What causes chronic fatigue? What we know, don’t know and suspect

Recommended Reading

February 2017
Persistent Neuropsychiatric Impairment in HCV Patients Despite Clearance of the Virus?!
Many patients with HCV infection report disabling chronic fatigue--even after viral clearance. Might HCV be implicated in a virus infection-associated chronic fatigue syndrome?

Link To Article: 2017 full-text article is open access over at Medscape (free registration required), discussion only, here (no registration). Patients can also read an overview with commentary at Infectious Disease Advisor. Original article was published 9 February 2017 in Journal of Viral Hepatitis.

May 16, 2018
Do fatigue and quality of life improve after hepatitis C is cured?
Keith Alcorn
Published: 16 May 2018
Patient-reported outcomes such as fatigue, vitality and mental health improve substantially in the two years following hepatitis C cure for people with cirrhosis, but people with cirrhosis are less likely than others to experience rapid resolution of severe fatigue after successful hepatitis C treatment, according to two studies from the Center for Outcomes Research in Liver Diseases reported last month at the 2018 International Liver Congress in Paris.

Today's Article

What causes chronic fatigue? What we know, don’t know and suspect

Mark Guthridge 

Senior Research Fellow, Monash University 

Source: The Conversation

Around 200,000 people in Australia suffer from a debilitating illness often branded with the unfortunate name of chronic fatigue syndrome (CFS). I say “unfortunate” because this implies patients are simply tired, run-down, burnt-out or overly stressed.

But myalgic encephalomyelitis, or ME/CFS as it is now more commonly called, is a serious and incapacitating disease that can have a devastating impact on a patient’s life. Symptoms include:

profound and unexplained fatigue for more than six months
memory or concentration difficulties
muscle pain (myalgia) and weakness
joint pain
sleep disturbances
flu-like symptoms
light headedness, palpitations, breathlessness
headaches
heightened sensitivity to light and sound
tender lymph nodes, sore throats
new sensitivities to food, medicines or chemicals.

Initially bewildered by their incapacitating fatigue, many ME/CFS patients continue trying to go about their daily lives. But such efforts come at a severe cost. Even small amounts of activity can trigger “crashes” called post-exertional malaise that worsen symptoms, sometimes for many days.

Simple activities such as showering, grocery shopping or meeting a friend for coffee become difficult, if not impossible. Sadly, for around 25% of patients, symptoms are so severe they remain bed-bound or house-bound, and suicide risk is elevated.

Most patients face a major challenge getting a diagnosis. One UK study found less than half of doctors were confident with the diagnosis or treatment of ME/CFS and more than 85% of patients go from doctor to doctor for over two years without a diagnosis.

What we know

The underlying causes of ME/CFS have proved difficult to pinpoint. For many patients, blood and pathology testing are entirely normal.

This has led some to suggest ME/CFS is a psychological condition. In 2011, the findings of a clinical trial suggested patients could recover through psychological therapy (cognitive behavioural therapy or CBT) and graded exercise therapy. These findings have fuelled debate as to whether ME/CFS might be a disease of the mind.

But a landmark US study examining nearly 10,000 research publications suggested otherwise, concluding that ME/CFS is a serious, chronic, complex and systemic disease.

Criticisms of psychological and exercise therapy for ME/CFS have been widespread, with over 50 published letters in leading scientific journals (BMJ, Journal of Health Psychology, Nature, Lancet) raising serious concerns about the robustness of the claims.

Australian guidelines continue to recommend exercise and CBT therapies despite the US Centers for Disease Control and Prevention discontinuing these recommendations.

While exercise can clearly benefit patients with a wide range of illnesses, physical activity can cause a rapid deterioration of symptoms in patients with ME/CFS.

What we don’t know

There are no laboratory tests available to categorically diagnose someone with ME/CFS. But Australian research is playing a leading role in the discovery of possible diagnostic markers. For example, inflammatory blood proteins such as activin B and interferon are increased in ME/CFS. Other studies have shown metabolic waste products from some gut bacteria accumulate in ME/CFS patients and so may also provide diagnostic information in the future.

Women are four times more likely to be diagnosed with ME/CFS than men, but the reason for this is unclear. Also, having a first-degree relative with ME/CFS more than doubles the risk of developing the disease, but the role of genetics is not known.

For some, the onset of symptoms is slow. In others, ME/CFS begins with infections causing glandular fever (infectious mononucleosis), respiratory or gastrointestinal illnesses.

While ME/CFS patients have immune disruptions and abnormal inflammatory responses, the underlying causes remain elusive. The vicious cycles of tissue damage typical of autoimmune diseases such as multiple sclerosis or lupus don’t seem to occur in ME/CFS.

One theory is that ME/CFS patients have a “chink” in their immunological armour, possibly leading to persistent “smouldering” infections and chronic inflammation.

But it’s remarkably difficult to find direct evidence for such ongoing infections in most ME/CFS patients. And antiviral drugs or antibiotics seem to have very modest activity in ME/CFS despite their life-saving activities in many other infectious diseases.

ME/CFS patients also have metabolic defects in the way energy is generated in their bodies - pointing to one reason why they rapidly succumb to muscle fatigue during exercise. But whether this metabolic defect is due to immune attack, chronic infection or some other cause is unknown.

With no approved treatments or cures for ME/CFS, more research is urgently needed. So far, clinical trials examining the effects of immunosuppressive drugs, antibody therapies, anti-viral drugs, attention deficit hyperactivity disorder therapies and anti-depressants have not led to major improvements.

Diets and nutritional supplements also seem to provide little help. While some dietary supplements involved in generating metabolic energy seem to improve some ME/CFS symptoms, larger and better studies are required.

A reboot of ME/CFS research is now underway. Sufferers are hopeful the recent establishment of a National Health and Medical Research Council ME/CFS Advisory Committee will reinvigorate Australian biomedical ME/CFS research to find new treatments and possibly a cure.

Read the original article.

Persistent Neuropsychiatric Impairment in HCV Patients Despite Clearance of the Virus?!

Persistent Neuropsychiatric Impairment in HCV Patients Despite Clearance of the Virus?!
Original article was published 9 February 2017 in Journal of Viral Hepatitis, the research article is open access over at Medscape, patient-friendly commentary published at Infectious Disease Advisor, discussion only provided below.

Many patients with HCV infection report disabling chronic fatigue--even after viral clearance. Might HCV be implicated in a virus infection-associated chronic fatigue syndrome?

Persistent Neuropsychiatric Impairment in HCV Patients Despite Clearance of the Virus?!

M. Dirks; H. Pflugrad; K. Haag; H. L. Tillmann; H. Wedemeyer; D. Arvanitis; H. Hecker; A. Tountopoulou; A. Goldbecker; H. Worthmann; K. Weissenborn
J Viral Hepat. 2017;24(7):541-550. 

Discussion Only

Full text article published @ Medscape 

To our knowledge the present study is the largest study concerning neuropsychiatric symptoms in PCR-positive and PCR-negative HCV-afflicted patients with only mild liver disease that combined the assessment of health-related quality of life with the assessment of chronic fatigue, mood disturbances and cognition.

The results of our study can be summarized as follows: (i) PCR+ and PCR− HCV-afflicted patients with only mild liver disease but neuropsychiatric symptoms do not differ with regard to the features and extent of these symptoms, (ii) chronic fatigue is the most frequent neuropsychiatric symptom and has the most significant impact on the patients' health-related quality of life, (iii) significant cognitive dysfunction is present in about one-third of the patients with neuropsychiatric symptoms and (iv) is not feigned by the presence of depression.

So far, the largest population sample related to cognitive function in HCV-afflicted patients was published by Fontana et al.[31] They analysed cognitive function in PCR−positive patients with advanced liver fibrosis (Ishak fibrosis score 3–6), who took part in the HALT-C trial—a prospective, randomized, controlled study of long-term pegylated interferon for chronic hepatitis C patients with advanced fibrosis who were nonresponders to prior interferon therapy. Two hundred and one patients were included of whom 38% had developed liver cirrhosis. Fifty-two per cent of their patients met DSM-IV criteria for a lifetime diagnosis of an alcohol use disorder, and 39% of subjects met DSM-IV criteria for a lifetime diagnosis of a drug use disorder. In analogy to our findings Fontana and co-workers reported that about 33% of their patients showed evidence of mild cognitive dysfunction. Domains predominantly affected were verbal recall and working memory. Of note and in line with our data, they did not find evidence for a significant effect of neither liver function nor grade of liver fibrosis or of former alcohol or drug abuse upon their neuropsychological results. Interestingly, the domains affected were congruent with those described in other studies upon cognitive dysfunction in HCV-afflicted patients but incongruent with the characteristic neuropsychological pattern of hepatic encephalopathy associated with liver cirrhosis.[32] Thus, there was clear evidence that cognitive dysfunction in the patients in Fontana's study was not due to hepatic encephalopathy, but instead probably due to HCV infection.

