Shingles Vaccine Seems Safe for Patients with Immune-Related Diseases.


Patients vaccinated against herpes zoster while under treatment for immune-related diseases do not face increased hazards for herpes zoster, a JAMA study suggests. Current guidelines consider vaccination contraindicated in such patients while on immunosuppressive drugs.

The retrospective cohort study comprised over 450,000 Medicare patients with immune-related diagnoses such as rheumatoid arthritis and inflammatory bowel disease. Roughly 20,000 received the vaccine — over 600 of whom were on immunosuppressive treatment around the time of vaccination. The investigators found no increase in risk for herpes zoster among vaccinated patients, even those vaccinated during treatment.

Writing in Journal Watch Infectious Diseases, Dr. Richard Ellison comments that the results “suggest both a benefit from the vaccine and relatively low risk.”

Source: JAMA

Methadone Accounts for a Third of Opioid Overdose Deaths.


Methadone accounted for nearly a third of opioid-related deaths in 2010, according to an MMWR article.

The CDC’s study of 13 states found that methadone represented 4.5% to 18.5% of all opioid prescriptions, but 31.4% of opioid-related deaths. Methadone can cause life-threatening complications through cardiac arrhythmia, cardiorespiratory depression due to its long half-life and accumulating toxic levels, and interactions with other drugs, including antianxiety drugs.

The CDC reminds clinicians of the following:

  • Methadone shouldn’t be used for mild, acute, or breakthrough pain, or on an as-needed basis.
  • It shouldn’t be given to patients who are opioid-naive or those taking benzodiazepine antianxiety drugs.
  • Those who prescribe methadone should have substantial experience with it and adhere to guidelines for appropriate opioid prescribing.

Source: MMWR

FDA Approves First Rapid, At-Home HIV Test .


The FDA has approved the first rapid, over-the-counter test for HIV infection.

The OraQuick In-Home HIV Test is done entirely at home by oral swab, and consumers get results in 20 to 40 minutes. Clinical studies indicate that the test is 92% sensitive and 99.9% specific. That is, there is expected to be one false-negative for every 12 test results in infected individuals, and one false-positive for every 5000 results in uninfected individuals.

The manufacturer will have a customer support center available around the clock that can help guide individuals once results are obtained.

Source: FDA news

Enhanced pseudotyping efficiency of HIV-1 lentiviral vectors by a rabies/vesicular stomatitis virus chimeric envelope glycoprotein.


Rabies virus glycoprotein (RVG) can pseudotype lentiviral vectors, although at a lower efficiency to that of vesicular stomatitis virus glycoprotein (VSVG). Transduction with VSVG-pseudotyped vectors of rodent central nervous system (CNS) leads to local neurotropic gene transfer, whereas with RVG-pseudotyped vectors additional disperse transduction of neurons located at distal efferent sites occurs via axonal retrograde transport. Attempts to produce high-titre RVG-pseudotyped lentiviral vectors for preclinical and clinical trials has to date been problematic. We have constructed several chimeric RVG/VSVG glycoproteins and found that a construct bearing the external/transmembrane domain of RVG and the cytoplasmic domain of VSVG shows increased incorporation onto HIV-1 lentiviral particles and has increased infectivity in vitro in 293T cells and in differentiated neuronal cell lines of human, rat and murine origin. Stereotactic application of vector pseudotyped with this RVG/VSVG chimera in the rat striatum resulted in efficient gene transfer at the site of injection showing both neuronal and glial tropism. Distal neuronal transduction in the substantia nigra, thalamus and olfactory bulb via retrograde axonal transport also occurs after intrastriatal administration of chimera-pseudotyped vectors at similar levels to that observed with a RVG-pseudotyped vector. This is the first report of distal transduction in the olfactory bulb. The enhanced pseudotyping with this envelope should enable easier production of higher-titre pseudotyped lentiviral vectors that exhibit efficient local and dispersed neuronal transduction in the CNS.

Source: Gene therapy.

