Showing papers by "University of Texas Medical Branch published in 2003"

Oxidation of tetrahydrobiopterin leads to uncoupling of endothelial cell nitric oxide synthase in hypertension

Abstract: Tetrahydrobiopterin is a critical cofactor for the NO synthases, and in its absence these enzymes become “uncoupled,” producing reactive oxygen species (ROSs) rather than NO. In aortas of mice with deoxycorticosterone acetate‐salt (DOCA-salt) hypertension, ROS production from NO synthase is markedly increased, and tetrahydrobiopterin oxidation is evident. Using mice deficient in the NADPH oxidase subunit p47 phox and mice lacking either the endothelial or neuronal NO synthase, we obtained evidence that hypertension produces a cascade involving production of ROSs from the NADPH oxidase leading to oxidation of tetrahydrobiopterin and uncoupling of endothelial NO synthase (eNOS). This decreases NO production and increases ROS production from eNOS. Treatment of mice with oral tetrahydrobiopterin reduces vascular ROS production, increases NO production as determined by electron spin resonance measurements of nitrosyl hemoglobin, and blunts the increase in blood pressure due to DOCA-salt hypertension. Endothelium-dependent vasodilation is only minimally altered in vessels of mice with DOCA-salt hypertension but seems to be mediated by hydrogen peroxide released from uncoupled eNOS, since it is inhibited by catalase. Tetrahydrobiopterin oxidation may represent an important abnormality in hypertension. Treatment strategies that increase tetrahydrobiopterin or prevent its oxidation may prove useful in preventing vascular complications of this common disease.

Perceptions and impact of bipolar disorder: how far have we really come? Results of the national depressive and manic-depressive association 2000 survey of individuals with bipolar disorder.

Abstract: Objective To assess the experience of selected individuals living with bipolar disorder and compare this experience with that of a similar group of individuals sampled in 1992. Method In June 2000, 4192 self-administered questionnaires were sent to National Depressive and Manic-Depressive Association chapters for distribution to support group participants diagnosed with bipolar disorder. By July 31, 2000, the first 600 completed surveys were analyzed. Results Over one third of respondents sought professional help within 1 year of the onset of symptoms. Unfortunately, 69% were misdiagnosed, with the most frequent misdiagnosis being unipolar depression. Those who were misdiagnosed consulted a mean of 4 physicians prior to receiving the correct diagnosis. Over one third waited 10 years or more before receiving an accurate diagnosis. Despite having underreported manic symptoms, more than half believe their physicians' lack of understanding of bipolar disorder prevented a correct diagnosis from being made earlier. In 2000, the respondents reported a greater negative impact of bipolar disorder on families, social relationships, and employment than did the respondents in 1992. Overall, respondents were satisfied with their current treatment, which often included medication, talk therapy, and support groups. Respondents who were highly satisfied with their treatment provider had a more positive outlook on their illness and their ability to cope with it. Conclusion Individuals with bipolar disorder reported that the illness manifests itself early in life but that accurate diagnosis lags by many years. The illness exacts great hardships on the individual and the family and has a profoundly negative effect on careers. These findings are very similar to those reported nearly a decade ago.

Regulation of Interferon Regulatory Factor-3 by the Hepatitis C Virus Serine Protease

Abstract: Persistent infections with hepatitis C virus (HCV) are likely to depend on viral inhibition of host defenses. We show that the HCV NS3/4A serine protease blocks the phosphorylation and effector action of interferon regulatory factor-3 (IRF-3), a key cellular antiviral signaling molecule. Disruption of NS3/4A protease function by mutation or a ketoamide peptidomimetic inhibitor relieved this blockade and restored IRF-3 phosphorylation after cellular challenge with an unrelated virus. Furthermore, dominant-negative or constitutively active IRF-3 mutants, respectively, enhanced or suppressed HCV RNA replication in hepatoma cells. Thus, the NS3/4A protease represents a dual therapeutic target, the inhibition of which may both block viral replication and restore IRF-3 control of HCV infection.

Cutting Edge: Different Toll-Like Receptor Agonists Instruct Dendritic Cells to Induce Distinct Th Responses via Differential Modulation of Extracellular Signal-Regulated Kinase-Mitogen-Activated Protein Kinase and c-Fos

Abstract: Dendritic cells (DCs) are pivotal in determining the class of an adaptive immune response. However, the molecular mechanisms within DCs that determine this decision-making process are unknown. Here, we demonstrate that distinct Toll-like receptor (TLR) ligands instruct human DCs to induce distinct Th cell responses by differentially modulating mitogen-activated protein kinase signaling. Thus, Escherichia coli LPS and flagellin, which trigger TLR4 and TLR5, respectively, instruct DCs to stimulate Th1 responses via IL-12p70 production, which depends on the phosphorylation of p38 and c-Jun N-terminal kinase 1/2. In contrast, the TLR2 agonist, Pam3cys, and the Th2 stimulus, schistosome egg Ags: 1) barely induce IL-12p70; 2) stimulate sustained duration and magnitude of extracellular signal-regulated kinase 1/2 phosphorylation, which results in stabilization of the transcription factor c-Fos, a suppressor of IL-12; and 3) yield a Th2 bias. Thus, distinct TLR agonists differentially modulate extracellular signal-regulated kinase signaling, c-Fos activity, and cytokine responses in DCs to stimulate different Th responses.

