Negative HPV screening test predicts low cervical cancer risk better than negative Pap test .


Based on a study that included more than 1 million women, investigators at the National Institutes of Health have determined that a negative test for human papillomavirus (HPV) infection compared to a negative Pap test provides greater safety, or assurance, against future risk of cervical cancer. That is, women who test negative on the HPV test have an extremely low risk of developing cervical cancer. This finding, by researchers at the National Cancer Institute (NCI), part of the NIH, and their colleagues, appeared online July 18, 2014, in the Journal of the National Cancer Institute.

HPV tests detect the DNA (or RNA) of the human papillomavirus types that cause nearly all cervical cancers. The Pap test detects abnormal cell changes associated with the development of cervical cancer. Both types of test are performed on a sample of cells collected from the cervix.

Once HPV is inside the cervix, it attacks cervical epithelial cells but if HPV infection persists, it can lead to abnormal cell changes and precursors of cervical cancer.

Since 2003, women between the ages of 30 and 64 enrolled in Kaiser Permanente Northern California’s health care system have had cervical cancer screening with concurrent HPV and Pap testing (called cotesting). This group of women is the largest known in the United States with the longest history of HPV testing in routine clinical practice. In 2011, NCI researchers and their colleagues published findings on screening outcomes for about 300,000 of the women in this group. Those data were used to inform current U.S. cervical screening and management guidelines, including those of the U.S. Preventive Services Task Force (USPSTF), which recommend Pap testing every three years (between the ages 21 to 65) or cotesting every five years (between the ages 30 to 65) for women with normal screening results.

In the new study, the researchers extended their 2011 analysis to more than 1 million women who were screened through December 31, 2012. They estimated cervical cancer risks among women who tested HPV-negative alone, Pap-negative alone, and cotest-negative. They compared risk estimates based on USPSTF Exit Disclaimer guidelines of pap testing every three years and cotesting every five years.

The researchers found that the risk of developing cervical cancer within three years following a negative HPV test result was about half of the already low risk following a negative Pap test. Cervical cancer risk within three years of a negative HPV test was similar to the risk of developing cancer within five years following a negative cotest. The researchers estimated that the following number of women would go on to develop cervical cancer after a negative test:

  • Pap-negative: 20 per 100,000 women over three years
  • HPV-negative: 11 per 100,000 women over three years
  • Cotest-negative: 14 per 100,000 women over five years

“Our results demonstrate the superior predictive value of a negative HPV test, compared with a negative Pap test. Our findings provide evidence to support the currently recommended cotesting guidelines, as well as the possibility of primary HPV testing as another alternative for cervical screening,” commented Julia Gage, Ph.D., first author of the study report and a research fellow in the Clinical Genetics Branch, Division of Cancer Epidemiology and Genetics, NCI.

Zinc deficiency worsens sepsis, causes ‘catastrophic malfunctioning’ of immune system, increases inflammation .


Zinc appears to play a key role in modulating the body’s response to severe infection, and deficiency may increase susceptibility to a lethal immune reaction, according to a study conducted by researchers from Ohio State University and published in the journal PLOS ONE.

zinc

“When the body detects an infection, zinc is recruited to help produce immune response proteins, and then it’s used to stop their production,” lead author Daren Knoell, PharmD, PhD, said. “But zinc deficiency during sepsis appears to cause a catastrophic malfunctioning of the system, resulting in a magnified and prolonged inflammatory response.”

The study was funded by the National Heart, Lung, and Blood Institute and received biostatistics support from the Ohio State Center for Clinical and Translational Science.

Zinc prevents immune over-reaction

Sepsis is a body-wide inflammatory reaction in response to a severe infection and is one of the main causes of death in intensive care units in the United States. One-fifth of all cases result in death, because the overload of inflammatory chemicals produced by the immune system eventually causes organ failure.

Prior research by the same team found that, when zinc-deficient mice developed sepsis, they were three times more likely to die than non-deficient mice with the same condition. They also found that, when zinc-deficient mice received zinc supplements, their sepsis survival rate improved.

In another study, the researchers discovered that zinc helps regulate the activity of an immune protein called IKK-beta, part of the NF-kappaB immune-regulating pathway. In the presence of more zinc, the pathway successfully lowers levels of inflammation and cell damage.

The new study expands upon this work.

“This research builds upon our past findings and further demonstrates that our immune system requires zinc to achieve a balanced and effective defense against overwhelming infection,” Knoell said. “This new evidence provides further incentive to determine the extent to which zinc may be useful to prevent or treat sepsis, particularly in patients that may be zinc deficient.”

Can zinc prevent Alzheimer’s, heart disease?

In the new study, the researchers performed a genome-wide microarray analysis on DNA taken from the lung tissue of zinc-deficient mice with sepsis. They had to examine the entire genome because zinc plays so many roles in the body — interacting with as many as 10,000 separate proteins — and its specific effects can therefore be hard to pinpoint through larger-scale observation.

