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Cardiac toxicity is a widely reported complication of fluoropyrimidine chemotherapies (5-fluorouracil and capecitabine); however, Takotsubo syndrome (TS) is less widely reported. There is little data available describing the viability of fluoropyrimidine rechallenge after fluoropyrimidine-induced TS. We report the case of Ms X, a 41-year-old woman with metastatic oesophageal cancer, who developed acute onset left ventricular dysfunction, with a measured left ventricular ejection fraction of 15% on cycle 1 day 3 of FOLFOX chemotherapy, after disconnection of the fluorouracil infusion pump. Her symptoms resolved over 2 days, and an echocardiogram returned to normal within 2 weeks. 5-Fluorouracil was discontinued, and replaced with capecitabine, without recurrence of symptoms. The remainder of her treatment was uneventful. This is the second case to describe successful capecitabine retreatment following 5-fluorouracil-induced TS. [ABSTRACT FROM AUTHOR]

Purpose: The circadian rhythm hypothesis of bipolar disorder (BD) suggests a role for melatonin in regulating mood, thus extending the interest toward the melatonergic antidepressant agomelatine as well as type I (acute) or II cases of bipolar depression. Patients and methods: Twenty-eight depressed BD-II patients received open label agomelatine (25 mg/bedtime) for 6 consecutive weeks as an adjunct to treatment with lithium or valproate, followed by an optional treatment extension of 30 weeks. Measures included the Hamilton depression scale, Pittsburgh Sleep Quality Index, the Clinical Global Impression Scale-Bipolar Version, Young Mania Rating Scale, and body mass index. Results: Intent to treat analysis results demonstrated that 18 of the 28 subjects (64%) showed medication response after 6 weeks (primary study endpoint), while 24 of the 28 subjects (86%) responded by 36 weeks. When examining primary mood stabilizer treatment, 12 of the 17 (70.6%) valproate and six of the 11 (54.5%) lithium patients responded by the first endpoint. At 36 weeks, 14 valproate treated (82.4%) and 10 lithium treated (90.9%) subjects responded. At 36 weeks, there was a slight yet statistically significant (P = 0.001) reduction in body mass index and Pittsburgh Sleep Quality Index scores compared to respective baseline values, regardless of mood stabilizer/outcome. Treatment related drop-out cases included four patients (14.28%) at week 6 two valproate-treated subjects with pseudo-vertigo and drug-induced hypomania, respectively, and two lithium-treated subjects with insomnia and mania, respectively. Week 36 drop outs were two hypomanic cases, one per group. Conclusion: Agomelatine 25 mg/day was an effective and well-tolerated adjunct to valproate/lithium for acute depression in BD-II, suggesting the need for confirmation by future double blind, controlled clinical trials. [ABSTRACT FROM AUTHOR]

Abstract: G-protein coupled receptor kinase-3 (GRK3), translated from the gene, ADRBK2 has been implicated as a candidate molecule for bipolar disorder through multiple, converging lines of evidence. In some individuals, the ADRBK2 gene harbors the A-haplotype, a collection of single nucleotide polymorphisms (SNPs) previously associated with an increased risk for bipolar disorder. Because the A-haplotype encompasses the ADRBK2 promoter, we hypothesized that it may alter the regulation of gene expression. Using histone H3 acetylation to infer promoter activity in lymphoblastoid cells from patients with bipolar disorder, we examined the A-haplotype within its genomic context and determined that at least four of its SNPs are present in transcriptionally active portions of the promoter. However, using chromatin immunoprecipitation followed by allele-specific PCR in samples heterozygous for the A-haplotype, we found no evidence of altered levels of acetylated histone H3 at the affected allele compared to the common allele. Similarly, using a transcribed SNP to discriminate expressed ADRBK2 mRNA strands by allele of origin; we found that the A-haplotype did not confer an allelic-expression imbalance. Our data suggest that while the A-haplotype is situated in active regulatory sequence, the risk-associated SNPs do not appear to affect ADRBK2 gene regulation at the level of histone H3 acetylation nor do they confer measurable changes in transcription in lymphoblastoid cells. However, tissue-specific mechanisms by which the A-haplotype could affect ADRBK2 in the central nervous system cannot be excluded. [Copyright &y& Elsevier]

The article reports that two research papers that focused on the beneficial effects of the blood pressure drug ramipril in patients with intermittent claudication resulting from peripheral artery disease were retracted after it was discovered that data were fabricated.