Screening for bipolar disorder in the community

Abstract: Background Our goal was to estimate the rate of positive screens for bipolar I and bipolar II disorders in the general population of the United States. Method The Mood Disorder Questionnaire (MDQ), a validated screening instrument for bipolar I and II disorders, was sent to a sample of 127,800 people selected to represent the U.S. adult population by demographic variables. 85,358 subjects (66.8% response rate) that were 18 years of age or above returned the survey and had usable data. Of the nonrespondents, 3404 subjects matched demographically to the 2000 U.S. Census data completed a telephone interview to estimate nonresponse bias. Results The overall positive screen rate for bipolar I and II disorders, weighted to match the 2000 U.S. Census demographics, was 3.4%. When adjusted for the nonresponse bias, the rate rose to 3.7%. Only 19.8% of the individuals with positive screens for bipolar I or II disorders reported that they had previously received a diagnosis of bipolar disorder from a physician, whereas 31.2% reported receiving a diagnosis of unipolar depression. An additional 49.0% reported receiving no diagnosis of either bipolar disorder or unipolar depression. Positive screens were more frequent in young adults and low income households. The rates of migraine, allergies, asthma, and alcohol and drug abuse were substantially higher among those with positive screens. Conclusion The positive MDQ screen rate of 3.7% suggests that nearly 4% of American adults may suffer from bipolar I and II disorders. Young adults and individuals with lower income are at greater risk for this largely underdiagnosed disorder.

Depression predicts increased incidence of adverse health outcomes in older Mexican Americans with type 2 diabetes.

Abstract: OBJECTIVE —To examine the separate and combined effects of depression and diabetes on the incidence of adverse health outcomes among older Mexican Americans. RESEARCH DESIGN AND METHODS —Longitudinal data from the Hispanic Established Population for the Epidemiologic Study of the Elderly (EPESE) survey were used to examine the main effects and interaction effects of diabetes and depressive symptoms (measured with the Center for Epidemiologic Study of Depression) or clinical diagnostic criteria (measured with the Composite International Diagnostic Interview Depression Module) on the development of macrovascular complications (including cardiovascular disease, stroke, and kidney disease), microvascular complications (including nephropathy, neuropathy, retinopathy, and amputations), functional disability, and mortality over 7 years in a sample of 2,830 Mexican Americans aged ≥65 years. RESULTS —The interaction of diabetes and depression was found to be synergistic, predicting greater mortality, greater incidence of both macro- and microvascular complications, and greater incidence of disability in activities of daily living, even when controlling for sociodemographic characteristics such as sex, age, education, acculturation, and marital status. Importantly, this interaction was found to predict not only greater incidence but also earlier incidence of adverse events in older adults. CONCLUSIONS —Whether a marker for underlying disease severity, an indicator of diminished self-care motivation, or the result of physiologic changes, the interaction of depression and diabetes has a synergistic effect on the health of older Mexican Americans, increasing the risk for poor outcomes. This is of particular clinical importance because although depression is often underrecognized in older adults, effective treatment is available and can result in improved medical outcomes.

Human Muscle Protein Synthesis is Modulated by Extracellular, Not Intramuscular Amino Acid Availability: A Dose‐Response Study

Abstract: To test the hypothesis that muscle protein synthesis (MPS) is regulated by the concentration of extracellular amino acids, we investigated the dose-response relationship between the rate of human MPS and the concentrations of blood and intramuscular amino acids. We increased blood mixed amino acid concentrations by up to 240 % above basal levels by infusion of mixed amino acids (Aminosyn 15, 44-261 mg kg−1 h−1) in 21 healthy subjects, (11 men 10 women, aged 29 ± 2 years) and measured the rate of incorporation of D5-phenylalanine or D3-leucine into muscle protein and blood and intramuscular amino acid concentrations. The relationship between the fold increase in MPS and blood essential amino acid concentration ([EAA], mM) was hyperbolic and fitted the equation MPS = (2.68 × [EAA])/(1.51 + [EAA]) (P < 0.01). The pattern of stimulation of myofibrillar, sarcoplasmic and mitochondrial protein was similar. There was no clear relationship between the rate of MPS and the concentration of intramuscular EAAs; indeed, when MPS was increasing most rapidly, the concentration of intramuscular EAAs was below basal levels. We conclude that the rates of synthesis of all classes of muscle proteins are acutely regulated by the blood [EAA] over their normal diurnal range, but become saturated at high concentrations. We propose that the stimulation of protein synthesis depends on the sensing of the concentration of extracellular, rather than intramuscular EAAs.