The researchers found that, when mice were suffering from sepsis, zinc deficiency caused changes in several different pathways, particularly the JAK-STAT3 pathway, which regulates the production of the inflammatory protein serum amyloid A (SAA). These changes prevented the body from being able to deactivate its inflammatory response, eventually leading to the destruction of healthy cells.

“Without zinc present in sufficient quantities, the JAK-STAT pathway keeps giving the genes the ‘on’ signal, and continues production of this inflammatory protein,” Knoell said. “When we add zinc back into the equation, it stops JAK-STAT, SAA production and the acute response activity.”

Knoell noted that SAA has also been linked with other inflammatory diseases, including cardiovascular and Alzheimer’s disease.

“These findings not only provide some evidence for why zinc-based cold remedies may work, but also provide hints of how a zinc imbalance might also play a role in chronic diseases connected with inflammation,” he said.

Unfortunately, doctors cannot prevent sepsis simply by supplementing deficient patients after they become sick. Instead, it is important that people get enough zinc in their diet and avoid deficiency in the first place.

“During illness, the body diverts zinc from the blood to the organs, so a deficiency is hard to detect, particularly in people who are already sick,” Knoell said. “Without a way to better define the deficiency, we aren’t able to define the ideal patient or a therapeutic dose of zinc.”

Sources for this article include: 

http://www.newswise.com

http://www.plosone.org

http://science.naturalnews.com

New Expensive Treatments for Hepatitis C Infection.


Treatment of infection with hepatitis C virus (HCV) has changed substantially in the last 3 years, with new therapies now reaching cure rates (defined by sustained virologic response) higher than 95%. As little as 3 years ago, treatment involved an arduous course of pegylated interferon and ribavirin, which caused serious adverse effects in more than 80% of patients; less than 50% of patients could finish the treatment course. Because HCV infection can be indolent, with slowly developing liver injury in the form of scarring and fibrosis, many patients were so-called warehoused by their physicians, followed up closely while waiting for more promising treatments.1

In 2011, introduction of the first generation of protease inhibitors, particularly telaprevir and boceprevir, heralded change. When combined with interferon and ribavirin, these medications produced much higher sustained viral responses in the HCV genotype 1 subclasses.1 However, these agents were much more expensive than standard therapy, at a cost of more than $80 000 per course of therapy, and were associated with high levels of viral resistance development if patients did not strictly adhere to therapy.
In 2014, the introduction of polymerase inhibitors set a new standard. The first in this class, sofosbuvir, manufactured by Gilead, has shown significant effectiveness when combined with ribavirin and interferon in patients with genotype 1 HCV. Sofosbuvir also can be combined with another new protease inhibitor, simeprevir, to treat patients in whom interferon-based therapy has failed. These regimens provide interferon-free treatment protocols that are shorter and well tolerated and have 80% to 95% cure rates.1 This fall, an oral combination of sofosbuvir and ledipasvir will be introduced that inhibits both the NS5B polymerase and NS5A polymerase and has been shown to reduce treatment to an 8-week course with cure rates of more than 95%.2 Now, a chronic disease that affects millions of Americans can be cured by well-tolerated oral medications.

Perhaps surprisingly, most media coverage of this important development in HCV treatment has not focused on the cure rates but, rather, on cost. The price of sofosbuvir is essentially $1000 per pill, or $84 000 for a standard 12-week course. The fact that pricing in the United Kingdom for a similar regimen is $54 000, and perhaps as low as $900 in Egypt and other developing countries,3indicates that the pricing in the United States is a purely financial decision by Gilead and has outraged many. Indeed, some pharmacy benefit managers are calling on their clients to boycott these products until alternatives are available late in 2014.4

But is the pricing unfair? This question can be considered from at least 2 perspectives—“return on investment” and “value driven.” In a market-driven health care system such as that in the United States, the manufacturer, Gilead, should be able to recoup its costs of development (ie, return on investment). With sofosbuvir, this is fairly straightforward. The medication was identified and initially tested by a different firm, Pharmasset, which Gilead bought in 2012 for $11 billion.5Although there were additional drug development costs, assume that sofosbuvir cost $11 billion to develop. If all of the approximately 3 million HCV carriers in the United States were treated with sofosbuvir at current prices, Gilead would net more than $250 billion dollars, or better than a 20-to-1 return on its investment, suggesting that pricing is inappropriately high. However, not all HCV-infected persons will be treated with sofosbuvir. A half dozen major competing medications are in development and expected to come to market in the next 4 years; as this occurs, price competition will likely drive down costs and the return for Gilead.
A value-driven approach to pricing focuses on how treatment with sofosbuvir compares with other treatments for HCV infection. For instance, according to the average wholesale price from Medi-Span, the cost of a 12-week course of sofosbuvir plus pegylated interferon and ribavirin is $116 910.72.6 This price is expensive, but the cost of a 24-week course of the first-generation protease inhibitor telaprevir plus pegylated interferon and ribavirin is $111 606.48, and the 48-week course that many patients need is $143 827.92.6

