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Too Much Vitamin D Can Be as Unhealthy as Too Little

Posted in Biological Networks, Gene Regulation and Evolution, Disease Biology, Small Molecules in Development of Therapeutic Drugs, tagged , , , , , , , on May 30, 2012| Leave a Comment »

Reporter: Prabodh Kandala, PhD

Scientists know that Vitamin D deficiency is not healthy. However, new research from the University of Copenhagen now indicates that too high a level of the essential vitamin is not good either. The study is based on blood samples from 247,574 Copenhageners. The results have just been published in the reputed scientific Journal of Clinical Endocrinology and Metabolism.

Vitamin D is instrumental in helping calcium reach our bones, thus lessening the risk from falls and the risk of broken hips. Research suggests that vitamin D is also beneficial in combating cardiac disease, depression and certain types of cancers. The results from a study conducted by the Faculty of Health and Medical Sciences now support the benefits of vitamin D in terms of mortality risk. However, the research results also show higher mortality in people with too high levels of vitamin D in their bloodstream:

“We have had access to blood tests from a quarter of a million Copenhageners. We found higher mortality in people with a low level of vitamin D in their blood, but to our surprise, we also found it in people with a high level of vitamin D. We can draw a graph showing that perhaps it is harmful with too little and too much vitamin D,” explains Darshana Durup, PhD student.

If the blood contains less than 10 nanomol (nmol) of vitamin per liter of serum, mortality is 2.31 times higher. However, if the blood contains more than 140 nmol of vitamin per liter of serum, mortality is higher by a factor of 1.42. Both values are compared to 50 nmol of vitamin per liter of serum, where the scientists see the lowest mortality rate.

More studies are needed

Darshana Durup emphasises that while scientists do not know the cause of the higher mortality, she believes that the new results can be used to question the wisdom of those people who claim that you can never get too much vitamin D:

“It is important to conduct further studies in order to understand the relationship. A lot of research has been conducted on the risk of vitamin D deficiency. However, there is no scientific evidence for a ‘more is better’ argument for vitamin D, and our study does not support the argument either. We hope that our study will inspire others to study the cause of higher mortality with a high level of vitamin D,” says Darshana Durup. She adds:

“We have moved into a controversial area that stirs up strong feelings just like debates on global warming and research on nutrition. But our results are based on a quarter of a million blood tests and provide an interesting starting point for further research.”

The largest study of its kind

The study is the largest of its kind — and it was only possible to conduct it because of Denmark’s civil registration system, which is unique in the Nordic countries. The 247,574 blood samples come from the Copenhagen General Practitioners Laboratory:

“Our data material covers a wide age range. The people who participated had approached their own general practitioners for a variety of reasons and had had the vitamin D level in their bloodstream measured in that context. This means that while the study can show a possible association between mortality and a high level of vitamin D, we cannot as yet explain the higher risk,” explains Darshana Durup.

Therefore in future research project scientists would like to compare the results with information from disease registers such as the cancer register. Financial support is currently being sought for such projects.

Ref:

http://www.sciencedaily.com/releases/2012/05/120529102346.htm

http://jcem.endojournals.org/content/early/2012/05/09/jc.2012-1176

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What the Cardiologist Needs to Know

Posted in Cardiovascular Pharmacogenomics, Infectious Disease & New Antibiotic Targets, Pharmacotherapy of Cardiovascular Disease, Population Health Management, Genetics & Pharmaceutical, tagged , , , , , , , , , , , , on May 29, 2012| Leave a Comment »

Guidelines for the Diagnosis and Treatment of Endocarditis

from

British Society of Antimicrobial Chemotherapy (BSAC)

Clinicians who care for patients diagnosed with infective endocarditis (IE) are (un)fortunate to be able to refer to several guidelines about its diagnosis and treatment. The guidelines vary considerably, especially with regards to antibiotic prescribing recommendations, which generally reflect local practice and expert opinion in light of largely observational data. All guidelines recommend a multidisciplinary approach to the management of IE.

Infective endocarditis

Infective endocarditis (Photo credit: Wikipedia)

Echocardiography remains a cornerstone of IE diagnosis but is neither 100% sensitive nor specific and multiple scans may be needed to identify vegetations. Echocardiography should also be used in all patients with Staphylococcus aureus bacteraemia. The prevalence of IE among patients with S aureus bacteraemia is variable but was reported as 13% in one large prospective US study and 22% in a recent European study. Clinical assessment is unreliable in diagnosing IE in patients with S aureus bacteraemia and without echocardiography the diagnosis may be missed. Transoesophageal echocardiography is now recommended in most cases of suspected or confirmed IE but may be unnecessary in patients with right-sided valve involvement.

