GSBS Student Publications Copyright (c) 2013 University of Massachusetts Medical School All rights reserved. http://escholarship.umassmed.edu/gsbs_sp Recent documents in GSBS Student Publications en-us Mon, 17 Jun 2013 14:18:40 PDT 3600 Translational control of mitochondrial energy production mediates neuron morphogenesis http://escholarship.umassmed.edu/gsbs_sp/1827 http://escholarship.umassmed.edu/gsbs_sp/1827 Wed, 05 Jun 2013 12:04:16 PDT Mitochondrial energy production is a tightly regulated process involving the coordinated transcription of several genes, catalysis of a plethora of posttranslational modifications, and the formation of very large molecular supercomplexes. The regulation of mitochondrial activity is particularly important for the brain, which is a high-energy-consuming organ that depends on oxidative phosphorylation to generate ATP. Here we show that brain mitochondrial ATP production is controlled by the cytoplasmic polyadenylation-induced translation of an mRNA encoding NDUFV2, a key mitochondrial protein. Knockout mice lacking the Cytoplasmic Polyadenylation Element Binding protein 1 (CPEB1) have brain-specific dysfunctional mitochondria and reduced ATP levels, which is due to defective polyadenylation-induced translation of electron transport chain complex I protein NDUFV2 mRNA. This reduced ATP results in defective dendrite morphogenesis of hippocampal neurons both in vitro and in vivo. These and other results demonstrate that CPEB1 control of mitochondrial activity is essential for normal brain development.

]]> Aparna Oruganty-Das et al. Adenosine Triphosphate Animals Cells, Cultured Electron Transport Complex I Female Gene Expression Mice Mice, Inbred C57BL Mice, Knockout Mitochondria Morphogenesis NADH Dehydrogenase Neurons Polyadenylation Protein Biosynthesis RNA Interference RNA, Messenger RNA, Small Interfering Transcription Factors mRNA Cleavage and Polyadenylation Factors Intracellular bacillary burden reflects a burst size for Mycobacterium tuberculosis in vivo http://escholarship.umassmed.edu/gsbs_sp/1826 http://escholarship.umassmed.edu/gsbs_sp/1826 Thu, 16 May 2013 12:56:34 PDT We previously reported that Mycobacterium tuberculosis triggers macrophage necrosis in vitro at a threshold intracellular load of ~25 bacilli. This suggests a model for tuberculosis where bacilli invading lung macrophages at low multiplicity of infection proliferate to burst size and spread to naïve phagocytes for repeated cycles of replication and cytolysis. The current study evaluated that model in vivo, an environment significantly more complex than in vitro culture. In the lungs of mice infected with M. tuberculosis by aerosol we observed three distinct mononuclear leukocyte populations (CD11b(-) CD11c(+/hi), CD11b(+/lo) CD11c(lo/-), CD11b(+/hi) CD11c(+/hi)) and neutrophils hosting bacilli. Four weeks after aerosol challenge, CD11b(+/hi) CD11c(+/hi) mononuclear cells and neutrophils were the predominant hosts for M. tuberculosis while CD11b(+/lo) CD11c(lo/-) cells assumed that role by ten weeks. Alveolar macrophages (CD11b(-) CD11c(+/hi)) were a minority infected cell type at both time points. The burst size model predicts that individual lung phagocytes would harbor a range of bacillary loads with most containing few bacilli, a smaller proportion containing many bacilli, and few or none exceeding a burst size load. Bacterial load per cell was enumerated in lung monocytic cells and neutrophils at time points after aerosol challenge of wild type and interferon-γ null mice. The resulting data fulfilled those predictions, suggesting a median in vivo burst size in the range of 20 to 40 bacilli for monocytic cells. Most heavily burdened monocytic cells were nonviable, with morphological features similar to those observed after high multiplicity challenge in vitro: nuclear condensation without fragmentation and disintegration of cell membranes without apoptotic vesicle formation. Neutrophils had a narrow range and lower peak bacillary burden than monocytic cells and some exhibited cell death with release of extracellular neutrophil traps. Our studies suggest that burst size cytolysis is a major cause of infection-induced mononuclear cell death in tuberculosis.