Average wholesale price is only part of the equation. Value also has to consider the efficacy of treatment and requires more sophisticated cost-effectiveness analyses, such as the incremental cost-effectiveness ratio, representing the added cost of an additional quality-adjusted life-year. The evidence documenting the effectiveness and tolerability of the newer sofosbuvir regimens, and the expected reductions in downstream costs associated with averted progression of disease, suggest that these newer expensive medications may represent a relatively good “deal” by typical cost-effectiveness thresholds. Indeed, the cost per additional quality-adjusted life-year may be quite comparable with other therapies.

Perhaps the controversy about sofosbuvir is really about the increasing total cost of specialty medications, considering both cost and prevalence of treatment targets. While a daily oral medication that costs $1000 per pill gains attention, the more important issue is the number of people eligible for treatment. With broader screening, the pool of eligible patients may be as high as 3 million in the United States alone.7 The simple math is that treatment of patients with HCV could add $200 to $300 per year to every insured American’s health insurance premium for each of the next 5 years. Thus sofosbuvir is not really a per-unit cost outlier but is a “total cost” outlier because of its high cost and very large population eligible for treatment—a beacon for costs of specialty medications generally.

These costs will be especially burdensome over the next year. Presently, Gilead has a monopoly, and its investors expect it to make a profit during this period. However, it is anticipated that by December, another highly effective oral regimen will become available.8 Pharmaceutical manufacturers know that monopolies are evanescent. With HCV treatment, that lesson is very recent: the manufacturers of telaprevir and boceprevir priced their products high and were profitable for 15 to 18 months, but now their products are essentially replaced by the new polymerase inhibitors.

Given this context, how should costs be managed? In some state Medicaid programs, the new medications have not been added to the formulary, despite the new practice guidelines. Physicians for whom the drug is denied by the state are going to Gilead, and, by report, the company is quietly subsidizing the costs—there is an official assistance program offered by Gilead.9 In states where managed care plans provide the Medicaid benefit, many are not adding sofosbuvir to their formulary until they convince the state to renegotiate or consider “carving out the drug”—ie, having the state pay directly for the therapy outside the capitated payment agreement.

Some private insurers have added sofosbuvir to the formulary and are absorbing the costs but also are taking steps to ensure appropriate utilization by developing prior authorization programs based on practice guidelines. Some insurers are asking physicians to treat only patients who absolutely need therapy now. Delaying treatment for some patients promises lower future costs, as competition generated by new drugs will likely cause prices to decrease as pharmacy benefit managers negotiate for best prices on behalf of health insurers and employers. This approach has been countenanced recently by expert panels.10

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The ultimate approach to cost will be lower prices, which will occur as more products create competition. However, it will likely entail narrower formularies, in which the physician choice of a particular medication is limited by the deals negotiated by insurers and pharmacy benefit managers. Even then, the costs could still be very high—restrictive formularies have led to discounts of 30% to 40% for branded medications, not the greater than 95% discounts that occur when drug patents expire and generic competitors enter.

In summary, the health care system is adjusting quickly, but perhaps not quickly enough, to compensate for the high prices of HCV medications and, more importantly, the high cost of treating all HCV-infected individuals. However, this is not an isolated phenomenon; other expensive specialty medications are in development, many with large potential pools of targeted patients. Effective approaches to control costs for high-priced medications need to be developed and evaluated to ensure broad, equitable, and appropriate use of these new interventions in an already stressed health care system.

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ARTICLE INFORMATION

Corresponding Author: Troyen Brennan, MD, MPH, CVS Caremark, One CVS Dr, Woonsocket, RI 08095 (troyen.brennan@cvscaremark.com).

Published Online: July 20, 2014. doi:10.1001/jama.2014.8897.

Conflict of Interest Disclosures: Drs Brennan and Shrank are employees of CVS Caremark, a retail pharmacy and pharmacy benefits management company that purchases and sells hepatitis C treatments.

