acetadote for use in pediatric patients. The Company also received FDA approval for updated labeling regarding the safety of Acetadote in 2008 based on new information from a post-marketing safety study reporting a lower-incidence of side effects compared to previously reported data.
Source: Cumberland Pharmaceuticals
Source
Cumberland Pharmaceuticals Inc. (Nasdaq: CPIX) today announced the U.S. Food and Drug Administration (FDA) has extended its review of the supplemental new drug application (sNDA) for the use of Acetadote® (acetylcysteine) Injection in patients with non-acetaminophen acute liver failure. The review has been extended by three months resulting in a new Prescription Drug User Fee Act (PDUFA) goal date in December 2010.
"We look forward to continued discussion with the FDA regarding this potentially life-saving treatment for patients who have few alternatives," said A.J. Kazimi, Chief Executive Officer of Cumberland Pharmaceuticals.
Acute liver failure is a rare syndrome associated with a high mortality rate and frequent need for liver transplantation. Approximately 50 percent of acute liver failure cases are caused by acetaminophen poisoning. Other causes of acute liver failure not induced by acetaminophen overdose include hepatitis B disease, autoimmune hepatitis, Wilson disease, fatty liver of pregnancy, and HELLP (hemolysis, elevated liver enzymes, low platelets) syndrome. Currently, transplantation of the liver is the only treatment for patients with liver failure not caused by acetaminophen overdose. In March 2010, Cumberland submitted the sNDA to the FDA for the use of Acetadote in patients with non-acetaminophen acute liver failure. The FDA formally accepted the application for review and designated the review classification as Priority in May 2010.
Acetadote was launched by Cumberland in 2004 as the first U.S.-approved injectable drug to treat acetaminophen overdose. In 2006, the FDA approved Acetadote for use in pediatric patients. The Company also received FDA approval for updated labeling regarding the safety of Acetadote in 2008 based on new information from a post-marketing safety study reporting a lower-incidence of side effects compared to previously reported data.
Source: Cumberland Pharmaceuticals
Source
In Practice: Dr. Google has mixed results
Using the search engine can be a boon for physicians — if they do it right.
By Rahul K. Parikh, Special to the Los Angeles Times
August 23, 2010
During an otherwise unremarkable afternoon at the office, I was sitting at my desk plowing through paperwork when a colleague came knocking — and forever changed how I practice medicine.
"Hey, Rahul, what's McMurray's sign?" he asked.
It is said that a physician needs to carry some 2 million facts to practice medicine. Though I knew that McMurray's sign had something to do with examining a patient's knee, it was one of the 2 million facts that, like some tattered scraps of paper pushed to the back of a file cabinet, I had long since forgotten.
I shrugged and turned toward my bookshelf to pull down a decade-old volume of Nelson's Textbook of Pediatrics. Somewhere in that tome was the definition of McMurray's sign and how to elicit it on exam.
Just as I was reaching for the book, I had another idea. I turned back to my workstation, clicked on that little "e" to bring up my Internet browser and went to Google. I typed "McMurray's sign" in the search box and hit "enter," and up popped several links to YouTube videos. We clicked on one and, like two medical students learning the basics of our craft, watched the short mini-lecture that showed an instructor moving the knee joint to check for a positive McMurray's sign. And with that, my colleague was off to try it on his own patient.
Eureka. No more pencils, no more books. With a computer and Google (sorry, Bing, statistics show that Google is where we go first and frequently) in your office and your exam rooms, it's a whole new world — for better or worse.
I've used Google regularly in my practice for the last four to five years, and statistics suggest I'm not alone (though it's Google's data, so it's perhaps best taken with a grain of salt): Eighty-six percent of doctors say they now regularly use the Internet on the job. Of that group, the majority start at Google, which they use as a springboard to look for general information about diseases and drugs.
And why not? As writer and physician Atul Gawande likes to point out, in medicine today there are 13,000 diseases, 6,000 drugs and 4,000 medical and surgical procedures. Even for the best and most motivated of physicians, it's a Sisyphean battle to keep up. Having the Internet at my fingertips makes me a better doctor, though I'll admit that sometimes it feels a bit like cheating on an exam.
Use it judiciously
I was sitting with the parent of a new patient a while back. As she was filling me in about her son's medical history, she told me his father has a history of retinitis pigmentosa. Like McMurray's sign, it was a distant but familiar phrase. As I was nodding my head listening, I stopped typing into his chart, brought up Google and typed in "retinitis pigmentosa."
A mere 0.36 seconds later, I got links 1-10 of 866,000. I clicked on a Medline link and glanced over some bullet points to see if I needed to send this child for any screening tests. Because, as I read, the "signs and symptoms often first appear in childhood, but severe vision problems do not usually develop until early adulthood," I knew I just had to make sure I did his vision test annually. Didn't miss a beat.
Most doctors seem to agree that using Google to educate yourself or patients makes sense (for a pediatrician like me, that means showing parents pictures of different diaper rashes and kids pictures of poison oak so they don't walk into a plant for the ninth time this summer). But things get trickier — and more controversial — when doctors start using Google to make diagnoses.
There's a now famous story first told in the New England Journal of Medicine about a trainee in allergy and immunology who was presenting a case to some colleagues. The audience included a visiting distinguished professor in the same field. The case was of an infant with diarrhea, an unusual rash and multiple immunologic abnormalities. The attending physicians and house staff discussed several diagnostic possibilities, but no consensus was reached. They were stumped. Finally, the visiting professor asked the trainee if she had made a diagnosis. She reported that she had: The child had a rare syndrome known as IPEX.
The distinguished physician asked the young trainee how she'd figured this out.
"Well, I had the skin biopsy report, and I had a chart of the immunologic tests. So I entered the salient features into Google, and it popped right up," she was quoted as saying. The author of that letter to the New England Journal, who was present at the meeting, wondered: "Are we physicians no longer needed? Is an observer who can accurately select the findings to be entered in a Google search all we need for a diagnosis to appear, as if by magic?"
He needn't worry. It turns out that we're not all as good at Googling as that young doctor was.
In a 2006 study published in the British Medical Journal, researchers had physicians read the histories of 26 tricky cases published in the New England Journal of Medicine and enter search terms into Google to see if they could make the diagnosis. They nailed it 58% of the time. Not bad, but not much better than the flip of a coin, either.
I tried this experiment myself with a handful of those New England Journal cases — I didn't get a single one right. So my advice is: Unless you're Internet savvy enough and have time to scan pages and pages of websites, skip Googling for diagnoses and just call your nearest specialist for help.
How scholarly?
Another of Google's potential pitfalls has to do with Google Scholar — a product the company launched in 2004 that searches academic publications and websites.
A colleague of mine recently declared that this was now his go-to site for medical research. And, in fact, more visitors were led to biomedical journal websites by Google Scholar within a year of its release than by PubMed, the free Internet database published by the National Library of Medicine and the standard-bearer for doctors and others looking for academic publications.
But at least one study, in the Journal of the Medical Library Assn. in 2007, suggests that Google Scholar may not be the best choice. In a head-to-head comparison of Google Scholar and PubMed, Scholar searches yielded significantly more total citations of primary research articles than did PubMed, suggesting it's less specific than PubMed.
Researchers also found that Google Scholar brings older articles to the top of the results. This is fine if you want a history lesson but problematic if you're looking for cutting-edge clinical data. (It turns out Google Scholar places more weight on studies that are cited more, regardless of their validity.)
Plus, the researchers concluded, users often don't search more than five pages to answer a question, leaving knowledge susceptible to the most popular articles, not necessarily the best.
This study raises an important point about Google, and really all search engines. These are businesses whose success largely rests on proprietary math and technology — algorithms, which in Google's case, are trade secrets, no different than the formula for Coca-Cola. As such, what you find on the top of the page depends on an often mysterious process.
That doesn't mean Google is doing something bad (the company's motto is "Don't be evil"). But it does mean users lack the kind of transparency some of us need when we place our professional faith in a search engine.
The solution for doctors (and everyone), I suspect, is best answered by taking note of that lack of transparency and by making it a professional priority to become search savvy. A growing number of medical professionals have suggested this as well.
Searchers also can use Google — and other sites — more narrowly. That little "advanced search" button next to the big search box, for example, can narrow the results, as can using quotation marks for exact phrases and excluding words by putting a minus sign in front of them. There are lots of tips about how to do this floating around on the Web (just Google "tips to using Google").
This little bit of expertise, especially in a world in which medical knowledge exponentially outpaces our ability to know it all, is a valuable skill set for young doctors to gain.
Parikh, a Walnut Creek, Calif., physician, writes the Vital Signs medical column for Salon.com. http://www.rahulkparikh.com/.
Source
By Rahul K. Parikh, Special to the Los Angeles Times
August 23, 2010
During an otherwise unremarkable afternoon at the office, I was sitting at my desk plowing through paperwork when a colleague came knocking — and forever changed how I practice medicine.
"Hey, Rahul, what's McMurray's sign?" he asked.
It is said that a physician needs to carry some 2 million facts to practice medicine. Though I knew that McMurray's sign had something to do with examining a patient's knee, it was one of the 2 million facts that, like some tattered scraps of paper pushed to the back of a file cabinet, I had long since forgotten.
I shrugged and turned toward my bookshelf to pull down a decade-old volume of Nelson's Textbook of Pediatrics. Somewhere in that tome was the definition of McMurray's sign and how to elicit it on exam.
Just as I was reaching for the book, I had another idea. I turned back to my workstation, clicked on that little "e" to bring up my Internet browser and went to Google. I typed "McMurray's sign" in the search box and hit "enter," and up popped several links to YouTube videos. We clicked on one and, like two medical students learning the basics of our craft, watched the short mini-lecture that showed an instructor moving the knee joint to check for a positive McMurray's sign. And with that, my colleague was off to try it on his own patient.
Eureka. No more pencils, no more books. With a computer and Google (sorry, Bing, statistics show that Google is where we go first and frequently) in your office and your exam rooms, it's a whole new world — for better or worse.
I've used Google regularly in my practice for the last four to five years, and statistics suggest I'm not alone (though it's Google's data, so it's perhaps best taken with a grain of salt): Eighty-six percent of doctors say they now regularly use the Internet on the job. Of that group, the majority start at Google, which they use as a springboard to look for general information about diseases and drugs.
And why not? As writer and physician Atul Gawande likes to point out, in medicine today there are 13,000 diseases, 6,000 drugs and 4,000 medical and surgical procedures. Even for the best and most motivated of physicians, it's a Sisyphean battle to keep up. Having the Internet at my fingertips makes me a better doctor, though I'll admit that sometimes it feels a bit like cheating on an exam.
Use it judiciously
I was sitting with the parent of a new patient a while back. As she was filling me in about her son's medical history, she told me his father has a history of retinitis pigmentosa. Like McMurray's sign, it was a distant but familiar phrase. As I was nodding my head listening, I stopped typing into his chart, brought up Google and typed in "retinitis pigmentosa."
A mere 0.36 seconds later, I got links 1-10 of 866,000. I clicked on a Medline link and glanced over some bullet points to see if I needed to send this child for any screening tests. Because, as I read, the "signs and symptoms often first appear in childhood, but severe vision problems do not usually develop until early adulthood," I knew I just had to make sure I did his vision test annually. Didn't miss a beat.