]]> Teresa Repasy et al. Mycobacterium tuberculosis Tuberculosis Cell Death Macrophages Transposition-driven genomic heterogeneity in the Drosophila brain http://escholarship.umassmed.edu/gsbs_sp/1825 http://escholarship.umassmed.edu/gsbs_sp/1825 Thu, 02 May 2013 19:29:03 PDT Recent studies in mammals have documented the neural expression and mobility of retrotransposons and have suggested that neural genomes are diverse mosaics. We found that transposition occurs among memory-relevant neurons in the Drosophila brain. Cell type-specific gene expression profiling revealed that transposon expression is more abundant in mushroom body (MB) αβ neurons than in neighboring MB neurons. The Piwi-interacting RNA (piRNA) proteins Aubergine and Argonaute 3, known to suppress transposons in the fly germline, are expressed in the brain and appear less abundant in αβ MB neurons. Loss of piRNA proteins correlates with elevated transposon expression in the brain. Paired-end deep sequencing identified more than 200 de novo transposon insertions in αβ neurons, including insertions into memory-relevant loci. Our observations indicate that genomic heterogeneity is a conserved feature of the brain.

]]> Paola N. Perrat et al. Animals Argonaute Proteins Brain Drosophila Proteins Drosophila melanogaster Gene Expression Regulation Genome, Insect Mushroom Bodies Neurons Peptide Initiation Factors RNA, Small Interfering Retroelements Transcriptome The role of MyD88 signaling in heterosubtypic influenza A virus infections http://escholarship.umassmed.edu/gsbs_sp/1824 http://escholarship.umassmed.edu/gsbs_sp/1824 Mon, 22 Apr 2013 07:47:47 PDT A mouse model of heterosubtypic influenza A virus infections was used to determine the role of MyD88 signaling in CD4+ T-cell, CD8+ T-cell, and IgG immune responses. We found that MyD88 signaling played an important role in anti-influenza A virus heterosubtypic lung and spleen CD4+ T-cell, and spleen CD8+ T-cell, immune responses. MyD88 dependent signaling was important for T-helper 1 cytokine production in anti-influenza A virus lung and spleen heterosubtypic CD4+ T-cells, but not for their frequencies. Toll-like receptor 7 dependent signaling played a partial role in anti-influenza A virus lung heterosubtypic CD4+ T-helper 1 responses and anti-influenza A virus heterosubtypic IgG2c antibody levels. Our results have important implications for the generation of effective universal influenza vaccines.

]]> Rachel F. Madera et al. Myeloid Differentiation Factor 88 Toll-Like Receptor 7 Influenza A virus CD40 Deficiency in Mice Exacerbates Obesity-induced Adipose Tissue Inflammation, Hepatic Steatosis and Insulin Resistance http://escholarship.umassmed.edu/gsbs_sp/1823 http://escholarship.umassmed.edu/gsbs_sp/1823 Fri, 22 Mar 2013 07:17:04 PDT The pathophysiology of obesity and type 2 diabetes in rodents and humans is characterized by low-grade inflammation in adipose tissue and liver. The CD40 receptor and its ligand, CD40L, initiate immune cell signaling promoting inflammation, but conflicting data on CD40L null mice confound its role in obesity-associated insulin resistance. Here we demonstrate that CD40 receptor deficient mice on a high fat diet display the expected decrease in hepatic cytokine levels, but paradoxically exhibit liver steatosis, insulin resistance and glucose intolerance compared to their age-matched wild type controls. Hyperinsulinemic-euglycemic clamp studies also demonstrated insulin resistance in glucose utilization by the CD40 null mice compared to wild type mice. In contrast to liver, adipose tissue in CD40 deficient animals harbors elevated cytokine levels and infiltration of inflammatory cells, particularly macrophages and CD8+ effector T-cells. In addition, ex vivo explants of epididymal adipose tissue from CD40(-/-) mice display elevated basal and isoproterenol-stimulated lipolysis, suggesting a potential increase of lipid efflux from visceral fat to the liver. These findings reveal that, 1) CD40 null mice represent an unusual model of hepatic steatosis with reduced hepatic inflammation, and 2) CD40 unexpectedly functions in adipose tissue to attenuate its inflammation in obesity, thereby protecting against hepatic steatosis.