REFERENCES

1
Ghany  MG, Liang  TJ.  Current and future therapies for hepatitis C virus infection. N Engl J Med. 2013;369(7):679-680.
PubMed   |  Link to Article
2
Kowdley  KV, Gordon  SC, Reddy  KR,  et al; ION-3 Investigators.  Ledipasvir and sofosbuvir for 8 or 12 weeks for chronic HCV without cirrhosis. N Engl J Med. 2014;370(20):1879-1888.
PubMed   |  Link to Article
3
TWN Info Service on Intellectual Property IssuesHealth: no sofosbuvir patent in Egypt, but Gilead deal still expensive. April 10, 2014.http://www.twnside.org.sg/title2/intellectual_property/info.service/2014/ip140408.htm. Accessed July 8, 2014.
4
Staton  T. Express Scripts assembling anti-Sovaldi coalition to shut out Gilead hep C drug. April 8, 2014http://www.fiercepharma.com/story/express-scripts-assembling-anti-sovaldi-coalition-shut-out-gilead-hep-c-dru/2014-04-08. Accessed July 3, 2014.
5
Gounder  C. A better treatment for hepatitis C.New Yorker. December 9, 2013.http://www.newyorker.com/online/blogs/elements/2013/12/a-new-treatment-for-hepatitis-c.html. Accessed July 8, 2014.
6
Medi-Span data monitor.Medi-Span Master Drug Data Base v2.5 (MDDB). Indianapolis, IN: Clinical Drug Information LLC; May 20, 2014.
7
Denniston  MM, Jiles  RB, Drobeniuc  J,  et al.  Chronic hepatitis C virus infection in the United States, National Health and Nutrition Examination Survey 2003 to 2010. Ann Intern Med. 2014;160(5):293-300.
PubMed   |  Link to Article
8
Feld  JJ, Kowdley  KV, Coakley  E,  et al.  Treatment of HCV with ABT-450/r–ombitasvir and dasabuvir with ribavirin. N Engl J Med. 2014;370(17):1594-1603.
PubMed   |  Link to Article
9
Gilead. Support path for Sovaldi.http://gilead.com/responsibility/us-patient-access/support%20path%20for%20sovaldi. Accessed July 3, 2014.
10
California Technology Assessment Forum. The Comparative Clinical Effectiveness and the Value of Simeprevir and Sofosbuvir in the Treatment of Chronic Hepatitis C Infection: Final Report. San Francisco: California Technology Assessment Forum; April 15, 2014.

Single-Pill Regimens for HIV-1 Infection.


In the latest Clinical Therapeutics review, a 52-year-old man with a history of HIV-1 infection and poor medication adherence presents for evaluation. A single-pill regimen is considered. For some patients with HIV-1 infection, combination regimens consisting of one pill to be taken daily can improve adherence.

With the advent and refinement of combination ART [antiretroviral therapy], the life expectancy of HIV-infected patients has risen dramatically. In addition to benefiting infected persons, ART almost completely blocks HIV-1 transmission to uninfected sexual partners. If we were able to treat most or all HIV-infected patients and thereby prevent new infections, “the beginning of the end of AIDS” would be in sight.

Clinical Pearls

• What are the currently available single-pill combinations marketed for HIV-1 treatment?

There are currently three single-pill combinations marketed for HIV-1 treatment, each containing the same combination of one nucleotide reverse-transcriptase inhibitor and one nucleoside reverse-transcriptase inhibitor (NRTIs): tenofovir disoproxil fumarate (TDF) at a dose of 300 mg and emtricitabine (FTC) at a dose of 200 mg, respectively. The first agent (Atripla, Bristol-Myers Squibb and Gilead Sciences), released in 2006, is a single pill that combines TDF-FTC with 600 mg of the nonnucleoside reverse-transcriptase inhibitor (NNRTI) efavirenz (EFV). The second agent (Complera, Gilead Sciences), approved in 2011, combines TDF-FTC with 25 mg of the NNRTI rilpivirine (RPV). The third agent (Stribild, Gilead Sciences), released in 2012, consists of TDF-FTC combined with 150 mg of the integrase strand-transfer inhibitor (INSTI) elvitegravir (EVG) and 150 mg of the pharmacoenhancer cobicistat (which boosts serum EVG levels). A fourth single-pill combination has not yet been approved for clinical use. This agent would combine two NRTIs — abacavir (ABC) at a dose of 600 mg and lamivudine (3TC) at a dose of 300 mg — with 50 mg of the recently approved INSTI dolutegravir DTG).

• In which patient populations should single-pill combinations be generally avoided?

Single-pill combinations should be avoided in patients with clinically significant renal disease because TDF, TC, and FTC all require dose reductions or elimination when the estimated creatine clearance is less than 50 ml per minute. The inability to adjust the dose of individual drug components in patients with renal insufficiency is an important limitation of single-pill combinations. In addition, patients who have drug-resistant HIV-1 infection often require agents that are not included in single-pill combinations.

Morning Report Questions

Q: When should a regimen containing a protease inhibitor be used?

A: None of the current single-pill combinations contain protease inhibitors, which should be used in patients with known viral resistance to NNRTIs or INSTIs. In addition, because transmitted resistance to protease inhibitors is uncommon and resistance to this class emerges relatively slowly, protease inhibitors are often favored when treatment decisions are required before resistance-testing results are available — for example, in the case of patients with acute HIV-1 infection or opportunistic infections. Protease inhibitors are also sometimes considered in patients with inconsistent adherence because multiple viral mutations are required to compromise the activity of these agents.

Q: How do currently available anchor medications for once daily regimens compare?

