Day: 01/21/2011

Resistance of Herpes Simplex Viruses to Nucleoside Analogues: Mechanisms, Prevalence, and Management

Posted by

0


Herpes simplex viruses (HSV) type 1 and type 2 are responsible for recurrent orolabial and genital infections. The standard therapy for the management of HSV infections includes acyclovir (ACV) and penciclovir (PCV) with their respective prodrugs valacyclovir and famciclovir. These compounds are phosphorylated by the viral thymidine kinase (TK) and then by cellular kinases. The triphosphate forms selectively inhibit the viral DNA polymerase (DNA pol)activity. Drug-resistant HSV isolates are frequently recovered from immunocompromised patients but rarely found in immunocompetent subjects. The gold standard phenotypic method for evaluating the susceptibility of HSV isolates to antiviral drugs is the plaque reduction assay. Plaque autoradiography allows the associated phenotype to be distinguished (TK-wild-type, TK-negative, TK-low-producer, or TK-altered viruses or mixtures of wild-type and mutant viruses). Genotypic characterization of drug-resistant isolates can reveal mutations located in the viral TK and/or in the DNA pol genes. Recombinant HSV mutants can be generated to analyze the contribution of each specific mutation with regard to the drug resistance phenotype. Most ACV-resistant mutants exhibit some reduction in their capacity to establish latency and to reactivate, as well as in their degree of neurovirulence in animal models of HSV infection. For instance, TK-negative HSV mutants establish latency with a lower efficiency than wild-type strains and reactivatepoorly. DNA pol HSV mutants exhibit different degrees of attenuation of neurovirulence. The management of ACV- or PCV-resistant HSV infections includes the use of the pyrophosphate analogue foscarnet and the nucleotide analogue cidofovir. There is a need to develop new antiherpetic compounds with different mechanisms of action.

source: journal of virology

 

Clinical manifestations and prognostic factors in cancer patients with bacteremia due to extended-spectrum β-lactamase-producing bacteria

Posted by

0


Clinical information about bacteremia due to extended-spectrum β-lactamase (ESBL)-producing pathogens in cancer patients was limited. The study was aimed to identify the clinical manifestations and risk factors for mortality in ESBL-producer bacteremia in cancer patients.

Methods

A retrospective study of bacteremia caused by ESBL-producing Escherichia coli or Klebsiella pneumoniae in adults with cancer in National Cheng Kung University Hospital and National Taiwan University Hospital from July 2002 to August 2007 was conducted. Clinical characteristics, initial manifestations, and antimicrobial therapy, were analyzed for their association with crude mortality at 14 days after bacteremia onset.

Results

A total 113 episodes of bacteremia caused by E. coli (59.3%), K. pneumoniae (39.8%) or both (0.9%) were included. Patients with hematological malignancy were younger (55±22 vs. 69±14 years, P<0.003) and had less co-morbidity, but were more likely to have neutropenia (73.1% vs. 4.6%, P<0.001) than those with solid tumor. By the univariate analysis in 113 episodes of ESBL-producer bacteremia, several risk factors, including pneumonia or soft tissue infection as the bacteremia source, initial manifestations with high Pitt bacteremia scores, shock, respiratory failure or severe sepsis, and inappropriate definitive therapy, were associated with 14-day crude mortality. By multivariate analysis, only pneumonia (adjust odds ratio [aOR], 5.2; 95% confident interval [CI], 1.3-21.0; P=0.021), severe sepsis (aOR, 24.3; 95% CI, 5.6-105.0; P<0.001), and inappropriate definitive therapy (aOR, 11.3; 95% CI, 1.7-72.8;P=0.011) were independently associated with a fatal outcome.

Conclusion

The presence of neutropenia or underlying hematological malignancy in cancer patients with ESBL-producer bacteremia was not associated with an increase in the mortality rate. Appropriate definitive antimicrobial therapy will be beneficial in improving clinical outcome.

source: science direct

Vitamin E and Fatty Acids May Ease PMS

Posted by

0


Study Suggests Supplement May Provide Relief for Symptoms of Premenstrual Syndrome
womans hand holding oil pill

Jan. 19, 2011 — A supplement containing vitamin E and essential fatty acids may help reduce symptoms of premenstrual syndrome(PMS), Brazilian researchers report in Reproductive Health.