]]> Chang-An Guo et al. Antigens, CD40 Fatty Liver Inflammation Obesity Adipose Tissue Insulin Resistance Using Mouse Models to Explore MDM-p53 Signaling in Development, Cell Growth, and Tumorigenesis http://escholarship.umassmed.edu/gsbs_sp/1822 http://escholarship.umassmed.edu/gsbs_sp/1822 Fri, 22 Mar 2013 07:17:04 PDT The p53 transcription factor regulates the expression of numerous genes whose products affect cell proliferation, senescence, cellular metabolism, apoptosis, and DNA repair. These p53-mediated effects can inhibit the growth of stressed or mutated cells and suppress tumorigenesis in the organism. However, the various growth-inhibitory properties of p53 must be kept in check in nondamaged cells in order to facilitate proper embryogenesis or the homeostatic maintenance of adult tissues. This requisite inhibition of p53 is performed primarily by the MDM oncoproteins, Mdm2 and MdmX. These p53-binding proteins limit p53 activity both in normal cells and in stressed cells seeking to promote resolution of their p53-stress response. Many mouse models bearing genetic alterations in Mdm2 or MdmX have been generated to explore the function and regulation of MDM-p53 signaling in development, in tissue homeostasis, in aging, and in cancer. These models not only have demonstrated a critical need for Mdm2 and MdmX in normal cell growth and in development but more recently have identified the MDM-p53 signaling axis as a key regulator of the cellular response to a wide variety of genetic or metabolic stresses. In this review, we discuss what has been learned from various studies of these Mdm2 and MdmX mouse models and highlight a few of the many important remaining questions.

]]> Hugh S. Gannon et al. A quantitative RNA code for mRNA target selection by the germline fate determinant GLD-1 http://escholarship.umassmed.edu/gsbs_sp/1821 http://escholarship.umassmed.edu/gsbs_sp/1821 Fri, 22 Mar 2013 07:17:03 PDT RNA-binding proteins (RBPs) are critical regulators of gene expression. To understand and predict the outcome of RBP-mediated regulation a comprehensive analysis of their interaction with RNA is necessary. The signal transduction and activation of RNA (STAR) family of RBPs includes developmental regulators and tumour suppressors such as Caenorhabditis elegans GLD-1, which is a key regulator of germ cell development. To obtain a comprehensive picture of GLD-1 interactions with the transcriptome, we identified GLD-1-associated mRNAs by RNA immunoprecipitation followed by microarray detection. Based on the computational analysis of these mRNAs we generated a predictive model, where GLD-1 association with mRNA is determined by the strength and number of 7-mer GLD-1-binding motifs (GBMs) within UTRs. We verified this quantitative model both in vitro, by competition GLD-1/GBM-binding experiments to determine relative affinity, and in vivo, by 'transplantation' experiments, where 'weak' and 'strong' GBMs imposed translational repression of increasing strength on a non-target mRNA. This study demonstrates that transcriptome-wide identification of RBP mRNA targets combined with quantitative computational analysis can generate highly predictive models of post-transcriptional regulatory networks.

]]> Jane E. Wright et al. Animals Binding, Competitive Caenorhabditis elegans Caenorhabditis elegans Proteins Computational Biology Gene Regulatory Networks Immunoprecipitation Microarray Analysis *Models, Biological Protein Interaction Domains and Motifs RNA, Messenger RNA-Binding Proteins Quaking regulates Hnrnpa1 expression through its 3' UTR in oligodendrocyte precursor cells http://escholarship.umassmed.edu/gsbs_sp/1820 http://escholarship.umassmed.edu/gsbs_sp/1820 Fri, 22 Mar 2013 07:17:02 PDT In mice, Quaking (Qk) is required for myelin formation; in humans, it has been associated with psychiatric disease. QK regulates the stability, subcellular localization, and alternative splicing of several myelin-related transcripts, yet little is known about how QK governs these activities. Here, we show that QK enhances Hnrnpa1 mRNA stability by binding a conserved 3' UTR sequence with high affinity and specificity. A single nucleotide mutation in the binding site eliminates QK-dependent regulation, as does reduction of QK by RNAi. Analysis of exon expression across the transcriptome reveals that QK and hnRNP A1 regulate an overlapping subset of transcripts. Thus, a simple interpretation is that QK regulates a large set of oligodendrocyte precursor genes indirectly by increasing the intracellular concentration of hnRNP A1. Together, the data show that hnRNP A1 is an important QK target that contributes to its control of myelin gene expression.