A: EFV, the anchor drug in EFV-TDF-FTC, is potent and, in recent years, the drug to which every newly developed anchor antiretroviral agent has been compared. EFV may cause neuropsychiatric effects (e.g., vivid dreams, insomnia, somnolence, and depression) or rash, although symptoms typically diminish over time. EFV is the preferred NNRTI during pregnancy, when initiated 8 weeks after conception. Rilpivirine (RPV)-based regimens are not recommended for patients whose pretherapy HIV-1 RNA level is more than 100,000 copies per milliliter or whose CD4+ T-cell count is 200 per cubic millimeter or less. RPV must be taken with a solid meal (greater than or equal to 390 kcal) and requires stomach acid for adequate absorption, precluding the concomitant use of proton-pump inhibitors. In addition to its use in initial therapy, RPV-TDF-FTC may have a role in patients with virologic suppression during treatment with a protease inhibitor-containing regimen who have a reason to change medications: in a recent trial, switching such patients to RPV-TDF-FTC maintained high rates of virologic suppression and improved lipid levels. Cobicistat-boosted EVG does not have neuropsychiatric effects and does not commonly cause rash. However, cobicistat inhibits tubular secretion of creatinine without reducing the creatine clearance. As a result, patients may have a mild increase in the serum creatinine level, typically less than 0.4 mg per deciliter (35 micromoles per liter), with this medication initially.

 

Beta-Blockers: No Broad Benefit in Stable Heart Disease?


Beta-blockers might reduce the risk of death or a repeat event in the first years after a heart attack but not in other newly-diagnosed heart disease, an observational study suggested.

The risk of mortality or myocardial infarction (MI) came in 9% lower and the risk of death 10% lower over 3.7 years of follow-up among beta-blocker users versus nonusers after controlling for other factors, Mark A. Hlatky, MD, of California’s Stanford University, and colleagues found.

But those associations were only significant in secondary prevention after a recent MI, with adjusted hazard ratios of 0.85 for mortality (95% confidence limit 0.79-0.92) and 0.87 for death or MI (95% CL 0.82-0.93), the researchers reported in the July 22 issue of the Journal of the American College of Cardiology.

For other new-onset acute coronary syndrome patients the adjusted hazard ratio of death with beta-blocker use was 1.02 (95% CL 0.91-1.15), and for mortality or MI it was 1.03 (95% CL 0.93-1.13), suggesting no hint of benefit.

“Despite a general belief that beta-blockers may reduce cardiac events in these lower-risk patients, this indication for use of beta-blockers only has a Class IIB recommendation, on the basis of ‘Level C’ evidence — expert opinion only,” the researchers pointed out.

These drugs became a cornerstone of medical management of angina due to symptom relief and extrapolation of advantages in hard outcomes seen in trials after recent MI, heart failure, and reduced left ventricular function, without high-quality randomized trials in other stable heart disease, they noted.

That relatively weak foundation was challenged by observational findings from the REACH registry in 2012, showing no significant association between beta-blockers and cardiac events among patients with stable coronary heart disease.

The researchers suggested randomized trials to settle the net clinical benefit of beta-blockers in coronary disease without recent MI.

However, that’s unlikely to happen in the real world, because an extremely large and expensive trial would be required, countered Philippe Gabriel Steg, MD, of Hôpital Bichat in Paris, and Ranil De Silva, PhD, of Imperial College London.

They criticized Hlatky’s study in an accompanying editorial, pointing to inability to fully adjust for confounding and uneven inclusion and event adjudication, as well as lack of data on “key clinical parameters, such as the presence and severity of anginal symptoms, ischemic burden, left ventricular function, and importantly, the type and dose of beta-blocker therapy.”

Also, about 80% of the study’s population of 26,793 consecutive integrated healthcare delivery system patients not on a beta-blocker in the prior year had been discharged after a first acute coronary syndrome.

The remaining 20% had been discharged after elective coronary revascularization.

That design excluded patients with incident, stable coronary artery disease managed medically without revascularization, the editorialists pointed out.

“Therefore, the results may be in part attributable to insufficient power to detect a benefit of beta-blockade in stable coronary artery disease patients without previous MI, and of uncertain relevance to the broader population of stable coronary artery disease patients not captured in the current analysis,” Steg and De Silva cautioned.

Importantly, none of the available observational research has suggested harm from beta-blocker use in stable heart disease patients, they noted.

While the study affirms that the drugs are not mandated for all stable coronary artery disease patients, Steg and De Silva recommended a tailored treatment approach for symptomatic angina relief.

Finding the “most parsimonious” regimen that leaves patients symptom-free with minimal side effects “is particularly important, to ensure treatment compliance as well as optimize quality-of-life and clinical outcomes, especially in an era of constrained healthcare resources,” they wrote.

weighty-issue-stress-and-high-fat-meals-combine-to-slow-metabolism-in-women


A new study in women suggests that experiencing one or more stressful events the day before eating a single high-fat meal can slow the body’s metabolism, potentially contributing to weight gain.

