Melatonin ameliorates calcium homeostasis in myocardial and ischemia-reperfusion injury in chronically hypoxic rats

Chronic hypoxia (CH) leads to the deterioration of myocardial functions with impaired calcium handling in the sarcoplasmic reticulum (SR), which may be mediated by oxidative stress. We hypothesized that administration of antioxidant melatonin would protect against cardiac and ischemia-reperfusion (I/R) injury by ameliorating SR calcium handling. Adult Sprague-Dawley rats that had received a daily injection of melatonin or vehicle were exposed to 10% oxygen for 4 wk. The heart of each rat was then dissected and perfused using a Langendorff apparatus. The ratio of heart-to-body weight, ventricular hypertrophy and hematocrit were increased in the hypoxic rats compared with the normoxic controls. Malondialdehyde levels were also increased in the heart of hypoxic rats and were lowered by the treatment of melatonin. The hearts were subjected to left coronary artery ischemia (30 min) followed by 120-min reperfusion. Lactate dehydrogenase leakage before ischemia, during I/R and infarct size of the isolated perfused hearts were significantly elevated in the vehicle-treated hypoxic rats but not in the melatonin-treated rats. Spectroflurometric studies showed that resting calcium levels and I/R-induced calcium overload in the cardiomyocytes were more significantly altered in the hypoxic rats than the normoxic controls. Also, the hypoxic group had decreased levels of the SR calcium content and reduced amplitude and decay time of electrically induced calcium transients, indicating impaired contractility and SR calcium re-uptake. Moreover, there were reductions in protein expression of calcium handling proteins, markedly shown at the level of SR-Ca2+ ATPase (SERCA) in the heart of hypoxic rats. Melatonin treatment significantly mitigated the calcium handling in the hypoxic rats by preserving SERCA expression. The results suggest that melatonin is cardioprotective against CH-induced myocardial injury by improving calcium handling in the SR of cardiomyocytes via an antioxidant mechanism. © 2008 The Authors.postprin

Melatonin attenuates pulmonary hypertension in chronically hypoxic rats

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Inhibition of class I histone deacetylases by romidepsin potently induces Epstein-Barr virus lytic cycle and mediates enhanced cell death with ganciclovir

Pan-histone deacetylase (HDAC) inhibitors, which inhibit 11 HDAC isoforms, are widely used to induce Epstein-Barr virus (EBV) lytic cycle in EBV-associated cancers in vitro and in clinical trials. Here, we hypothesized that inhibition of one or several specific HDAC isoforms by selective HDAC inhibitors could potently induce EBV lytic cycle in EBV-associated malignancies such as nasopharyngeal carcinoma (NPC) and gastric carcinoma (GC). We found that inhibition of class I HDACs, particularly HDAC-1, -2 and -3, was sufficient to induce EBV lytic cycle in NPC and GC cells in vitro and in vivo. Among a panel of selective HDAC inhibitors, the FDA-approved HDAC inhibitor romidepsin was found to be the most potent lytic inducer, which could activate EBV lytic cycle at ∼0.5 to 5 nM (versus ∼800 nM achievable concentration in patients' plasma) in more than 75% of cells. Upregulation of p21WAF1 , which is negatively regulated by class I HDACs, was observed before the induction of EBV lytic cycle. The upregulation of p21WAF1 and induction of lytic cycle were abrogated by a specific inhibitor of PKC-δ but not the inhibitors of PI3K, MEK, p38 MAPK, JNK or ATM pathways. Interestingly, inhibition of HDAC-1, -2 and -3 by romidepsin or shRNA knockdown could confer susceptibility of EBV-positive epithelial cells to the treatment with ganciclovir (GCV). In conclusion, we demonstrated that inhibition of class I HDACs by romidepsin could potently induce EBV lytic cycle and mediate enhanced cell death with GCV, suggesting potential application of romidepsin for the treatment of EBV-associated cancers.postprin

Comparative evaluation of a point-of-care immunochromatographic test SNAP 4Dx with molecular detection tests for vector-borne canine pathogens in Hong Kong

There are no comprehensive studies on the performance of commonly used point-of-care diagnostic enzyme immunoassay for common arthropod-borne canine pathogens. A comparative evaluation of an immunochromatographic test for these infections with a comprehensive polymerase chain reaction (PCR) test panel was performed on 100 pet dogs and 100 stray dogs without obvious clinical symptoms. Of the 162 positive test results from both immunochromatographic test and PCR, there was 85.2% concordance. The 24 discordant results between serology and PCR occurred in tests involving Ehrlichia canis (14) and Anaplasma platys (10), which may be related to the time of infection. No positive cases of borreliosis or rickettsiosis were detected. One important limitation of the immunochromatographic test was its lack of testing for babesiosis and hepatozoonosis. The former is the most prevalent arthropod-borne canine infection in our cohort (41%). Coinfections were found in 19% stray dogs and 6% of pet dogs with both tests (p<0.01). Seventeen and 8 samples from stray and pet dogs, respectively, were initially positive in the PCR test for Ehrlichia. However, on sequencing of the PCR amplicon, 10 from stray and 2 from pet dogs were found to be Wolbachia sequences instead, with 100% nucleotide identity to the 16S rRNA sequence of Wolbachia endosymbiont of Dirofilaria immitis. The presence of Wolbachia DNAemia (6%) correlated well with the molecular test and immunochromatographic antigen test for D. immitis. © Copyright 2011, Mary Ann Liebert, Inc.published_or_final_versio