Most doctors seem to agree that using Google to educate yourself or patients makes sense (for a pediatrician like me, that means showing parents pictures of different diaper rashes and kids pictures of poison oak so they don't walk into a plant for the ninth time this summer). But things get trickier — and more controversial — when doctors start using Google to make diagnoses.
There's a now famous story first told in the New England Journal of Medicine about a trainee in allergy and immunology who was presenting a case to some colleagues. The audience included a visiting distinguished professor in the same field. The case was of an infant with diarrhea, an unusual rash and multiple immunologic abnormalities. The attending physicians and house staff discussed several diagnostic possibilities, but no consensus was reached. They were stumped. Finally, the visiting professor asked the trainee if she had made a diagnosis. She reported that she had: The child had a rare syndrome known as IPEX.
The distinguished physician asked the young trainee how she'd figured this out.
"Well, I had the skin biopsy report, and I had a chart of the immunologic tests. So I entered the salient features into Google, and it popped right up," she was quoted as saying. The author of that letter to the New England Journal, who was present at the meeting, wondered: "Are we physicians no longer needed? Is an observer who can accurately select the findings to be entered in a Google search all we need for a diagnosis to appear, as if by magic?"
He needn't worry. It turns out that we're not all as good at Googling as that young doctor was.
In a 2006 study published in the British Medical Journal, researchers had physicians read the histories of 26 tricky cases published in the New England Journal of Medicine and enter search terms into Google to see if they could make the diagnosis. They nailed it 58% of the time. Not bad, but not much better than the flip of a coin, either.
I tried this experiment myself with a handful of those New England Journal cases — I didn't get a single one right. So my advice is: Unless you're Internet savvy enough and have time to scan pages and pages of websites, skip Googling for diagnoses and just call your nearest specialist for help.
How scholarly?
Another of Google's potential pitfalls has to do with Google Scholar — a product the company launched in 2004 that searches academic publications and websites.
A colleague of mine recently declared that this was now his go-to site for medical research. And, in fact, more visitors were led to biomedical journal websites by Google Scholar within a year of its release than by PubMed, the free Internet database published by the National Library of Medicine and the standard-bearer for doctors and others looking for academic publications.
But at least one study, in the Journal of the Medical Library Assn. in 2007, suggests that Google Scholar may not be the best choice. In a head-to-head comparison of Google Scholar and PubMed, Scholar searches yielded significantly more total citations of primary research articles than did PubMed, suggesting it's less specific than PubMed.
Researchers also found that Google Scholar brings older articles to the top of the results. This is fine if you want a history lesson but problematic if you're looking for cutting-edge clinical data. (It turns out Google Scholar places more weight on studies that are cited more, regardless of their validity.)
Plus, the researchers concluded, users often don't search more than five pages to answer a question, leaving knowledge susceptible to the most popular articles, not necessarily the best.
This study raises an important point about Google, and really all search engines. These are businesses whose success largely rests on proprietary math and technology — algorithms, which in Google's case, are trade secrets, no different than the formula for Coca-Cola. As such, what you find on the top of the page depends on an often mysterious process.
That doesn't mean Google is doing something bad (the company's motto is "Don't be evil"). But it does mean users lack the kind of transparency some of us need when we place our professional faith in a search engine.
The solution for doctors (and everyone), I suspect, is best answered by taking note of that lack of transparency and by making it a professional priority to become search savvy. A growing number of medical professionals have suggested this as well.
Searchers also can use Google — and other sites — more narrowly. That little "advanced search" button next to the big search box, for example, can narrow the results, as can using quotation marks for exact phrases and excluding words by putting a minus sign in front of them. There are lots of tips about how to do this floating around on the Web (just Google "tips to using Google").
This little bit of expertise, especially in a world in which medical knowledge exponentially outpaces our ability to know it all, is a valuable skill set for young doctors to gain.
Parikh, a Walnut Creek, Calif., physician, writes the Vital Signs medical column for Salon.com. http://www.rahulkparikh.com/.
Source
Hepatitis C, Hispanic Ethnicity Linked to HCC Mortality
Those with HCV infection have 18-fold higher risk of hepatocellular carcinoma mortality
Publish date: Aug 20, 2010
FRIDAY, Aug. 20 (HealthDay News) -- Hepatitis C infection and Hispanic ethnicity are associated with a higher risk of hepatocellular carcinoma (HCC)-related mortality, according to research published in the August issue of Clinical Gastroenterology and Hepatology.
Zobair M. Younossi, M.D., and Maria Stepanova, Ph.D., of the Inova Fairfax Hospital in Falls Church, Va., analyzed data from 15,866 participants in the Third National Health and Nutrition Examination Survey from 1988 to 1994.
The researchers found that, over a median follow-up of 160 months, 14.55 percent of the subjects had died, with 25 of the deaths related to HCC and 58 deaths non-HCC liver related. Factors that predicted mortality related to HCC were hepatitis C infection (hazard ratio [HR], 18.12), Hispanic ethnicity (HR, 5.14), and age (HR, 1.10). Factors predicting non-HCC liver-related mortality included hepatitis C (HR, 27.00), nonalcoholic fatty liver disease (HR, 11.56), alcoholic liver disease (HR, 10.81), and iron overload (HR, 6.18).
"Although early diagnosis and treatment of all liver diseases and diabetes mellitus may favorably impact all liver-related mortality, screening and treatment of hepatitis C virus may specifically improve the rate of HCC-related mortality. In addition, screening and treatment programs must target all individuals at risk for HCC, including Hispanic Americans," the authors conclude.
Abstract
Full Text (subscription or payment may be required)
Source
Publish date: Aug 20, 2010
FRIDAY, Aug. 20 (HealthDay News) -- Hepatitis C infection and Hispanic ethnicity are associated with a higher risk of hepatocellular carcinoma (HCC)-related mortality, according to research published in the August issue of Clinical Gastroenterology and Hepatology.
Zobair M. Younossi, M.D., and Maria Stepanova, Ph.D., of the Inova Fairfax Hospital in Falls Church, Va., analyzed data from 15,866 participants in the Third National Health and Nutrition Examination Survey from 1988 to 1994.
The researchers found that, over a median follow-up of 160 months, 14.55 percent of the subjects had died, with 25 of the deaths related to HCC and 58 deaths non-HCC liver related. Factors that predicted mortality related to HCC were hepatitis C infection (hazard ratio [HR], 18.12), Hispanic ethnicity (HR, 5.14), and age (HR, 1.10). Factors predicting non-HCC liver-related mortality included hepatitis C (HR, 27.00), nonalcoholic fatty liver disease (HR, 11.56), alcoholic liver disease (HR, 10.81), and iron overload (HR, 6.18).
"Although early diagnosis and treatment of all liver diseases and diabetes mellitus may favorably impact all liver-related mortality, screening and treatment of hepatitis C virus may specifically improve the rate of HCC-related mortality. In addition, screening and treatment programs must target all individuals at risk for HCC, including Hispanic Americans," the authors conclude.
Abstract
Full Text (subscription or payment may be required)
Source
August 20, 2010
Cancer journal: A happy birthday despite grim news
I don't usually post things like this, but after reading the strength and courage that this man has, I just had to share it. God Bless you Mike Celizic!
A day that begins with a fateful choice ends with a celebration
By Mike Celizic
TODAYshow.com contributor
updated 8/19/2010 12:45:22 PM ET
Journal
Editor's note: Mike Celizic is TODAYshow.com’s ace morning news reporter as well as a sports columnist for msnbc.com. He is renowned for his ability to write compelling, accurate stories at lightning speed, as well as for his trademark hat, which he never removes, even when appearing as a guest commentator on MSNBC.
Last year Mike was diagnosed with T-cell lymphoma. As a dyed-in-the-wool journalist, his first instinct was: Report on it. Thus he is sharing this cancer journal with TODAYshow.com and msnbc.com readers as he turns his reporting skills to his most difficult subject: his own mortality.
I’m dying.
The lymphoma we’d thought we’d beaten into remission back in May came roaring back last month. We threw some really nasty chemo at it. The cancer ate it up and came back for more.
And so I’m going to die, and not in four or five months. I’ve got probably a couple of halfway decent weeks left. Then the lymphoma will take over my bloodstream and kill me.
I don’t have to die that quickly. I could undergo months of brutal and debilitating chemo that will leave me racked by pain and barely in control of what few senses I have.
The chemo itself could kill me. And even if it didn’t, I wouldn’t have a single day when I’d feel even vaguely normal. I would then have to get a bone marrow transplant — if a match could be found. There’s about a 10 percent chance that I’d survive, and a smaller chance that I’d be cured.
Taking that chance might be worth it to some, but not to me.
The object isn’t to live as long as you can, but as well as you can. I’ve lived very well; had a grand and glorious life. I’ve done everything I’ve ever wanted to do except meet Al Roker. I’m not afraid to die. But I don’t want to die, and there’s the problem. I love life, love this glorious planet, love simple pleasures, love living.
The choice
I learned my situation Wednesday. I’ve spent a lot of the time since crying like Glenn Beck, only for real.
But there’s no other choice for me. It’s about controlling what life I have left. Enter treatment, and you surrender all control for a tiny chance of survival at a diminished capacity.
I already tried that. I’m not going to do it again.
So I’ve made the most personal decision I ever will make. It’s taken every ounce of my courage and 40 years of philosophizing and thinking and reading and traveling and learning to make. The easy choice would have been to go into chemo. For me, it would also be the wrong choice.
I’m writing this because I owe it to all the wonderful people who started reading the blog I started when I began treatment for lymphoma last year. It was called “Adventures in Cancerland.” I wrote two really swell entries, I say with no modesty at all, full of insight and humor and perspective.
Related: Adventures in Cancerland, Part 1 — The diagnosis
Related: Adventures in Cancerland, Part 2 — Lust for life
Then I quit.
Sorry about that. It wasn’t that I didn’t want to write; it was just that I was waiting for an adventure, and one never presented itself. Getting treated for lymphoma turned out to be as tedious as picking cat hairs off a cashmere coat. It was not exciting. The painful parts weren’t that painful. Nothing gruesome happened.
I left the hospital in December, spent three months in isolation at home, and was cleared to return to real life. Sometime in May, I was officially in remission.\
But it didn’t last long. The cancer came back in July, and this time it’s not messing around.
My oncologist, Dr. Ariela Noy, came into my room early Wednesday here at Memorial Sloan-Kettering Cancer Center in New York City. She’s an extraordinary doctor and person; tenacious, dedicated, talented, caring — name a quality you want in a doctor, and she’s got it.
It was my birthday, and she fidgeted as she told me the situation. We’d talked about this scenario, and she wasn’t surprised at my choice. I did promise to sleep on it, and then we had a good hug and cry. (I’m not usually given to crying, but this has opened the floodgates.)
I called my wife and told her. I promised to sleep on it, and she promised to come in today to collect me and my belongings.