The mechanical stability of ubiquitin is linkage dependent.

Abstract: Ubiquitin chains are formed through the action of a set of enzymes that covalently link ubiquitin either through peptide bonds or through isopeptide bonds between their C terminus and any of four lysine residues. These naturally occurring polyproteins allow one to study the mechanical stability of a protein, when force is applied through different linkages. Here we used single-molecule force spectroscopy techniques to examine the mechanical stability of N-C–linked and Lys48-C–linked ubiquitin chains. We combined these experiments with steered molecular dynamics (SMD) simulations and found that the mechanical stability and unfolding pathway of ubiquitin strongly depend on the linkage through which the mechanical force is applied to the protein. Hence, a protein that is otherwise very stable may be easily unfolded by a relatively weak mechanical force applied through the right linkage. This may be a widespread mechanism in biological systems.

Origin and Evolution of Japanese Encephalitis Virus in Southeast Asia

Abstract: Since it emerged in Japan in the 1870s, Japanese encephalitis has spread across Asia and has become the most important cause of epidemic encephalitis worldwide. Four genotypes of Japanese encephalitis virus (JEV) are presently recognized (representatives of genotypes I to III have been fully sequenced), but its origin is not known. We have determined the complete nucleotide and amino acid sequence of a genotype IV Indonesian isolate (JKT6468) which represents the oldest lineage, compared it with other fully sequenced genomes, and examined the geographical distribution of all known isolates. JKT6468 was the least similar, with nucleotide divergence ranging from 17.4 to 19.6% and amino acid divergence ranging from 4.7 to 6.5%. It included an unusual series of amino acids at the carboxy terminus of the core protein unlike that seen in other JEV strains. Three signature amino acids in the envelope protein (including E327 Leu-->Thr/Ser on the exposed lateral surface of the putative receptor binding domain) distinguished genotype IV strains from more recent genotypes. Analysis of all 290 JEV isolates for which sequence data are available showed that the Indonesia-Malaysia region has all genotypes of JEV circulating, whereas only more recent genotypes circulate in other areas (P < 0.0001). These results suggest that JEV originated from its ancestral virus in the Indonesia-Malaysia region and evolved there into the different genotypes which then spread across Asia. Our data, together with recent evidence on the origins of other emerging viruses, including dengue virus and Nipah virus, imply that tropical southeast Asia may be an important zone for emerging pathogens.

Caspase‐12 and endoplasmic reticulum stress mediate neurotoxicity of pathological prion protein

Abstract: Prion diseases are characterized by accumulation of misfolded prion protein (PrPSc), and neuronal death by apoptosis. Here we show that nanomolar concentrations of purified PrPSc from mouse scrapie brain induce apoptosis of N2A neuroblastoma cells. PrPSc toxicity was associated with an increase of intracellular calcium released from endoplasmic reticulum (ER) and up-regulation of several ER chaperones. Caspase-12 activation was detected in cells treated with PrPSc, and cellular death was inhibited by overexpression of a catalytic mutant of caspase-12 or an ER-targeted Bcl-2 chimeric protein. Scrapie-infected N2A cells were more susceptible to ER-stress and to PrPSc toxicity than non-infected cells. In scrapie-infected mice a correlation between caspase-12 activation and neuronal loss was observed in histological and biochemical analyses of different brain areas. The extent of prion replication was closely correlated with the up-regulation of ER-stress chaperone proteins. Similar results were observed in humans affected with sporadic and variant Creutzfeldt–Jakob disease, implicating for the first time the caspase-12 dependent pathway in a neurodegenerative disease in vivo, and thus offering novel potential targets for the treatment of prion disorders.

Cardiac troponin T and C-reactive protein for predicting prognosis, coronary atherosclerosis, and cardiomyopathy in patients undergoing long-term hemodialysis.