Middle East respiratory syndrome coronavirus M protein suppresses type I interferon expression through the inhibition of TBK1-dependent phosphorylation of IRF3

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Lineage Divergence and Historical Gene Flow in the Chinese Horseshoe Bat (Rhinolophus sinicus)

PMCID: PMC3581519This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited

Use and limitations of malaria rapid diagnostic testing by community health workers in war-torn Democratic Republic of Congo

<p>Abstract</p> <p>Background</p> <p>Accurate and practical malaria diagnostics, such as immunochromatographic rapid diagnostic tests (RDTs), have the potential to avert unnecessary treatments and save lives. Volunteer community health workers (CHWs) represent a potentially valuable human resource for expanding this technology to where it is most needed, remote rural communities in sub-Saharan Africa with limited health facilities and personnel. This study reports on a training programme for CHWs to incorporate RDTs into their management strategy for febrile children in the Democratic Republic of Congo, a tropical African setting ravaged by human conflict.</p> <p>Methods</p> <p>Prospective cohort study, satisfaction questionnaire and decision analysis.</p> <p>Results</p> <p>Twelve CHWs were trained to safely and accurately perform and interpret RDTs, then successfully implemented rapid diagnostic testing in their remote community in a cohort of 357 febrile children. CHWs were uniformly positive in evaluating RDTs for their utility and ease of use. However, high malaria prevalence in this cohort (93% by RDTs, 88% by light microscopy) limited the cost-effectiveness of RDTs compared to presumptive treatment of all febrile children, as evidenced by findings from a simplified decision analysis.</p> <p>Conclusions</p> <p>CHWs can safely and effectively use RDTs in their management of febrile children; however, cost-effectiveness of RDTs is limited in zones of high malaria prevalence.</p

Accelerated search for biomolecular network models to interpret high-throughput experimental data

<p>Abstract</p> <p>Background</p> <p>The functions of human cells are carried out by biomolecular networks, which include proteins, genes, and regulatory sites within DNA that encode and control protein expression. Models of biomolecular network structure and dynamics can be inferred from high-throughput measurements of gene and protein expression. We build on our previously developed fuzzy logic method for bridging quantitative and qualitative biological data to address the challenges of noisy, low resolution high-throughput measurements, i.e., from gene expression microarrays. We employ an evolutionary search algorithm to accelerate the search for hypothetical fuzzy biomolecular network models consistent with a biological data set. We also develop a method to estimate the probability of a potential network model fitting a set of data by chance. The resulting metric provides an estimate of both model quality and dataset quality, identifying data that are too noisy to identify meaningful correlations between the measured variables.</p> <p>Results</p> <p>Optimal parameters for the evolutionary search were identified based on artificial data, and the algorithm showed scalable and consistent performance for as many as 150 variables. The method was tested on previously published human cell cycle gene expression microarray data sets. The evolutionary search method was found to converge to the results of exhaustive search. The randomized evolutionary search was able to converge on a set of similar best-fitting network models on different training data sets after 30 generations running 30 models per generation. Consistent results were found regardless of which of the published data sets were used to train or verify the quantitative predictions of the best-fitting models for cell cycle gene dynamics.</p> <p>Conclusion</p> <p>Our results demonstrate the capability of scalable evolutionary search for fuzzy network models to address the problem of inferring models based on complex, noisy biomolecular data sets. This approach yields multiple alternative models that are consistent with the data, yielding a constrained set of hypotheses that can be used to optimally design subsequent experiments.</p

A study of a culturally focused psychiatric consultation service for Asian American and Latino American primary care patients with depression

<p>Abstract</p> <p>Background</p> <p>Ethnic minorities with depression are more likely to seek mental health care through primary care providers (PCPs) than mental health specialists. However, both provider and patient-specific challenges exist. PCP-specific challenges include unfamiliarity with depressive symptom profiles in diverse patient populations, limited time to address mental health, and limited referral options for mental health care. Patient-specific challenges include stigma around mental health issues and reluctance to seek mental health treatment. To address these issues, we implemented a multi-component intervention for Asian American and Latino American primary care patients with depression at Massachusetts General Hospital (MGH).</p> <p>Methods/Design</p> <p>We propose a randomized controlled trial to evaluate a culturally appropriate intervention to improve the diagnosis and treatment of depression in our target population. Our goals are to facilitate a) primary care providers' ability to provide appropriate, culturally informed care of depression, and b) patients' knowledge of and resources for receiving treatment for depression. Our two-year long intervention targets Asian American and Latino American adult (18 years of age or older) primary care patients at MGH screening positive for symptoms of depression. All eligible patients in the intervention arm of the study who screen positive will be offered a culturally focused psychiatric (CFP) consultation. Patients will meet with a study clinician and receive toolkits that include psychoeducational booklets, worksheets and community resources. Within two weeks of the initial consultation, patients will attend a follow-up visit with the CFP clinicians. Primary outcomes will determine the feasibility and cost associated with implementation of the service, and evaluate patient and provider satisfaction with the CFP service. Exploratory aims will describe the study population at screening, recruitment, and enrollment and identify which variables influenced patient participation in the program.</p> <p>Discussion</p> <p>The study involves an innovative yet practical intervention that builds on existing resources and strives to improve quality of care for depression for minorities. Additionally, it complements the current movement in psychiatry to enhance the treatment of depression in primary care settings. If found beneficial, the intervention will serve as a model for care of Asian American and Latino American patients.</p> <p>Trial Registration</p> <p>ClinicalTrials.gov: <a href="http://www.clinicaltrials.gov/ct2/show/NCT01239407">NCT01239407</a></p