Birthday contraband
I sent some e-mails to some close friends. One, Joe, e-mailed telling me to hide the nurses and be ready for an 11:30 a.m. visit. He showed up with major contraband: a huge bacon cheeseburger with wedge fries, an ice-cold Corona and cups and plates. My nurse, who should probably remain nameless, thought it was pretty funny.
I could only manage about four sips of beer, but the first one was the most perfect beer experience of my life. After six weeks without one, the hops exploded on my palate. There was barley, a perfect, cold crispness; it was the best beer I’d ever tasted.
It was the same for the burger. Juicy goodness with bacon and tomato and lettuce, salt and pepper. I only managed about five bites, but after three weeks of pudding cups, I was in heaven.
We went up to the 15th-floor terrace to sit in the sun. I smelled cigarette smoke — a good smell for me — and it was coming from a cancer patient in the farthest corner. I had given up smoking when I was first diagnosed a year ago, but there’s no point to that now, so I bummed a smoke.
For a day that started out with “You’re going to die,” this was turning out all right.
I went back to my room, Joe went back to work, my nurse grinned at her naughty boy. About an hour later, she came back in carrying a birthday cake, leading all the nurses and aides on the floor as they sang “Happy Birthday” to me.
I totally lost it. When she came back later with a bunch of birthday balloons, I was reduced to a soggy mess.
When I could talk, I told my nurse friends, “This is one of the best days of my life.”
I never thought I’d say that about the day I learned I would die, but it’s the absolute truth. The big things are great and memorable, but it’s the little, unexpected pleasures that make life so wonderful.
I’m going to miss it. Terribly.
© 2010 MSNBC Interactive
Source
Continuing Our Commitment to Prioritizing HIV/AIDS
Policy
August 20, 2010
By Jeffrey S. Crowley, M.P.H., Director, Office of National AIDS Policy (Cross-posted from the Office of National AIDS Policy Blog)
Today, the Obama Administration is taking new action to prioritize support for Federal HIV/AIDS prevention and care programs. We are sending to the Congress an amendment to the President’s FY 2011 budget request to increase HIV/AIDS funding by $65 million. This is comprised of a requested $35 million increase for HIV prevention in order to continue exciting new HIV prevention activities described below to support the National HIV/AIDS Strategy and a $30 million increase for State AIDS drug assistance programs to respond to the ongoing crisis States are facing in operating these essential programs. These resources come on top of proposed increases for HIV prevention and care at the Centers for Disease Control and Prevention (CDC) and the Health Resources and Services Administration (HRSA) that were included in the original budget submission. Ultimately, the Congress will enact a budget that will establish Federal funding levels for the fiscal year that begins on October 1st.
Last month, the Obama Administration released the National HIV/AIDS Strategy. This was the product of a robust dialogue with the HIV community and other members of the public and identifies a small set of priority action steps for moving the Nation forward in responding to the domestic HIV epidemic. On the evening of July 13th, the President hosted a reception for the HIV community at the White House where he spoke about the Strategy and his commitment to fighting HIV/AIDS. He said the following,
Now, I know that this strategy comes at a difficult time for Americans living with HIV/AIDS, because we’ve got cash-strapped States who are being forced to cut back on essentials, including assistance for AIDS drugs. I know the need is great. And that’s why we’ve increased Federal assistance each year that I’ve been in office, providing an emergency supplement this year to help people get the drugs they need, even as we pursue a national strategy that focuses on three central goals.
We recognize that times are tough and there are significant challenges faced by people living with HIV/AIDS and other Americans that must be addressed. The Federal government cannot tackle these problems alone, but we can do our part.
In the current fiscal year, FY2010, Congress appropriated funding of $835 million for the AIDS Drug Assistance Program (ADAP). In July, due to the serious shortfalls in State ADAPs resulting largely from State cutbacks, HHS Secretary Sebelius took an emergency step by re-allocating $25 million for ADAPs for a total of $860 million. Our FY 2011 budget request had included increased ADAP funding, but today’s proposed $30 million increase would continue funding in FY 2011 for the emergency supplemental funds announced last month. If the Congress follows our recommendation, Federal funding for ADAPs would rise to $885 million next year—a $50 million increase from the level appropriated by Congress for this year. This action, alone, will not resolve the challenges faced by ADAPs. We need States to continue to prioritize their funding for ADAPs even in these difficult times, and we need our pharmaceutical company partners, businesses, foundations, and community-based organizations to do their part as well.
On the issue of HIV prevention, Secretary Sebelius announced new investments in HIV prevention when we released the National HIV/AIDS Strategy. To ensure that these initiatives continue, we are requesting $35 million in additional funds for next year. In FY 2010, these resources are supporting:
• Comprehensive HIV prevention ($11.6 million): This will fund the implementation and evaluation of effective combinations of behavioral and biomedical prevention interventions in the highest prevalence jurisdictions. These jurisdictions will compete to scale-up effective comprehensive approaches in subsequent years. The funding opportunity announcement (FOA) for this initiative is available on Grants.gov. Be sure to type “CDC-RFA-PS10-10181” as the Funding Opportunity Number to download the FOA.
• Increased testing and linkage to care ($4.4 million): Building on CDC’s new Expanded Testing Initiative, these funds will ensure that resources are provided to support targeted testing and linkage services for high prevalence communities, including Black, Latino, injection drug using (IDU), and gay male communities.
• Expanded HIV surveillance ($5.5 million): This will support work with jurisdictions to ensure that all jurisdictions report CD4 cell counts and viral loads to the public health surveillance system, enable jurisdictions to estimate community viral load, and take other steps to improve the surveillance system.
• Consultation, evaluation, technical support and annual MSM survey ($6.5 million): These resources will support evaluation and monitoring, assisting with developing and implementing new activities and conducting an annual internet survey for men who have sex with men (MSM) to collect behavioral, HIV testing, and other information.
• HIV, viral hepatitis, STD prevention and sexual health promotion with Tribal Communities ($1 million): CDC will partner with the Indian Health Service (IHS) to work with Tribal communities on prevention and health promotion.
These activities reflect a new direction that we believe will have a greater impact at lowering the number of new HIV infections in the United States.
Today’s announcement demonstrates that we are committed to implementing the National HIV/AIDS Strategy and ensuring that necessary investments in prevention and care services for people living with HIV continue.
Source
August 20, 2010
By Jeffrey S. Crowley, M.P.H., Director, Office of National AIDS Policy (Cross-posted from the Office of National AIDS Policy Blog)
Today, the Obama Administration is taking new action to prioritize support for Federal HIV/AIDS prevention and care programs. We are sending to the Congress an amendment to the President’s FY 2011 budget request to increase HIV/AIDS funding by $65 million. This is comprised of a requested $35 million increase for HIV prevention in order to continue exciting new HIV prevention activities described below to support the National HIV/AIDS Strategy and a $30 million increase for State AIDS drug assistance programs to respond to the ongoing crisis States are facing in operating these essential programs. These resources come on top of proposed increases for HIV prevention and care at the Centers for Disease Control and Prevention (CDC) and the Health Resources and Services Administration (HRSA) that were included in the original budget submission. Ultimately, the Congress will enact a budget that will establish Federal funding levels for the fiscal year that begins on October 1st.
Last month, the Obama Administration released the National HIV/AIDS Strategy. This was the product of a robust dialogue with the HIV community and other members of the public and identifies a small set of priority action steps for moving the Nation forward in responding to the domestic HIV epidemic. On the evening of July 13th, the President hosted a reception for the HIV community at the White House where he spoke about the Strategy and his commitment to fighting HIV/AIDS. He said the following,
Now, I know that this strategy comes at a difficult time for Americans living with HIV/AIDS, because we’ve got cash-strapped States who are being forced to cut back on essentials, including assistance for AIDS drugs. I know the need is great. And that’s why we’ve increased Federal assistance each year that I’ve been in office, providing an emergency supplement this year to help people get the drugs they need, even as we pursue a national strategy that focuses on three central goals.
We recognize that times are tough and there are significant challenges faced by people living with HIV/AIDS and other Americans that must be addressed. The Federal government cannot tackle these problems alone, but we can do our part.
In the current fiscal year, FY2010, Congress appropriated funding of $835 million for the AIDS Drug Assistance Program (ADAP). In July, due to the serious shortfalls in State ADAPs resulting largely from State cutbacks, HHS Secretary Sebelius took an emergency step by re-allocating $25 million for ADAPs for a total of $860 million. Our FY 2011 budget request had included increased ADAP funding, but today’s proposed $30 million increase would continue funding in FY 2011 for the emergency supplemental funds announced last month. If the Congress follows our recommendation, Federal funding for ADAPs would rise to $885 million next year—a $50 million increase from the level appropriated by Congress for this year. This action, alone, will not resolve the challenges faced by ADAPs. We need States to continue to prioritize their funding for ADAPs even in these difficult times, and we need our pharmaceutical company partners, businesses, foundations, and community-based organizations to do their part as well.
On the issue of HIV prevention, Secretary Sebelius announced new investments in HIV prevention when we released the National HIV/AIDS Strategy. To ensure that these initiatives continue, we are requesting $35 million in additional funds for next year. In FY 2010, these resources are supporting:
• Comprehensive HIV prevention ($11.6 million): This will fund the implementation and evaluation of effective combinations of behavioral and biomedical prevention interventions in the highest prevalence jurisdictions. These jurisdictions will compete to scale-up effective comprehensive approaches in subsequent years. The funding opportunity announcement (FOA) for this initiative is available on Grants.gov. Be sure to type “CDC-RFA-PS10-10181” as the Funding Opportunity Number to download the FOA.
• Increased testing and linkage to care ($4.4 million): Building on CDC’s new Expanded Testing Initiative, these funds will ensure that resources are provided to support targeted testing and linkage services for high prevalence communities, including Black, Latino, injection drug using (IDU), and gay male communities.
• Expanded HIV surveillance ($5.5 million): This will support work with jurisdictions to ensure that all jurisdictions report CD4 cell counts and viral loads to the public health surveillance system, enable jurisdictions to estimate community viral load, and take other steps to improve the surveillance system.
• Consultation, evaluation, technical support and annual MSM survey ($6.5 million): These resources will support evaluation and monitoring, assisting with developing and implementing new activities and conducting an annual internet survey for men who have sex with men (MSM) to collect behavioral, HIV testing, and other information.
• HIV, viral hepatitis, STD prevention and sexual health promotion with Tribal Communities ($1 million): CDC will partner with the Indian Health Service (IHS) to work with Tribal communities on prevention and health promotion.
These activities reflect a new direction that we believe will have a greater impact at lowering the number of new HIV infections in the United States.
Today’s announcement demonstrates that we are committed to implementing the National HIV/AIDS Strategy and ensuring that necessary investments in prevention and care services for people living with HIV continue.
Source
Drug addicts: criminals or patients?
Lynda Moyo reports on the pipe dream of decriminalising drugs
Date Published: 20/08/2010 12:32:12
In the same week Phil Mitchell went from meat-head to crack-head in Eastenders, British Medical Journal (BMJ) writer Stephen Rolles - along with the backing of distinguished outing physician, Professor Sir Ian Gilmore - has suggested we’re fighting a losing battle against the war on drugs in the UK.
Rolles clams we need to end the criminalisation of drugs and instead set up regulatory models that will control drug markets and reduce the health and social harms caused by current policy.