Researchers questioned study participants about the previous day’s stressors before giving them a meal consisting of 930 calories and 60 grams of fat. The scientists then measured their metabolic rate – how long it took the women to burn calories and fat – and took measures of blood sugar, triglycerides, insulin and the stress hormone cortisol.

On average, the women in the study who reported one or more stressors during the previous 24 hours burned 104 fewer calories than nonstressed women in the seven hours after eating the high-fat meal – a difference that could result in weight gain of almost 11 pounds in one year.

The stressed women also had higher levels of insulin, which contributes to the storage of fat, and less fat oxidation – the conversion of large fat molecules into smaller molecules that can be used as fuel. Fat that is not burned is stored.

“This means that, over time, stressors could lead to weight gain,” said Jan Kiecolt-Glaser, professor of psychiatry and psychology at The Ohio State University and lead author of the study. “We know from other data that we’re more likely to eat the wrong foods when we’re stressed, and our data say that when we eat the wrong foods, weight gain becomes more likely because we are burning fewer calories.”

Previous research also has shown that people who experience stress and other mood disruptions are at higher risk of becoming overweight or obese. This study, the researchers say, appears to illustrate at least one mechanism behind that connection.

The research is published in the journal Biological Psychiatry.

The study was conducted in 58 women, average age 53, and included two admissions to Ohio State’s Clinical Research Center for daylong analyses. To regulate their food intake for 24 hours before eating the high-fat meal, researchers supplied the participants with three standardized meals on the previous day and instructed them to fast for 12 hours before reporting for their study visit.

On the day of admission, the participants completed several questionnaires to assess their depressive symptoms and physical activity and were interviewed about stressful events on the prior day. Thirty-one women reported at least one prior day stressor on one visit and 21 reported stressors at both visits. Six women reported no stressors.

Most of the reported stressors were interpersonal in nature: arguments with co-workers or spouses, disagreements with friends, trouble with children or work-related pressures.

The research meal consisted of eggs, turkey sausage, biscuits and gravy – roughly equivalent in calories and fat to a loaded two-patty hamburger and French fries at a fast-food restaurant. Participants were required to eat the entire meal within 20 minutes.

“This is not an extraordinary meal compared to what many of us would grab when we’re in a hurry and out getting some food,” said Kiecolt-Glaser, also director of the Institute for Behavioral Medicine at Ohio State.

The control for comparison in this randomized trial was that one meal contained saturated fat and another was high in a different kind of fat: sunflower oil containing monounsaturated fat, which is associated with a variety of health benefits.

“We suspected that the saturated fat would have a worse impact on metabolism in women, but in our findings, both high-fat meals consistently showed the same results in terms of how stressors could affect their energy expenditure,” said Martha Belury, professor of human nutrition at Ohio State and a co-author of the study.

Before the meal, participants rested for 30 minutes and their energy expenditure – or calories burned by converting food to energy – was tested during that time. After they ate their meal, their metabolic rate was tested for 20 minutes of every hour for the next seven hours. Researchers obtained this data by using equipment that measured inhaled and exhaled airflow of oxygen and carbon dioxide.

“By measuring the gas exchange, we can determine their metabolic rate: how much energy their body needs during the time being measured,” Belury said. “The participants burned fewer calories over the seven hours after the meal when they had a stressor in their life the day before the meal.”

Researchers also took multiple blood samples “so we could follow throughout the day what was happening metabolically after eating the high-fat meal,” Kiecolt-Glaser said.

The stressors’ effects of increasing insulin had a time element: Insulin spiked soon after the high-fat meal was consumed and then decreased to roughly match insulin levels in nonstressed women after another 90 minutes.

A history of depression alone did not affect metabolic rate, but depression combined with previous stressors led to a steeper immediate rise in triglycerides after the meal. Triglycerides are a form of fat in the blood, and high levels are considered a risk for cardiovascular disease.

“With depression, we found there was an additional layer. In women who had stress the day before and a history of depression, triglycerides after the meal peaked the highest,” Kiecolt-Glaser said. “The double whammy of past depression as well as daily stressors was a really bad combination.”

The researchers are reluctant to extend these findings to men because men tend to have more muscle than women, which would affect their metabolic rate, Belury said.

But the findings do offer one more motivation to keep healthful foods nearby.

“We know we can’t always avoid stressors in our life, but one thing we can do to prepare for that is to have healthy food choices in our refrigerators and cabinets so that when those stressors come up, we can reach for something healthy rather than going to a very convenient but high-fat choice,” Belury said.

MUTATION STOPS WORMS FROM GETTING DRUNK.


Neuroscientists at The University of Texas at Austin have generated mutant worms that do not get intoxicated by alcohol, a result that could lead to new drugs to treat the symptoms of people going through alcohol withdrawal.