Reports on community-associated meticillin-resistant Staphylococcus aureus or CA-MRSA, which are resitant to all β-lactam antibiotics, including cephalosporins. Virulence of CA-MRSA in some United States communities; Outbreak among prison inmates and others; Indication that hospital strains are resistant to several drugs; Characteristics that distinguish CA-MRSA strains from hospital MRSA strains; Mention of pediatric research and mortality by Robert Daum and co-workers in Chicago and by Sheldon Kaplan and co-workers in Texas; How β-lactam antibiotics kill staphylococci; Significance of the mecA gene and cassette in MRSA strains; Efforts to determine the virulence and prevalence of CA-MRSA; Recommended first-line therapy.

Focuses on the ALLHAT hypertension and lipid treatment trial. Comment of epidemiology professor, Paul Whelton, who was on the ALLHAT steering committee; Details of the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack study which compared calcium-channel blocker amlopidine, the angiotensin-converting enzyme (ACE) inhibitor lisinopril, and the α-adrenergic blocker doxazosin with chlorthalidone, an old thiazide diuretic; Reaction of drug companies to the results; Discussion of the outlook for marketing campaigns.

The article informs that a panel of the U.S. Preventive Services Task Force suggests physicians to prescribe breast cancer drugs such as tamoxifen or raloxifene to women who have higher risk of breast cancer and lower risk of side effect.

This article reports on the spread of drug-resistant gonorrhoeae in the United States. The U.S. Centers for Disease Control and Prevention (CDC) no longer recommends fluoroquinolones for the treatment of Neisseria gonorrhoeae. The drugs have lost their therapeutic effect as a drug resistant strain of the disease, believed to have come from south east Asia, took hold in America. The CDC is recommending the use of ceftriaxone or cefixime in the treatment of uncomplicated urogenital or anorectal gonorrhoeae. Cephalosporins are the last class of antibiotic for which resistance has not been detected.

The article profiles Tadtaka Yamada, president of the Bill and Melinda Gates Foundation Global Health Program. Yamada was enlightened regarding the problems of world health when his employer, SmithKline Beecham, sued to keep South Africa from obtaining cheap generic copies of its HIV drug. Yamada went from academic medicine to industry at SmithKline. After the South Africa suit, Yamada set up the Developing World Drug Discovery Unit in the company to find treatments and cures for malaria and tuberculosis.

The narrative describes the author's travel experience, which began at the Mumbai airport where he had symptoms of gastroenteritis. He was relieved to think that the abdominal pain that subsided during the flight to London was caused by a kidney stone. The hotel doctor concurred that the pain and vomiting was caused by "gravel". The author decided not to go to the hospital and continued his chosen treatment of water and ibuprofen. After a flight to America, the condition was diagnosed as nephrolithiasis. The recommended treatment was fluids and ibuprofen.

Reports that the U.S. Food and Drug Administration has decided to reapprove the use of alosetron hydrochloride to treat irritable bowel syndrome. Controversy about the drug, which was pulled from the market after reports of dangerous side effects; Restrictions on the use of the drug; Response of the drug's manufacturer, GlaxoSmithKline.

Focuses on drugs that appear to be potent against HIV, including strains that are resistant, according to research presented at the 9th Annual Conference on Retroviruses and Opportunistic Infections, which was held in Seattle, Washington in February 2002. Mention of anti-HIV drugs that are entry inhibitors and integrase inhibitors.; Discussion of non-nucleoside reverse transcriptase inhibitors (NNRTI) and of TMC 125, a drug developed by Tibotec-Virco in Belgium.

Reports that weeds may have more medicinal value than jungle plants. How weeds are more likely to rely on chemical warfare to fight off plant-eating animals and insects than are jungle plants, which increases their likelihood of containing compounds that have pharmacological effects; Details of studies on the medicinal plant use of residents of Chiapas, Mexico, and of native Americans.

Reports a revision of United States HIV treatment guidelines which reflects a more conservative approach to patients who have not developed symptoms. Effect on the use of antiretroviral agents; Role of the Department of Health and Human Services and the Henry J Kaiser Foundation; Recommendations for conditions under which treatment should begin that should minimize side effects and reduce the likelihood of drug-resistant strains.

Reports on the concern over the use of psychotropic drugs to treat young children with attention deficit hyperactivity disorder (ADHD) in the United States. Efforts of First Lady Hillary Rodham Clinton to launch an initiative to improve care of children with ADHD; Four federal programs included in the initiative; Concern that psychotropic drugs are being overprescribed.

Reports that neostigmine, an inhibitor of acetylcholinesterase can effectively decompress dilated colons of patients with acute colonic pseudo-obstruction. Severe form of adynamic ileus; Loss of normal colonic motility by imbalance in the parasympathetic and sympathetic stimulation of the bowel.