Establishing a microbiological diagnosis in an era of increasingly complex infections with unpredictable resistance patterns is important. However, traditional recommendations for blood culture sampling have been amended for patients with suspected IE and severe sepsis or septic shock. In this situation, two (rather than three) sets of blood cultures, taken at different times within an hour before the start of empirical treatment, are now advised. This is a pragmatic recommendation to avoid undue delay in starting empirical antimicrobial treatment. In other patients, the usual need for three sets of blood cultures is recommended but with at least 6 h between sampling times; an important aim of multiple sampling is to demonstrate the presence of a sustained or persistent bacteraemia, which is characteristic of IE. Identification of atypical micro-organisms using serology in culture-negative cases should be limited to Coxiella and Bartonella in the first instance—a reflection of the extremely small numbers of reported cases of IE caused by Mycoplasma, Brucella and Legionella.

Fungal causes of IE should be considered in culture-negative IE if serology is non-diagnostic and the patient is immunocompromised, has a prosthetic valve, is an intravenous drug user or is not responding to empirical antibacterial treatment. The application of broad-range (16S ribosomal RNA gene) PCR on surgically resected valves or embolic material should be used when culture has failed. False-negative 16S ribosomal RNA gene PCR reactions can occur in the presence of inhibitors of the DNA polymerase within clinical samples or as a result of the vagaries of sampling (ie, processing a piece of tissue that does not contain any bacteria). Bacterial DNA has been shown to be present within cardiac tissue several years after successful treatment of IE, so results should be interpreted with caution in a patient with a previous diagnosis of IE. Application of 16S ribosomal gene PCR to blood in patients with IE is problematic owing to the low levels of bacteria present (1–10 fu/ml) and subsequent difficulty in DNA extraction; as a result it is not currently available for routine clinical use.

Empirical treatment (that started before obtaining a microbiological diagnosis) is generally discouraged, except in those who are acutely unwell or shocked. There is no clear evidence that speeding up the diagnosis, and instigation of treatment, improves outcomes, although this would seem intuitive. Early treatment (started within days of onset of symptoms rather than weeks) is a laudable aim, but the few days delay in hospital while appropriate echocardiographic and microbiological tests are undertaken on a stable patient are unlikely to have a negative impact on outcome. Conversely, the administration of broad-spectrum antibiotics when the diagnosis of IE has not been considered (and often when inadequate samples have been obtained) may have considerable impact on the ability to establish the diagnosis and subsequently deliver effective treatment.

Outpatient antibiotic treatment (OPAT) for IE is included in the BSAC guidelines in response to increasing efforts to expand these services and manage more patients outside hospital. Patients who might be considered for OPAT include those who are stable and responding well to treatment, are without signs of heart failure and without any indications for surgery or uncontrolled extracardiac foci of infection. Delivery of OPAT requires appropriate funding, support and infrastructure, coupled with the ability to rapidly access inpatient services and obtain urgent expert advice if needed. This has been proved to be feasible and safe in the UK, even in high-risk IE cases.

Although the guidelines include recommendations for most causes of IE, the predominant pathogens remain staphylococci, streptococci and enterococci. Routine addition of gentamicin to flucloxacillin for the treatment of native valve staphylococcal IE is no longer recommended (see Table 1). This recommendation is unchanged from previous BSAC guidelines but the ESC continue to include gentamicin as an optional addition. Further evidence of the toxicity of gentamicin has been published, based on findings from a randomised controlled trial comparing daptomycin with either vancomycin or cloxacillin plus gentamicin for the treatment of S aureus bloodstream infection or IE Recommendations for meticillin-resistant staphylococci also differ from those of the ESC; although vancomycin is the primary agent in both sets of guidelines, rifampicin is recommended by BSAC in place of gentamicin because of concerns about efficacy and toxicity. Daptomycin, a recently licensed lipopeptide, is also recommended as an alternative agent for patients who are intolerant to vancomycin or have infection caused by vancomycin-resistant isolates.

Previous recommendations for treatment of streptococcal IE have been simplified, with greater emphasis placed on benzylpenicillin rather than amoxicillin as the primary agent to reduce risk of Clostridium difficile infection. Enterococcal treatment regimens are largely consistent with the ESC guidelines, though a low threshold for withdrawing gentamicin in patients with deteriorating renal function or other signs of toxicity is advised, based on observational data that shorter gentamicin courses are not associated with worse outcomes.