Our study included patients with mild liver disease, exclusively, thereby even further eliminating the confounding of advanced liver disease on brain function. Nevertheless, we found deficits in the recognition of words or figures in 45% and attention deficits in 30% of the patients. About 77% showed chronic fatigue, and 50%-60% mild to moderate anxiety and depression. Health-related quality of life correlated negatively with fatigue, as did the patients' attention ability. Of note, the patients' cognitive function was independent from their mood status. The significant correlation between attention test sum score and the fatigue and depression scores would indicate otherwise on the first view, multiple regression analysis, however, identified the extent of fatigue as the main and single independent predictor of attention deficit. The positive correlation between the attention test sum score and the LLW sum score relates to the fact that LLW tests working memory and learning ability and thus attentional function. Memory function in our patients did not show a correlation with either fatigue or depression scores and was even independent from the attention test performance, thus also indicating that cognitive dysfunction in the patients is independent from mood alterations.

Of note, we did not find a fundamental difference in the neuropsychiatric symptom profile considering the PCR status or treatment history.

Chronic fatigue has been identified as the most frequent complication of HCV infection years ago.[2] For a long time, however, the patients' complaints about disabling fatigue have not directly been linked to the virus. Symptoms were classified as reaction to the knowledge of being infected or as a consequence of advanced liver disease. Patients showing sustained response to antiviral therapy were and are still in general considered to be cured. Our data, however, show that the neuropsychiatric symptoms, if present, feature identical in PCR-positive and PCR-negative HCV-afflicted patients. Former studies showed similar alterations of brain metabolite levels, cerebral glucose utilization and dopaminergic neurotransmission in PCR-positive and PCR-negative patients, as well as a relationship between these parameters and the patients' cerebral function.[33–35] This indicates that clearance of the virus in the periphery is not equivalent to cure from neuropsychiatric sequelae of HCV infection. It has still to be clarified, for example, if quasispecies of the virus are able to persist within the brain after successful clearance in the periphery, or if the virus induces a neuroinflammatory response that carries on independent of the presence or absence of the virus. Recently, HCV RNA was detected in peripheral blood mononuclear cells (PBMCs) in patients with sustained viral response (SVR) 52–66 months after pegylated IFN and ribavirin therapy.[36] In addition, it has been shown that cure of HCV infection does not lead to complete restoration of the altered cytokine and chemokine milieu. According to a recent paper by Hengst and colleagues, several soluble inflammatory mediators that are suppressed in HCV patients before successful antiviral therapy remain suppressed thereafter.[37]

Patients in both PCR-negative groups were more impaired than those in the PCR-positive groups in this study. This, however, can reflect a selection bias, because PCR-negative patients without any further symptoms are less likely to present in a hepatitis outpatient clinic or to seek support in a patient support group and to take part in a study upon neuropsychiatric symptoms than PCR-negative patients with symptoms. The same aspect holds true of course also for PCR-positive patients and might lead to an overestimation of the frequency of neuropsychiatric symptoms in HCV patients.

Recent therapeutic studies were able to show that virus eradication results in clinically meaningful improvements in several HRQoL domains.[11–14] These studies also showed that improvement was likely to be achieved in physical but not in mental health scores. Based on these findings Bonkovsky et al.[14] suggested that HCV infection per se has an effect on emotional states. Accompanying cognitive deficits in HCV-infected patients, however, was suggested to result from underlying conditions such as anxiety and depression or use of psychotropic medications rather than from HCV infection itself.[14] This explanation is disproved by our findings as we did not observe a significant correlation between cognitive function and anxiety or depression and had excluded patients on psychotropic drugs. Comparing the results of patients who had been interferon/ribavirin exposed to those who had never been treated, we were able to show that the neuropsychiatric symptoms in formerly treated HCV-afflicted patients cannot be ascribed to interferon/ribavirin therapy.

Today we have growing evidence for HCV invasion into and replication within the brain.[38–42] Interestingly, evidence for virus replication was found in about 50% of the samples studied. That is nearly identical with the percentage of HCV patients with neuropsychiatric symptoms in population studies.[2,18,43] In a recent autopsy study, microglia and astrocytes were identified as host cells for the virus.[42] The alterations of magnetic resonance spectra of the brain of HCV patients suggested a neuroinflammatory response to the virus.[8–10,35] This assumption was supported by the finding of an activation of brain microglia cells in autopsy brain tissue from HCV-positive patients.[44] Therefore, evidence for microglia activation in patients with HCV−associated encephalopathy was searched using 11C- PK11195 positron emission tomography. 11C-PK11195 binds to the translocator protein (TSPO) which is located amongst others on the outer mitochondrial membrane of microglia, and which is expressed especially in activated microglia.[45,46] Indeed, microglia activation was observed compared to controls both in PCR-positive and in PCR-negative patients.[47,48] Differences in 11C-PK11195 binding, however, were found between patients with and without cognitive dysfunction. Preserved cognitive function was associated with significantly increased microglia activation indicating a neuroprotective role of microglia activation in the HCV−exposed patients.[48]

In our study, PCR+ and PCR− patients scored similarly in all assessed domains, while both patient groups scored significantly worse than the healthy controls. The data clearly show that neither the HRQOL, nor the extent of fatigue, nor cognitive or mental function in HCV-exposed patients depend on their PCR status. This finding is in line with earlier studies including large and representative cohorts of women infected through anti-D prophylaxis. In both cohorts, from Ireland[49] and from Germany,[43] fatigue was a frequently observed phenomenon, but unrelated to liver disease and virological status.

The observation that the neuropsychiatric syndrome in HCV-exposed patients is independent of the virus replication state as measured in the patients' blood is in favour of the hypothesis that the symptoms are unrelated to HCV infection. However, the development of an HCV infection triggered autoimmune process, which continues after clearance of the virus, or—alternatively—the possibility of a virus variant persisting in the brain should seriously be discussed. Considering the data upon virus infection-associated chronic fatigue syndrome HCV just appears to be more capable to induce this disorder than other viruses, while the clinical features are similar irrespective of the underlying cause.[50] It will be of outmost interest to observe whether sustained response to the new direct acting antivirals will be more effective with regard to neuropsychiatric manifestations of HCV than the interferon/ribavirin combination therapy.

Continue to full text article published @ Medscape
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Chronic fatigue syndrome is in your gut, not your head

Chronic fatigue syndrome is in your gut, not your head

Physicians have been mystified by chronic fatigue syndrome, a condition where normal exertion leads to debilitating fatigue that isn't alleviated by rest. There are no known triggers, and diagnosis requires lengthy tests administered by an expert.

Now, for the first time, Cornell University researchers report they have identified biological markers of the disease in gut bacteria and inflammatory microbial agents in the blood.

In a study published June 23 in the journal Microbiome, the team describes how they correctly diagnosed myalgic encephalomyeletis/chronic fatigue syndrome (ME/CFS) in 83 percent of patients through stool samples and blood work, offering a noninvasive diagnosis and a step toward understanding the cause of the disease.

"Our work demonstrates that the gut bacterial microbiome in chronic fatigue syndrome patients isn't normal, perhaps leading to gastrointestinal and inflammatory symptoms in victims of the disease," said Maureen Hanson, the Liberty Hyde Bailey Professor in the Department of Molecular Biology and Genetics at Cornell and the paper's senior author. "Furthermore, our detection of a biological abnormality provides further evidence against the ridiculous concept that the disease is psychological in origin."

"In the future, we could see this technique as a complement to other noninvasive diagnoses, but if we have a better idea of what is going on with these gut microbes and patients, maybe clinicians could consider changing diets, using prebiotics such as dietary fibers or probiotics to help treat the disease," said Ludovic Giloteaux, a postdoctoral researcher and first author of the study.