Reports on results of a phase II study of nose drops containing IM862. The ability of this peptide to inhibit production of vascular endothelial growth factor and basic fibroblast growth factor; The success rate of this treatment in patients with AIDS-related Kaposi's sarcoma; Trials of the drug for other cancers.

Reports on the findings of three studies done regarding possible treatments for HIV. Use of a protein which causes HIV-infected cells to under go apoptosis, or cell death; Efforts to settle the debate regarding the role of HIV-specific CD8 cytoxic T lymphocytes (CTLs) in HIV infection; Indications that HIV may reduce CD4 T-cell counts by inhibiting their production.

Reports on studies being conducted to determine whether the human adult can manufacture new T-cells. How T cell counts in patients with HIV-1 rebound after highly active antiretroviral therapy (HAART); Search for T-cell-receptor rearrangement excision circles (TRECs); Findings.

Reports that patients with metastatic prostate cancer treated with the antiandrogen flutamide after orchiectomy reported a lower quality of life (Qol). Carol Moinpour and co-workers in Seattle, Washington conducting a Qol study; Brief details of the study; The suspected ability of flutamide to block androgen receptors in the brain.

Reports on the United States National heart, Lung, and Blood Institute working group's advise to the United States emergency departments on their patient evaluation procedures for heart attack patients. Identification of four points by the National Heart Attack Alert Program (NHAAP); Recommendation of the NHAAP report.

Reports on the preventive treatment of neonatal jaundice with tin-mesoporphyrin (SnMP) or other synthetic haem analogues. Usefulness in developing countries where it is not possible to provide phototherapy or exchange transfusions; Test on 517 preterm babies born at Athen's Metera Maternity Hospital; Efficacy of the injections; Photosensitivity as a side-effect.

Reports on the proposed bill that would place a 25 percent sales tax on firearms and increase the fee for a three-year federal gun dealer's license, which will all help pay for the health care reform. Federal expenses incurred by medical care for gunshot victims; Placing of the generated revenues in a health care trust fund; Rationale of the bill's opponents.

Focuses on the guidelines issued by the US Agency for Health Care Policy and Research on the treatment of depression for primary-care doctors which urges them to be more aggressive in their diagnosis and treatment of the disease. Numbers of Americans not being properly diagnosed and treated; Recommendations for medication; Other conclusions.

Reports on the work of Richard Morgan who, along with colleagues, investigated the use of gene therapy in the treatment of HIV-1 infection. Details of the study; Findings.

States the United States Food and Drug Administration banned the sale of Cholestin, made by Pharmanex. The drug used as a dietary supplement to lower cholesterol; Cholestin containing red yeast rice; How the product is made; Manipulation of the fermentation process to produce lovastatin; The pharmaceutical company, Merck, marketing the drug under the name Mevcor. INSET: And AFCAPS/TexCAPS reports.

Reports on a United States study which suggests that doctors taking care of patients with cerebral arteriovenous malformations (AVM) may do less harm by simply leaving them alone. The findings in the journal `Stroke,' (1998; 29: 931-934), by Andreas Hartmann and colleagues of the Neurological Institute at Columbia-Presbyterian Medical Center in New York City.

To generate potent vaccine responses, subunit protein antigens typically require coformulation with an adjuvant. Oil-in-water emulsions are among the most widely investigated adjuvants, based on their demonstrated ability to elicit robust antibody and cellular immune responses in the clinic. However, most emulsions cannot be readily frozen or lyophilized, on account of the risk of phase separation, and may have a deleterious effect on protein antigen stability when stored long term as a liquid coformulation. To circumvent this, current emulsion-formulated vaccines generally require a complex multivial presentation with obvious drawbacks, making a single-vial presentation for such products highly desirable. We describe the development of a stable, lyophilized squalene emulsion adjuvant through innovative formulation and process development approaches. On reconstitution, freeze-dried emulsion preparations were found to have a minimal increase in particle size of ∼20 nm and conferred immunogenicity in BALB/c mice similar in potency to freshly prepared emulsion coformulations in liquid form. [ABSTRACT FROM AUTHOR]