He said: ‘Evidence is mounting that this policy has not only exacerbated many public health problems, such as adulterated drugs and the spread of HIV and hepatitis B and C infection among injecting drug users, but has created a much larger set of secondary harms associated with the criminal market.’
Professor Gilmore is the president of the Royal College of Physicians (RCP). He seconded Rolles’ article by sending a scathing email to the RCP’s 25,000 members. Deemed as controversial to some, the email not only detailed the war on drugs from a health perspective, but also outlined how changes to drug laws could reduce crime. Speaking to the BBC, Gilmore said the present policy of prohibition ‘is not a success', citing his experience working as a liver specialist as a major cause for concern.
"Every day in our hospital wards we see drug addicts with infections from dirty needles; we see heroin addicts with complications from contaminated drugs," he said. He argued that many of the problems health staff encountered were the consequences of prohibition, not drugs, endorsing a BMJ article titled An alternative to the war on drugs.
The Home Office has restated its position on drugs, following the BMJ report and Gilmore’s call for a review of the law. A spokesperson said: “Drugs such as heroin, cocaine and cannabis are extremely harmful and can cause misery to communities across the country.
“The government does not believe that decriminalisation is the right approach. Our priorities are clear; we want to reduce drug use, crack down on drug-related crime and disorder and help addicts come off drugs for good.”
Opinion is clearly mixed on the issue. Those against decriminalisation believe legalising drugs would simply result in a lot more people taking them, whilst those in favour often refer to the success of decriminalisation in other European countries. In Portugal, changes to the law in 2001 led to a cut in overdoses and a fall in the number of young users.
It’s certainly provided a talking point over what appear to be a growing problem in the UK. Police revealed this week that more than 6,800 cannabis farms and factories were discovered in the UK last year alone. They also reported that cannabis growers are often involved in other crimes, ranging from counterfeiting currency and money laundering to firearms, prostitution, and people trafficking.
Whilst it may be unpleasant to think of drug users and the associated health and crime implications, the problem isn’t going away.
As Eastenders actress Tanya Franks said, in response to viewer complaints about the Phil Mitchell storyline: "I wasn't surprised that people complained because it's pushed a boundary. But in my opinion, the good that comes from storylines like this far outweighs whatever concerns people might have. We shouldn't shy away from it."
Source
Date Published: 20/08/2010 12:32:12
In the same week Phil Mitchell went from meat-head to crack-head in Eastenders, British Medical Journal (BMJ) writer Stephen Rolles - along with the backing of distinguished outing physician, Professor Sir Ian Gilmore - has suggested we’re fighting a losing battle against the war on drugs in the UK.
Rolles clams we need to end the criminalisation of drugs and instead set up regulatory models that will control drug markets and reduce the health and social harms caused by current policy.
He said: ‘Evidence is mounting that this policy has not only exacerbated many public health problems, such as adulterated drugs and the spread of HIV and hepatitis B and C infection among injecting drug users, but has created a much larger set of secondary harms associated with the criminal market.’
Professor Gilmore is the president of the Royal College of Physicians (RCP). He seconded Rolles’ article by sending a scathing email to the RCP’s 25,000 members. Deemed as controversial to some, the email not only detailed the war on drugs from a health perspective, but also outlined how changes to drug laws could reduce crime. Speaking to the BBC, Gilmore said the present policy of prohibition ‘is not a success', citing his experience working as a liver specialist as a major cause for concern.
"Every day in our hospital wards we see drug addicts with infections from dirty needles; we see heroin addicts with complications from contaminated drugs," he said. He argued that many of the problems health staff encountered were the consequences of prohibition, not drugs, endorsing a BMJ article titled An alternative to the war on drugs.
Phil Mitchell's story is part of a bigger picture
The Home Office has restated its position on drugs, following the BMJ report and Gilmore’s call for a review of the law. A spokesperson said: “Drugs such as heroin, cocaine and cannabis are extremely harmful and can cause misery to communities across the country.
“The government does not believe that decriminalisation is the right approach. Our priorities are clear; we want to reduce drug use, crack down on drug-related crime and disorder and help addicts come off drugs for good.”
Opinion is clearly mixed on the issue. Those against decriminalisation believe legalising drugs would simply result in a lot more people taking them, whilst those in favour often refer to the success of decriminalisation in other European countries. In Portugal, changes to the law in 2001 led to a cut in overdoses and a fall in the number of young users.
It’s certainly provided a talking point over what appear to be a growing problem in the UK. Police revealed this week that more than 6,800 cannabis farms and factories were discovered in the UK last year alone. They also reported that cannabis growers are often involved in other crimes, ranging from counterfeiting currency and money laundering to firearms, prostitution, and people trafficking.
Whilst it may be unpleasant to think of drug users and the associated health and crime implications, the problem isn’t going away.
As Eastenders actress Tanya Franks said, in response to viewer complaints about the Phil Mitchell storyline: "I wasn't surprised that people complained because it's pushed a boundary. But in my opinion, the good that comes from storylines like this far outweighs whatever concerns people might have. We shouldn't shy away from it."
Source
A new opportunity for hepatitis C research
The hepatitis C virus is highly specialised. We humans are its natural hosts. The only other living organisms that could be infected with the hepatitis C virus in the lab are chimpanzees. Nevertheless it is – from the viewpoint of the virus – highly successful: around 170 million people are chronically infected with the virus. And with the chronic infection the risk of developing liver cancer also increases.
Researchers worldwide are working to develop vaccines and medication to combat the virus. The problem is that although they are able to research in liver cell cultures, when they want to find out how the immune system controls an infection or whether possible vaccines are effective research comes up against a brick wall: tests at such an early stage are unthinkable for humans or chimpanzees.
At TWINCORE researchers are now adapting the HCV to mice, thus enabling immunologists and vaccine researchers to take the next steps against this illness in the future. Because the immune system of mice is very similar to that of humans and it is only when vaccines are successful and safe in animal experiments that researchers can take the risk of transferring them to humans.
The fact that HCV can only infect humans and chimpanzees is partly down to the highly complicated mechanism with which it accesses the cell. The virus has to first bind four different molecules on the surface of our liver cells. This triggers a mechanism in our cells that transports the virus into the liver cells. “Mice also have these receptors on their liver cells in principle,” says scientist Julia Bitzegeio of the Department of Experimental Virology at TWINCORE, “however, they do not fit those on the surface of the virus.”
The two molecules that cause particular difficulty are called CD81 and occludin – these need to be human, otherwise the virus has no chance of infecting the cell. To make the HCV “mouse-capable” the researchers resorted to a trick: they have removed the CD81 receptor from human liver cells and replaced it with mouse CD81. In an electrical field they then tore tiny holes in the cell membrane before inserting the HC virus artificially through these holes. “The virus reproduced inside the cells and we repeatedly inserted the virus into the altered liver cells,” explains Julia Bitzegeio. This led to the highly transformable virus gradually changing until it was able to penetrate the cells with mouse CD81 receptor even without assistance.
“In this selection process the surface of the virus altered so much that it continued to infect human cells very quickly, but also simple mouse cells containing the four mouse variants of the HCV receptors,” says Research Group Leader Professor Thomas Pietschmann. The mouse-adapted virus is able to penetrate the mouse cells; however, the human specialisation of the HC virus is so high that it is unable to reproduce in the cells. “Successful infiltration is the first step towards a new small animal model, one that is urgently required for immunological investigations and the development of vaccines against HCV.”
Source : Helmholtz Association of German Research Centres
Source: BiologyNews – Microbiology
Source
Researchers worldwide are working to develop vaccines and medication to combat the virus. The problem is that although they are able to research in liver cell cultures, when they want to find out how the immune system controls an infection or whether possible vaccines are effective research comes up against a brick wall: tests at such an early stage are unthinkable for humans or chimpanzees.
At TWINCORE researchers are now adapting the HCV to mice, thus enabling immunologists and vaccine researchers to take the next steps against this illness in the future. Because the immune system of mice is very similar to that of humans and it is only when vaccines are successful and safe in animal experiments that researchers can take the risk of transferring them to humans.
The fact that HCV can only infect humans and chimpanzees is partly down to the highly complicated mechanism with which it accesses the cell. The virus has to first bind four different molecules on the surface of our liver cells. This triggers a mechanism in our cells that transports the virus into the liver cells. “Mice also have these receptors on their liver cells in principle,” says scientist Julia Bitzegeio of the Department of Experimental Virology at TWINCORE, “however, they do not fit those on the surface of the virus.”
The two molecules that cause particular difficulty are called CD81 and occludin – these need to be human, otherwise the virus has no chance of infecting the cell. To make the HCV “mouse-capable” the researchers resorted to a trick: they have removed the CD81 receptor from human liver cells and replaced it with mouse CD81. In an electrical field they then tore tiny holes in the cell membrane before inserting the HC virus artificially through these holes. “The virus reproduced inside the cells and we repeatedly inserted the virus into the altered liver cells,” explains Julia Bitzegeio. This led to the highly transformable virus gradually changing until it was able to penetrate the cells with mouse CD81 receptor even without assistance.
“In this selection process the surface of the virus altered so much that it continued to infect human cells very quickly, but also simple mouse cells containing the four mouse variants of the HCV receptors,” says Research Group Leader Professor Thomas Pietschmann. The mouse-adapted virus is able to penetrate the mouse cells; however, the human specialisation of the HC virus is so high that it is unable to reproduce in the cells. “Successful infiltration is the first step towards a new small animal model, one that is urgently required for immunological investigations and the development of vaccines against HCV.”
Source : Helmholtz Association of German Research Centres
Source: BiologyNews – Microbiology
Source
AIDS virus changes in semen make it different than in blood
Scanning electron micrograph of HIV-1 budding from cultured lymphocyte. Image source: Centers for Disease Control & Prevention.
The new findings are significant because the nature of the virus in the male genital tract is of central importance to understanding the transmission process and the selective pressures that may impact the transmitted virus.
Media contacts: Leslie Lang (919) 966-9366, llang@med.unc.edu or Tom Hughes (919) 966-6047 or tahughes@unch.unc.edu
Embargoed until 5 p.m. EDT Thursday, August 19, 2010
CHAPEL HILL – The virus that causes AIDS may undergo changes in the genital tract that make HIV-1 in semen different than what it is in the blood, according to a study led by researchers from the University of North Carolina at Chapel Hill.
Worldwide much of the transmission of HIV-1 is through sexual contact, men being the transmitting partner in a majority of cases. The new findings are significant because the nature of the virus in the male genital tract is of central importance to understanding the transmission process and the selective pressures that may impact the transmitted virus. Ultimately it is the transmitted virus that must be blocked by a vaccine or microbicide.
“If everything we know about HIV is based on the virus that is in the blood, when in fact the virus in the semen can evolve to be different, it may be that we have an incomplete view of what is going on in the transmission of the virus,” said senior study author Ronald Swanstrom, PhD, professor of biochemistry and biophysics and of microbiology and immunology at the UNC School of Medicine.
The results of his research appear August 19, 2010 in the online journal PLoS Pathogens.