In the study, Ithaca campus researchers collaborated with Dr. Susan Levine, an ME/CFS specialist in New York City, who recruited 48 people diagnosed with ME/CFS and 39 healthy controls to provide stool and blood samples.

The researchers sequenced regions of microbial DNA from the stool samples to identify different types of bacteria. Overall, the diversity of types of bacteria was greatly reduced and there were fewer bacterial species known to be anti-inflammatory in ME/CFS patients compared with healthy people, an observation also seen in people with Crohn's disease and ulcerative colitis.

At the same time, the researchers discovered specific markers of inflammation in the blood, likely due to a leaky gut from intestinal problems that allow bacteria to enter the blood, Giloteaux said.

Bacteria in the blood will trigger an immune response, which could worsen symptoms.

The researchers have no evidence to distinguish whether the altered gut microbiome is a cause or a whether it is a consequence of disease, Giloteaux added.

In the future, the research team will look for evidence of viruses and fungi in the gut, to see whether one of these or an association of these along with bacteria may be causing or contributing to the illness.

###

The study was funded by the National Institutes of Health.
http://mediarelations.cornell.edu/2016/06/27/3770/

Brain Imaging Reveals Clues About Chronic Fatigue Syndrome

Brain Imaging Reveals Clues About Chronic Fatigue Syndrome

 Differences in basal ganglia, similarity to inflammation-induced fatigue

In previous published studies by Emory researchers, people taking interferon alpha as a treatment for hepatitis C, which can induce severe fatigue, also show reduced activity in the basal ganglia. Interferon alpha is a protein naturally produced by the body, as part of the inflammatory response to viral infection. Inflammation has also been linked to fatigue in other groups such as breast cancer survivors.

A brain imaging study shows that patients with chronic fatigue syndrome may have reduced responses, compared with healthy controls, in a region of the brain connected with fatigue. The findings suggest that chronic fatigue syndrome is associated with changes in the brain involving brain circuits that regulate motor activity and motivation.

Compared with healthy controls, patients with chronic fatigue syndrome had less activation of the basal ganglia, as measured by fMRI (functional magnetic resonance imaging). This reduction of basal ganglia activity was also linked with the severity of fatigue symptoms.

According to the Centers for Disease Control and Prevention, chronic fatigue syndrome is a debilitating and complex disorder characterized by intense fatigue that is not improved by bed rest and that may be worsened by exercise or mental stress.

The results are scheduled for publication in the journal PLOS One.

“We chose the basal ganglia because they are primary targets of inflammation in the brain,” says lead author Andrew Miller, MD. “Results from a number of previous studies suggest that increased inflammation may be a contributing factor to fatigue in CFS patients, and may even be the cause in some patients.”

Miller is William P. Timmie professor of psychiatry and behavioral sciences at Emory University School of Medicine. The study was a collaboration among researchers at Emory University School of Medicine, the CDC’s Chronic Viral Diseases Branch, and the University of Modena and Reggio Emilia in Italy. The study was funded by the CDC.

The basal ganglia are structures deep within the brain, thought to be responsible for control of movements and responses to rewards as well as cognitive functions. Several neurological disorders involve dysfunction of the basal ganglia, including Parkinson’s disease and Huntington’s disease, for example.

In previous published studies by Emory researchers, people taking interferon alpha as a treatment for hepatitis C, which can induce severe fatigue, also show reduced activity in the basal ganglia. Interferon alpha is a protein naturally produced by the body, as part of the inflammatory response to viral infection. Inflammation has also been linked to fatigue in other groups such as breast cancer survivors.

“A number of previous studies have suggested that responses to viruses may underlie some cases of CFS,” Miller says. “Our data supports the idea that the body’s immune response to viruses could be associated with fatigue by affecting the brain through inflammation. We are continuing to study how inflammation affects the basal ganglia and what effects that has on other brain regions and brain function. These future studies could help inform new treatments.”

Treatment implications might include the potential utility of medications to alter the body’s immune response by blocking inflammation, or providing drugs that enhance basal ganglia function, he says.

The researchers compared 18 patients diagnosed with chronic fatigue syndrome with 41 healthy volunteers. The 18 patients were recruited [not referred] based on an initial telephone survey followed by extensive clinical evaluations. The clinical evaluations, which came in two phases, were completed by hundreds of Georgia residents. People with major depression or who were taking antidepressants were excluded from the imaging study, although those with anxiety disorders were not.

For the brain imaging portion of the study, participants were told they’d win a dollar if they correctly guessed whether a preselected card was red or black. After they made a guess, the color of the card was revealed, and at that point researchers measured blood flow to the basal ganglia.

The key measurement was: how big is the difference in activity between a win or a loss? Participants’ scores on a survey gauging their levels of fatigue were tied to the difference in basal ganglia activity between winning and losing. Those with the most fatigue had the smallest changes, especially in the right caudate and the right globus pallidus, both parts of the basal ganglia.

Ongoing studies at Emory are further investigating the impact of inflammation on the basal ganglia, including studies using anti-inflammatory treatments to reduce fatigue and loss of motivation in patients with depression and other disorders with inflammation including cancer.

Source: Emory Health Sciences

Chronic Fatigue Syndrome Is Not Linked To Suspect Viruses

 Chronic fatigue syndrome is not linked to suspect viruses

Multi-site blinded study puts to rest the notion that these viruses cause the mysterious ailment

The causes of chronic fatigue syndrome (CFS) have long eluded scientists. In 2009, a paper in the journal Science linked the syndrome—sometimes called myalgic encephalomyelitis (ME)—to infection with a mouse retrovirus called XMRV (xenotropic murine leukemia virus (MLV)-related virus).

Given that affected patients often have symptoms consistent with a chronic infection, this viral connection seemed plausible, and the findings were celebrated as a major achievement for a complex disease that afflicts nearly 1 million in the U.S. Another study in early 2010 published in Proceedings of the National Academy of Sciences detected murine retrovirus-like sequences (designated pMLV: polytropic MLV) in CFS/ME patients, which provided further support for a viral theory.

Follow-up investigations by several laboratories were unable to detect XMRV or pMLV in CFS patients. However, none of them examined a sufficiently large population of well-characterized CFS/ME patients to rigorously test the validity of those findings. In the absence of a definitive study, many in the general public may have retained the opinion that XMRV and/or pMLV are responsible for the disease, and some clinicians continue the "off-label" prescription of antiretroviral drugs.

To definitively resolve this issue, the National Institute of Allergy and Infectious Diseases, part of the National Institutes of Health (NIH), commissioned a study under the auspices of the Center for Infection and Immunity at Columbia University's Mailman School of Public Health, in partnership with the Centers for Disease Control and Prevention, the Food and Drug Administration, and the NIH's National Cancer Institute and Warren G. Magnuson Clinical Center.

The research is published in mBio.
A total of 293 subjects, 147 with CFS/ME and 146 matched controls, were recruited from six sites across the United States following extensive clinical assessments and laboratory screening. Clinical sites included Brigham and Women's Hospital (Boston, MA), the Simmaron Research Institute (Incline Village, NV), Miami Veterans Affairs Medical Center (Miami, FL), the Infectious Disease Clinic at Stanford University (Palo Alto, CA), the Levine Clinic (New York, NY), and the Fatigue Consultation Clinic (Salt Lake City, UT).

All CFS/ME patients chosen for the study: 1) were between the ages of 18 and 70; 2) had never suffered from another neurologic or psychiatric illness; 3) met both the "Fukuda" and "Canadian Consensus" criteria for CFS/ME; 4) were suffering from symptoms of a viral infection prior to CFS onset; 5) had reduced scores on the RAND36 quality-of-life survey (vitality subscale <35, social functioning subscale <62.5, role-physical subscale <50) and the Karnofsky Performance Scale (<70%); 6) were not pregnant, lactating, or less than 3 months postpartum to prevent maternity-related fatigue from being confused for CFS/ME.

Control subjects were recruited to match age, sex/gender distribution, race/ethnicity, and geographic location. Controls had no previous contact with individuals with CFS/ME. All potential subjects were then tested for evidence of any metabolic, endocrine, or infectious disease that might cause fatigue.

Blood from CFS/ME and control subjects who met this selection criteria was collected for blinded XMRV and/or pMLV analysis using molecular, culture and serological methods, which were previously established in the individual laboratories where evidence of XMRV or pMLV had been reported or ruled out.