]]> Nancy R. Zearfoss et al. *3' Untranslated Regions Alternative Splicing Animals Base Sequence Cell Differentiation Cell Line Conserved Sequence Exons *Gene Expression Regulation Heterogeneous-Nuclear Ribonucleoprotein Group A-B Humans Mice Myelin-Associated Glycoprotein Oligodendroglia Oligonucleotide Array Sequence Analysis RNA Stability RNA, Small Interfering RNA-Binding Proteins Rats Sequence Alignment FBF represses the Cip/Kip cell-cycle inhibitor CKI-2 to promote self-renewal of germline stem cells in C. elegans http://escholarship.umassmed.edu/gsbs_sp/1819 http://escholarship.umassmed.edu/gsbs_sp/1819 Fri, 22 Mar 2013 07:17:01 PDT Although the decision between stem cell self-renewal and differentiation has been linked to cell-cycle modifications, our understanding of cell-cycle regulation in stem cells is very limited. Here, we report that FBF/Pumilio, a conserved RNA-binding protein, promotes self-renewal of germline stem cells by repressing CKI-2(Cip/Kip), a Cyclin E/Cdk2 inhibitor. We have previously shown that repression of CYE-1 (Cyclin E) by another RNA-binding protein, GLD-1/Quaking, promotes germ cell differentiation. Together, these findings suggest that a post-transcriptional regulatory circuit involving FBF and GLD-1 controls the self-renewal versus differentiation decision in the germline by promoting high CYE-1/CDK-2 activity in stem cells, and inhibiting CYE-1/CDK-2 activity in differentiating cells.

]]> Irene Kalchhauser et al. Animals Caenorhabditis elegans Caenorhabditis elegans Proteins *Cell Cycle Cells, Cultured Cyclin-Dependent Kinase Inhibitor Proteins *Gene Expression Regulation RNA-Binding Proteins Stem Cells POS-1 and GLD-1 repress glp-1 translation through a conserved binding-site cluster http://escholarship.umassmed.edu/gsbs_sp/1818 http://escholarship.umassmed.edu/gsbs_sp/1818 Fri, 22 Mar 2013 07:17:00 PDT RNA-binding proteins (RBPs) coordinate cell fate specification and differentiation in a variety of systems. RNA regulation is critical during oocyte development and early embryogenesis, in which RBPs control expression from maternal mRNAs encoding key cell fate determinants. The Caenorhabditis elegans Notch homologue glp-1 coordinates germline progenitor cell proliferation and anterior fate specification in embryos. A network of sequence-specific RBPs is required to pattern GLP-1 translation. Here, we map the cis-regulatory elements that guide glp-1 regulation by the CCCH-type tandem zinc finger protein POS-1 and the STAR-domain protein GLD-1. Our results demonstrate that both proteins recognize the glp-1 3' untranslated region (UTR) through adjacent, overlapping binding sites and that POS-1 binding excludes GLD-1 binding. Both factors are required to repress glp-1 translation in the embryo, suggesting that they function in parallel regulatory pathways. It is intriguing that two equivalent POS-1-binding sites are present in the glp-1 3' UTR, but only one, which overlaps with a translational derepression element, is functional in vivo. We propose that POS-1 regulates glp-1 mRNA translation by blocking access of other RBPs to a key regulatory sequence.

]]> Brian M. Farley et al. Amphetamine use in Rhode Island Hospital trauma patients http://escholarship.umassmed.edu/gsbs_sp/1817 http://escholarship.umassmed.edu/gsbs_sp/1817 Fri, 22 Mar 2013 07:17:00 PDT Jeanine Ward et al. Adolescent Adult Age Factors Amphetamine-Related Disorders Amphetamines Female Humans Male Middle Aged Rhode Island Substance Abuse Detection Trauma Centers Wounds and Injuries Young Adult Methoxetamine: a novel ketamine analog and growing health-care concern http://escholarship.umassmed.edu/gsbs_sp/1816 http://escholarship.umassmed.edu/gsbs_sp/1816 Fri, 22 Mar 2013 07:16:59 PDT Jeanine Ward et al. Cyclohexanones Cyclohexylamines Humans Internet Male Street Drugs United States Young Adult Amatoxin poisoning: case reports and review of current therapies http://escholarship.umassmed.edu/gsbs_sp/1814 http://escholarship.umassmed.edu/gsbs_sp/1814 Fri, 22 Mar 2013 07:16:58 PDT BACKGROUND: Diagnosis and management of Amanita mushroom poisoning is a challenging problem for physicians across the United States. With 5902 mushroom exposures and two resultant deaths directly linked to Amanita ingestion in 2009, it is difficult for physicians to determine which patients are at risk for lethal toxicity. Identification of amatoxin poisoning can prove to be difficult due to delay in onset of symptoms and difficulty with identification of mushrooms. Consequently, it is difficult for the Emergency Physician to determine proper disposition. Further, treatment options are controversial.

