Prevalence of contraindications to mefloquine use among USA military personnel deployed to Afghanistan

<p>Abstract</p> <p>Background</p> <p>Mefloquine has historically been considered safe and well-tolerated for long-term malaria chemoprophylaxis, but its prescribing requires careful attention to rule out contraindications to its use, including a history of certain psychiatric and neurological disorders. The prevalence of these disorders has not been defined in cohorts of U.S. military personnel deployed to areas where long-term malaria chemoprophylaxis is indicated.</p> <p>Methods</p> <p>Military medical surveillance and pharmacosurveillance databases were utilized to identify contraindications to mefloquine use among a cohort of 11,725 active duty U.S. military personnel recently deployed to Afghanistan.</p> <p>Results</p> <p>A total of 9.6% of the cohort had evidence of a contraindication. Females were more than twice as likely as males to have a contraindication (OR = 2.48, P < 0.001).</p> <p>Conclusion</p> <p>These findings underscore the importance of proper systematic screening prior to prescribing and dispensing mefloquine, and the need to provide alternatives to mefloquine suitable for long-term administration among deployed U.S. military personnel.</p

Human Telomerase Reverse Transcriptase (hTERT) Q169 Is Essential for Telomerase Function In Vitro and In Vivo

BACKGROUND:Telomerase is a reverse transcriptase that maintains the telomeres of linear chromosomes and preserves genomic integrity. The core components are a catalytic protein subunit, the telomerase reverse transcriptase (TERT), and an RNA subunit, the telomerase RNA (TR). Telomerase is unique in its ability to catalyze processive DNA synthesis, which is facilitated by telomere-specific DNA-binding domains in TERT called anchor sites. A conserved glutamine residue in the TERT N-terminus is important for anchor site interactions in lower eukaryotes. The significance of this residue in higher eukaryotes, however, has not been investigated. METHODOLOGY/PRINCIPAL FINDINGS:To understand the significance of this residue in higher eukaryotes, we performed site-directed mutagenesis on human TERT (hTERT) Q169 to create neutral (Q169A), conservative (Q169N), and non-conservative (Q169D) mutant proteins. We show that these mutations severely compromise telomerase activity in vitro and in vivo. The functional defects are not due to abrogated interactions with hTR or telomeric ssDNA. However, substitution of hTERT Q169 dramatically impaired the ability of telomerase to incorporate nucleotides at the second position of the template. Furthermore, Q169 mutagenesis altered the relative strength of hTERT-telomeric ssDNA interactions, which identifies Q169 as a novel residue in hTERT required for optimal primer binding. Proteolysis experiments indicate that Q169 substitution alters the protease-sensitivity of the hTERT N-terminus, indicating that a conformational change in this region of hTERT is likely critical for catalytic function. CONCLUSIONS/SIGNIFICANCE:We provide the first detailed evidence regarding the biochemical and cellular roles of an evolutionarily-conserved Gln residue in higher eukaryotes. Collectively, our results indicate that Q169 is needed to maintain the hTERT N-terminus in a conformation that is necessary for optimal enzyme-primer interactions and nucleotide incorporation. We show that Q169 is critical for the structure and function of human telomerase, thereby identifying a novel residue in hTERT that may be amenable to therapeutic intervention

ARID1B is a specific vulnerability in ARID1A-mutant cancers

Summary Recent studies have revealed that ARID1A is frequently mutated across a wide variety of human cancers and also has bona fide tumor suppressor properties. Consequently, identification of vulnerabilities conferred by ARID1A mutation would have major relevance for human cancer. Here, using a broad screening approach, we identify ARID1B, a related but mutually exclusive homolog of ARID1A in the SWI/SNF chromatin remodeling complex, as the number one gene preferentially required for the survival of ARID1A-mutant cancer cell lines. We show that loss of ARID1B in ARID1A-deficient backgrounds destabilizes SWI/SNF and impairs proliferation. Intriguingly, we also find that ARID1A and ARID1B are frequently co-mutated in cancer, but that ARID1A-deficient cancers retain at least one ARID1B allele. These results suggest that loss of ARID1A and ARID1B alleles cooperatively promotes cancer formation but also results in a unique functional dependence. The results further identify ARID1B as a potential therapeutic target for ARID1A-mutant cancers