 

 

 

 

Strengthening of antitumor immune memory and prevention of thymic atrophy mediated by adenovirus expressing IL-12 and GM-CSF.


Interleukin (IL)-12 and granulocyte-monocyte colony-stimulating factor (GM-CSF) have recently been used as immunotherapeutic agents in cancer gene therapy. IL-12 and GM-CSF have differential roles in the antitumor immune response, as IL-12 targets T, NK and natural killer T (NKT) cells and GM-CSF principally targets antigen-presenting cells (APCs). To strengthen the therapeutic efficacy of these two cytokines, we generated an oncolytic adenovirus (Ad), Ad-ΔB7/IL12/GMCSF, coexpressing IL-12 and GM-CSF. Using a murine B16-F10 syngeneic tumor model, we show that Ad-ΔB7/IL12/GMCSF promoted antitumor responses and increased survival compared with an oncolytic Ad expressing IL-12 or GM-CSF alone (Ad-ΔB7/IL12 or Ad-ΔB7/GMCSF, respectively). By measuring cytotoxic T lymphocyte activity and interferon-γ production, we show that the enhanced therapeutic effect was mediated by the induction of immune cell cytotoxicity. In situ delivery of Ad-ΔB7/IL12/GMCSF resulted in massive infiltration of CD4+ T cells, CD8+ T cells, NK cells and CD86+ APCs into the tissue surrounding the necrotic area of the tumor. Moreover, GM-CSF effectively promoted antitumor immune memory, which was significantly augmented by IL-12. Lastly, IL12-expressing oncolytic Ads prevented tumor-induced thymic atrophy and was associated with reduced apoptosis and increased proliferation in the thymus. Taken together, these data demonstrate that an oncolytic Ad coexpressing IL-12 and GM-CSF is a potential therapeutic tool for the treatment of cancer.

Source: Gene therapy.

 

 

Ultrasound-targeted microbubble destruction enhances naked plasmid DNA transfection in rabbit Achilles tendons in vivo.


The study was to investigate the probability of increasing the transfection of the gene in tendons by ultrasound-targeted microbubble destruction (UTMD), and to search for the most suitable transfection conditions. A mixture of microbubbles and enhanced green fluorescent protein (EGFP) plasmids was injected into rabbit Achilles tendons by different administration routes and the tendons were ultrasound pulse by different ultrasonic conditions in order to determine the most appropriate conditions. Then, the rabbits were divided into four groups: (1) ultrasound + microbubbles + plasmid; (2) ultrasound+ plasmid; (3) microbubble + plasmid; (4) plasmid only. EGFP expression in the tendons and other tissues, and the damage to tendon and paratenon were all observed. The results showed that EGFP expression in the tendon was higher by ultrasound pulse with 2 W cm−2 of output intensity and a 20% duty cycle for 10 min. Local injection was determined to be the better administration route. Among the four groups, EGFP expression in Group 1 was higher than that in other groups. EGFP expression was highest on seventh day, then it gradually decrease over time, and lasted more than 56 days. EGFP expression was not found in other tissues. There was no obvious injury caused by UTMD. Under suitable conditions, it is feasible to use UTMD as a safe and effective gene transfection therapy for tendon injuries.

Source: Gene therapy.

 

Which body parts should you be allowed to sell?


Sperm. Plasma. Eggs. Hair. What do all these things have in common? They’re parts of your body you can legally sell in the United States. This last fall bone marrow joined that list says Alice Park of TIME.com.

Since 1984 the National Organ Transplantation Act (NOTA) has outlawed the sale of body organs, including bone marrow. But new bone marrow technology called aphoresis allows doctors to harvest marrow cells from the blood instead of the hip bones, as it was previously collected.

Plaintiffs last fall argued that this technique takes bone marrow out of the category of organs, and reclassifies it as a liquid. The U.S. Court of Appeals for the Ninth Circuit ruled in their favor, permitting the sale of bone marrow for up to $3000 USD in the form of a voucher.