OBJECTIVES: To review current data to help health care providers effectively identify and treat potentially deadly Amanita mushroom ingestions.

CASE REPORTS: We present two cases of Amanita mushroom ingestion in the northeastern United States treated with N-acetylcysteine, high-dose penicillin, cimetidine, and silibinin, a semi-purified fraction of milk thistle-derived silymarin, as part of their treatment regimen. The mushroom species was identified by a consultant as Amanita Ocreata.

CONCLUSIONS: We present the successful treatment of 2 patients who ingested what we believe to be an Amanita species never before identified in the northeastern United States.

]]> Jeanine Ward et al. Herbal medicines for the management of opioid addiction: safe and effective alternatives to conventional pharmacotherapy http://escholarship.umassmed.edu/gsbs_sp/1815 http://escholarship.umassmed.edu/gsbs_sp/1815 Fri, 22 Mar 2013 07:16:58 PDT Striking increases in the abuse of opioids have expanded the need for pharmacotherapeutic interventions. The obstacles that confront effective treatment of opioid addiction - shortage of treatment professionals, stigma associated with treatment and the ability to maintain abstinence - have led to increased interest in alternative treatment strategies among both treatment providers and patients alike. Herbal products for opioid addiction and withdrawal, such as kratom and specific Chinese herbal medications such as WeiniCom, can complement existing treatments. Unfortunately, herbal treatments, while offering some advantages over existing evidence-based pharmacotherapies, have poorly described pharmacokinetics, a lack of supportive data derived from well controlled clinical trials, and severe toxicity, the cause for which remains poorly defined. Herbal products, therefore, require greater additional testing in rigorous clinical trials before they can expect widespread acceptance in the management of opioid addiction.

]]> Jeanine Ward et al. Analgesics, Opioid Animals Behavior, Addictive Drugs, Chinese Herbal use Humans Plant Preparations use Substance-Related Disorders Endotoxin-induced inhibition of growth hormone receptor signaling in rat liver in vivo http://escholarship.umassmed.edu/gsbs_sp/1813 http://escholarship.umassmed.edu/gsbs_sp/1813 Fri, 22 Mar 2013 07:16:57 PDT The bacterial lipopolysaccharide endotoxin induces a catabolic response characterized by resistance to multiple anabolic hormones. The objective of this study was to determine the effects of endotoxin on the GH signaling pathway in rat liver in vivo. After the iv injection of Escherichia coli endotoxin (1 mg/kg), there was a progressive decrease in liver STAT5 (signal transducer and activator of transcription-5) tyrosine phosphorylation in response to GH (40% decrease 6 h after endotoxin), which occurred in the absence of a change in abundance of the STAT5 protein. Endotoxin resulted in a rapid 40-fold increase in liver Janus family kinase-2 (JAK2) messenger RNA, followed by a 2-fold increase in JAK2 protein abundance. This was associated with a 50% decrease in phosphorylated/total JAK2 after GH stimulation. GH receptor abundance was unchanged, suggesting a postreceptor site of endotoxin-induced GH resistance. Rat complementary DNAs for three members of the suppressor of cytokine signaling gene family were cloned [cytokine-inducible sequence (CIS), suppressor of cytokine signaling-2 (SOCS-2), and SOCS-3] and, using these probes, messenger RNAs for SOCS-3 and CIS were shown to be increased 10- and 4-fold above control values, respectively, 2 h after endotoxin infusion. The finding of endotoxin inhibition of in vivo STAT5 tyrosine phosphorylation in response to a supramaximal dose of GH in the absence of a change in GH receptor abundance or total GH-stimulated JAK2 tyrosine phosphorylation provides the first demonstration of acquired postreceptor GH resistance. We hypothesize that this may occur through a specificity-spillover mechanism involving the induction of SOCS genes by cytokines released in response to endotoxin and subsequent SOCS inhibition of GH signaling.