The timing of cardiac surgery in IE should be evaluated by the multidisciplinary team on a case by case basis. Attempts to advise whether cardiac surgery should be emergent, urgent or elective can seem artificial. The traditional indications for surgery in IE are well established but it is becoming apparent that patients with IE caused by S aureus, or patients with evidence of systemic embolisation, should also be considered for early surgery, which may confer a mortality benefit.

Device-related infections have been deliberately omitted from the current BSAC guidance as the challenges in preventing, diagnosing and treating cases of intracardiac device IE are different from ‘traditional’ native or prosthetic valve IE. Further specific device-related guidance is likely to be published in the future and a joint working party involving the BSAC, BCS and Heart Rhythm UK has been established. IE guidelines are always imperfect owing to the difficulties in studying this relatively uncommon condition and the scarcity of randomised trials. At present, we are uncertain of the incidence, risk factors, causative micro-organisms (and their antimicrobial sensitivities), and patient outcomes in IE affecting the UK population. A recently established national endocarditis database may help to answer some of these questions, but its success will be crucially determined by the degree of support and national participation. See http://www.neemo.leedsth.nhs.uk/ (only via the N3 network) for details.

see source for more

Reported by: Dr. V. S. Karra, Ph.D

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Zithromax – likely to ‘max’ Heart Attack

Posted in Cardiovascular Pharmacogenomics, Health Economics and Outcomes Research, Infectious Disease & New Antibiotic Targets, Pharmacotherapy of Cardiovascular Disease, Population Health Management, Genetics & Pharmaceutical, tagged , , , , , , , , , , , , on May 18, 2012| 4 Comments »

A Word of Caution especially to Cardiacs’

Zithromax (azithromycin), is not only a more expensive antibiotic than other antibiotics but also seems to be an expensive one at Heart. Doctors should weigh other options for people already prone to heart problems, the researchers and other experts suggested. It is a popular antibiotic because it often can be taken for a fewer days compared to other antibiotics, for example: about 10 days for amoxicillin and other antibiotics and five-day course will suffice in case of Zithromax.

Azithromycin

Azithromycin (Photo credit: Wikipedia)

It is widely used for bronchitis, sinus infections and pneumonia, and other common infections but seems to increase chances for sudden deadly heart problems. A rare but surprising risk found in a 14-year study. Also, antibiotics in the same class as Zithromax have been linked with sudden cardiac death. In the current study, patients those on Zithromax were about as healthy as those on other antibiotics, making it unlikely that an underlying condition might explain the increased death risk, researchers said.

Researchers analysis at Vanderbilt University indicates that there were 29 heart-related deaths among those who took Zithromax during five days of treatment. Their risk of death while taking the drug was more than double that of patients on another antibiotic, amoxicillin, or those who took none.

To compare risks, the researchers calculated that the number of deaths per 1 million courses of antibiotics would be about 85 among Zithromax patients versus 32 among amoxicillin patients and 30 among those on no antibiotics. The highest risks were in Zithromax patients with existing heart problems. Patients in each group started out with comparable risks for heart trouble, the researchers said. The results suggest there would be 47 extra heart-related deaths per 1 million courses of treatment with Zithromax. The risk of cardiovascular death was significantly greater with azithromycin than with ciprofloxacin but did not differ significantly from that with levofloxacin.

Dr. Harlan Krumholz, a Yale University health outcomes specialist who was not involved in the study said that “People need to recognize that the overall risk is low,”. More research is needed to confirm the findings, but still, he said patients with heart disease “should probably be steered away” from Zithromax for now.

At the same time, Dr. Bruce Psaty, a professor of medicine at the University of Washington, of opinion that doctors and patients need to know about the potential risks. He said the results also raise concerns about long-term use of Zithromax, which other research suggests could benefit people with severe lung disease. Additional research is needed to determine if that kind of use could be dangerous, he said.

The study appears in the New England Journal of Medicine. The National Heart, Lung and Blood Institute helped pay for the research. Wayne Ray, a Vanderbilt professor of medicine, studied the drug’s risks because of evidence linking it with potential heart rhythm problems.

Pfizer is committed to patients safety and issued a statement saying it would thoroughly review the study and “Patient safety is of the utmost importance to Pfizer and we continuously monitor the safety and efficacy of our products to ensure that the benefits and risks are accurately described,” the company said.