Abstract: Context Cardiac troponin T (cTnT) and C-reactive protein (CRP) are prognostic markers in acute coronary syndromes. However, for patients with end-stage renal disease (ESRD) the ability of combinations of these markers to predict outcomes, and their association with cardiac pathology, are unclear. Objective To investigate the association between levels of cTnT and CRP and longterm risk of cardiac pathology and death in patients with ESRD. Design, Setting, and Participants A prospective cohort study initiated February through June 1998 and enrolling 224 patients with ESRD from 5 hemodialysis centers in the Houston-Galveston region of Texas. Levels of cTnT and CRP were analyzed at study entry in patients without ischemic symptoms. MainOutcomeMeasures All-causemortalityduringameanfollow-upof827(range, 29-1327) days. Secondary outcomes in predefined substudies were coronary artery disease (CAD), decreased (40%) left ventricular ejection fraction (LVEF), and presence of left ventricular hypertrophy (LVH). Results One hundred seventeen (52%) patients died during follow-up. For levels of cTnT and CRP, progressively higher levels predicted increased risk of death compared with the lowest quartile (for cTnT quartile 2: unadjusted hazard ratio [HR], 2.2; 95% confidence interval [CI], 1.2-4.1; quartile 3: HR, 2.7; 95% CI, 1.5-4.9; quartile 4: HR, 3.0; 95% CI, 1.6-5.3. For CRP quartile 2: HR, 0.9; 95% CI, 0.5-1.6; quartile 3: HR, 1.8; 95% CI, 1.1-3.1; quartile 4: HR, 1.8; 95% CI, 1.1-3.2). Both cTnT and CRP remained independent predictors of death after adjusting for a number of potential confounders. The combination of cTnT and CRP results provided prognostic information when patients were divided into groups at or above and below the biomarker medians (high cTnT/high CRP levels vs low cTnT/low CRP levels for risk of death: HR, 2.5; 95% CI, 1.5-4.0). Elevated levels of cTnT, but not CRP, were strongly associated with diffuse CAD (n=67; 0%, 25%, 50%, and 62% prevalence of multivessel CAD across progressive cTnT quartiles, P.001). An LVEF of 40% or less was identified in 4 (9%), 3 (8%), 10 (27%), and 7 (19%) of patients across cTnT quartiles (P=.07). No trend for cTnT levels was found among patients with LVH (P=.45); similarly, no trend for CRP was found among patients with LVH (P=.65) or an LVEF of 40% or less (P=.75). Conclusions Among stable patients with ESRD, increasing levels of cTnT and CRP are associated with increased risk of death. Furthermore, higher levels of cTnT may identify patients with severe angiographic coronary disease.

Efficacy of sertraline in the treatment of children and adolescents with major depressive disorder: two randomized controlled trials.

Abstract: ContextThe efficacy, safety, and tolerability of selective serotonin reuptake inhibitors (SSRIs) in the treatment of adults with major depressive disorder (MDD) are well established. Comparatively few data are available on the effects of SSRIs in depressed children and adolescents.ObjectiveTo evaluate the efficacy and safety of sertraline compared with placebo in treatment of pediatric patients with MDD.Design and SettingTwo multicenter randomized, double-blind, placebo-controlled trials were conducted at 53 hospital, general practice, and academic centers in the United States, India, Canada, Costa Rica, and Mexico between December 1999 and May 2001 and were pooled a priori.ParticipantsThree hundred seventy-six children and adolescents aged 6 to 17 years with Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition–defined MDD of at least moderate severity.InterventionPatients were randomly assigned to receive a flexible dosage (50-200 mg/d) of sertraline (n = 189) or matching placebo tablets (n = 187) for 10 weeks.Main Outcome MeasuresChange from baseline in the Children's Depression Rating Scale–Revised (CDRS-R) Best Description of Child total score and reported adverse events.ResultsSertraline-treated patients experienced statistically significantly greater improvement than placebo patients on the CDRS-R total score (mean change at week 10, –30.24 vs –25.83, respectively; P = .001; overall mean change, –22.84 vs –20.19, respectively; P = .007). Based on a 40% decrease in the adjusted CDRS-R total score at study end point, 69% of sertraline-treated patients compared with 59% of placebo patients were considered responders (P = .05). Sertraline treatment was generally well tolerated. Seventeen sertraline-treated patients (9%) and 5 placebo patients (3%) prematurely discontinued the study because of adverse events. Adverse events that occurred in at least 5% of sertraline-treated patients and with an incidence of at least twice that in placebo patients included diarrhea, vomiting, anorexia, and agitation.ConclusionThe results of this pooled analysis demonstrate that sertraline is an effective and well-tolerated short-term treatment for children and adolescents with MDD.

Gene Sequence-Based Criteria for Identification of New Rickettsia Isolates and Description of Rickettsia heilongjiangensis sp. nov.