]]> Yilei Mao et al. Animals DNA-Binding Proteins Endotoxins Escherichia coli Gene Expression Human Growth Hormone Janus Kinase 2 Liver Male *Milk Proteins Phosphorylation Phosphotyrosine Protein-Tyrosine Kinases Proteins *Proto-Oncogene Proteins RNA, Messenger Rats Rats, Sprague-Dawley Receptors, Somatotropin *Repressor Proteins STAT5 Transcription Factor *Signal Transduction Suppressor of Cytokine Signaling Proteins Trans-Activators *Transcription Factors Mortality in diastolic heart failure: an update http://escholarship.umassmed.edu/gsbs_sp/1812 http://escholarship.umassmed.edu/gsbs_sp/1812 Fri, 22 Mar 2013 07:16:56 PDT In 2003, the prevalence of heart failure in the United States was 5 million persons. Although historically at least one-third of these patients were considered to have diastolic heart failure (DHF) or "heart failure with preserved ejection fraction," contemporary cohort studies have shown that the prevalence of DHF in the community is not only higher than previously thought, but is actually rising. The increasing prevalence of this disorder has been attributed, in part, to the increasing mean age of the population and a progressive increase in the prevalence of associated risk factors, such as hypertension, obesity, and diabetes mellitus. New data suggest that mortality from DHF is high, if not equivalent, to that of systolic heart failure. For example, 2 recent retrospective studies found that the for 1 year all-cause mortality after an admission for DHF was 22% and 29%. Additional results from the Cardiovascular Health Study suggest that despite marginal differences in mortality rates, DHF has a greater attributable mortality rate because there are greater numbers of patients with HF with normal ejection fraction.

Several important conclusions should be drawn from these data. One, the prevalence of DHF is high and is increasing. Second, the associated mortality is high, and comparable to systolic heart failure.

Finally, efforts to reduce the prevalence of risk factors for DHF should be redoubled, and prospective clinical trials should be designed to help us better understand the pathophysiology and treatment of this disorder.

]]> Timothy P. Fitzgibbons et al. Cardiotonic Agents Diagnosis, Differential Heart Failure, Diastolic Heart Failure, Systolic Humans Prevalence United States Prevalence and clinical characteristics of right ventricular dysfunction in transient stress cardiomyopathy http://escholarship.umassmed.edu/gsbs_sp/1811 http://escholarship.umassmed.edu/gsbs_sp/1811 Fri, 22 Mar 2013 07:16:55 PDT Transient stress cardiomyopathy (TSC) is a cause of reversible left ventricular (LV) dysfunction that is increasingly recognized. Reports to date have focused primarily on LV involvement, with little attention paid to associated right ventricular (RV) dysfunction. With other forms of LV dysfunction, RV involvement has been shown to confer an adverse prognosis. Prevalence, clinical characteristics, and short-term prognosis of RV dysfunction in TSC remain ill-defined. Presenting echocardiograms of 40 patients with TSC were reviewed. RV function was assessed by evaluating regional wall motion and calculating a wall motion score index (WMSI). RV dysfunction was defined as a WMSI >1.0. Clinical and demographic characteristics of patients with and without RV dysfunction were compared. RV dysfunction was identified in 27% of patients (11 of 40). RV WMSI was 1.20 +/- 0.30 for the entire cohort compared with 1.72 +/- 0.30 for those with RV dysfunction (p 1/4 of cases of TSC. Although associated with higher B-type natriuretic peptide levels, higher pulmonary artery systolic pressures, and longer hospital stays, RV dysfunction was not associated with significant differences in short-term cardiac morbidity or increased early mortality.

]]> Timothy P. Fitzgibbons et al. Aged Cardiomyopathies Cohort Studies Coronary Angiography Female Humans Male Massachusetts Middle Aged Prevalence Prognosis Retrospective Studies Stress, Physiological Stress, Psychological Time Factors Ventricular Dysfunction, Right Acquired long QT syndrome from stress cardiomyopathy is associated with ventricular arrhythmias and torsades de pointes http://escholarship.umassmed.edu/gsbs_sp/1810 http://escholarship.umassmed.edu/gsbs_sp/1810 Fri, 22 Mar 2013 07:16:54 PDT BACKGROUND: Stress cardiomyopathy (SCM) is a syndrome of transient ventricular dysfunction triggered by severe emotional or physical stress, likely resulting from catecholamine-mediated myocardial toxicity. Repolarization abnormalities associated with other hyperadrenergic states can cause QT prolongation and lethal arrhythmia including torsades de pointes (TdP). Despite the development of repolarization abnormalities and QT prolongation in SCM, little is known about the risk of ventricular fibrillation (VF) and TdP.