Of 120 women with PMS or the more severe premenstrual dysphoric disorder (PMDD), those who took 1- or 2-gram capsules of vitamin E and a combination of gamma linolenic acid, oleic acid, linoleic acid, and other polyunsaturated acids daily showed marked improvements in their PMS symptoms at six months, compared to women who received dummy pills.

The capsules were provided by the Brazilian supplement company Hebron Farmaceutica.

The women who received the higher 2-gram dose of the new supplement showed greater improvements in PMS symptoms than those who received the lower 1-gram dose, the study shows.

PMS symptoms were assessed over six menstrual cycles using the Prospective Record of the Impact and Severity of Menstruation (PRISM), a standardized tool that measures PMS symptoms and their intensity.

Precisely how these supplements combat the symptoms of PMS is not fully understood. But the researchers speculate that the essential fatty acids may affect production of chemicals called prostaglandins, which, in turn, reduce the effects of the hormone prolactin. Too much prolactin or an abnormal response to this hormone may cause PMS symptoms.

The physical and emotional symptoms of PMS symptoms can range from the mild to severe; they usually begin five to 12 days before menstruation and disappear once menstruation starts.

“The results of the current study present some evidence in support of the use of essential fatty acids in PMS patients,” conclude researchers who were led by Edilberto A. Rocha Filho, MD, of the Federal University of Pernambuci in Recife, Pernambuco, Brazil.

The new supplement was safe and the fatty acids did not raise women’s totalcholesterol levels.

Potential PMS Remedy

“A lot of women don’t like to talk about PMS because it is the brunt of bad jokes, but PMS symptoms are no joke and can range from the annoying, like acne and bloating, to serious mood and sleep disruptions,” says Donnica Moore, MD, president of Sapphire Women’s Health in Far Hills, N.J. “PMS is a serious medical problem that affects a majority of women to varying extents.”

“This PMS remedy in the new study can’t be interpreted as a cure, but it is very promising option for women with PMS,” she says. ”The only cure for PMS is menopause.”

Other PMS treatments include oral contraceptives which stop ovulation, exercise,antidepressants, calcium and vitamin D supplements, and nonsteroidal anti-inflammatory medications, Moore says. “Some women respond to all of the above, and some don’t respond to any.”

More PMS treatments are needed, agrees Samantha Meltzer-Brody, MD, director of the perinatal psychiatry of the University of North Carolina at Chapel Hill’s Center for Women’s Mood Disorders.

“Currently available treatments only help half of women with PMS, which means that the other 50% continue to struggle. So anything that shows a promise, such as essential fatty acids, and has minimal side effects, would be a useful contribution,” she says.

Women who think they may have PMS should keep a daily mood-rating diary and follow their moods for two months consecutively, she says. “Really track how your mood fluctuates and correlate it with your menstrual cycle.”

The first step is to make lifestyle changes such as eating a healthy diet and taking a daily multivitamin, exercising, minimizing caffeine intake, and getting good sleep, she says.

These may help minimize PMS symptoms. Also, “Talk to doctor about available options, which would include oral contraceptives and antidepressants,” Meltzer-Brody says.

 

Alcohol May Raise Risk of Irregular Heart Rhythm

Posted by

0


Study Shows Link Between Heavy Drinking and Atrial Fibrillation

glass of beer

Jan. 17, 2011 — People who regularly drink a lot of alcohol are more likely to develop a life-threatening irregular heart rhythm, called atrial fibrillation, than nondrinkers, according to a new study.

Atrial fibrillation is a common type of irregular heart rhythm. Typically, it causes episodes of very fast, irregular heartbeats, which may or may not cause many symptoms. Atrial fibrillation can cause chest pain, shortness of breath, and increase your risk for heart failure and stroke.

Drinking more than a moderate amount of alcohol daily (two drinks for men, one for women) greatly increases your risk for atrial fibrillation, scientists report in the Jan. 25 issue of the Journal of the American College of Cardiology. Until now, studies evaluating the link between habitual alcohol use and atrial fibrillation have not provided consistent results.