Abstract: We propose genetic guidelines for the classification of rickettsial isolates at the genus, group, and species levels by using sequences of the 16S rRNA (rrs) gene and four protein-coding genes, the gltA, ompA, and ompB genes and gene D. To be classified as a member of the genus Rickettsia, an isolate should exhibit degrees of rrs and gltA homology with any of the 20 Rickettsia species studied of ≥98.1 and ≥86.5%, respectively. A member of the typhus group should fulfill at least two of the following four criteria: pairwise nucleotide sequence homologies with rrs, gltA, ompB, and gene D of either Rickettsia typhi or Rickettsia prowazekii of ≥99.4, ≥96.6, ≥92.4, and ≥91.6%, respectively. A member of the spotted fever group should either possess the ompA gene or fulfill at least two of the following four criteria: pairwise nucleotide sequence homologies with rrs, gltA, ompB, and gene D of any member of this group of ≥98.8, ≥92.7, ≥85.8, and ≥82.2%, respectively. The existence of a distinct “ancestral” group should be questioned. To be classified as a new Rickettsia species, an isolate should not exhibit more than one of the following degrees of nucleotide similarity with the most homologous validated species: ≥99.8 and ≥ 99.9% for the rrs and gltA genes, respectively, and, when amplifiable, ≥98.8, ≥99.2, and ≥99.3% for the ompA and ompB genes and gene D, respectively. By use of our classification scheme, “Rickettsia heilongjiangii” belongs to a new species for which we officially propose the name Rickettsia heilongjiangensis sp. nov.

Abnormal anxiety-related behavior in serotonin transporter null mutant mice: the influence of genetic background

Abstract: Serotonin transporter (5-HTT) null mutant mice provide a model system to study the role genetic variation in the 5-HTT plays in the regulation of emotion. Anxiety-like behaviors were assessed in 5-HTT null mutants with the mutation placed on either a B6 congenic or a 129S6 congenic background. Replicating previous findings, B6 congenic 5-HTT null mutants exhibited increased anxiety-like behavior and reduced exploratory locomotion on the light dark exploration and elevated plus-maze tests. In contrast, 129S6 congenic 5-HTT null mutant mice showed no phenotypic abnormalities on either test. 5-HTT null mutants on the 129S6 background showed reduced 5-HT(1A) receptor binding (as measured by quantitative autoradiography) and reduced 5-HT(1A) receptor function (as measured by 8-OH-DPAT-induced hypothermia). These data confirm that the 5-HTT null mutation produced alterations in brain 5-HT function in mice on the 129S6 background, thereby discounting the possibility that the absence of an abnormal anxiety-like phenotype in these mice was due to a suppression of the mutation by 129 modifier genes. Anxiety-like behaviors in the light dark exploration and elevated plus-maze tests were significantly higher in 129S6 congenic +/+ mice as compared to B6 congenic +/+ mice. This suggests that high baseline anxiety-like behavior in the 129S6 strain might have precluded detection of the anxiety-like effects of the 5-HTT null mutation on this background. Present findings provide further evidence linking genetic variation in the 5-HTT to abnormalities in mood and anxiety. Furthermore, these data highlight the utility of conducting behavioral phenotyping of mutant mice on multiple genetic backgrounds.

An open conformation of mammalian cytochrome P450 2B4 at 1.6-Å resolution

Abstract: The xenobiotic metabolizing cytochromes P450 (P450s) are among the most versatile biological catalysts known, but knowledge of the structural basis for their broad substrate specificity has been limited. P450 2B4 has been frequently used as an experimental model for biochemical and biophysical studies of these membrane proteins. A 1.6-A crystal structure of P450 2B4 reveals a large open cleft that extends from the protein surface directly to the heme iron between the α-helical and β-sheet domains without perturbing the overall P450 fold. This cleft is primarily formed by helices B′ to C and F to G. The conformation of these regions is dramatically different from that of the other structurally defined mammalian P450, 2C5/3LVdH, in which the F to G and B′ to C regions encapsulate one side of the active site to produce a closed form of the enzyme. The open conformation of 2B4 is trapped by reversible formation of a homodimer in which the residues between helices F and G of one molecule partially fill the open cleft of a symmetry-related molecule, and an intermolecular coordinate bond occurs between H226 and the heme iron. This dimer is observed both in solution and in the crystal. Differences between the structures of 2C5 and 2B4 suggest that defined regions of xenobiotic metabolizing P450s may adopt a substantial range of energetically accessible conformations without perturbing the overall fold. This conformational flexibility is likely to facilitate substrate access, metabolic versatility, and product egress.