The scientists accomplished this feat by inserting a modified human alcohol target into the worms, as reported this week in The Journal of Neuroscience.

“This is the first example of altering a human alcohol target to prevent intoxication in an animal,” says corresponding author, Jon Pierce-Shimomura, assistant professor in the university’s College of Natural Sciences and Waggoner Center for Alcohol and Addiction Research.

An alcohol target is any neuronal molecule that binds alcohol, of which there are many.

One important aspect of this modified alcohol target, a neuronal channel called the BK channel, is that the mutation only affects its response to alcohol. The BK channel typically regulates many important functions including activity of neurons, blood vessels, the respiratory tract and bladder. The alcohol-insensitive mutation does not disrupt these functions at all.

“We got pretty lucky and found a way to make the channel insensitive to alcohol without affecting its normal function,” says Pierce-Shimomura.

The scientists believe the research has potential application for treating people addicted to alcohol.

“Our findings provide exciting evidence that future pharmaceuticals might aim at this portion of the alcohol target to prevent problems in alcohol abuse disorders,” says Pierce-Shimomura. “However, it remains to be seen which aspects of these disorders would benefit.”

 

Unlike drugs such as cocaine, which have a specific target in the nervous system, the effects of alcohol on the body are complex and have many targets across the brain. The various other aspects of alcohol addiction, such as tolerance, craving and the symptoms of withdrawal, may be influenced by different alcohol targets.

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The worms used in the study, Caenorhabditis elegans, model intoxication well. Alcohol causes the worms to slow their crawling with less wriggling from side to side. The intoxicated worms also stop laying eggs, which build up in their bodies and can be easily counted.

Unfortunately, C. elegans are not as ideal for studying the other areas of alcohol addiction, but mice make an excellent model. The modified human BK channel used in the study, which is based on a mutation discovered by lead author and graduate student Scott Davis, could be inserted into mice. These modified mice would allow scientists to investigate whether this particular alcohol target also affects tolerance, craving and other symptoms relevant to humans.

Pierce-Shimomura speculated that their research could even be used to develop a ‘James Bond’ drug someday, which would enable a spy to drink his opponent under the table, without getting drunk himself. Such a drug could potentially be used to treat alcoholics, since it would counteract the intoxicating and potentially addicting effects of the alcohol.

 

 

SMOKING MAY CONTRIBUTE TO SUICIDE RISK.


Cigarette smokers are more likely to commit suicide than people who don’t smoke, studies have shown. This reality has been attributed to the fact that people with psychiatric disorders, who have higher suicide rates, also tend to smoke. But new research at Washington University School of Medicine in St. Louis finds that smoking itself may increase suicide risk and that policies to limit smoking reduce suicide rates.

In a study published online July 16 in the journal Nicotine & Tobacco Research, a team led by Richard A. Grucza, PhD, reports that suicide rates declined up to 15 percent, relative to the national average, in states that implemented higher taxes on cigarettes and stricter policies to limit smoking in public places.

“Our analysis showed that each dollar increase in cigarette taxes was associated with a 10 percent decrease in suicide risk,” said Grucza, associate professor of psychiatry. “Indoor smoking bans also were associated with risk reductions.”

Grucza’s team analyzed data compiled as individual states took different approaches to taxing cigarettes and limiting when and where people could smoke. From 1990 to 2004, states that adopted aggressive tobacco-control policies saw their suicide rates decrease, compared with the national average.

The opposite was true in states with lower cigarette taxes and more lax policies toward smoking in public. In those states, suicide rates increased up to 6 percent, relative to the national average, during the same time period. From 1990 to 2004, the average annual suicide rate was about 14 deaths for every 100,000 people.

“States started raising their cigarette taxes, first as a way to raise revenue but then also as a way to improve public health,” Grucza explained. “Higher taxes and more restrictive smoking policies are well-known ways of getting people to smoke less. So it set a natural experiment, which shows that the states with more aggressive policies also had lower rates of smoking. The next thing we wanted to learn was whether those states experienced any changes in suicide rates, relative to the states that didn’t implement these policies as aggressively.”

Suicide is the 10th leading cause of death in the United States, according to the Centers for Disease Control and Prevention. In 2010, nearly 40,000 people died of suicide across the nation.

Every death that occurs in the United States is recorded in a database managed by the National Center for Health Statistics. Grucza’s team classified each suicide death based on the state where the victim had lived, as well as how aggressive that state’s tobacco policies were.

Using statistical methods, the researchers compared rates of suicide in states with stricter tobacco policies to rates in states with more lenient laws and lower taxes. They also determined whether people who had committed suicide were likely to have smoked. They learned that suicide risk among people most likely to smoke was associated with policies related to tobacco taxes and smoking restrictions.

