Massachusetts General Hospital (MGH) investigators have found that an enzyme with several important roles in energy metabolism also helps to turn off the body's generation of fats and cholesterol under conditions of fasting. The report in Genes & Development describes how SIRT1, one of a group of enzymes called sirtuins, suppresses the activity of a family of proteins called SREBPs, which control the body's synthesis and handling of fats and cholesterol. The findings could lead to new approaches to treating conditions involving elevated cholesterol and lipid levels.
"SIRT1 had previously been shown to act as an energy sensor, promoting the use of stored fat in response to food deprivation; however, its function in shutting down fat and cholesterol synthesis was unknown," says Amy Walker, PhD, of the MGH Cancer Center, the study's lead author. "These findings point to SIRT1 as a master regulator of physiologic energy stability that controls the synthesis and storage of fat, as well as its usage as fuel."
Under normal conditions, the body produces appropriate levels of fats and cholesterol, both of which are essential to life. A high-fat diet can cause abnormal elevations in fat and cholesterol levels in the blood, which may lead to cardiovascular disease, type 2 diabetes, hypertension and other serious disorders. If the body is deprived of food for a short time, it shuts down the production and storage of fat and cholesterol and shifts to using stored fats as the primary source of energy. Fasting also is known to turn off the activity of SREBP proteins, and the research team investigated whether direct suppression of SREBPs by SIRT1 was responsible for the metabolic shift.
A series of experiments in worms, fruitflies and mice showed that the versions of SIRT1 present in those animals suppressed SREBP activity and the associated synthesis and storage of fats. They also showed in mouse and human cells that SIRT1 acts on SREBP by removing a protective molecule, marking the protein for degradation, and that inhibiting SIRT1 activity caused levels of SREBP to rise. Treating genetically obese mice fed a high-fat diet with an agent that increases sirtuin activity suppressed the expression of SREBP-regulated fat synthesis genes and also reduced the amount of fat stored in the animals livers.
"This study is significant because it explains the signals that tell the body to burn fat in response to fasting or dieting," says David Sinclair, PhD, a professor of Pathology at Harvard Medical School (HMS) who helped discover the genes that code for sirtuins but was not involved with this MGH-led study. "This improved understanding could help treat and prevent metabolic diseases such as atherosclerosis and type 2 diabetes."
Sirtuins have also been associated with the increased longevity in response to reduced calorie intake observed in several species of animals. Drugs that stimulate sirtuin activity are currently being investigated for treatment of diabetes and related conditions.
"Sirtuin activators could strengthen SIRT1 functions that may be suppressed in individuals with cardiometabolic disorders," explains Anders Näär, PhD, of the MGH Center for Cancer Research, senior author of the current study. "Our results suggest these agents may be able to 'trick' the body into responding as though it was experiencing fasting, with beneficial metabolic consequences, but that hypothesis needs to be tested in future studies." Näär is an associate professor of Cell Biology and Walker is an instructor in Medicine at HMS.
The study was supported by the Paul F. Glenn Laboratories for the Biological Mechanisms of Aging at HMS and grants from the National Institutes of Health. Additional co-authors of the Genes & Development article are Fajun Yang, Karen Jiang, Jun-Yuan Ji, Toshi Shioda, Peter Mulligan, Hani Najafi-Shoushtari, Josh Black, Jitendra Thakur, Johnathan Whetstein, Raul Mostoslavsky and Nicholas Dyson, MGH Cancer Center; Jennifer Watts, Washington State University; Aparna Purushotham and Xiaoling Li, National Institute of Environmental Health Sciences; Olivier Boss, Michael Hirsch, Scott Ribich, Jesse Smith, Kristine Israelian and Christoph Westphal, Sirtris Pharmaceuticals; Joseph Rodgers and Pere Puigserver, Dana-Farber Cancer Institute, Sarah Elson and Lisa Kadyk, Exelixis, Inc., and Anne Hart, Brown University.
Source:
Sue McGreevey
Massachusetts General Hospital
Herbalife Ltd. (NYSE: HLF) and the Fraud Discovery Institute announced that the Fraud Discovery Institute retracts its accusations against multi-level marketer Herbalife. Herbalife and the Fraud Discovery Institute reached the agreement to avoid litigation.
Upon further investigation by FDI founder Barry Minkow, the Fraud Discovery Institute became convinced that Herbalife employs systematic internal controls, including the use of outside, independent laboratory testing, which ensures their products are manufactured safely and in compliance with California law. It is evident to the Fraud Discovery Institute that Herbalife produces products that are safe, and that the company strives for continuous improvement in product quality.