None of the laboratories found evidence of XMRV or pMLV in samples from the recruited CFS/ME or control subjects. For quality assurance of the molecular tests, separate positive controls (blood samples intentionally spiked with XMRV/pMLV) and negative controls (blood samples prescreened and lacking the retroviruses) were used and confirmed that the diagnostic assays were functioning properly.

Nine control and nine CFS/ME blood samples were positive for XMRV/pMLV-reactive antibodies.

The accuracy of this assay cannot be determined because there are no positive controls in the general population with XMRV serology. Nonetheless, there was no correlation of antibody reactivity in blood from CFS/ME and controls.

Statement from Dr. Mikovits, the author of the Science paper wherein XMRV was first linked to CFS: "I greatly appreciated the opportunity to fully participate in this unprecedented study.

Unprecedented because of the level of collaboration, the integrity of the investigators, and the commitment of the NIH to provide its considerable resources to the CFS community for this important study. Although I am disappointed that we found no association of XMRV/pMLV to CFS, the silver lining is that our 2009 Science report resulted in global awareness of this crippling disease and has sparked new interest in CFS research. I am dedicated to continuing to work with leaders in the field of pathogen discovery in the effort to determine the etiologic agent for CFS."

"Although the once promising XMRV and pMLV hypotheses have been excluded, the consequences of the early reports linking these viruses to disease are that new resources and investigators have been recruited to address the challenge of the CFS/ME", said W. Ian Lipkin, MD, director of the multi-site study and John Snow Professor of Epidemiology in the Mailman School of Public Health of Columbia University. "We are confident that these investments will yield insights into the causes, prevention and treatment of CFS/ME."

###

This study was funded by National Institutes of Health award AI1057158 (NBC-Lipkin).
Collaborating Research Groups

Department of Transfusion Medicine, Warren G. Magnuson Clinical Center, National Institutes of Health, Bethesda, MD.

Mikovits Consulting, Oxnard, CA.

Division of HIV/AIDS Prevention, Centers for Disease Control and Prevention, Atlanta, GA.

Cancer and Inflammation Program, Frederick National Laboratory for Cancer Research, Frederick, MD.

Tissue Safety Laboratory, Office of Cellular, Tissue and Gene Therapies, Center for Biologics Evaluation and Research, Food and Drug Administration, Bethesda, MD.

Nova Southeastern University, Fort Lauderdale FL.

Miami Veterans Affairs Medical Center, Miami, FL.

Brigham and Women's Hospital, Boston, MA.

Infectious Disease Clinic, Stanford University, Palo Alto, CA.

Fatigue Consultation Clinic, Salt Lake City, UT.

Levine Clinic, New York, NY.

Simmaron Research Institute, Incline Village, NV.

Department of Biostatistics, Columbia University, New York, NY.

Department of Molecular Biology and Genetics, Cornell University, Ithaca, NY.

Center for Infection and Immunity, Columbia University, New York, NY.

Department of Molecular Biology and Microbiology, Tufts University, Boston, MA.

About Columbia University's Mailman School of Public Health Founded in 1922 as one of the first three public health academies in the nation, Columbia University's Mailman School of Public Health pursues an agenda of research, education, and service to address the critical and complex public health issues affecting New Yorkers, the nation and the world. The Mailman School is the third largest recipient of NIH grants among schools of public health. Its over 450 multi-disciplinary faculty members work in more than 100 countries around the world, addressing such issues as preventing infectious and chronic diseases, environmental health, maternal and child health, health policy, climate change & health, and public health preparedness. It is a leader in public health education with over 1,300 graduate students from more than 40 nations pursuing a variety of master's and doctoral degree programs. The Mailman School is also home to numerous world-renowned research centers including the International Center for AIDS Care and Treatment Programs (ICAP), the National Center for Disaster Preparedness, and the Center for Infection and Immunity.

For more information, please visit http://www.mailman.columbia.edu/news/chronic-fatigue-syndrome-not-linked-suspect-viruses

Chronic Fatigue Syndrome Linked To Reduced Activity In Brain’s Reward Center

Finding adds to evidence about the biology of this mysterious disease

Chronic fatigue syndrome, a medical disorder characterized by extreme and ongoing fatigue with no other diagnosed cause, remains poorly understood despite decades of scientific study. Although researchers estimate that more than 1 million Americans are affected by this condition, the cause for chronic fatigue syndrome, a definitive way to diagnose it, and even its very existence remain in question. In a new study, researchers have found differing brain responses in people with this condition compared to healthy controls, suggesting an association between a biologic functional response and chronic fatigue syndrome.

The findings show that patients with chronic fatigue syndrome have decreased activation of an area of the brain known as the basal ganglia in response to reward. Additionally, the extent of this lowered activation was associated with each patient’s measured level of fatigue. The basal ganglia are at the base of the brain and are associated with a variety of functions, including motor activity and motivation. Diseases affecting basal ganglia are often associated with fatigue. These results shed more light on this mysterious condition, information that researchers hope may eventually lead to better treatments for chronic fatigue syndrome.

The study was conducted by Elizabeth R. Unger, James F. Jones, and Hao Tian of the Centers for Disease Control and Prevention (CDC), Andrew H. Miller and Daniel F. Drake of Emory University School of Medicine, and Giuseppe Pagnoni of the University of Modena and Reggio Emilia. An abstract of their study entitled, “Decreased Basal Ganglia Activation in Chronic Fatigue Syndrome Subjects is Associated with Increased Fatigue,” will be discussed at the meeting Experimental Biology 2012, being held April 21-25 at the San Diego Convention Center. The abstract is sponsored by the American Society for Investigative Pathology (ASIP), one of six scientific societies sponsoring the conference which last year attracted some 14,000 attendees.

More Fatigue, Less Activation

Dr. Unger says that she and her colleagues became curious about the role of the basal ganglia after previous studies by collaborators at Emory University showed that patients treated with interferon alpha, a common treatment for chronic hepatitis C and several other conditions, often experienced extreme fatigue. Further investigation into this phenomenon showed that basal ganglia activity decreased in patients who received this immune therapy. Since the fatigue induced by interferon alpha shares many characteristics with chronic fatigue syndrome, Unger and her colleagues decided to investigate whether the basal ganglia were also affected in this disorder.

The researchers recruited 18 patients with chronic fatigue syndrome, as well as 41 healthy volunteers with no symptoms of CFS. Each study participant underwent functional magnetic resonance imaging, a brain scan technique that measures activity in various parts of the brain by blood flow, while they played a simple card game meant to stimulate feelings of reward. The participants were each told that they’d win a small amount of money if they correctly guessed whether a preselected card was red or black. After making their choice, they were presented with the card while researchers measured blood flow to the basal ganglia during winning and losing hands.

The researchers showed that patients with chronic fatigue syndrome experienced significantly less change in basal ganglia blood flow between winning and losing than the healthy volunteers. When the researchers looked at scores for the Multidimensional Fatigue Inventory, a survey often used to document fatigue for chronic fatigue syndrome and various other conditions, they also found that the extent of a patient’s fatigue was tightly tied with the change in brain activity between winning and losing. Those with the most fatigue had the smallest change.

Results Suggest Role of Inflammation

Unger notes that the findings add to our understanding of biological factors that may play a role in chronic fatigue syndrome. “Many patients with chronic fatigue syndrome encounter a lot of skepticism about their illness,” she says. “They have difficulty getting their friends, colleagues, coworkers, and even some physicians to understand their illness. These results provide another clue into the biology of chronic fatigue syndrome.”

The study also suggests some areas of further research that could help scientists develop treatments for this condition in the future, she adds. Since the basal ganglia use the chemical dopamine as their major neurotransmitter, dopamine metabolism may play an important role in understanding and changing the course of this illness. Similarly, the difference in basal ganglia activation between the patients and healthy volunteers may be caused by inflammation, a factor now recognized as pivotal in a variety of conditions, ranging from heart disease to cancer.

Estimates from the CDC suggest that annual medical costs associated with chronic fatigue syndrome total about $14 billion in the United States. Annual losses to productivity because of lost work time range between $9 and $37 billion, with costs to individual households ranging between $8,000 and $20,000 per year.