A Critical Role for Induced IgM in the Protection against West Nile Virus Infection

Abstract: In humans, the elderly and immunocompromised are at greatest risk for disseminated West Nile virus (WNV) infection, yet the immunologic basis for this remains unclear. We demonstrated previously that B cells and IgG contributed to the defense against disseminated WNV infection (Diamond, M.S., B. Shrestha, A. Marri, D. Mahan, and M. Engle. 2003. J. Virol. 77:2578–2586). In this paper, we addressed the function of IgM in controlling WNV infection. C57BL/6J mice (sIgM−/−) that were deficient in the production of secreted IgM but capable of expressing surface IgM and secreting other immunoglobulin isotypes were vulnerable to lethal infection, even after inoculation with low doses of WNV. Within 96 h, markedly higher levels of infectious virus were detected in the serum of sIgM−/− mice compared with wild-type mice. The enhanced viremia correlated with higher WNV burdens in the central nervous system, and was also associated with a blunted anti-WNV IgG response. Passive transfer of polyclonal anti-WNV IgM or IgG protected sIgM−/− mice against mortality, although administration of comparable amounts of a nonneutralizing monoclonal anti-WNV IgM provided no protection. In a prospective analysis, a low titer of anti-WNV IgM antibodies at day 4 uniformly predicted mortality in wild-type mice. Thus, the induction of a specific, neutralizing IgM response early in the course of WNV infection limits viremia and dissemination into the central nervous system, and protects against lethal infection.

Myopericarditis Following Smallpox Vaccination Among Vaccinia-Naive US Military Personnel

Abstract: ContextIn the United States, the annual incidence of myocarditis is estimated at 1 to 10 per 100 000 population. As many as 1% to 5% of patients with acute viral infections involve the myocardium. Although many viruses have been reported to cause myopericarditis, it has been a rare or unrecognized event after vaccination with the currently used strain of vaccinia virus (New York City Board of Health).ObjectiveTo describe a series of probable cases of myopericarditis following smallpox vaccination among US military service members reported since the reintroduction of vaccinia vaccine.Design, Setting, ParticipantsSurveillance case definitions are presented. The cases were identified either through sentinel reporting to US military headquarters surveillance using the Defense Medical Surveillance System or reports to the Vaccine Adverse Event Reporting System using International Classification of Diseases, Ninth Revision. The cases occurred among individuals vaccinated from mid-December 2002 to March 14, 2003.Main Outcome MeasureElevated serum levels of creatine kinase (MB isoenzyme), troponin I, and troponin T, usually in the presence of ST-segment elevation on electrocardiogram and wall motion abnormalities on echocardiogram.ResultsAmong 230 734 primary vaccinees, 18 cases of probable myopericarditis after smallpox vaccination were reported (an incidence of 7.8 per 100 000 over 30 days). No cases of myopericarditis following smallpox vaccination were reported among 95 622 vaccinees who were previously vaccinated. All cases were white men aged 21 years to 33 years (mean age, 26.5 years), who presented with acute myopericarditis 7 to 19 days following vaccination. A causal relationship is supported by the close temporal clustering (7-19 days; mean, 10.5 days following vaccination), wide geographic and temporal distribution, occurrence in only primary vaccinees, and lack of evidence for alternative etiologies or other diseases associated with myopericarditis. Additional supporting evidence is the observation that the observed rate of myopericarditis among primary vaccinees is 3.6-fold (95% confidence interval, 3.33-4.11) higher than the expected rate among personnel who were not vaccinated. The background incidence of myopericarditis did not show statistical significance when stratified by age (20-34 years: 2.18 expected cases per 100 000; 95% confidence interval [CI], 1.90-2.34), race (whites: 1.82 per 100 000; 95% CI, 1.50-2.01), and sex (males: 2.28 per 100 000; 95% CI, 2.04-2.54).ConclusionAmong US military personnel vaccinated against smallpox, myopericarditis occurred at a rate of 1 per 12 819 primary vaccinees. Myopericarditis should be considered an expected adverse event associated with smallpox vaccination. Clinicians should consider myopericarditis in the differential diagnosis of patients presenting with chest pain 4 to 30 days following smallpox vaccination and be aware of the implications as well as the need to report this potential adverse advent.

Independent and combined effects of amino acids and glucose after resistance exercise.

Abstract: MILLER, S. L., K. D. TIPTON, D. L. CHINKES, S. E. WOLF, and R. R. WOLFE. Independent and Combined Effects of Amino Acids and Glucose after Resistance Exercise. Med. Sci. Sports Exerc., Vol. 35, No. 3, pp. 449–455, 2003.PurposeThis study was designed to assess the independent and combined eff

Therapeutic alliance in depression treatment: controlling for prior change and patient characteristics.

Abstract: Although many studies report that the therapeutic alliance predicts psychotherapy outcome, few exclude the possibility that this association is accounted for by 3rd variables, such as prior improvement and prognostically relevant patient characteristics. The authors treated 367 chronically depressed patients with the cognitive-behavioral analysis system of psychotherapy (CBASP), alone or with medication. Using mixed effects growth-curve analyses, they found the early alliance significantly predicted subsequent improvement in depressive symptoms after controlling for prior improvement and 8 prognostically relevant patient characteristics. In contrast, neither early level nor change in symptoms predicted the subsequent level or course of the alliance. Patients receiving combination treatment reported stronger alliances with their psychotherapists than patients receiving CBASP alone. However, the impact of the alliance on outcome was similar for both treatment conditions.