“If you’re not a smoker, or not likely ever to become a smoker, then your suicide risk shouldn’t be influenced by tobacco policies,” Grucza said. “So the fact that we saw this influence among people who likely were smokers provides additional support for our idea that smoking itself is linked to suicide, rather than some other factor related to policy.”

Although scientists have known for years that people who smoke have a higher risk for suicide, they had assumed the risk was related to the psychiatric disorders that affect many smokers. These new findings, however, suggest smoking may increase the risk for psychiatric disorders, or make them more severe, which, in turn, can influence suicide risk.

“We really need to look more closely at the effects of smoking and nicotine, not only on physical health but on mental health, too,” Grucza said. “We don’t know exactly how smoking influences suicide risk. It could be that it affects depression or increases addiction to other substances. We don’t know how smoking exerts these effects, but the numbers show it clearly does something.”

He explained that many states still have low cigarette taxes, while other states haven’t adopted comprehensive smoke-free air policies. Grucza predicts that if these states raise their cigarette taxes and restrict smoking in public, their suicide rates likely would fall.

Grucza suspects nicotine may be an important influence on suicide risk. Based on the study’s results, he said he is concerned that many new restrictions on public smoking don’t cover newer e-cigarettes, which deliver nicotine but release vapor rather than smoke. This mechanism purportedly allows those addicted to nicotine to get a “fix” without affecting the air others breathe.

“Nicotine is a plausible candidate for explaining the link between smoking and suicide risk,” Grucza said. “Like any other addicting drug, people start using nicotine to feel good, but eventually they need it to feel normal. And as with other drugs, that chronic use can contribute to depression or anxiety, and that could help to explain the link to suicide.”

World Health Organisation recommends that all gay men should take antiretroviral medicine to halt HIV epidemic.


The World Health Organisation has announced for the first time that all men who have sex with men should take antiretroviral drugs, in a bid to try and contain the growing rates of HIV in gay communities around the world.

Studies show that antiretroviral drug use can reduce the chance of passing on HIV by up to 92 per cent

The report says that in addition to other forms of protection like condoms and regular testing, increased use of antiretroviral drugs in the gay community could have a significant impact in stopping the spread of HIV and could prevent a million new infections in the next ten years, according to the WHO.

In the report, it says that homosexual men are 19 times more likely to have HIV than the rest of the population, and it is believed that encouraging gay men to take the antiretroviral medicine could decrease this significantly.

According to the report, HIV rates in gay communities are still on the rise

According to the report, HIV rates in gay communities are still on the riseSome scientists predict that the antiretroviral drug use for all gay men could lower the spread of HIV by 20 to 25 per cent.

Speaking after the release of the report, Gottfried Hirnschall, who heads WHO’s HIV department, said that they were seeing an “exploding epidemic” when it came to HIV rates in the gay community around the world.

He said this was largely down to a more relaxed attitude to HIV, which were the result of new drugs that made it possible to live with the disease.

He said that antiretroviral drugs could help stop this growth and supported the WHO’s recommendations.

A number of studies looking into the impact antiretroviral drugs have on preventing the transmission of HIV have shown that those who regularly take the drug have a significantly smaller chance of contracting or passing on the virus.

The Pre-Exposure Prophylaxis as HIV Prevention Among Men who Have Sex with Men (Iprex) study published in 2010, the most in-depth study into this area,  found that the use of antiretroviral drugs could reduce the risk of infection in men who have sex with men by up to 92 per cent.

As well as looking at how to best prevent the spread of HIV in the gay community, the report also focussed on other high-risk groups including transgender women, sex workers and people that inject drugs.

According to the study, transgender women and those that inject drugs are 50 times more likely to catch HIV, while sex workers are 14 times more likely to get the disease when compared with the rest of the population.

The report recommended that national agencies that deal with preventing the spread of HIV should spend more time focusing on these groups as they account for just under half of all new HIV infections worldwide.

COPD: New BODE Index May Be Better Predictor of Mortality.


MedicalResearch.com Interview with:
Dr. Juan P de Torres
Pulmonary Department
Clínica Universidad de Navarra
Pamplona, Spain;

MedicalResearch: What are the main findings of the study?

Dr. Torres: The BODE Index (BMI, Obstruction, Dyspnea, Exercise ) predicts mortality better than the GOLD ABCD (The Global Obstructive Lung Disease) grading and adding the COTE (Copd cO-morbidity TEst ) comorbidity Index to the BODE Index is complementary and provides an excellent predictive capacity for all-cause mortality in COPD patients.

 

MedicalResearch: What should clinicians and patients take away from your report?

Dr. Torres: Multidimensional evaluation in COPD patients including comorbidities allows us to more precisely predict short and long-term all-cause mortality.

MedicalResearch: What recommendations do you have for future research as a result of this study?

Dr. Torres: Future research in other COPD cohorts should confirm our findings and give support to the use of the BODE and COTE indexes in daily clinical practice.

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