The findings are based on a review of results from 14 different studies involving 130,820 participants. Researchers only included studies in which the highest alcohol intake category was defined as two or more drinks per day for men, one or more drinks per day for women, and 1.5 or more drinks per day for both men and women. The team then compared the risk of atrial fibrillation in those who drank the most alcohol and in those with drank the least amount of alcohol.

Who’s at Highest Risk for Atrial Fibrillation?

The researchers discovered that the more a person drank, the higher their risk for atrial fibrillation. Specifically, the risk for atrial fibrillation increased 8% for each standard drink containing 10 grams of alcohol. In other words, one drink per day increases your risk of atrial fibrillation by 8% and two drinks per day increases your risk by 16%.

Study participants who drank the most alcohol were 50% more likely to develop atrial fibrillation than those who drank the least.

It’s not exactly known how alcohol use leads to atrial fibrillation. Some believe that alcohol itself causes biological changes that affect the heart’s ability to maintain a normal rhythm. Others say that long-term, excessive alcohol use is known to lead to heart failure, and that makes irregular heart rhythms more likely.

“Not consuming alcohol at all is the most favorable behavior for avoiding AF [atrial fibrillation],” the researchers write.

 

FDA Approves New Head Lice Treatment

Posted by

0


Drugmaker Says One Application of Natroba Can Treat Head Lice in 10 Minutes
close-up of young girls head and lice comb

Jan. 19, 2011 — The FDA has approved a new treatment for controllinghead lice, called Natroba Topical Suspension 0.9%, and says the substance can be safely used for infestations in children as young as age 4, as well as in older youths and adults.

The manufacturer, ParaPro LLC of Carmel, Ind., says that one application of the treatment, an insecticide, can resolve most problems with head lice in about 10 minutes.

Head lice feed several times daily on human blood and can be found on peoples’ heads and in their eyebrows and eyelashes. Head lice are annoying but are not known to cause disease.

They are spread mainly by direct head-to-head contact. The tiny bugs move by crawling and can easily pass from child to child because kids play closely together, often in large groups. Lice also are spread by sharing of hats, combs, brushes, or towels, and can affect all age groups.

“Natroba provides another option for the topical treatment of head lice infestations, which are especially prevalent in the pediatric population,” Julie Beitz, MD, of the FDA’s Center for Drug Evaluation and Research, says in a news release. “Head lice is a common problem among school children in the United States.”

Safety Record

Natroba is a topical drug that the FDA says should be applied only to the scalp orhair of a child, and exactly as prescribed by a doctor or other health care professional.

The FDA says that Natroba’s safety and effectiveness have been established in two studies.

The agency says 552 people received a 10-minute treatment with Natroba, and that if live lice were seen a week later, another application was tried. The percentage of participants who were lice free after the final Natroba treatment was 86%, compared to 44% in a comparison group.

Side effects included redness and irritation of the eyes and skin, the FDA says.

The agency says safety of Natroba (spinosad) has not been established for children under age 4, and therefore the topical treatment isn’t approved for kids younger than that.

The FDA cautions that the product should not be used in infants because it contains benzyl alcohol, which has been associated with serious adverse reactions, including death, when applied topically to the skin of children younger than 6 months.

ParaPro says in a news release that the medication will become available in the first six months of 2011.

“We believe Natroba gives physicians and parents a game-changing solution to the problem of head lice,” Bill Culpepper III, president of the ParaPro, says in the company’s news release. “Natroba is the only head lice treatment whose approval is supported by superiority studies versus permethrin 1%.” Permethrin 1% is a lotion used to treat head lice.

Culpepper says the FDA’s approval of Natroba is “a significant step forward in the longstanding struggle to treat head lice infestations and we look forward to making the product available in pharmacies nationwide as soon as possible.”

Unlike treatments now available, he says, most children who use Natroba will need only one application and won’t be forced “to sit through extensive, time-consuming nit combing sessions.”