Functional Characterization of Polymorphisms in DNA Repair Genes Using Cytogenetic Challenge Assays

Abstract: A major barrier to understanding the role of polymorphic DNA repair genes for environmental cancer is that the functions of variant genotypes are largely unknown. Using our cytogenetic challenge assays, we conducted an investigation to address the deficiency. Using X-rays or ultraviolet (UV) light, we irradiated blood lymphocytes from 80 nonsmoking donors to challenge the cells to repair the induced DNA damage, and we analyzed expression of chromosome aberrations (CA) specific to the inducing agents. We have genotyped polymorphic DNA repair genes preferentially involved with base excision repair (BER) and nucleotide excision repair (NER) activities (XRCC1, XRCC3, APE1, XPD) corresponding to the repair of X-ray- and UV light-induced DNA damage, respectively. We expected that defects in specific DNA repair pathways due to polymorphisms would cause corresponding increases of specific CA. From our data, XRCC1 399Gln and XRCC3 241Met were associated with significant increases in chromosome deletions compared with the corresponding homozygous wild types (18.27 1.1 vs 14.79 1.2 and 18.22 0.99 vs 14.20 1.39, respectively); XPD 312Asn and XPD 751Gln were associated with significant increases in chromatid breaks compared with wild types (16.09 1.36 vs 11.41 0.98 and 16.87 1.27 vs 10.54 0.87, respectively), p < 0.05. The data indicate that XRCC1 399Gln and XRCC3 241Met are significantly defective in BER, and the XPD 312Asn and XPD 751Gln are significantly defective in NER. In addition, the variant genotypes interact significantly, with limited overlap of the two different repair pathways.

Impact of bipolar disorder on a u.s. community sample

Abstract: Background: Bipolar disorder is a chronic psychiatric illness characterized by depression and at least 1 manic or hypomanic episode during the lifetime of the illness. Bipolar symptoms have been associated with significant functional impairment. We conducted a study to determine the psychosocial impact of bipolar disorder in a U.S. community sample. Method: 3059 subjects were selected from a large epidemiologic study of bipolar prevalence that used the Mood Disorder Questionnaire (MDQ) to screen for bipolar I and II disorder. Subjects were surveyed from April 24, 2001, to August 6, 2001, using the Sheehan Disability Scale and the Social Adjustment Scale-Self Report. Comorbid disease data were also collected. Results: Of the 3059 subjects surveyed, 2450 (80%) returned completed surveys: 1167 (48%) subjects screened positive for bipolar disorder based on MDQ scores; 1283 (52%) screened negative. MDQ-positive subjects reported significantly (p <.0001) more difficulties with work-related performance, social/leisure activities, and social/family interactions compared with MDQ-negative subjects. Younger subjects, aged 18 to 34 years, reported significantly (p =.003) more symptom days than did older MDQ-positive subjects. MDQ-positive women reported more disruption in social and family life, while MDQ-positive men reported being jailed, arrested, and convicted for crimes. Anxiety (30% vs. 6%), panic attacks (18% vs. 4%), migraine (24% vs. 11%), asthma (17% vs. 10%), and allergies (42% vs. 29%) were significantly (p <.05) more common in MDQ-positive versus MDQ-negative subjects. Conclusion: Bipolar disorder, as identified in a community sample using the Mood Disorder Questionnaire, was significantly associated with negative impact on the performance of work-related, leisure, and interpersonal activities.

Lipid peroxidation and cell cycle signaling: 4-hydroxynonenal, a key molecule in stress mediated signaling.