In the study, Swanstrom and his colleagues compared viral populations in blood and semen samples collected from 16 men with chronic HIV-1 infection. Using an expensive and labor-intensive laboratory technique called single genome sequencing, they analyzed the gene coding for the major surface protein of the virus -- called envelope or Env – in the samples. The differences between the viruses from the two sources were striking.
“The sequence differences between the blood and the semen were like a flashing red light, it was a big hint about the biology of virus in the seminal tract” said Swanstrom. “When we looked at sequences in the blood, we hardly found any that were the same, it was a very complex and diverse population. But when we looked in the semen, suddenly we were getting the same sequence over and over again.”
They found two mechanisms that significantly altered the viral population in the semen, which they called clonal amplification and compartmentalization. In the first, one to several viruses are rapidly expanded over a short period of time such that the viral population is relatively homogeneous (compared to the complex population in the blood). In the second, the virus replicates in T cells in the seminal tract over a long period of time, creating a separate population of virus that is both complex and distinct from the virus in the blood.
To begin to answer why these mechanisms are at play, the researchers measured the levels of 19 cytokines and chemokines in the blood and semen samples. They discovered a significant concentration of these immune system modulators in the semen relative to the blood, which could boost viral replication by creating an environment where target cells are kept in an activated state.
Swanstrom’s laboratory is now exploring whether evolutionary selection for some special property of the virus is occurring in the seminal tract that does not happen in the blood. Knowing how the virus in the semen is different is an important part of understanding the HIV transmission puzzle.
The UNC research was funded by the National Institutes of Health in the context of the Center for HIV/AIDS Immunology (CHAVI). Study co-authors include Jeffrey A. Anderson, Li-Hua Ping, Oliver Dibben, Cassandra Jibara, Leslie Arney, Laura Kinser, Yuyang Tang, Marcia Hobbs, Irving Hoffman, Peter Kazembe, Corbin D. Jones, Persephone Borrow, Susan Fiscus and Myron S. Cohen. Volunteers participating in this study were attending the Kamuzu Central Hospital and the UNC Project in Lilongwe, Malawi.
Source
Researchers Identify Two FDA Approved Drugs That May Fight HIV
ScienceDaily (Aug. 20, 2010) — Researchers at the University of Minnesota Academic Health Center have identified two drugs that, when combined, may serve as an effective treatment for HIV.
The two drugs, decitabine and gemcitabine -- both FDA approved and currently used in pre-cancer and cancer therapy -- were found to eliminate HIV infection in the mouse model by causing the virus to mutate itself to death -- an outcome researchers dubbed "lethal mutagenesis."
This is a landmark finding in HIV research because it is the first time this novel approach has been used to attack the deadly virus without causing toxic side effects. Because decitabine and gemcitabine are already FDA approved, researchers believe that if their research is effective in large animal models, it will be much easier to expedite the development of the drugs for human use.
The study is a collaboration between molecular virologists Louis Mansky, Ph.D., and Christine Clouser, Ph.D., of the Institute for Molecular Virology and School of Dentistry, as well as medicinal chemist Steven Patterson, Ph.D., from the Center for Drug Design. The findings were recently published online in the Journal of Virology.
"The findings provide hope that such an approach will someday help the 33 million people worldwide who currently live with HIV," Mansky said.
Lethal mutagenesis
HIV mutates and evolves quickly. Rather than inhibiting virus growth and replication like current HIV drugs, this new drug combination forces the virus to do just the opposite -- evolve beyond control, to the point of extinction.
"HIV's ability to mutate makes it difficult to target and treat," Mansky said. "We wanted to take advantage of this behavior by stimulating HIV's mutation rate, essentially using the virus as a weapon against itself."
Drug repositioning
One way to decrease cost and expedite the development of novel drugs is by the use of drug repositioning, the process of taking a drug that is used to treat one medical condition, and using it to treat a different illness.
By examining drugs that are already approved by the Food and Drug Administration, the researchers hope to expedite the development of this drug combination because the safety profiles of the two drugs are known.
U of M researchers found that the drug concentrations needed to eliminate HIV infection cause no measureable cell toxicity and were effective against HIV cultures at concentrations well below the current levels used for cancer treatment.
The path ahead
Gemcitabine and decitabine have been administered in pre-clinical trials with mice. Initial findings confirm that the drugs are an effective antiviral therapy for HIV.
The researchers are now in the process of modifying the drugs to forms that can be absorbed by the human body when taken orally.
The study was funded by the Center for Drug Design, Academic Health Center and the National Institutes of Health.
Source
The two drugs, decitabine and gemcitabine -- both FDA approved and currently used in pre-cancer and cancer therapy -- were found to eliminate HIV infection in the mouse model by causing the virus to mutate itself to death -- an outcome researchers dubbed "lethal mutagenesis."
This is a landmark finding in HIV research because it is the first time this novel approach has been used to attack the deadly virus without causing toxic side effects. Because decitabine and gemcitabine are already FDA approved, researchers believe that if their research is effective in large animal models, it will be much easier to expedite the development of the drugs for human use.
The study is a collaboration between molecular virologists Louis Mansky, Ph.D., and Christine Clouser, Ph.D., of the Institute for Molecular Virology and School of Dentistry, as well as medicinal chemist Steven Patterson, Ph.D., from the Center for Drug Design. The findings were recently published online in the Journal of Virology.
"The findings provide hope that such an approach will someday help the 33 million people worldwide who currently live with HIV," Mansky said.
Lethal mutagenesis
HIV mutates and evolves quickly. Rather than inhibiting virus growth and replication like current HIV drugs, this new drug combination forces the virus to do just the opposite -- evolve beyond control, to the point of extinction.
"HIV's ability to mutate makes it difficult to target and treat," Mansky said. "We wanted to take advantage of this behavior by stimulating HIV's mutation rate, essentially using the virus as a weapon against itself."
Drug repositioning
One way to decrease cost and expedite the development of novel drugs is by the use of drug repositioning, the process of taking a drug that is used to treat one medical condition, and using it to treat a different illness.
By examining drugs that are already approved by the Food and Drug Administration, the researchers hope to expedite the development of this drug combination because the safety profiles of the two drugs are known.
U of M researchers found that the drug concentrations needed to eliminate HIV infection cause no measureable cell toxicity and were effective against HIV cultures at concentrations well below the current levels used for cancer treatment.
The path ahead
Gemcitabine and decitabine have been administered in pre-clinical trials with mice. Initial findings confirm that the drugs are an effective antiviral therapy for HIV.
The researchers are now in the process of modifying the drugs to forms that can be absorbed by the human body when taken orally.
The study was funded by the Center for Drug Design, Academic Health Center and the National Institutes of Health.
Source
Cells' demise provides clues about cancer
Derek Parker From: The Australian
August 21, 2010
APOPTOSIS may sound like an unfortunate malady.
In fact, it may be the secret to understanding the development of cancer and devising better cancer therapies.
Ultimately, it may provide an alternative to invasive surgery or debilitating chemotherapy.
Research into apoptosis is taking place worldwide, with several large drug companies pouring money into the area, but critical work is being undertaken in Australia.
"The key is to look at how cancer cells differ from healthy cells," says Andreas Strasser, of the molecular genetics of cancer division at Melbourne's Walter and Eliza Hall Institute.
"We need to understand how cells function and, even more importantly, how they die.
"Apoptosis is the study of programmed cell death and it is taking us into very promising areas of research, including towards a whole new generation of anti-cancer drugs."
All healthy cells in the body have genes that can cause or program them to die. Cell suicide and replenishment are crucial to all living organisms and play critical roles in the body's development even before birth.
But many cancer cells can override or ignore their programmed death machinery. They grow, mutate and multiply at a rate enabling them to take over and eventually destroy their host.
There's also good evidence that subversion of the cell death machinery is necessary for the transformation of normal cells into cancer cells.
Although the principle of apoptosis was recognised in the 19th century, much of the fundamental work in translating the idea into possible therapies can be traced to a 1988 paper published by WEHI researchers David Vaux, Suzanne Cory and Jerry Adams.
They showed that a cancer-causing gene, Bcl-2, inhibits apoptosis. The finding was the critical breakthrough in the field.
Little wonder that as a postdoctoral researcher Strasser was excited by the opportunity to continue the work. And followed up the research in a 1990 paper he co-authored with Alan Harris and Cory. It demonstrated that blocking apoptosis in mice could cause cancer. It also revealed that combined abnormalities in cell death and the control of cell division co-operated in tumour development.
"The field of cancer biology has come to the realisation that a cancer is caused by a string of abnormalities, maybe five or six, in critical cellular processes, including a lack of cell death," he says. "If we can reliably overcome or restore one or even several of the processes in that string, it would be a major advance for cancer therapy."
Strasser's WEHI team recently announced findings that could lead to a new class of anti-cancer drugs.
"Until now, everybody believed that a failure of damaged cells to undergo suicide allowed mutated cells to proliferate, which contributes to tumour development," he says. "That's certainly true, but we discovered that, in certain settings, the opposite can also hold, that the body's natural cell-suicide program can fuel tumour development."
Specifically, their experiments with mice showed this could happen if cellular DNA was damaged, say, by repeated exposure to low doses of radiation. When the body attempts to replace the damaged tissue it drives tumour development because the damaged cells will divide quickly, promoting tumour development.
The critical issue, Strasser notes, is whether a gene called Puma is present. His group found that if mice with the Puma gene were given a low dose of radiation it destroyed about 80 per cent of the mature white blood cells.
This means stem cells in the bone marrow must work extra hard to replace the white cells, many of which may themselves be damaged. The result: leukaemia, cancer of the blood or bone marrow.
"The surprise was that mice that don't carry the Puma gene are fully protected from this type of tumour development," says Strasser. "Puma is essential for the death of cells that have damaged DNA. If mice don't have the Puma gene when they receive low doses of radiation the white blood cells aren't destroyed, so they don't force stem cells to become activated to replenish the blood system."
This suggests the risk of cancer is increased in people who experience cycles of tissue destruction followed by tissue repopulation by stem cells. Such a process may account for the liver cancers frequently associated with viral infections, such as hepatitis C, or alcohol-related liver damage.
The finding also helps explain why secondary cancers sometimes arise in patients who were cured of their primary cancer. The secondary cancer was triggered by the DNA damaged from the original life-saving chemotherapy.
To transform its research into therapeutic products, WEHI has entered into a collaborative agreement with US medical giants Genentech and Abbott. The agreement involves funding support for WEHI, as well as data sharing between the parties.
The present focus of research is to develop drugs targeted at a specific protein that would activate the suicide process in existing cancer cells or in other cells likely to become cancerous if genetic activity overrode their programmed cell death.
Early phase clinical trials with people are under way in several places across the world using a compound called ABT-263, which is showing promising signs.
Apoptosis is also revealing other strategies for dealing with cancer, according to Paul Ekert of the Children's Cancer Centre at the Murdoch Childrens Research Institute in Melbourne.
"Building on the basic work from WEHI, we've been looking at how the apoptosis pathways are activated, or how activation fails in response to signals that originate from outside the cell," he explains. "We want to understand the biochemical processes [that] underpin how signals originate and are transmitted."