Respiratory syncytial virus (RSV) infection of children previously immunized with a nonlive, formalin-inactivated (FI)-RSV vaccine has been associated with serious enhanced respiratory disease (ERD). Consequently, detailed studies of potential ERD are a critical step in the development of nonlive RSV vaccines targeting RSV-naive children and infants. The fusion glycoprotein (F) of RSV in either its postfusion (post-F) or prefusion (pre-F) conformation is a target for neutralizing antibodies and therefore an attractive antigen candidate for a pediatric RSV subunit vaccine. Here, we report the evaluation of RSV post-F and pre-F in combination with glucopyranosyl lipid A (GLA) integrated into stable emulsion (SE) (GLA-SE) and alum adjuvants in the cotton rat model. Immunization with optimal doses of RSV F antigens in the presence of GLA-SE induced high titers of virus-neutralizing antibodies and conferred complete lung protection from virus challenge, with no ERD signs in the form of alveolitis. To mimic a waning immune response, and to assess priming for ERD under suboptimal conditions, an antigen dose de-escalation study was performed in the presence of either GLA-SE or alum. At low RSV F doses, alveolitis-associated histopathology was unexpectedly observed with either adjuvant at levels comparable to FI-RSV-immunized controls. This occurred despite neutralizing-antibody titers above the minimum levels required for protection and with no/low virus replication in the lungs. These results emphasize the need to investigate a pediatric RSV vaccine candidate carefully for priming of ERD over a wide dose range, even in the presence of strong neutralizing activity, Th1 bias-inducing adjuvant, and protection from virus replication in the lower respiratory tract. [ABSTRACT FROM AUTHOR]

Background: Benznidazole is recommended for treatment of Chagas infection. Effects of combination therapy with benznidazole and posaconazole have not been tested in Trypanosoma cruzi carriers.Objectives: The purpose of this study was to determine whether posaconazole alone or combined with benznidazole were superior to benznidazole monotherapy in eliminating T. cruzi parasites measured by real time polymerase chain reaction (RT-PCR) in asymptomatic Chagas carriers.Methods: A prospective, multicenter randomized placebo-controlled study was conducted in 120 subjects from Latin America and Spain who were randomized to 4 groups: posaconazole 400 mg twice a day (b.i.d.); benznidazole 200 mg + placebo b.i.d.; benznidazole 200 mg b.i.d. + posaconazole 400 mg b.i.d.; or placebo 10 mg b.i.d. T. cruzi deoxyribonucleic acid was detected by RT-PCR at 30, 60, 90, 120, 150, 180, and 360 days. The primary efficacy outcome is the proportion of subjects with persistent negative RT-PCR by day 180; the secondary outcome was negative RT-PCR at 360 days.Results: Only 13.3% of those receiving posaconazole and 10% receiving placebo achieved the primary outcome, compared with 80% receiving benznidazole + posaconazole and 86.7% receiving benznidazole monotherapy (p < 0.0001 vs. posaconazole/placebo). Posaconazole monotherapy or posaconazole combined with benznidazole achieved high RT-PCR conversion rates during treatment (30 days; 93.3% and 88.9% and 60 days; 90%, and 92.3%) that were similar to benznidazole (89.7% and 89.3%); all were superior to placebo or posaconazole (10% and 16.7%, p < 0.0001). This was not observed at 360 days; benznidazole + posaconazole and benznidazole monotherapy (both 96%) versus placebo (17%) and posaconazole (16%, p < 0.0001). Serious adverse events were rare (6 patients) and were observed in the benznidazole-treated patients. Permanent discontinuation was reported in 19 patients (31.7%) receiving either benznidazole monotherapy or combined with posaconazole.Conclusions: Posaconazole demonstrated trypanostatic activity during treatment, but it is ineffective long-term in asymptomatic T. cruzi carriers. Benznidazole monotherapy is superior to posaconazole, with high RT-PCR conversion rates sustained at 1 year. Side effects lead to therapy discontinuation in 32%. No advantages were observed with combined therapy versus benznidazole monotherapy. (A Study of the Use of Oral Posaconazole [POS] in the Treatment of Asymptomatic Chronic Chagas Disease [P05267] [STOP CHAGAS]: NCT01377480). [ABSTRACT FROM AUTHOR]

Respiratory syncytial virus (RSV) is the most common cause of serious viral bronchiolitis in infants, young children, and the elderly. Currently, there is not an FDA-approved vaccine available for RSV, though the mAb palivizumab is licensed to reduce the incidence of RSV disease in premature or at-risk infants. The palivizumab epitope is a well-characterized, approximately 24-aa helix-loop-helix structure on the RSV fusion (F) protein (F254-277). Here, we genetically inserted this epitope and multiple site variants of this epitope within a versatile woodchuck hepadnavirus core-based virus-like particle (WHcAg-VLP) to generate hybrid VLPs that each bears 240 copies of the RSV epitope in a highly immunogenic arrayed format. A challenge of such an epitope-focused approach is that to be effective, the conformational F254-277 epitope must elicit antibodies that recognize the intact virus. A number of hybrid VLPs containing RSV F254-277 were recognized by palivizumab in vitro and elicited high-titer and protective neutralizing antibody in rodents. Together, the results from this proof-of-principle study suggest that the WHcAg-VLP technology may be an applicable approach to eliciting a response to other structural epitopes. [ABSTRACT FROM AUTHOR]