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Anxiety, Depression Linked to Fatigue in Cirrhosis

HIV
FDA: Important drug interactions between Victrelis (boceprevir) and ritonavir-boosted human immunodeficiency virus (HIV) protease inhibitor drugs

Big Pharma
Hepatitis C and Orphan Diseases Driving Big Biotech Potential: Geoff Meacham

In The News

From Medscape Gastroenterology > Ask the Experts

When Will We Have Interferon-Free Treatment for Hepatitis C?
William F. Balistreri, MD
Posted: 02/09/2012

Question:

Is it true that we are close to treatment of patients with chronic hepatitis C virus (HCV) infection with an interferon-free regimen?

Response from William F. Balistreri, MD

Professor of Medicine, University of Cincinnati College of Medicine; Staff Physician, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio 

A New Era of Therapy

Combination therapy with pegylated interferon (PEG-IFN) and ribavirin long stood as the standard of care for chronic hepatitis C virus (HCV) infection. Although effective in achieving high rates of sustained virologic response (SVR), this combination regimen was associated with troublesome side effects.[1] Therefore, the development of 2 effective protease inhibitors -- telaprevir and boceprevir -- was hailed as a new era of therapy for patients with HCV genotype 1 infection.[2] These direct-acting antiviral agents act at specific steps in the viral lifecycle and allow more effective treatment with a shorter duration.

Telaprevir and boceprevir, linear inhibitors of the HCV nonstructural protein 3/4A (NS3/4A) serine protease, were approved by the US Food and Drug Administration for HCV treatment in May 2011. However, the recent American Association for the Study of Liver Diseases (AASLD) recommendations indicate that these direct-acting antiviral agents must be used in combination with PEG-IFN and ribavirin.[1] This is far from the ideal regimen; because of poor tolerability, many treatment candidates will decide not to pursue treatment or to defer treatment until an IFN-free regimen is available. 

An Ideal Strategy for HCV

It is true that an IFN-free regimen is "no longer a dream."[3] It is now viewed as part of a larger goal: the development and validation of an ideal strategy to treat HCV infection. The long sought-after therapeutic objective is to define a strategy that would be highly effective against allHCV genotypes, simple (oral drugs only, low pill burden, and short duration), and safe and tolerable, with low rates of resistance emergence. The recommended strategy would also assess each potential treatment candidate for interleukin 28B genotype, which is a robust pretreatment predictor of SVR to therapy in patients with genotype 1 chronic HCV infection.[1]

How close are we? Various compounds, encompassing at least 5 distinct drug classes, are currently under development for the treatment of chronic HCV infection, and the results of trials of several investigational agents were recently published.[3-5] Many other drug trials were presented at The Liver Meeting 2011: The AASLD 62nd Annual Meeting. These drugs bring us one step closer to the long sought-after ideal: the ability to delete noisome IFN injections from treatment strategies. 

Promising Preliminary Results

Let me illustrate by focusing on phase 2 studies presented by 2 groups who reported exciting preliminary results of an investigational agent (PSI-7977) even in the absence of IFN coadministration.[6,7] PSI-7977, a uridine nucleotide analog polymerase inhibitor, is administered orally once daily and has strong antiviral activity against HCV genotype 1 when used in combination with PEG-IFN and ribavirin. A double-blind placebo-controlled dose-ranging study of PSI-7977 in patients with HCV genotype 1 documented a rapid virologic response (RVR) in 98% of patients, with an end-of-treatment response at 24 weeks in 91%.[6] The RVR in the placebo group was 19%, and the end-of-treatment response was 50%. Of specific note, all patients with the difficult-to-treat interleukin 28B single-nucleotide polymorphism T/T mutation had an RVR -- all became HCV-negative by week 3, and 100% went on to achieve an SVR.

In another phase 2 study, this investigational compound allowed all patients to achieve an RVR. More than 80% of the treatment group had nondetectable HCV RNA at 2 weeks, and all patients had undetectable levels at 3 weeks.[7] All patients achieved normalization of serum alanine aminotransferase levels. No serious adverse events were attributable to PSI-7977, and as expected, safety and tolerability were greatest in the IFN-free treatment group.

Thus, PSI-7977 exhibits high-potency antiviral activity against a broad range of HCV genotypes, has a high barrier to resistance, and has a reassuring safety profile. This drug also allowed a shorter duration of therapy for viral clearance. These studies support the continued exploration of this drug and related compounds -- alone, with other direct-acting antiviral agents, or with shorter duration of IFN therapy in patients with all HCV genotypes. Further studies will hopefully confirm the initial excitement and optimism and, of note, will document the spectrum of potential adverse effects. 

Getting to IFN-Free Regimens

Within the next 5 years, IFN-free regimens may be a reality and available in the clinic. As Sharma and Lok[3] stated, "[I]t is possible that some of these regimens will also be ribavirin free. This will be good news for patients who wish to be treated but have to defer treatment because of contraindications to use of PEG-IFN or ribavirin, or out of concerns about their ability to tolerate these medications." The ideal strategy is on the horizon.

1. Ghany MG, Nelson DR, Strader DB, Thomas DL, Seeff LB; American Association for the Study of Liver Diseases. An update on treatment of genotype 1 chronic hepatitis C virus infection: 2011 practice guideline by the American Association for the Study of Liver Diseases. Hepatology. 2011;54:1433-1444. Abstract
2. Jensen DM. A new era of hepatitis C therapy begins. N Engl J Med. 2011;364:1272-1274. Abstract
3. Sharma P, Lok AS. Interferon-free treatment regimens for hepatitis C: are we there yet? Gastroenterology. 2011;141:1963-1967.
4. Gane EJ, Roberts SK, Stedman CA, et al. Oral combination therapy with a nucleoside polymerase inhibitor (RG7128) and danoprevir for chronic hepatitis C genotype 1 infection (INFORM-1): a randomised, double-blind, placebo-controlled, dose-escalation trial. Lancet. 2010;376:1467-1475. Abstract
5. Zuezem S, Asselah T, Angus P, et al. Efficacy of the protease inhibitor BI 201335, polymerase inhibitor BI 207127, and ribavirin in patients with chronic HCV infection. Gastroenterology. 2011;141:2047-2055. Abstract
6. Lawitz E, Lalezar JP, Hassanein T, et al. Once-daily PSI-7977 plus PEG/RBV in treatment-naive patients with HCV GT1: robust end of treatment response rates are sustained post-treatment. Program and abstracts of The Liver Meeting 2011: American Association for the Study of Liver Diseases (AASLD) 62nd Annual Meeting; November 9-13, 2011; Boston, Massachusetts. Abstract 225.
7. Gane EJ, Stedman CA, Hyland RH, et al. Once daily PSI-7977 plus RBV: pegylated interferon-alfa not required for complete rapid viral response in treatment-naive patients with HCV GT2 or GT3. Program and abstracts of The Liver Meeting 2011: American Association for the Study of Liver Diseases (AASLD) 62nd Annual Meeting; November 9-13, 2011; Boston, Massachusetts. Abstract 34. 

Chronic Liver Disease Foundation Issues Statement in Support of Birth-Cohort Screening for Hepatitis C
Recommendations Include Expanded Testing with Rapid Point-of-Care HCV TestCLARK, N.J., Feb. 9, 2012 (GLOBE NEWSWIRE) -- The Chronic Liver Disease Foundation (CLDF), a leading educational organization dedicated to increasing awareness of the effect of chronic liver disease (CLD) in the United States, issued today a position paper in support of expanding screening for hepatitis C (HCV) in the United States.

The position paper, "Endorsement of Birth-Cohort Approach to Expand Screening for Hepatitis C," outlines the CLDF's recommendations for a more effective strategy to identify patients with HCV infection and link such patients to expert care and treatment.
HCV is the most common blood-borne chronic viral infection in the U.S., with more than four million Americans currently infected with the HCV virus. Of these, up to 75 percent are unaware of their infection. Individuals born between the years of 1945 and 1965 have an HCV prevalence level four times higher than those born outside the birth cohort.

While the CDC currently recommends HCV screening only for individuals found to be at risk for the HCV infection, it is currently evaluating the potential benefits of using a birth-cohort based approach to HCV screening to help increase identification of HCV-positive patients.
The CLDF issued the following recommendations in support of the expansion of HCV screening efforts:

• Routine screening for HCV among persons born between 1945 and 1965
• Use of the OraQuick HCV rapid point-of-care test to expand testing opportunities and facilitate immediate care
• Educational programs aimed at primary care providers to increase awareness of HCV risk factors
• Testing for HCV in primary care setting with established linkages to HCV
• Creative ways to increase access to HCV testing and care for injection-drug users and other underserved populations.