Source

Additional info on Zithromax

Reported by Dr. Venkat Karra, Ph.D

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Arthritis, Cancer: New Screening Technique Yields Elusive Compounds to Block Immune-Regulating Enzyme

Posted in Bone Disease and Musculoskeletal Disease, CANCER BIOLOGY & Innovations in Cancer Therapy, Cell Biology, Signaling & Cell Circuits, tagged , , , , , on May 11, 2012| 1 Comment »

Reporter: Prabodh Kandala, PhD

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Word Cloud By Danielle Smolyar

Scientists at The Scripps Research Institute have found the first chemical compounds that act to block an enzyme that has been linked to inflammatory conditions such as asthma and arthritis, as well as some inflammation-promoted cancers.

The new study, published recently by the journal ACS Chemical Biology, describes new compounds that inhibit an important enzyme called PRMT1 (protein arginine methyltransferase 1). The new inhibitors will be useful to scientists who study PRMT1-related biological pathways in cells and who are developing drug treatments for PRMT1-related inflammatory conditions and cancers.

Standard screening techniques had been unable to distinguish between compounds that inhibit PRMT1 and those that inhibit other common PRMT family enzymes. In the new study, scientists from several Scripps Research laboratories collaborated to devise the first PRMT1-specific screening technique. “We were able to target a screening probe to a specific amino acid found on PRMT1, but not on most other PRMT enzymes,” said the study’s principal investigator Scripps Research Assistant Professor Kerri A. Mowen.

Mowen has been studying PRMT1 since her graduate school days, and, like others in the field, has been acutely aware of the need for selective PRMT1 inhibitors. The enzyme modifies the functionality of proteins by attaching a methyl group to their arginine amino acids; as such, it is involved in some of the most basic processes in cells. For example, Mowen and her colleagues showed in 2004 that PRMT1 helps drive the production of the key immune-stimulating proteins interferon-gamma and interleukin-4.

But although PRMT1 was known to be responsible for nearly all the arginine methylation that goes in mammalian cells, no one had been able to develop selective PRMT1 inhibitors, since the 10 other PRMT enzymes are nearly identical, structurally and biochemically. Even the removal of PRMT1’s gene from lab mice as an alternative way to study its functions was problematic, since mouse embryos can’t survive without the protein.

Inspiration Close By

The inspiration for the new PRMT1-selective screening technique came from research performed in the neighboring laboratory of co-author Benjamin F. Cravatt III, who chairs the Scripps Research Department of Chemical Physiology. As reported in 2010 in the journal Nature, Cravatt and his team screened tens of thousands of human and mouse proteins for the presence of hyper-reactive cysteine amino acids, which almost certainly mark functional sites on those proteins. PRMT1 was found to be one of the reactive-cysteine-containing proteins — and all but one other, comparatively rare PRMT enzyme was known to lack that cysteine.

“We took that discovery a step further, and we were able to find a probe that specifically would recognize that cysteine in PRMT1,” said Mowen, who was one of Cravatt’s collaborators on the 2010 study.

She and her colleagues first verified that the reactive cysteine in PRMT1 is in the active site of the enzyme. They then found a fluorescent probe that would bind to that cysteine. If a test compound acted as an inhibitor by fastening to PRMT1’s active site, it should interfere with the probe’s binding, and the probe’s fluorescence-based signal therefore should be lower. By contrast, if a test compound failed to bind to PRMT1’s active site, the probe should bind normally and its signal should remain elevated.

“We were able to verify, using available non-specific inhibitors of PRMT enzymes, that they did indeed bind to PRMT1 and prevent the probe from binding, and that was the proof-of-concept that enabled us to go ahead with a screen,” said Myles B. C. Dillon, a graduate student in Mowen’s lab who was lead author of the study.

Exploring Libraries of Potential

Dillon and Mowen turned to collaborator Scripps Research Professor Hugh Rosen, curator of a library of 16,000 chemical compounds known as the Maybridge Hitfinder Collection. By applying these compounds, one by one, along with the probe molecule, to solutions of PRMT1, the team was able to determine the compounds’ abilities to bind PRMT1’s active site and thus act as inhibitors. Importantly, the setup was simple enough to be adapted, with Rosen’s help, as an automated, “high-throughput” technique, capable of screening thousands of compounds.

In this way, the scientists were able to sift through the compound library to find two candidate PRMT1-selective inhibitors. “They have good efficacy and specificity, and we might be able to modify them to make them even better,” said Dillon.