The Fraud Discovery Institute immediately withdraws all accusations against Herbalife, including any Proposition 65 allegation relating to any Herbalife product and any contentions against the Herbalife business model.
About Herbalife Ltd.
Herbalife Ltd. is a global network marketing company that sells weight-management, nutrition, and personal care products intended to support a healthy lifestyle. Herbalife products are sold in 66 countries through a network of over 1.8 million independent distributors. The company supports the Herbalife Family Foundation and its Casa Herbalife program to bring good nutrition to children. Please visit Herbalife Investor Relations for additional financial information.
Herbalife Ltd.
Inappropriate use of abbreviations and illegible writing on hospital prescription charts are leading to prescription errors, according to findings presented this week at Diabetes UK's Annual Professional Conference in Liverpool.
Researchers from the Royal Liverpool University Hospital looked at 75 prescription charts of people with diabetes and found that in 5 per cent of cases, the use of doctors' own abbreviations and hastily written notes could easily be misread by the nursing staff.
The audit also reveals that one in six charts had prescription errors. The majority of these were illegible, a few were not dated and some were not signed by the prescribing doctors. Medication must only be given if the prescription is signed by a doctor, which means there was delay in the administration of insulin. In addition, one in three charts did not have the correct timings for insulin injections.
Extreme concern
"Diabetes UK is extremely concerned at this audit's startling revelations," said Simon O'Neill, Director of Care, Information and Advocacy at Diabetes UK. "Correct insulin doses and the timely co-ordination of medication and meals are basic, but essential factors for good diabetes management and improved health.
"At least ten per cent of people in hospital have diabetes. Although not all people with diabetes treat their condition with insulin, the potential health risks to tens of thousands of people can be avoided with simple measures.
"Hospitals should ensure that specialist diabetes teams are available to assure competences of non-diabetes staff and provide appropriate support to ensure that people with diabetes in hospital are able to access the high quality care they should expect."
Serious consequences
Dr Nagaraj Malipatil, lead researcher at the Royal Liverpool University Hospital, said: "Insulin prescribing, has for a long time been subject to less scrutiny and is prescribed less diligently because it is such a common medication in hospitals. Our audit has demonstrated an unacceptably high percentage of errors.
"A misunderstanding from an abbreviation for insulin units could have serious if not fatal consequences. For example, a doctor should prescribe insulin as "10 units" at a specified time, if written as "10 I U" or "10 I units", this could be easily misread as 101 units.
Following guidelines
"There are guidelines and medicines policies on writing correct prescriptions. It is this strict adherence to the medicines policy that forms the basis to reduce the incidence of potential errors in patients' treatment. Doctors must avoid the use of abbreviations for insulin units and all hospitals need to ensure that correct insulin prescribing is covered in junior doctor training as part of their risk management strategy.
"We undertook a re-audit after intensive training of junior doctors and members of the team have shown significant reduction in prescription errors."
Source
Diabetes UK
The Medical Defence Union (MDU), the UK's leading medical defence organisation, says that civil litigation costs need to be controlled to make the civil justice system fairer to defendant doctors and dentists, but this will not mean patients are unable to seek compensation through the courts.
In its response to the Government's consultation about civil litigation funding*, the MDU says it strongly supports the proposals to address the disproportionate costs awarded to claimants in Conditional Fee Arrangement (CFA) cases. Costs can far exceed the compensation awarded to the damaged patient such as in the case where a patient was paid damages of £8,000 but their lawyer's costs totalled £62,000 which included a 90% success fee and an 'After the Event' insurance premium of £18,375.
Jill Harding, head of claims at the MDU said: "We believe that the current system is unfair to the doctors and dentists we represent who are funding these spiralling legal costs through their subscriptions and to taxpayers who are funding the cases indemnified by NHS bodies. The MDU wholeheartedly supports the changes proposed which address the problem of excessive and disproportionate costs, without affecting the ability of patients to seek compensation when they have been negligently harmed.
"We agree with the proposal that defendants will not recover costs from losing claimants in CFA-funded cases and in return claimants won't need to take out insurance against these costs. Claimants themselves should be expected to fund their solicitors' success fee from any damages awarded and would then have an interest in the costs incurred on their behalf. To ensure fairness to claimants, we agree that the success fee needs to be capped and that there should be a 10% increase in the general damages that claimants are awarded. We think this approach strikes the right balance and hope that the proposed changes will be introduced."