OBJECTIVE: The aim of this study was to assess the prevalence and clinical predictors of ventricular arrhythmias in a cohort of patients with SCM.

METHODS: Data from a registry of consecutive patients with SCM from 2 institutions were reviewed. Patients who developed VF or TdP were identified. Clinical characteristics and outcomes were analyzed and compared with a control group of patients with SCM without VF/TdP.

RESULTS: Of 93 patients with SCM, 8 (8.6%) experienced VF/TdP. Of these 8 patients, 2 presented with VF and were subsequently diagnosed with SCM. Six other patients experienced pause-dependent TdP or VF after SCM diagnosis in the setting of substantial QT prolongation. Prolongation of the corrected QT interval (QTc) was significantly associated with the occurrence of ventricular arrhythmia (odds ratio 1.28 for each 10 ms increase in QTc, 95% confidence interval 1.10 to 1.50).

CONCLUSION: SCM can be associated with life-threatening ventricular arrhythmia in over 8% of cases. SCM should be recognized among the causes of acquired long QT syndrome and can be associated with a risk of TdP. reserved.

]]> Christopher Madias et al. Aged *Electrocardiography Female Follow-Up Studies Humans Long QT Syndrome Male Massachusetts Middle Aged Prevalence Retrospective Studies Risk Factors Takotsubo Cardiomyopathy Torsades de Pointes Similarity of mouse perivascular and brown adipose tissues and their resistance to diet-induced inflammation http://escholarship.umassmed.edu/gsbs_sp/1809 http://escholarship.umassmed.edu/gsbs_sp/1809 Fri, 22 Mar 2013 07:16:53 PDT Thoracic perivascular adipose tissue (PVAT) is a unique adipose depot that likely influences vascular function and susceptibility to pathogenesis in obesity and the metabolic syndrome. Surprisingly, PVAT has been reported to share characteristics of both brown and white adipose, but a detailed direct comparison to interscapular brown adipose tissue (BAT) has not been performed. Here we show by full genome DNA microarray analysis that global gene expression profiles of PVAT are virtually identical to BAT, with equally high expression of Ucp-1, Cidea, and other genes known to be uniquely or very highly expressed in BAT. PVAT and BAT also displayed nearly identical phenotypes upon immunohistochemical analysis, and electron microscopy confirmed that PVAT contained multilocular lipid droplets and abundant mitochondria. Compared with white adipose tissue (WAT), PVAT and BAT from C57BL6/J mice fed a high-fat diet for 13 wk had markedly lower expression of immune cell-enriched mRNAs, suggesting resistance to obesity-induced inflammation. Indeed, staining of BAT and PVAT for macrophage markers (F4/80 and CD68) in obese mice showed virtually no macrophage infiltration, and FACS analysis of BAT confirmed the presence of very few CD11b(+)/CD11c(+) macrophages in BAT (1.0%) compared with WAT (31%). In summary, murine PVAT from the thoracic aorta is virtually identical to interscapular BAT, is resistant to diet-induced macrophage infiltration, and thus may play an important role in protecting the vascular bed from inflammatory stress.

]]> Timothy P. Fitzgibbons et al. Adipose Tissue Adipose Tissue, Brown Animals Aorta, Thoracic Apoptosis Regulatory Proteins Blood Vessels Diet Dietary Fats Flow Cytometry Immunohistochemistry Inflammation Insulin Ion Channels Male Mice Mice, Inbred C57BL Microarray Analysis Microscopy, Electron, Transmission Mitochondria, Heart Mitochondrial Proteins Neutrophil Infiltration Reverse Transcriptase Polymerase Chain Reaction Cardiac remodeling in obesity http://escholarship.umassmed.edu/gsbs_sp/1808 http://escholarship.umassmed.edu/gsbs_sp/1808 Fri, 22 Mar 2013 07:16:52 PDT Gerard P. Aurigemma et al. *Cardiovascular Diseases *Diagnostic Imaging Disease Progression Humans Obesity Ventricular Remodeling