Mowen, Dillon, and their colleagues now have a National Institutes of Health (NIH) grant to use their screening technique with a 300,000-compound NIH library, also curated at Scripps Research. “Once we get the results from this larger screen, we’ll consider our best inhibitor compounds and decide which ones to start optimizing,” said Dillon.

To Mowen, the success of the project owes much to the collaborative spirit at Scripps Research. “Many labs here are developing cutting-edge technologies that empower other labs’ work, and certainly we were able to benefit from that,” she said. “It’s a very supportive, synergistic environment.”

http://www.sciencedaily.com/releases/2012/05/120511104815.htm

Journal reference: Myles B. C. Dillon, Daniel A. Bachovchin, Steven J. Brown, M. G. Finn, Hugh Rosen, Benjamin F. Cravatt, Kerri A. Mowen. Novel Inhibitors for PRMT1 Discovered by High-Throughput Screening Using Activity-Based Fluorescence Polarization. ACS Chemical Biology, 2012; : 120420132930009 DOI: 10.1021/cb300024c

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SMOKING GETS AHOLD OF YOU: a worse prognosis in coronary heart disease

Posted in Biological Networks, Gene Regulation and Evolution, Cardiovascular Pharmacogenomics, Disease Biology, Small Molecules in Development of Therapeutic Drugs, Health Economics and Outcomes Research, Pharmacotherapy of Cardiovascular Disease, Population Health Management, Genetics & Pharmaceutical, tagged , , , , , , , , on May 10, 2012| 1 Comment »

Methylation of the gene F2RL3—which has been linked with platelet activation and inflammation—was lowest in smokers and highest in nonsmokers. Methylation is an important source of variation and regulation in the genome in Epigenetic modification of DNA. In a prospective study in patients with stable coronary heart disease, lower F2RL3 methylation in smokers and former smokers indicated a worse prognosis with excess cardiovascular mortality as well as overall mortality.

The authors found a correlation between F2RL3 methylation intensity and established prognostic markers, including natriuretic peptide, C-reactive protein, and interleukin-6. Current standard medical treatment for coronary artery disease did not affect F2RL3 methylation.

This article was published in European Heart Journal

L. P. Breitling et al., Smoking, F2RL3 methylation, and prognosis in stable coronary heart disease. Eur. Heart J. 17 April 2012

http://eurheartj.oxfordjournals.org/content/early/2012/04/16/eurheartj.ehs091.abstract

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Researchers develop cancer cell-screening biochip to understand the efficacy of especially anti-cancer drugs against CSCs.

Posted in CANCER BIOLOGY & Innovations in Cancer Therapy, Cell Biology, Signaling & Cell Circuits, Disease Biology, Small Molecules in Development of Therapeutic Drugs, tagged , , , , , , , , , , , , on May 9, 2012| 2 Comments »

Reporter: Venkat Karra, Ph.D.

Researchers at Singapore’s Institute of Bioengineering and Nanotechnology (IBN) have developed a miniaturized biochip that promises to boost the development of more effective cancer drugs.

The Agency for Science, Technology and Research said on Wednesday that its research into the effect of drugs on cancer stem cells (CSCs) would shed light on cells that are resistant to drugs, local TV Channel NewsAsia reported.

It also explained how the technology works on CSCs, which form a small and distinct class of cancer cells in a tumor.

CSCs are more resistant to chemotherapy and if they are not eradicated, CSCs can repopulate the tumor and lead to cancer recurrence. It is therefore important for researchers to understand the efficacy of anti-cancer drugs against CSCs.

However, CSCs are scarce, making up about 1 percent of cancer cells.

This hampers studies using conventional drug screening methods, which require large sample volumes and are slow and expensive.

The IBN researchers found an answer, by developing a miniaturized biological assay, called the Droplet Array. It performs cheaper, faster and more convenient drug screening using limited samples.

In traditional biological assays, microplates — a flat plate with multiple wells in which samples are placed – are commonly used. Each requires at least 2,500 or 5,000 cells, to be present for viable analysis. IBN’s Droplet Array requires only 500 cells for screening. This massive reduction in sample volume saves money and makes it easier to study scarce quantities of target cells, such as CSCs.

IBN executive director, Professor Jackie Y Ying, who led the study, was quoted as saying that the Droplet Array marks a significant breakthrough in nanotechnology and lab-on-a-chip concepts. It also provides an efficient platform to speed up drug screening and development.

source:

http://www.chinadaily.com.cn/xinhua/2012-05-09/content_5868419.html

Reporter: Venkat Karra

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