The CDC estimates that 6 million-12 million cases of head lice infestation occur annually among children ages 3 to 11.

source:FDA

 

Epstein barr virus and the human immune system

Posted by

0


Despite triggering strong immune responses, Epstein-Barr virus (EBV) has colonized more than 90% of the adult human population. Successful persistence of EBV depends on the establishment of a balance between host immune responses and viral immune evasion. Here we have extended our studies on the EBV-encoded BILF1 protein,which was recently identified as an immunoevasin that functions by enhancing degradation of major histocompatibility complex class I (MHC-I) antigens via lysosomes. We now demonstrate that disruption of the EKT signaling motif of BILF1 by a K122A mutation impairs the ability of BILF1 to enhance endocytosis of surface MHC-I molecules, while subsequent lysosomal degradation was impaired by deletion of the 21-residue C-terminal tail of BILF1. Furthermore, we identified another mechanism of BILF1 immunomodulation: it targets newly synthesized MHC-I/peptide complexes en route to the cell surface. Importantly, although the diversion of MHC-I on the exocytic pathway caused a relatively modest reduction in cell surface MHC-I, presentation of endogenously processed target peptides to immune CD8+effector T cells was reduced by around 65%. The immune-modulating functions of BILF1 in the context of the whole virus were confirmed in cells lytically infected with a recombinant EBV in which BILF1 was deleted. This study therefore extends our initial observations on BILF1 to show that this immunoevasin can target MHC-I antigen presentation via both the exocytic and endocytic trafficking pathways. The results also emphasize the merits of including functional Tcell recognition assays to gain a more complete picture of immunoevasin effects on the antigen presentation pathway.

soure: journal of virology

 

Two edges of sickle cell disease

Posted by

0


A U.S.-China team has shown that inhibiting signaling between adenosine and the adenosine A2B receptor in blood could prevent vaso-occlusion and consequent organ damage in sickle cell disease.1 The researchers already are in talks with companies to run clinical trials of antagonists of the receptor.

Sickle cell disease results from a mutant form of β-hemoglobin (HBB) that is prone to polymerization under hypoxic conditions, resulting in the collapse of red blood cells (RBCs) into a characteristic sickle shape. The sickled RBCs can block blood vessels to cause acute episodes (vaso-occlusive crises) of pain, ischemia, tissue necrosis, organ damage and mortality.

Hydroxyurea is the only approved drug to prevent vaso-occlusive crises. However, the generic chemotherapeutic increases the risks of anemia, life-threatening infections, teratogenicity and cancer.

There are no therapies approved to treat vaso-occlusive crises once they begin, and the precise molecular mechanisms underlying RBC sickling and vaso-occlusion are poorly understood.

To better understand those mechanisms and identify new disease targets, the U.S.-China team looked for molecules in blood that might drive RBC sickling.

First, metabolomic screens showed that adenosine levels were higher in the blood of sickle cell disease patients and mouse models of the disease than in blood from healthy controls.

Next, the team sought to identify which of the four known adenosine receptors interacted with adenosine to promote RBC sickling. They examined RBCs from transgenic mice lacking each receptor in turn to determine that adenosine A2B receptor (Adora2B)—but none of the other three receptors—was involved in RBC sickling.

To confirm the findings in humans, the team showed that a research-grade ADORA2B antagonist, PAB1115, decreased hypoxia-induced sickling in RBCs from sickle cell patients compared with no treatment. A pegylated formulation of adenosine deaminase (PEG-ADA), which is an enzyme that metabolizes adenosine, generated similar results.

In mouse models, PAB1115 or PEG-ADA also decreased RBC sickling compared with no treatment. Treated animals experienced less vaso-occlusion and less damage to the lungs, liver, spleen and kidneys than untreated controls.

Data were reported in Nature Medicine.1

The team was led by Yang Xia, associate professor of biochemistry and molecular biology at The University of Texas Health Science Center at Houston. The group also included researchers from Central South University,The First Xiangya Hospital, The Third Xiangya Hospital, the University of Colorado Denver and Metabolon Inc., which performed the metabolomic screens in mouse blood.

Xia told SciBX her team is negotiating with undisclosed drug companies to conduct clinical trials of ADORA2Bantagonists to prevent vaso-occlusive crises in sickle cell disease.

source: nature medicine