*Proposals for the reform of civil litigation funding and costs in England and Wales: Implementation of Lord Justice Jackson's recommendations, Ministry of Justice consultation paper, November 2010
Source:
MDU
Actelion Pharmaceuticals US, Inc., announced that the U.S. Food and Drug Administration (FDA) has approved the brand name VELETRI® for the company's epoprostenol for injection therapy. VELETRI has been commercially available since April 2010 as Epoprostenol for Injection for the treatment of moderate to severe pulmonary arterial hypertension (PAH) and PAH associated with the scleroderma spectrum of disease. Actelion plans to release VELETRI-labeled product by early fourth quarter of 2010.
VELETRI is an improved formulation of epoprostenol that offers greater convenience to patients than other epoprostenol formulations. VELETRI is stable at room temperature for up to 24 hours when diluted as directed and put into the pump for administration, eliminating the need for ice packs.
"VELETRI is a proven therapy for the treatment of PAH patients who don't respond adequately to conventional treatment, and rounds out a portfolio of therapies designed to address the diverse needs of patients with this chronic and life-threatening disease," said Shal Jacobovitz, president of Actelion Pharmaceuticals US, Inc. "As the pioneer in PAH, we are committed to transforming the lives of patients by developing efficacious therapies that also offer flexibility and convenience in treatment."
In conjunction with the launch of VELETRI, Actelion opened its fourth PAH patient registry in the United States. PROSPECT, the registry to PROSPECTively evaluate use of VELETRI in patients with PAH, is a multicenter, observational, U.S.-based registry, which is currently ongoing.
Actelion will also provide further information on VELETRI at the American Heart Association Scientific Sessions 2010 in Chicago with a poster entitled "Biocomparability of Two Formulations of Epoprostenol, Epoprostenol for Injection (ACT-385781A) And Flolan®, Via Pharmacokinetic Assessment of Two Primary Metabolites."
The registration process for Epoprostenol for Injection is ongoing outside the US, initially in France, also with VELETRI as proposed brand name.
About VELETRI®
VELETRI is indicated for the long-term intravenous treatment of primary pulmonary hypertension and pulmonary hypertension associated with the scleroderma spectrum of disease in NYHA Class III and Class IV patients who do not respond adequately to conventional therapy. Unlike other epoprostenol formulations approved for PAH, VELETRI is stable at room temperature (77 F, 25 C), for up to 24 hours after it has been diluted, making the use of frozen gel packs unnecessary. VELETRI can be reconstituted with either Sterile Water for Injection, USP, or Sodium Chloride 0.9% Injection, USP, eliminating the need for drug-specific diluents.
Accredo Health Group, Inc. is the sole specialty pharmacy provider of VELETRI. Accredo offers an enhanced level of personalized service to patients with chronic and complex disease, and will provide call center, nursing and reimbursement support services for patients using VELETRI and their healthcare providers.
About Pulmonary Arterial Hypertension (PAH)
Pulmonary arterial hypertension (PAH) is a chronic, life-threatening disorder characterized by abnormally high blood pressure in the arteries between the heart and lungs of an affected individual. The function of the heart and lungs is severely compromised, manifested by a limited exercise capacity, and, ultimately, a reduced life expectancy. Approximately 100,000 people in Europe and the United States are afflicted with either primary or secondary forms of the disease related to conditions or tissue disorders that affect the lungs, such as scleroderma, lupus, HIV/AIDS or congenital heart disease.
PAH is associated with structural changes in both the pulmonary vasculature and the right ventricle. Recent advances [1] in the understanding of the pathogenic factors leading to the pulmonary vascular disease have led to the development of new therapies targeting specific pathways (the prostacyclin pathway; the endothelin pathway; and the nitric oxide pathway) (2). The available therapies have positive effects in PAH, but they do not provide a cure, and in many patients the disease will progress. PAH remains a serious life-threatening condition (2,3). Early recognition and an understanding of the selection and timing of therapeutic options remain critical elements in the optimal management of patients with this disorder.
References
(1) Farber HW; Loscalzo J. Mechanisms of disease: pulmonary arterial hypertension. N. Eng. J. Med. 2004; 351:1655-65.
(2) Humbert M; Sitbon O; Simonneau G. Treatment of pulmonary arterial hypertension. N. Eng. J. Med. 2004; 351:1425-36.
(3) Humbert M; Morrell NW; Archer SL; et al. Cellular and molecular pathobiology of pulmonary arterial hypertension. J. Am. Coll. Cardiol. 2004; 43: Suppl. 12: 13S-24S.
Source: Actelion Pharmaceuticals US, Inc