In particular, this research is examining the role of a family of genes called the Hox genes, which appears to regulate critical aspects of the apoptosis pathway.
"Originally we were simply using the Hox gene to create large numbers of cells for experimentation purposes," Ekert says. "But then we began to think about how it could be manipulated for possible therapeutic purposes."
According to Ekert, the idea is to inhibit the division of some cells while not affecting others.
This could be especially relevant to treating leukaemia-type cancers, although the applications could be broad.
"The way signals from the outside of the cells regulate apoptosis pathways is still something of a black box, where you can see things going in and things coming out, but you don't know much about what happens inside," Ekert says. "We are starting to lift the lid."
He is collecting proof-of-principle data as the basis for early-stage testing.
Another area of apoptosis research focuses on the nature of the suicide trigger.
"There are cells [that] require constant signals to stay alive and they die when those signals cease," says John Silke of the biology department at La Trobe University, where he heads a team looking at apoptosis-related proteins.
"There are others [that] require a particular signal to activate the suicide trigger," says Silke.
"Understanding those processes would go a long way to understanding not just cancer but a whole gamut of cell-related diseases."
This research has already led to a drug, at present in phase one trials in the US, he says. The drug mimics a natural protein that activates apoptosis, amplifying the signal so cells commit suicide.
"There's still a long way to go, but there is the potential to focus on specific types of cells, avoiding the system damage generated by approaches like chemotherapy," Silke says.
"It would be like using a sniper rifle rather than a hand grenade."
For his part, Strasser underlines the importance of fighting cancer at the fundamental level: "It's a matter of understanding your enemy."
As he notes, cancer cells are an excellent example of so-called generational evolution.
"Our medium-term goal is to be able to disrupt that process, to give the body of a person with cancer a good fighting chance."
His long-term goal?
"To fight cancer at the time in the early stages of its development, hopefully preventing it from becoming a danger in the first place."
Source
August 21, 2010
APOPTOSIS may sound like an unfortunate malady.
In fact, it may be the secret to understanding the development of cancer and devising better cancer therapies.
Ultimately, it may provide an alternative to invasive surgery or debilitating chemotherapy.
Research into apoptosis is taking place worldwide, with several large drug companies pouring money into the area, but critical work is being undertaken in Australia.
"The key is to look at how cancer cells differ from healthy cells," says Andreas Strasser, of the molecular genetics of cancer division at Melbourne's Walter and Eliza Hall Institute.
"We need to understand how cells function and, even more importantly, how they die.
"Apoptosis is the study of programmed cell death and it is taking us into very promising areas of research, including towards a whole new generation of anti-cancer drugs."
All healthy cells in the body have genes that can cause or program them to die. Cell suicide and replenishment are crucial to all living organisms and play critical roles in the body's development even before birth.
But many cancer cells can override or ignore their programmed death machinery. They grow, mutate and multiply at a rate enabling them to take over and eventually destroy their host.
There's also good evidence that subversion of the cell death machinery is necessary for the transformation of normal cells into cancer cells.
Although the principle of apoptosis was recognised in the 19th century, much of the fundamental work in translating the idea into possible therapies can be traced to a 1988 paper published by WEHI researchers David Vaux, Suzanne Cory and Jerry Adams.
They showed that a cancer-causing gene, Bcl-2, inhibits apoptosis. The finding was the critical breakthrough in the field.
Little wonder that as a postdoctoral researcher Strasser was excited by the opportunity to continue the work. And followed up the research in a 1990 paper he co-authored with Alan Harris and Cory. It demonstrated that blocking apoptosis in mice could cause cancer. It also revealed that combined abnormalities in cell death and the control of cell division co-operated in tumour development.
"The field of cancer biology has come to the realisation that a cancer is caused by a string of abnormalities, maybe five or six, in critical cellular processes, including a lack of cell death," he says. "If we can reliably overcome or restore one or even several of the processes in that string, it would be a major advance for cancer therapy."
Strasser's WEHI team recently announced findings that could lead to a new class of anti-cancer drugs.
"Until now, everybody believed that a failure of damaged cells to undergo suicide allowed mutated cells to proliferate, which contributes to tumour development," he says. "That's certainly true, but we discovered that, in certain settings, the opposite can also hold, that the body's natural cell-suicide program can fuel tumour development."
Specifically, their experiments with mice showed this could happen if cellular DNA was damaged, say, by repeated exposure to low doses of radiation. When the body attempts to replace the damaged tissue it drives tumour development because the damaged cells will divide quickly, promoting tumour development.
The critical issue, Strasser notes, is whether a gene called Puma is present. His group found that if mice with the Puma gene were given a low dose of radiation it destroyed about 80 per cent of the mature white blood cells.
This means stem cells in the bone marrow must work extra hard to replace the white cells, many of which may themselves be damaged. The result: leukaemia, cancer of the blood or bone marrow.
"The surprise was that mice that don't carry the Puma gene are fully protected from this type of tumour development," says Strasser. "Puma is essential for the death of cells that have damaged DNA. If mice don't have the Puma gene when they receive low doses of radiation the white blood cells aren't destroyed, so they don't force stem cells to become activated to replenish the blood system."
This suggests the risk of cancer is increased in people who experience cycles of tissue destruction followed by tissue repopulation by stem cells. Such a process may account for the liver cancers frequently associated with viral infections, such as hepatitis C, or alcohol-related liver damage.
The finding also helps explain why secondary cancers sometimes arise in patients who were cured of their primary cancer. The secondary cancer was triggered by the DNA damaged from the original life-saving chemotherapy.
To transform its research into therapeutic products, WEHI has entered into a collaborative agreement with US medical giants Genentech and Abbott. The agreement involves funding support for WEHI, as well as data sharing between the parties.
The present focus of research is to develop drugs targeted at a specific protein that would activate the suicide process in existing cancer cells or in other cells likely to become cancerous if genetic activity overrode their programmed cell death.
Early phase clinical trials with people are under way in several places across the world using a compound called ABT-263, which is showing promising signs.
Apoptosis is also revealing other strategies for dealing with cancer, according to Paul Ekert of the Children's Cancer Centre at the Murdoch Childrens Research Institute in Melbourne.
"Building on the basic work from WEHI, we've been looking at how the apoptosis pathways are activated, or how activation fails in response to signals that originate from outside the cell," he explains. "We want to understand the biochemical processes [that] underpin how signals originate and are transmitted."
In particular, this research is examining the role of a family of genes called the Hox genes, which appears to regulate critical aspects of the apoptosis pathway.
"Originally we were simply using the Hox gene to create large numbers of cells for experimentation purposes," Ekert says. "But then we began to think about how it could be manipulated for possible therapeutic purposes."
According to Ekert, the idea is to inhibit the division of some cells while not affecting others.
This could be especially relevant to treating leukaemia-type cancers, although the applications could be broad.
"The way signals from the outside of the cells regulate apoptosis pathways is still something of a black box, where you can see things going in and things coming out, but you don't know much about what happens inside," Ekert says. "We are starting to lift the lid."
He is collecting proof-of-principle data as the basis for early-stage testing.
Another area of apoptosis research focuses on the nature of the suicide trigger.
"There are cells [that] require constant signals to stay alive and they die when those signals cease," says John Silke of the biology department at La Trobe University, where he heads a team looking at apoptosis-related proteins.
"There are others [that] require a particular signal to activate the suicide trigger," says Silke.
"Understanding those processes would go a long way to understanding not just cancer but a whole gamut of cell-related diseases."
This research has already led to a drug, at present in phase one trials in the US, he says. The drug mimics a natural protein that activates apoptosis, amplifying the signal so cells commit suicide.
"There's still a long way to go, but there is the potential to focus on specific types of cells, avoiding the system damage generated by approaches like chemotherapy," Silke says.
"It would be like using a sniper rifle rather than a hand grenade."
For his part, Strasser underlines the importance of fighting cancer at the fundamental level: "It's a matter of understanding your enemy."
As he notes, cancer cells are an excellent example of so-called generational evolution.
"Our medium-term goal is to be able to disrupt that process, to give the body of a person with cancer a good fighting chance."
His long-term goal?
"To fight cancer at the time in the early stages of its development, hopefully preventing it from becoming a danger in the first place."
Source
HBV DNA Decline at 24 Weeks Predicts Sustained Response to Pegylated Interferon for Chronic Hepatitis B
SUMMARY: Patients who experience a significant decrease in hepatitis B virus (HBV) DNA, or viral load, during the first 24 weeks of treatment with pegylated interferon were more likely to achieve a long-term response, according to a study described in the July 2010 Journal of Medical Virology. If HBV DNA does not decline by at least 100-fold during this period, however, treatment is unlikely to be successful and should be discontinued, the researchers recommended.
By Liz Highleyman
Bettina Hansen from Erasmus University Medical Center in Rotterdam and colleagues aimed to develop a model that could better predict at baseline which chronic hepatitis B patients would respond to pegylated interferon, and to establish an early indicator for when treatment should be halted.
Pegylated interferon leads to virological response (undetectable HBV DNA) and hepatitis B "e" antigen (HBeAg) loss in only a minority of patients with HBeAg positive chronic hepatitis B. The treatment is expensive and can cause difficult side effects, so clinicians want to know when to stop therapy that is unlikely to produce a favorable outcome.
Known baseline predictors of response to pegylated interferon include HBV genotype (B responds better than D), pre-treatment HBV viral load, and alanine aminotransferase (ALT) level. The investigators looked at whether viral load reduction early in treatment also has predictive value.
This analysis included 136 chronic hepatitis B patients treated with pegylated interferon. Response was defined as HBV DNA < 10,000 copies/mL and HBeAg loss 26 weeks after completion of treatment. The researchers used logistic regression analysis to develop a dynamic prediction model using HBV DNA during the first 32 weeks of therapy.
Results
"The model strongly supports individual decision making on treatment (dis)continuation in patients with HBeAg positive chronic hepatitis B," they continued. "It is recommended that pegylated interferon treatment is stopped by 24 weeks if HBV DNA declined < 2?log(10)."
Investigator affiliations: Departments of Gastroenterology & Hepatology, Biostatistics, and Public Health, Erasmus MC, University Medical Center Rotterdam, Rotterdam, Netherlands; Department of L-Biostat, Catholic University of Leuven, Leuven, Belgium.
8/20/10
Reference
BE Hansen, EHCJ Buster, EW Steyerberg, and others. Prediction of the response to peg-interferon-alfa in patients with HBeAg positive chronic hepatitis B using decline of HBV DNA during treatment. Journal of Medical Virology 82(7): 1135-1142 (Abstract). July 2010.
Source
By Liz Highleyman
Bettina Hansen from Erasmus University Medical Center in Rotterdam and colleagues aimed to develop a model that could better predict at baseline which chronic hepatitis B patients would respond to pegylated interferon, and to establish an early indicator for when treatment should be halted.
Pegylated interferon leads to virological response (undetectable HBV DNA) and hepatitis B "e" antigen (HBeAg) loss in only a minority of patients with HBeAg positive chronic hepatitis B. The treatment is expensive and can cause difficult side effects, so clinicians want to know when to stop therapy that is unlikely to produce a favorable outcome.