Abstract: Role of lipid peroxidation products, particularly 4-hydroxynonenal (4-HNE) in cell cycle signaling is becoming increasingly clear. In this article, recent studies suggesting an important role of 4-HNE in stress mediated signaling for apoptosis are critically evaluated. Evidence demonstrating the modulation of UV, oxidative stress, and chemical stress mediated apoptosis by blocking lipid peroxidation by the alpha-class glutathione S-transferases (GSTs) is presented which suggest an important role of these enzymes in protection against oxidative stress and a role of lipid peroxidation products in stress mediated signaling. Overexpression of 4-HNE metabolizing GSTs (mGSTA4-4, hGSTA4-4, or hGST5.8) protects cells against 4-HNE, oxidative stress (H(2)O(2) or xanthine/xanthine oxidase), and UV-A mediated apoptosis by blocking JNK and caspase activation suggesting a role of 4-HNE in the mechanisms of apoptosis caused by these stress factors. The intracellular concentration of 4-HNE appears to be crucial for the nature of cell cycle signaling and may be a determinant for the signaling for differentiation, proliferation, transformation, or apoptosis. The intracellular concentrations of 4-HNE are regulated through a coordinated action of GSTs (GSTA4-4 and hGST5.8) which conjugate 4-HNE to GSH to form the conjugate (GS-HNE) and the transporter 76 kDa Ral-binding GTPase activating protein (RLIP76), which catalyze ATP-dependent transport of GS-HNE. A mild stress caused by heat, UV-A, or H(2)O(2)with no apparent effect on the cells in culture causes a rapid, transient induction of hGST5.8 and RLIP76. These stress preconditioned cells acquire ability to metabolize and exclude 4-HNE at an accelerated pace and acquire relative resistance to apoptosis by UV and oxidative stress as compared to unconditioned control cells. This resistance of stress preconditioned cells can be abrogated by coating the cells with anti-RLIP76 antibodies which block the transport of GS-HNE. These studies and previous reports discussed in this article strongly suggest a key role of 4-HNE in stress mediated signaling.

SDAP: database and computational tools for allergenic proteins

Abstract: SDAP (Structural Database of Allergenic Proteins) is a web server that provides rapid, cross-referenced access to the sequences, structures and IgE epitopes of allergenic proteins. The SDAP core is a series of CGI scripts that process the user queries, interrogate the database, perform various computations related to protein allergenic determinants and prepare the output HTML pages. The database component of SDAP contains information about the allergen name, source, sequence, structure, IgE epitopes and literature references and easy links to the major protein (PDB, SWISS-PROT/TrEMBL, PIR-ALN, NCBI Taxonomy Browser) and literature (PubMed, MEDLINE) on-line servers. The computational component in SDAP uses an original algorithm based on conserved properties of amino acid side chains to identify regions of known allergens similar to user-supplied peptides or selected from the SDAP database of IgE epitopes. This and other bioinformatics tools can be used to rapidly determine potential cross-reactivities between allergens and to screen novel proteins for the presence of IgE epitopes they may share with known allergens. SDAP is available via the World Wide Web at http://fermi.utmb.edu/SDAP/.

The Pedigree Rate of Sequence Divergence in the Human Mitochondrial Genome: There Is a Difference Between Phylogenetic and Pedigree Rates

Abstract: We have extended our previous analysis of the pedigree rate of control-region divergence in the human mitochondrial genome. One new germline mutation in the mitochondrial DNA (mtDNA) control region was detected among 185 transmission events (generations) from five Leber hereditary optic neuropathy (LHON) pedigrees. Pooling the LHON pedigree analyses yields a control-region divergence rate of 1.0 mutation/bp/106 years (Myr). When the results from eight published studies that used a similar approach were pooled with the LHON pedigree studies, totaling >2,600 transmission events, a pedigree divergence rate of 0.95 mutations/bp/Myr for the control region was obtained with a 99.5% confidence interval of 0.53–1.57. Taken together, the cumulative results support the original conclusion that the pedigree divergence rate for the control region is ∼10-fold higher than that obtained with phylogenetic analyses. There is no evidence that any one factor explains this discrepancy, and the possible roles of mutational hotspots (rate heterogeneity), selection, and random genetic drift and the limitations of phylogenetic approaches to deal with high levels of homoplasy are discussed. In addition, we have extended our pedigree analysis of divergence in the mtDNA coding region. Finally, divergence of complete mtDNA sequences was analyzed in two tissues, white blood cells and skeletal muscle, from each of 17 individuals. In three of these individuals, there were four instances in which an mtDNA mutation was found in one tissue but not in the other. These results are discussed in terms of the occurrence of somatic mtDNA mutations.

Importance of Respiratory Viruses in Acute Otitis Media

Abstract: Acute otitis media is usually considered a simple bacterial infection that is treated with antibiotics. However, ample evidence derived from studies ranging from animal experiments to extensive clinical trials supports a crucial role for respiratory viruses in the etiology and pathogenesis of acute otitis media. Viral infection of the upper respiratory mucosa initiates the whole cascade of events that finally leads to the development of acute otitis media as a complication. The pathogenesis of acute otitis media involves a complex interplay between viruses, bacteria, and the host’s inflammatory response. In a substantial number of children, viruses can be found in the middle-ear fluid either alone or together with bacteria, and recent studies indicate that at least some viruses actively invade the middle ear. Viruses appear to enhance the inflammatory process in the middle ear, and they may significantly impair the resolution of otitis media. Prevention of the predisposing viral infection by vaccination against the major viruses would probably be the most effective way to prevent acute otitis media. Alternatively, early treatment of the viral infection with specific antiviral agents would also be effective in reducing the occurrence of acute otitis media.