"Today, more than 4 million Americans are infected with hepatitis C and the vast majority does not know it," said Dr. Willis C. Maddrey, President of the Chronic Liver Disease Foundation. "Hepatitis C is a leading cause of chronic liver disease, cirrhosis and liver cancer. However, new therapies are now available that can effectively treat a high percentage of people with HCV infection, making expanded and accessible testing for HCV – particularly among those born between 1945 and 1965 – a critical step in fighting this epidemic."

About the Chronic Liver Disease Foundation
Established in 2001, the Chronic Liver Disease Foundation is a nonprofit 501(c)(3) educational organization dedicated to providing hepatology related continuing medical education, news and information to healthcare professionals across the US. The CLDF is led by a Board of Trustees comprised of nationally renowned liver disease specialists. Furthermore, the CLDF believes that educational programs should be developed by the specialists who are actively involved in the research, treatment and management of a disease. As such, the CLDF has developed a network of 75 Centers of Educational Expertise and multiple Advisory Boards who are actively involved in program creation related to specific disease topics which include: hemochromatosis, hepatic encephalopathy, hepatitis B, hepatitis C, hepatocellular carcinoma, HIV co-infection, liver transplantation and NASH/NAFLD. The CLDF's educational opportunities are offered in a variety of formats including an interactive web site, live meetings, teleconferences, print pieces, webcasts and other electronic mediums.  For more information, please visit www.chronicliverdisease.org.

Newsletter-February  

GI & Hepatology News

GI & Hepatology News is the official newspaper of the AGA Institute and provides the gastroenterologist with timely and relevant news and commentary about clinical developments and about the impact of health-care policy. The newspaper is led by an internationally renowned board of editors.GI & Hepatology News is published monthly

Big Pharma

BOSTON (MarketWatch) — 

Can Vertex Pharmaceuticals Inc. shares stage a comeback?

That’s a nagging question for investors, who have watched Vertex’s once-bright star fade as the shares of rival hepatitis C-drug developers supernovae. But Vertex shares could get a good stoking by mid-year, when the results of three key drug studies are due out.

Vertex’s stock had a banner 2011, its shares propelled to new heights by enthusiasm for its drug Incivek, a treatment for the hepatitis C virus, or HCV, a potentially deadly disease that attacks the liver. The drug belongs to a class of medications known as protease inhibitors that also includes Merck & Co.’ss new HCV drug Victrelis. 

In recent months, however, investor faith in Incivek’s long-term marketability has been deeply shaken by positive news about rival HCV drugs in development, particularly those in a class of drugs known as nucleotides, or “nukes.” 

As a result, shares of Vertex swung from a 52-week peak of $58.87 in mid-May 2011, to a low of $26.50 by late November, when Gilead Sciences Inc. announced it was buying nuke-drug developer Pharmasset Inc. for $11 billion, a move that further underscored the perceived value of nuke drugs. 

Over the past couple of months, the stock has managed to climb back into the upper $30s, due largely to anticipation ahead of the expected approval of the company’s drug Kalydeco. A novel treatment for the genetic disease cystic fibrosis, or CF, Kalydeco won approval earlier this month.

What’s still haunting the stock, say analysts, is concern about how well Incivek sales will hold up when the first nuke drugs hit the market and how well Vertex will be able to build-out its HCV and CF franchises. 

With key clinical data for both drug programs looming on the horizon, many analysts have taken a wait-and-see approach to the stock. According to FactSet, the average analyst rating currently for Vertex is overweight, with a price target of just over $46 a share.

Two upcoming events, however, could give the shares a needed jolt. 

The first is the expected release of early clinical data for two HCV nuke drugs that Vertex is co-developing with Alios BioPharma. The data is expected in the second quarter.

“Vertex’s HCV franchise is quickly becoming obsolete; to stay in the race, Vertex has to develop all oral, pan-genotypic combinations as quickly as possible, and the Alios nukes are the key to such hope,” wrote William Blair analyst Katherine Xu in a recent note, about the significance of the data.

Xu recently lowered her price target for Vertex to $44 from $45, citing slower than expected sales of Incivek, but maintained her buy rating on the stock. 

The second set of data, which involves the company’s CF drugs, could be the real market mover, however.

“Positive results in CF could get the stock moving again,” said Needham & Co. analyst Alan Carr, who also has a hold rating on the stock. 

The CF data will be from a Phase II trial that is testing Kalydeco, which is only approved for use in about CF patients with a rare gene mutation called G551D, or about 4% of CF patients, with another experimental CF drug dubbed VX-809. 

Vertex is banking that the Kalydeco/VX-809 combo can successfully treat patients with the F508del gene mutation, which is carried by up to 90% of all CF patients. The data is expected mid-year.

Kalydeco, by the way, isn’t cheap. At nearly $300,000 a year, it ranks as one of the most expensive drugs on the market. It’s high price is due in part to its regulatory status as an “ultra-orphan” drug. The regulatory designation is designed to encourage the development of drugs for life-threatening and extremely rare conditions by offering certain financial incentives, such as market exclusivity.

Carr said that even with its current narrow prescribing indication, Kalydeco could reach peak sales of $1 billion a year. Even if Vertex were forced to lower the price of the product, which would like happen if it were approved for a much larger patient population, sales could still be in the billions.

“According to our probability-adjusted net present value model, for every 10% increase in the probability of success for the combo, Vertex’s stock will have $4-$5 per share in upside, representing a powerful lever,” wrote Xu, of the CF drugs. 

“We believe there is a good chance for the Phase II combo data to be successful, which may compensate for the decline of the HCV franchise and lead to the next leg of growth for Vertex,” Xu added. 

That said, the Kalydeco data may also prove to be a bust. Data from an earlier segment of the Phase II trial showed the combination to be only modestly effective. Vertex is hoping that data from a second segment of the trial, which is administering VX-809 in higher doses over a longer period of time, yields more impressive results.

“People are getting pretty excited, but I’m just not there yet,” said JMP Securities analyst Liisa Bayko in a recent interview. Bayko currently has a hold rating on the stock.

FDA sets draft rules for biotech drug copies
Thu Feb 9, 2012 4:46pm EST
By Deena Beasley
(Reuters) - The Food and Drug Administration's long-awaited guidelines for the sale of lower-cost versions of biotechnology drugs leave open the possibility that some products might not need to be tested in humans.

China: Drugs Cut Cost, But Highten the Risks

Shan Juan and Wang Qingyun

(China Daily, February 3, 2012)

"Analysis by Medicins sans Frontieres, an international health organization, suggests India now makes one-fifth of the world's generic drugs, with about 50 percent shipped abroad and sold (often illegally) at a fraction of the cost…To tackle the problem of illegally imported drugs, the State Council last year launched a special health campaign. 'It mainly aimed at Internet scams in which profiteers promoted and sold fake drugs or those sourced through illegal channels,' said Bian Zhenjia, deputy director of the State Food and Drug Administration, who added that medication designed for long-term use, such as treatments for impotence, diabetes, hypertension and cancer, are major targets for criminals…Jia Ping [a Beijing lawyer who specializes in public health cases] said he fears that the drugs market is not currently a priority for authorities in China…Although there is no legal barrier to such a system in China, 'no domestic pharmaceutical company has so far applied for compulsory licensing of a foreign patent drug,' he said, adding that Chinese manufacturers had a 'relatively poor understanding about World Trade Organization treaties and public health.'"

Healthy You

Fallout From Fatigue Syndrome Retraction Is Wide
 David Tuller 
(The New York Times, February 6, 2012) 
"When scientists reported in 2009 that a little-known mouse retrovirus was present in a large number of people with chronic fatigue syndrome, suggesting a possible cause of the condition, the news made international headlines. For patients desperate for answers, many of them severely disabled for years, the finding…seemed a godsend…In hopes of treating their condition, some patients even began taking antiretroviral drugs used to treat H.I.V., a retrovirus related to the murine leukemia viruses suddenly suspected of involvement in chronic fatigue syndrome. More recently, however, the hopes of these patients have suffered an extraordinary battering. In a scientific reversal as dramatic and strange as any in recent memory, the finding has been officially discredited; a string of subsequent studies failed to confirm it, and most scientists have attributed the initial results to laboratory contamination. In late December, the original paper, published in the journal Science, and one other study that appeared to support it were retracted within days of each other. As the published evidence for the hypothesis fell apart, a legal melodrama erupted, dismaying and demoralizing patients and many members of the scientific community."