Bone marrow is an important exception the pre-existing list of body parts legal to sell, Park points out:

For now, legally “sellable” human body parts aren’t ones that could be used to cure fatal diseases, which prevents a market frenzy. But if the bone-marrow case starts changing that — and experts say it could — it might jumpstart a dangerous trend in which lower-income groups were disproportionately targeted or incentivized to give up their marrow and people with rarer blood types demanded more money for their valuable cells.

But, Jeffrey Kahn, professor of bioethics and public policy at the Johns Hopkins University Berman Institute of Bioethics tells Park that he sees the bone marrow ruling as a policy experiment. If it promotes more people to donate much-needed bone marrow, “maybe we should think about this for other kinds of donations.”

For example, a number of U.S. patients already travel out of the country to obtain kidney transplants from donors matched online, Kahn says. At the moment this practice is highly unregulated and usually involves people from developing nations. Allowing such transactions within the U.S. could decrease their sketch factor.

Or, we could look to the donation models of other countries, Dr. Robert Klitzman, director of the bioethics program at Columbia University, tells Park. In Spain people all people are organ donors by default, they don’t have to opt in like they do in the U.S. Israel entices people to elect postmortem donorship by promising living family members priority on organ waitlists should they ever need one.

Source: TIME.com

 

 

Oakland gets first city-wide network of CO2 sensors.


The City of Oakland will soon be able to provide a neighborhood-by-neighborhood analysis of its carbon dioxide emissions, making it the first network of its kind.

Researchers at the University of California, Berkeley will install 40 sensors on local schools across a 27 square-mile grid throughout the city, providing a more accurate picture of CO2 levels at a micro level. The sensors will also make it easier to verify state-mandated emission-cutting strategies.

Known as the BEACON network, the sensors will also measure carbon monoxide, nitrogen dioxide, and ozone levels along with temperature, pressure, and humidity. All of that data will be available on their website.

“Today, we monitor air quality in the entire East Bay from only about a dozen stations, but that gives you an average that may not be representative of what’s happening where you live,” said project leader Ron Cohen, UC Berkeley professor of chemistry, in a statement. “The advantage of many, many sensors is that the network captures the whole range of pollutant sources, from freeways to homes. This could inspire communities to think about local actions to change the CO2 they emit.”

But the sensors could also have an impact on businesses. In 2008, the Bay Area Air Quality Management District placed a carbon fee on regional businesses. With better data the fees can be accessed more accurately.

The new sensors will cost about one-twelfth as much as more detailed sensors Cohen and his team have created in the past. But the large numbers of the sensors — and the ability to have more in a city — will make up for the fact that they are less sensitive tools.

“A massive number of inexpensive sensors as common as cell phone towers will fundamentally change our knowledge,” said Cohen, who directs the Berkeley Atmospheric Science Center. “Real time observations will enable rapid verification of the effectiveness of policy and compliance with treaties and other agreements and commitments.”

Source: IBM Smart Planet.

 

Effects of Dietary Composition on Energy Expenditure During Weight-Loss Maintenance.


Context  Reduced energy expenditure following weight loss is thought to contribute to weight gain. However, the effect of dietary composition on energy expenditure during weight-loss maintenance has not been studied.

Objective  To examine the effects of 3 diets differing widely in macronutrient composition and glycemic load on energy expenditure following weight loss.

Design, Setting, and Participants  A controlled 3-way crossover design involving 21 overweight and obese young adults conducted at Children’s Hospital Boston and Brigham and Women’s Hospital, Boston, Massachusetts, between June 16, 2006, and June 21, 2010, with recruitment by newspaper advertisements and postings.

Intervention  After achieving 10% to 15% weight loss while consuming a run-in diet, participants consumed an isocaloric low-fat diet (60% of energy from carbohydrate, 20% from fat, 20% from protein; high glycemic load), low–glycemic index diet (40% from carbohydrate, 40% from fat, and 20% from protein; moderate glycemic load), and very low-carbohydrate diet (10% from carbohydrate, 60% from fat, and 30% from protein; low glycemic load) in random order, each for 4 weeks.