Known baseline predictors of response to pegylated interferon include HBV genotype (B responds better than D), pre-treatment HBV viral load, and alanine aminotransferase (ALT) level. The investigators looked at whether viral load reduction early in treatment also has predictive value.
This analysis included 136 chronic hepatitis B patients treated with pegylated interferon. Response was defined as HBV DNA < 10,000 copies/mL and HBeAg loss 26 weeks after completion of treatment. The researchers used logistic regression analysis to develop a dynamic prediction model using HBV DNA during the first 32 weeks of therapy.
Results
- The researchers identified an early clinically useful rule for continuation or discontinuation of treatment, with a grid of cut-off values for HBV DNA decline during treatment.
- Adding HBV DNA decline at weeks 4, 12, and 24 to baseline factors improved predictions of sustained response.
- HBV DNA decline of at least 2?log(10), or 100-fold, within 24 weeks of starting therapy was strongly associated with response when added to baseline predictors.
"The model strongly supports individual decision making on treatment (dis)continuation in patients with HBeAg positive chronic hepatitis B," they continued. "It is recommended that pegylated interferon treatment is stopped by 24 weeks if HBV DNA declined < 2?log(10)."
Investigator affiliations: Departments of Gastroenterology & Hepatology, Biostatistics, and Public Health, Erasmus MC, University Medical Center Rotterdam, Rotterdam, Netherlands; Department of L-Biostat, Catholic University of Leuven, Leuven, Belgium.
8/20/10
Reference
BE Hansen, EHCJ Buster, EW Steyerberg, and others. Prediction of the response to peg-interferon-alfa in patients with HBeAg positive chronic hepatitis B using decline of HBV DNA during treatment. Journal of Medical Virology 82(7): 1135-1142 (Abstract). July 2010.
Source
Silymarin Milk Thistle Extract May Inhibit Hepatitis C Virus Entry into Cells
SUMMARY: Silymarin, an extract from the milk thistle plant, has an inhibitory effect on the hepatitis C virus (HCV) polymerase in laboratory studies, but its anti-HCV action also appears to include blocking HCV from entering cells and preventing cell-to-cell transmission, according to research described in the June 2010 issue of Hepatology.
Milk thistle (Silybum marianum) has an extensive history of use as a remedy for liver problems in both Eastern and Western traditional medicine. Silymarin is a flavonoid comprised of a mix of milk thistle components including silibinin. Most silymarin studies have looked at its effect on liver fibrosis, but in recent years researchers have studied its direct activity against HCV in the laboratory and in vivo.
A survey of participants in the HALT-C trial -- which evaluated the benefits of long-term pegylated interferon for patients who did not respond to standard treatment with pegylated interferon plus ribavirin -- found that participants who said they used silymarin did not have lower HCV viral load on average than non-users. Another recent study, however, showed that silymarin inhibited activity of the HCV polymerase, which copies viral genetic material as part of replication.
In the present study, Jessica Wagoner from the University of Washington in Seattle and colleagues further characterized the antiviral action of silymarin in the laboratory.
Results
Investigator affiliations: Departments of Laboratory Medicine, Microbiology, and Global Health, University of Washington, Seattle, WA; Center for Engineering in Medicine, Massachusetts General Hospital, Boston, MA; Department of Pediatrics, University of Texas Medical Branch, Galveston, TX; School of Medicine, University of Texas Southwestern Medical Center, Dallas, TX; Hepatitis C Virus Research Group, Institute of Biomedical Research, University of Birmingham, Birmingham, UK; Institut de Biologie et Chimie des Protéines, Université Lyon 1, IFR128 Lyon Biosciences Gerland, CNRS-Universite Claude Bernard, Lyon, France; Department of Chemistry and Biochemistry, University of North Carolina at Greensboro, Greensboro, NC; Department of Molecular Virology, University of Heidelberg, Heidelberg, Germany; Department of Molecular Microbiology and Immunology, Saint Louis University School of Medicine, St. Louis, MO.
8/20/10
Reference
J Wagoner, A Negash, OJ Kane, and others. Multiple effects of silymarin on the hepatitis C virus lifecycle. Hepatology 51(6): 1912-1921 (Abstract). June 2010.
Source
Milk thistle (Silybum marianum) has an extensive history of use as a remedy for liver problems in both Eastern and Western traditional medicine. Silymarin is a flavonoid comprised of a mix of milk thistle components including silibinin. Most silymarin studies have looked at its effect on liver fibrosis, but in recent years researchers have studied its direct activity against HCV in the laboratory and in vivo.
A survey of participants in the HALT-C trial -- which evaluated the benefits of long-term pegylated interferon for patients who did not respond to standard treatment with pegylated interferon plus ribavirin -- found that participants who said they used silymarin did not have lower HCV viral load on average than non-users. Another recent study, however, showed that silymarin inhibited activity of the HCV polymerase, which copies viral genetic material as part of replication.
In the present study, Jessica Wagoner from the University of Washington in Seattle and colleagues further characterized the antiviral action of silymarin in the laboratory.
Results
- Silymarin had antiviral effects against HCV in cell cultures, including inhibition of virus entry into cells, HCV RNA and protein expression, and production of infectious virus particles.
- Silymarin did not block HCV binding to cells, but did inhibit entry of viral pseudoparticles and fusion of HCV pseudoparticles with liposomes, or fat bubbles.
- Silymarin -- but not silibinin -- inhibited activity of the HCV genotype 2a NS5B RNA-dependent RNA polymerase at concentrations 5-10 times higher than required for an anti-HCV effect in cell culture.
- Silymarin had only minimal activity against genotype 1b isolate BK and 4 genotype 1b polymerases derived from HCV-infected patients, however.
- Silymarin did not inhibit HCV replication in 5 independent genotype 1a, 1b, and 2a replicon model cell lines that did not produce infectious virus.
- Silymarin inhibited microsomal triglyceride transfer protein activity, apolipoprotein B secretion, and infectious virion production in cell culture medium.
- Silymarin also blocked cell-to-cell spread of HCV.
Investigator affiliations: Departments of Laboratory Medicine, Microbiology, and Global Health, University of Washington, Seattle, WA; Center for Engineering in Medicine, Massachusetts General Hospital, Boston, MA; Department of Pediatrics, University of Texas Medical Branch, Galveston, TX; School of Medicine, University of Texas Southwestern Medical Center, Dallas, TX; Hepatitis C Virus Research Group, Institute of Biomedical Research, University of Birmingham, Birmingham, UK; Institut de Biologie et Chimie des Protéines, Université Lyon 1, IFR128 Lyon Biosciences Gerland, CNRS-Universite Claude Bernard, Lyon, France; Department of Chemistry and Biochemistry, University of North Carolina at Greensboro, Greensboro, NC; Department of Molecular Virology, University of Heidelberg, Heidelberg, Germany; Department of Molecular Microbiology and Immunology, Saint Louis University School of Medicine, St. Louis, MO.
8/20/10
Reference
J Wagoner, A Negash, OJ Kane, and others. Multiple effects of silymarin on the hepatitis C virus lifecycle. Hepatology 51(6): 1912-1921 (Abstract). June 2010.
Source
Acute Hepatitis C as a Sexually Transmitted Infection in HIV Positive Men
SUMMARY: Sexual transmission of hepatitis C virus (HCV) among HIV positive men who have sex with men has now been recognized for a decade, occurring in cities in Europe, North America, and Australia. Since acute HCV outbreaks occur almost exclusively among men with HIV, being HIV positive probably plays a critical role, according to the authors of a review article in the July 31, 2010 issue of AIDS.
By Liz Highleyman
Thijs van de Laar from the Amsterdam Public Health Service and colleagues presented an overview of acute HCV infection among gay/bisexual men with HIV, including epidemiology, risk factors, natural history, disease progression, and challenges of management. The review was based on published studies identified through a MEDLINE search and relevant conference abstracts.
HCV Transmission
HCV is usually transmitted through direct blood contact, for example, via shared needles for injection drug use (IDU) or blood transfusions before donated blood was screened. Due to common transmission routes, an estimated 4-5 million people -- or approximately one-third of people with HIV -- are HIV/HCV coinfected.
Sexual transmission of HCV was traditionally thought to be uncommon (less than 1%) based on studies of monogamous heterosexual couples. Early cross-sectional studies found a relatively high HCV prevalence rate among men who have sex with men (MSM), but these often did not take into account injection drug use.
Since 2000, however, several outbreaks of acute hepatitis C among HIV positive gay and bisexual men who denied injection drug use have been reported, first in the U.K., then in other large cities in France, Germany, and the Netherlands, followed by Australia, the U.S., and Canada.
ACUTE HEPATITIS C
"Given the burden of liver disease, in particular HCV, on the morbidity and mortality in HIV patients in the era of combination antiretroviral therapy, the rapid and significant rise in the incidence of HCV in the HIV-infected MSM population in high-income countries is alarming," the review authors wrote. "This relates to a significant change in the epidemiology of HCV that has occurred, with HCV emerging as a sexually transmitted infection within this population."
In the Netherlands, for example, a biannual survey among sexually transmitted infection (STI) clinic attendees showed an increase in HCV prevalence among HIV positive MSM from 1%-4% before 2000 to 15% in 2007 and 21% in 2008. HCV prevalence among HIV negative gay/bisexual men, however, remains comparable to that of the general population.
Most cases of acute hepatitis C among MSM in Europe involve hard-to-treat HCV genotypes 1a and 4d, the latter of which is otherwise uncommon in Europe and the U.S. Genetic sequencing has revealed closely related virus strains coinciding with sexual networks.
Evolutionary analysis "suggests multiple independent introductions of HCV into the MSM community, some as early as the 1980s," the authors surmised. "Most likely, these strains were introduced from the IDU population." They noted that the recent increase in HCV sexual transmission coincides with a rise in sexual risk behavior and increased STI rates in the era of effective combination ART, some of which is due to serosorting, or HIV positive men have unprotected sex with other positive men.
Research to date indicates that HCV transmission is associated with a variety of sexual practices -- including fisting, unprotected anal intercourse, use of shared sex toys, group sex, and sex while on drugs -- though specific activities vary from study to study. Other risk factors include non-injection drug use and presence of other sexually transmitted diseases.
These studies show that "most MSM with HCV report a combination of various, potentially high-risk, sexual and drug practices," the authors wrote. "The interaction between sex and drugs is complex, and many of these factors are highly correlated and difficult to disentangle."
"Given this occurs almost exclusively in HIV-infected MSM, HIV probably has a critical role mediated either through behavioral and/or biological factors," they stated. "It is not yet known whether lower CD4 cell count increases the risk of acquiring HCV, but the fact that many MSM with acute HCV have relatively preserved CD4 cell counts suggests this may not be a critical factor."
Disease Progression and Treatment
Turning to hepatitis C disease progression in this population, they wrote, "The natural history of HCV is determined by host-viral interactions, which are perturbed in HIV coinfection, resulting in accelerated liver fibrosis, higher HCV loads, and poorer responses to interferon-based therapy when compared with HCV monoinfection."