Diet & Chronic Disease Prevention

Trans-Fat Blood Levels Plummet After FDA Food-Labeling Regulation

David Brown

(The Washington Post, February 8, 2012)"The amount of trans fat in the American bloodstream fell by more than half after the Food and Drug Administration [FDA] required food manufacturers to label how much of the unhealthful ingredient is in their products, according to a new study. Blood levels of trans fat declined 58 percent from 2000 to 2008. FDA began requiring trans-fat labeling in 2003. During the same period several parts of the country -- New York most famously -- passed laws limiting trans fats in restaurant food and cooking. The makers of processed food also voluntarily replaced trans fats with less harmful oils. The decline, unusually big and abrupt, strongly suggests government regulation was effective in altering a risk factor for heart disease for a broad swath of the population. Researchers at the Centers for Disease Control and Prevention discovered the decline by analyzing blood drawn as part of the National Health and Nutrition Examination Survey, which interviews and examines a sample of Americans at least once a decade. The trend was seen in white adults; researchers are looking to see if it occurred in other ethnic and racial groups, too. Trans fats, which are used for deep-frying and as an ingredient in baked goods and spreads, increase the risk of heart disease.

Processed Foods

Scope:

Here’s an interesting video from Stefani Bardin, a TEDxManhattan 2011 fellow, and Braden Kuo, MD, a gastroenterology instructor at Harvard. According to their description, the video uses “the M2A and SmartPill devices to look at how the human body responds to processed versus whole foods.” While I’m by no means an expert on this subject, the video makes for some interesting watching.

Via Devour

 FYI

The Price of Information

(The Economist, London, February 4, 2012)

"More than 2,700 researchers from around the world have so far signed an online pledge…promising not to submit their work to Elsevier’s journals, or to referee or edit papers appearing in…[they agree with Cambridge University mathematician Timothy Gowers] First, that Elsevier charges too much for its products. Second, that its practice of 'bundling' journals forces libraries which wish to subscribe to a particular publication to buy it as part of a set that includes several others they may not want. And third, that it supports legislation…that would forbid the government requiring that free access be given to taxpayer-funded research. Elsevier insists it is being misrepresented…[the] petition, though, is symptomatic of a wider conflict between academics and their publishers -- a conflict that is being thrown into sharp relief by the rise of online publishing…This situation has been simmering for years…And there have indeed been attempts to create alternatives to commercial publishing…But despite the enthusiasm…there are reasons for the continued dominance of traditional publishers…Commercial publishers have begun to experiment with open-access ideas, such as charging authors for publication rather than readers for reading. But...things could become more urgent. After all, publishers need academics more than academics need publishers."

Hepatitis Weekend News;Response to standard of care antiviral treatment in patients with HCV liver cirrhosis - a systematic review

Response to standard of care antiviral treatment in patients with HCV liver cirrhosis - a systematic review.
Bota S, Sporea I, Popescu A, Sirli R, Neghina AM, Danila M, Strain M.

Abstract Only For Full Text Download Full Article (PDF file)

SourceDepartment of Gastroenterology and Hepatology, University of Medicine and Pharmacy, Timisoara, Romania; Email: isporea@umft.ro.

Abstract

BACKGROUND:

Patients with HCV liver cirrhosis are a category difficult to treat. The AIM of this study was to establish the sustained virological response (SVR) rates in HCV patients with liver cirrhosis treated with standard of care therapy (Pegylated Interferon and Ribavirin for 48 weeks in genotypes 1 and 4 and 24 weeks in genotypes 2 and 3).

METHODS:
Searching the PubMed, Medline, Lilacs, Scopus, Ovid and Medscape databases we identified all the articles published until February 2011 that included only HCV cirrhotic patients. These studies evaluated the SVR after standard of care treatment: Pegylated Interferon alpha 2a (doses ranging between 135-180 µg/week) or Pegylated Interferon alpha 2b (1 or 1.5 µg/kg/week) and Ribavirin (doses ranging between 800-1200 mg/day). We used the following key words: HCV, liver cirrhosis, sustained virological response (SVR).

RESULTS:
The overall SVR rate was 33.3% (95%CI-confidence interval=30.6-36.2%). SVR was significantly higher in patients with genotypes 2 and 3 (422 patients) as compared to those with genotypes 1 and 4 (692 patients): 55.4% (95%CI=50.7-60.1) versus 21.7% (95%CI=18.7-25), p less then 0.0001.

CONCLUSION:
The overall SVR rate in cirrhotic patients treated with standard of care therapy is 33.3%, but lower in cases affected by genotypes 1 and 4 (21.6%) which makes them a priority regarding the development of more potent drugs for effective treatment.
Full Text

Study finds curcumin able to inhibit traumatic death of liver cells
2011/10/08 17:35:21Taipei, Oct. 8 (CNA)
Taiwanese researchers have discovered that curcumin, a compound that gives turmeric its yellow color, is effective in inhibiting liver cells from turning fibrous before they lead to cirrhosis and liver cancer.

National Taiwan University assistant professor Chiu Chih-hsien and his research team found that feeding laboratory mice with high concentrations of curcumin extract brought about "apoptosis" in their inflamed liver cells. Apoptosis is a process describing programmed cell death. Normally, liver cells are replaced by new ones after their life circle ends through the naturally controlled process.

But when the cells develop inflammation under the influence of alcohol, drugs and chemical substances, they undergo traumatic deaths, called "necrosis." In the process of necrosis, liver cells gradually turn fibrous and stiffen, and then become cirrhotic and carcinogenic, Chiu said. "(The natural substance) can bring injured liver cells under the process of apoptosis, preventing their taumatic death," according to the team's study, the first anywhere in the world to focus on the effect of curcumin in inhibiting fibrosis on the liver. They discovered that "curcumin can control the way liver cells die," the professor said.

The research was conducted through the cooperation of National Taiwan University Department of Animnal Science and Technology and Kaohsiung Veterans General Hospital. The results will be published in the Journal of Nutritional Biochemistry by the end of this year, Chiu revealed. Curcumin is one of the most common ingredients in curry, and is frequently used as a herbal medicine in India and China to fight inflammation.

In recent years, it has also been touted by some as effective in combating cancer and even Alzheimer's disease. Chiu said the study could help scientists learn more about how the liver turns fibrous and would also pave the way for people to develop drugs to treat liver fibrosis. Asked if eating foods containing curry or taking curcumin food supplements would have the same effect they had in the laboratory, Chiu said it would not help because the amounts were too low

Translocation of gut-derived bacterial products such as endotoxin is a major problem in liver cirrhosis.

Methods:
To assess the hepatic clearance of bacterial products in individuals with cirrhosis, we tested concentrations of Gram-negative bacterial lipopolysaccharide (LPS), LPS-binding protein (LBP), and the precursor of nitric oxide (NO), L-arginine, in a cohort of 8 stable patients with liver cirrhosis before and after elective transjugular portosystemic shunt (TIPS) implantation, including central venous, hepatic venous, and portal venous measurements.

Results:
Using an adapted LPS assay, we detected high portal venous LPS concentrations (mean 1743+/-819 pg/mL). High concentrations of LPS were detectable in the central venous blood (931+/-551 pg/mL), as expected in persons with cirrhosis, The transhepatic LPS gradient was found to be 438+/-287 pg/mL, and 25+/-12% of portal LPS was cleared by the cirrhotic liver.After TIPS, central venous LPS concentrations increased in the hepatic and central veins, indicating shunting of LPS with the portal blood through the stent. This paralleled a systemic increase of L-arginine, whereas the NO synthase asymmetric dimethylarginine (ADMA) remained unchanged, suggesting that bacterial translocation may contribute to the pathogenesis of circulatory dysfunction post-TIPS.

Conclusions:
This study provides quantitative estimates of the role of the liver in the pathophysiology of bacterial translocation.The data indicate that the cirrhotic liver retains the capacity for clearance of bacterial endotoxin from the portal venous blood and that TIPS implantation attenuates this clearance. Thus, increased endotoxin concentrations in the systemic circulation provide a possible link to the increased encephalopathy in TIPS patients.