Main Outcome Measures  Primary outcome was resting energy expenditure (REE), with secondary outcomes of total energy expenditure (TEE), hormone levels, and metabolic syndrome components.

Results  Compared with the pre–weight-loss baseline, the decrease in REE was greatest with the low-fat diet (mean [95% CI], –205 [–265 to –144] kcal/d), intermediate with the low–glycemic index diet (–166 [–227 to –106] kcal/d), and least with the very low-carbohydrate diet (−138 [–198 to –77] kcal/d; overallP = .03; P for trend by glycemic load = .009). The decrease in TEE showed a similar pattern (mean [95% CI], −423 [–606 to –239] kcal/d; −297 [–479 to –115] kcal/d; and −97 [–281 to 86] kcal/d, respectively; overallP = .003; P for trend by glycemic load < .001). Hormone levels and metabolic syndrome components also varied during weight maintenance by diet (leptin, P < .001; 24-hour urinary cortisol, P = .005; indexes of peripheral [P = .02] and hepatic [P = .03] insulin sensitivity; high-density lipoprotein [HDL] cholesterol,P < .001; non-HDL cholesterol, P < .001; triglycerides, P < .001; plasminogen activator inhibitor 1, P for trend = .04; and C-reactive protein, P for trend = .05), but no consistent favorable pattern emerged.

Conclusion  Among overweight and obese young adults compared with pre–weight-loss energy expenditure, isocaloric feeding following 10% to 15% weight loss resulted in decreases in REE and TEE that were greatest with the low-fat diet, intermediate with the low–glycemic index diet, and least with the very low-carbohydrate diet.

Source:  JAMA.

Inhibiting PI3K reduces mammary tumor growth and induces hyperglycemia in a mouse model of insulin resistance and hyperinsulinemia.


Women with type 2 diabetes mellitus (T2DM) are at a greater risk of developing and dying from breast cancer than women without T2DM. Insulin resistance and hyperinsulinemia underlie the pathogenesis of T2DM. In the MKR mouse model of insulin resistance, we have previously shown increased activation of the phosphatidylinositol 3-kinase (PI3K)/Akt/mTOR pathway in association with accelerated mammary tumor growth. In this study, we demonstrate that inhibiting PI3K with the oral pan-class I PI3K inhibitor, NVP-BKM120 reduced the growth of Met-1 and MCNeuA mammary tumor orthografts in the MKR mouse. NVP-BKM120 treatment decreased phosphorylation of Akt and S6 ribosomal protein (S6rp); no change in Erk1/2 phosphorylation was seen. Hyperglycemia, hypertriglyceridemia and greater hyperinsulinemia developed in the MKR mice treated with NVP-BKM120. We previously reported reduced tumor growth using intraperitoneal rapamycin in the MKR mouse, with the development of hyperglycemia and hypertriglyceridemia. Therefore, we examined whether the oral PI3K/mTOR inhibitor NVP-BEZ235 augmented the tumor suppressing effects of PI3K inhibition. We also investigated the effect of targeted PI3K/mTOR inhibition on PI3K/Akt/mTOR and Erk1/2 signaling, and the potential effects on glycemia. NVP-BEZ235 suppressed the growth of Met-1 and MCNeuA tumor orthografts, and decreased Akt and S6rp phosphorylation, despite increased Erk1/2 phosphorylation in Met-1 orthografts of MKR mice. Less marked hyperglycemia and hyperinsulinemia developed with NVP-BEZ235 than NVP-BKM120. Overall, the results of this study demonstrated that inhibiting PI3K/Akt/mTOR signaling with the oral agents NVP-BKM120 and NVP-BEZ235 decreased mammary tumor growth in the hyperinsulinemic MKR mouse. Inhibiting PI3K alone led to more severe metabolic derangement than inhibiting both PI3K and mTOR. Therefore, PI3K may be an important target for the treatment of breast cancer in women with insulin resistance. Monitoring for hyperglycemia and dyslipidemia should be considered when using these agents in humans, given the metabolic changes detected in this study.

Source: Oncogene.