While about 25% of HIV negative individuals spontaneously clear HCV without treatment, this is less likely among people with HIV -- as low as 5% in one study -- perhaps due to reduced T-cell responses. HIV/HCV coinfection is associated with more rapid liver fibrosis. Some studies indicate that progression is especially fast among people who already have HIV at the time of HCV infection, but other data are conflicting.
Hepatitis C treatment using pegylated interferon (with or without ribavirin) is quite successful during acute HCV infection. Because they receive regular liver function tests to monitor drug toxicity, people with HIV are more likely to have HCV infection diagnosed during the acute stage. Acute hepatitis C cure rates among HIV positive people are around 60%-80% in most studies.
Optimal timing and duration of therapy for acute HCV infection is not well defined, but most experts recommend waiting 12 weeks to see if spontaneous clearance will occur. Most favor combination therapy over pegylated interferon monotherapy and a treatment duration of 24 weeks for coinfected patients.
"Targeted prevention such as raising awareness, regular screening and treatment of acute and chronic infections are needed to stop the further spread among MSM," the review authors concluded. "It is clear that a message of 'safe sex' through condom use during anal intercourse could be provided, but given the practice of negotiated unprotected sex among HIV-infected MSM might not be accepted. In addition, it may not cover practices that increase risk of blood-to-blood contact (e.g. fisting). Furthermore, MSM population needs to be informed that reinfection is an ongoing risk, given the recent reports of HCV reinfection following successful treatment and documented clearance of HCV."
Cluster of Infectious Diseases, Public Health Service, Amsterdam, Netherlands; Viral Hepatitis Clinical Research Program, National Centre for HIV Epidemiology and Clinical Research, University of New South Wales, Sydney, Australia; Department of Internal Medicine, Centre for Infection and Immunity Amsterdam, Academic Medical Centre, University of Amsterdam, Amsterdam, Netherlands; St. Vincent's Clinical School, Faculty of Medicine, University of New South Wales, Sydney, Australia.
8/20/10
Reference
TJ van de Laar, GV Matthews, M Prins, and M Danta. Acute hepatitis C in HIV-infected men who have sex with men: an emerging sexually transmitted infection. AIDS 24(12): 1799-1812 (Abstract). July 31, 2010.
Source
By Liz Highleyman
Thijs van de Laar from the Amsterdam Public Health Service and colleagues presented an overview of acute HCV infection among gay/bisexual men with HIV, including epidemiology, risk factors, natural history, disease progression, and challenges of management. The review was based on published studies identified through a MEDLINE search and relevant conference abstracts.
HCV Transmission
HCV is usually transmitted through direct blood contact, for example, via shared needles for injection drug use (IDU) or blood transfusions before donated blood was screened. Due to common transmission routes, an estimated 4-5 million people -- or approximately one-third of people with HIV -- are HIV/HCV coinfected.
Sexual transmission of HCV was traditionally thought to be uncommon (less than 1%) based on studies of monogamous heterosexual couples. Early cross-sectional studies found a relatively high HCV prevalence rate among men who have sex with men (MSM), but these often did not take into account injection drug use.
Since 2000, however, several outbreaks of acute hepatitis C among HIV positive gay and bisexual men who denied injection drug use have been reported, first in the U.K., then in other large cities in France, Germany, and the Netherlands, followed by Australia, the U.S., and Canada.
ACUTE HEPATITIS C
"Given the burden of liver disease, in particular HCV, on the morbidity and mortality in HIV patients in the era of combination antiretroviral therapy, the rapid and significant rise in the incidence of HCV in the HIV-infected MSM population in high-income countries is alarming," the review authors wrote. "This relates to a significant change in the epidemiology of HCV that has occurred, with HCV emerging as a sexually transmitted infection within this population."
In the Netherlands, for example, a biannual survey among sexually transmitted infection (STI) clinic attendees showed an increase in HCV prevalence among HIV positive MSM from 1%-4% before 2000 to 15% in 2007 and 21% in 2008. HCV prevalence among HIV negative gay/bisexual men, however, remains comparable to that of the general population.
Most cases of acute hepatitis C among MSM in Europe involve hard-to-treat HCV genotypes 1a and 4d, the latter of which is otherwise uncommon in Europe and the U.S. Genetic sequencing has revealed closely related virus strains coinciding with sexual networks.
Evolutionary analysis "suggests multiple independent introductions of HCV into the MSM community, some as early as the 1980s," the authors surmised. "Most likely, these strains were introduced from the IDU population." They noted that the recent increase in HCV sexual transmission coincides with a rise in sexual risk behavior and increased STI rates in the era of effective combination ART, some of which is due to serosorting, or HIV positive men have unprotected sex with other positive men.
Research to date indicates that HCV transmission is associated with a variety of sexual practices -- including fisting, unprotected anal intercourse, use of shared sex toys, group sex, and sex while on drugs -- though specific activities vary from study to study. Other risk factors include non-injection drug use and presence of other sexually transmitted diseases.
These studies show that "most MSM with HCV report a combination of various, potentially high-risk, sexual and drug practices," the authors wrote. "The interaction between sex and drugs is complex, and many of these factors are highly correlated and difficult to disentangle."
"Given this occurs almost exclusively in HIV-infected MSM, HIV probably has a critical role mediated either through behavioral and/or biological factors," they stated. "It is not yet known whether lower CD4 cell count increases the risk of acquiring HCV, but the fact that many MSM with acute HCV have relatively preserved CD4 cell counts suggests this may not be a critical factor."
Disease Progression and Treatment
Turning to hepatitis C disease progression in this population, they wrote, "The natural history of HCV is determined by host-viral interactions, which are perturbed in HIV coinfection, resulting in accelerated liver fibrosis, higher HCV loads, and poorer responses to interferon-based therapy when compared with HCV monoinfection."
While about 25% of HIV negative individuals spontaneously clear HCV without treatment, this is less likely among people with HIV -- as low as 5% in one study -- perhaps due to reduced T-cell responses. HIV/HCV coinfection is associated with more rapid liver fibrosis. Some studies indicate that progression is especially fast among people who already have HIV at the time of HCV infection, but other data are conflicting.
Hepatitis C treatment using pegylated interferon (with or without ribavirin) is quite successful during acute HCV infection. Because they receive regular liver function tests to monitor drug toxicity, people with HIV are more likely to have HCV infection diagnosed during the acute stage. Acute hepatitis C cure rates among HIV positive people are around 60%-80% in most studies.
Optimal timing and duration of therapy for acute HCV infection is not well defined, but most experts recommend waiting 12 weeks to see if spontaneous clearance will occur. Most favor combination therapy over pegylated interferon monotherapy and a treatment duration of 24 weeks for coinfected patients.
"Targeted prevention such as raising awareness, regular screening and treatment of acute and chronic infections are needed to stop the further spread among MSM," the review authors concluded. "It is clear that a message of 'safe sex' through condom use during anal intercourse could be provided, but given the practice of negotiated unprotected sex among HIV-infected MSM might not be accepted. In addition, it may not cover practices that increase risk of blood-to-blood contact (e.g. fisting). Furthermore, MSM population needs to be informed that reinfection is an ongoing risk, given the recent reports of HCV reinfection following successful treatment and documented clearance of HCV."
Cluster of Infectious Diseases, Public Health Service, Amsterdam, Netherlands; Viral Hepatitis Clinical Research Program, National Centre for HIV Epidemiology and Clinical Research, University of New South Wales, Sydney, Australia; Department of Internal Medicine, Centre for Infection and Immunity Amsterdam, Academic Medical Centre, University of Amsterdam, Amsterdam, Netherlands; St. Vincent's Clinical School, Faculty of Medicine, University of New South Wales, Sydney, Australia.
8/20/10
Reference
TJ van de Laar, GV Matthews, M Prins, and M Danta. Acute hepatitis C in HIV-infected men who have sex with men: an emerging sexually transmitted infection. AIDS 24(12): 1799-1812 (Abstract). July 31, 2010.
Source
Adoptive transfer of splenocytes to study cell-mediated immune responses in hepatitis C infection using HCV transgenic mice
Hepatitis C virus (HCV) is a major cause of chronic hepatitis and a health problem affecting over 170 million people around the world. We previously studied transgenic mice that express HCV Core, Envelope 1 and Envelope 2 proteins predominantly in the liver, resulting in steatosis, liver and lymphoid tumors, and hepatocellular carcinoma.
Herein, the immune-mediated cell response to hepatitis C antigens was evaluated by adoptive transfers of carboxyfluorescein succinimidyl ester (CFSE) labelled splenocytes from HCV immunized mice into HCV transgenic mice.
Results: In comparison to non-transgenic mice, there was a significant decrease in the percentage of CFSE-labeled CD4+ and CD8+ T cells in transgenic mouse peripheral blood receiving adoptive transfers from immunized donors. Moreover, the percentage of CFSE-labeled CD4+ and CD8+ T cells were significantly higher in the spleen of transgenic and non-transgenic mice when they received splenocytes from non-immunized than from immunized mice.
On the other hand, the percentages of CD4+ and CD8+ T cells in the non-transgenic recipient mouse lymph nodes were significantly higher than the transgenic mice when they received the adoptive transfer from immunized donors. Interestingly, livers of transgenic mice that received transfers from immunized mice had a significantly higher percentage of CFSE labeled T cells than livers of non-transgenic mice receiving non-immunized transfers.
Conclusions: These results suggest that the T cells from HCV immunized mice recognize the HCV proteins in the liver of the transgenic mouse model and homed to the HCV antigen expression sites.
We propose using this model system to study active T cell responses in HCV infection.
Author: Turaya NaasMasoud GhorbaniCatalina SoareNicole SherlingRudy MullerPeyman GhorbaniFrancisco Diaz-Mitoma
Credits/Source: Comparative Hepatology 2010, 9:7
Published on: 2010-08-20
Source
Herein, the immune-mediated cell response to hepatitis C antigens was evaluated by adoptive transfers of carboxyfluorescein succinimidyl ester (CFSE) labelled splenocytes from HCV immunized mice into HCV transgenic mice.
Results: In comparison to non-transgenic mice, there was a significant decrease in the percentage of CFSE-labeled CD4+ and CD8+ T cells in transgenic mouse peripheral blood receiving adoptive transfers from immunized donors. Moreover, the percentage of CFSE-labeled CD4+ and CD8+ T cells were significantly higher in the spleen of transgenic and non-transgenic mice when they received splenocytes from non-immunized than from immunized mice.
On the other hand, the percentages of CD4+ and CD8+ T cells in the non-transgenic recipient mouse lymph nodes were significantly higher than the transgenic mice when they received the adoptive transfer from immunized donors. Interestingly, livers of transgenic mice that received transfers from immunized mice had a significantly higher percentage of CFSE labeled T cells than livers of non-transgenic mice receiving non-immunized transfers.
Conclusions: These results suggest that the T cells from HCV immunized mice recognize the HCV proteins in the liver of the transgenic mouse model and homed to the HCV antigen expression sites.
We propose using this model system to study active T cell responses in HCV infection.
Author: Turaya NaasMasoud GhorbaniCatalina SoareNicole SherlingRudy MullerPeyman GhorbaniFrancisco Diaz-Mitoma
Credits/Source: Comparative Hepatology 2010, 9:7
Published on: 2010-08-20
Source
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