Author: Daniel Benten Julian Schulze zur Wiesch Karsten SydowAnd reas KoopsPeter Buggisch Rainer BogerCharlotte GaydosHelen WonVeronica Franco Ansgar LohseStuart RayAshwin Balagopal
Credits/Source: BMC Gastroenterology 2011, 11:107

Coffee Helps Reduce Side Effects in HIV/HCV Coinfected People during Interferon-based Therapy
Oct 7
HIV/HCV coinfected people who drink at least 3 cups of coffee daily were less likely to experienced adverse events related to interferon-based therapy for hepatitis C, according to a French study presented at the 10th AIDS Impact Conference last month in Santa Fe. However, whether coffee somehow directly relieves side effects remains unknown.
Several studies have shown that coffee appears to have a beneficial effect on liver inflammation and fibrosis among people with hepatitis C, and it has also been linked to higher rates of sustained response to interferon-based treatment.......

Hepatitis C Report: Four Food Groups to Lift Depression
October 6, 2011
Applicable to many with chronic Hepatitis C, eating foods rich in these four elements has been shown to help depression sufferers lift their spirits.
by Nicole Cutler, L.Ac.
More than most other populations, people with chronic Hepatitis C are particularly prone to depression. Getting relief from clinical depression typically requires a physician's guidance; but eating the right foods is a relatively simple way to help those affected get started on feeling better. Food can be either beneficial or detrimental to one's health. As such, diet can be a powerful tool for lifting depression. Even more specifically, the four food groups described below are known to help boost emotional well-being....

Lifetime probabilities of needing an organ transplant vs donating an organ
A study in the most recent issue of the American Journal of Transplantation investigates lifetime probabilities of needing an organ transplant vs donating an organ after death.
The lifetime probabilities of becoming a deceased organ donor and requiring or receiving an organ transplant are unknown.

An actuarial analysis was performed in a representative Canadian sample.
Dr Sam Shemie and colleagues from Canada used Canadian organ donation data from 1999 to 2007, provincial waiting list and population census data, actuarial rates were produced that provide the probabilities, by age band and gender, of becoming a deceased organ donor, needing an organ transplant, and receiving all organs needed.

Regardless of age, the lifetime probability of needing a transplant for males is approximately twice that of females.

Depending on age, Canadians are 5 to 6 times more likely to need an organ transplant than to become a deceased organ donor.

The lifetime probabilities of not receiving a required organ transplant, expressed as a percentage of individuals on the waiting list, ranges from approximately 30% at birth, 20 years and 40 years to approximately 40% at 60 years.
Across provinces and genders, Canadians at all ages are much more likely to need an organ transplant than to become an organ donor.

Approximately one-third of those in need of a transplant will never receive one. How this information may influence organ donation decisions is currently under study.
Am J Transplant 2011: 11(10): 2085–2092
07 October 2011

Cleveland Clinic study discovers new targets for treating inflammatory, autoimmune diseases
Researchers find pathway to potentially block disease-inducing inflammation
Friday, October 7, 2011, Cleveland: Researchers have discovered a cellular pathway that promotes inflammation in diseases like asthma, rheumatoid arthritis, psoriasis, inflammatory bowel disease, and multiple sclerosis. Understanding the details of this pathway may provide opportunities for tailored treatments of inflammatory and autoimmune diseases.
Discovery of this pathway was the work of an active collaboration between Xiaoxia Li, Ph.D., and Thomas Hamilton, Ph.D., Department Chair, both of the Department of Immunology at Lerner Research Institute of Cleveland Clinic.

Their publications in Nature Immunology, selected for a News and Views article in the same issue, portray how a protein molecule known as interleukin-17 (IL-17) spurs inflammation by recruiting specific white blood cells to sites of infection and injury, producing a strong, pathogenic response.

Being able to block this pathway may treat IL-17-induced inflammatory diseases. Molecular factors discovered by Li and Hamilton make this concept a potential strategy.
"We are excited by the possibilities that this new research opens up for developing improved therapeutics for these difficult diseases," Hamilton said.
"Being able to collaborate like this really expedites the science," Li added, "ultimately leading, we hope, to profound improvement for those suffering from these autoimmune and inflammatory conditions."
###
About Cleveland Clinic
Celebrating its 90th anniversary, Cleveland Clinic is a nonprofit multispecialty academic medical center that integrates clinical and hospital care with research and education. It was founded in 1921 by four renowned physicians with a vision of providing outstanding patient care based upon the principles of cooperation, compassion and innovation. Cleveland Clinic has pioneered many medical breakthroughs, including coronary artery bypass surgery and the first face transplant in the United States. U.S.News & World Report consistently names Cleveland Clinic as one of the nation's best hospitals in its annual "America's Best Hospitals" survey. About 2,800 full-time salaried physicians and researchers and 11,000 nurses represent 120 medical specialties and subspecialties. Cleveland Clinic Health System includes a main campus near downtown Cleveland, eight community hospitals and 16 Family Health Centers in Northeast Ohio, Cleveland Clinic Florida, the Lou Ruvo Center for Brain Health in Las Vegas, Cleveland Clinic Canada, and opening in 2013, Cleveland Clinic Abu Dhabi. In 2010, there were 4 million visits throughout the Cleveland Clinic health system and 155,000 hospital admissions. Patients came for treatment from every state and from more than 100 countries. Visit us at http://www.clevelandclinic.org/.
Follow us at www.twitter.com/ClevelandClinic.

Stem Cells

Stem Cell Breakthrough Means Human Cloning Possible
By Clint Demeritt October 8, 2011 10:25 AM EDT
Stem cells are young cells that have yet to be developed into a specific cell type and are used by the body to renew tissue and repair damage. In adult stem cells, there are only so many types the cell can develop into. Embryonic stem cells are those present in a developing person when they are still in its mother's womb. Embryonic stem cells have the ability to become any cell in the body, which have a much better applications for medical use........

Stem cell research has a number of applications in the medical field. Stem cells can help with heart diseases, diabetes and cancer. It can also help cure aliments like Parkinson's Disease and Alzheimer's. The cloning techniques can also be used to grow organs for patients with a failing liver or kidney. The cloned organs will be much less likely to be rejected than those donated from other individuals, since the new organs will be genetically identical to the one being replaced.

Pharmaceuticals

Developers should fess up about drug trial failures, researchers say
October 7, 2011 — 11:38am ET
By Ryan McBride
Naturally, drug researchers like to tout their victories and downplay their failures. But there are ramifications of not reporting results of experiments that go poorly, and two academics recently took on the issue in an a Science Translational Medicine article that says "translational medicine cannot approach its full potential if negative drug developments are unpublished," as Pharmalot's Ed Silverman cited in his interview with one of the authors. Michael Rogawski, chair of the department of neurology at UC Davis School of Medicine, talks to Silverman about his efforts to get developers to publish data they might rather keep under wraps. Interview

There’s no tiring of controversy in the XMRV–chronic fatigue syndrome link
It’s been a hectic couple of weeks for Judy Mikovits. First, her controversial research on the viral cause of chronic fatigue syndrome was condemned by the journal that published it. Then, her alternative hypothesis — that a new gammaretrovirus closely related to the originally proposed culprit, xenotropic murine leukemia virus-related virus (XMRV), is responsible for chronic fatigue — was received with misgivings by the scientific community at a major international conference. Add to the mix allegations of fabricated results and a blow-out with her boss, and Mikovits ended up being fired from her job at the Whittemore Peterson Institute (WPI) for Neuro-Immune Disease in Reno, Nevada.

The research that spawned the drama was originally published in Science in October 2009, and purported to show a link between the infectious retrovirus XMRV and chronic fatigue syndrome in two-thirds of CFS patients examined. The study, conducted by Mikovits and her collaborators, was the first sign of an infectious cause for the disease. However, follow-up studies since 2009 showed that other labs could not reproduce these results and scientists began to suspect that Mikovits’ original patient samples had been contaminated.

On 22 September, a large study published by Science showed that, of nine national laboratories, none could find XMRV in their patients’ blood — including Mikovits’ own lab. Notably, Science issued a partial retraction of the original 2009 paper on the same day, stating that one of Mikovits’ collaborators had found XMRV contamination in the patient blood samples. The saga was documented in a long feature by Science, ending with Mikovits pledging to continue studying the CFS and its viral links.

U.S. Attorneys in California Set Crackdown on Marijuana
By JENNIFER MEDINA
Prosecutors said they would concentrate on large, for-profit operations that use the medical law as a cover for large-scale drug operations, with marijuana being sent across state lines...