Resistance to Wheat streak mosaic virus identified in synthetic wheat lines

Citation: Shoup Rupp, J. L., Simon, Z. G., Gillett-Walker, B., & Fellers, J. P. (2014). Resistance to Wheat streak mosaic virus identified in synthetic wheat lines. Retrieved from http://krex.ksu.eduWheat streak mosaic virus (WSMV) is an important pathogen in wheat that causes significant yield losses each year. WSMV is typically controlled using cultural practices such as the removal of volunteer wheat. Genetic resistance is limited. Until recently, no varieties have been available with major resistance genes to WSMV. Two resistance genes have been derived from Thinopyrum intermedium through chromosome engineering, while a third gene was transferred from bread wheat through classical breeding. New sources of resistance are needed and synthetic wheat lines provide a means of accessing genetic variability in wheat progenitors. A collection of wheat synthetic lines was screened for WSMV resistance. Four lines, 07-SYN-27, -106, -164, and -383 had significant levels of resistance. Resistance was effective at 18 °C and virus accumulation was similar to the resistant control, WGGRC50 containing Wsm1. At 25 °C, resistance was no longer effective and virus accumulation was similar to the susceptible control, Tomahawk

Relationships Linking Amplification Level to Gene Over-Expression in Gliomas

Background: Gene amplification is thought to promote over-expression of genes favouring tumour development. Because amplified regions are usually megabase-long, amplification often concerns numerous syntenic or non-syntenic genes, among which only a subset is over-expressed. The rationale for these differences remains poorly understood. Methodology/Principal Finding: To address this question, we used quantitative RT-PCR to determine the expression level of a series of co-amplified genes in five xenografted and one fresh human gliomas. These gliomas were chosen because we have previously characterised in detail the genetic content of their amplicons. In all the cases, the amplified sequences lie on extra-chromosomal DNA molecules, as commonly observed in gliomas. We show here that genes transcribed in nonamplified gliomas are over-expressed when amplified, roughly in proportion to their copy number, while non-expressed genes remain inactive. When specific antibodies were available, we also compared protein expression in amplified and nonamplified tumours. We found that protein accumulation barely correlates with the level of mRNA expression in some of these tumours. Conclusions/Significance: Here we show that the tissue-specific pattern of gene expression is maintained upon amplification in gliomas. Our study relies on a single type of tumour and a limited number of cases. However, it strongly suggests that, even when amplified, genes that are normally silent in a given cell type play no role in tumour progression

Search for new phenomena in final states with an energetic jet and large missing transverse momentum in pp collisions at √ s = 8 TeV with the ATLAS detector

Results of a search for new phenomena in final states with an energetic jet and large missing transverse momentum are reported. The search uses 20.3 fb−1 of √ s = 8 TeV data collected in 2012 with the ATLAS detector at the LHC. Events are required to have at least one jet with pT > 120 GeV and no leptons. Nine signal regions are considered with increasing missing transverse momentum requirements between Emiss T > 150 GeV and Emiss T > 700 GeV. Good agreement is observed between the number of events in data and Standard Model expectations. The results are translated into exclusion limits on models with either large extra spatial dimensions, pair production of weakly interacting dark matter candidates, or production of very light gravitinos in a gauge-mediated supersymmetric model. In addition, limits on the production of an invisibly decaying Higgs-like boson leading to similar topologies in the final state are presente

Are mild head injuries as mild as we think? Neurobehavioral concomitants of chronic post-concussion syndrome

BACKGROUND: Mild traumatic brain injury (MTBI) can sometimes lead to persistent postconcussion symptoms. One well accepted hypothesis claims that chronic PCS has a neural origin, and is related to neurobehavioral deficits. But the evidence is not conclusive. In the attempt to characterise chronic MTBI consequences, the present experiment used a group comparison design, which contrasted persons (a) with MTBI and PCS, (b) MTBI without PCS, and (c) matched controls. We predicted that participants who have experienced MTBI but show no signs of PCS would perform similar to controls. At the same time, a subgroup of MTBI participants would show PCS symptoms and only these volunteers would have poorer cognitive performance. Thereby, the performance deficits should be most noticeable in participants with highest PCS severity. METHOD: 38 patients with a single MTBI that had occurred at least 12 month prior to testing, and 38 matched controls, participated in the experiment. A combination of questionnaires and neuropsychological test batteries were used to assess the extent of PCS and related deficits in neurobehavioral performance. RESULTS: 11 out of 38 MTBI participants (29%) were found to suffer from PCS. This subgroup of MTBI patients performed poorly on neuropsychological test batteries. Thereby, a correlation was found between PCS symptom severity and test performance suggesting that participants with more pronounced PCS symptoms performed worse in cognitive tasks. In contrast, MTBI patients with no PCS showed performed similar to matched control. We further found that loss of consciousness, a key criterion for PCS diagnosis, was not predictive of sustained PCS. CONCLUSION: The results support the idea that MTBI can have sustained consequences, and that the subjectively experienced symptoms and difficulties in everyday situations are related to objectively measurable parameters in neurocognitive function

The physical and mental health of a large military cohort: baseline functional health status of the Millennium Cohort

<p>Abstract</p> <p>Background:</p> <p>The US military is currently involved in large, lengthy, and complex combat operations around the world. Effective military operations require optimal health of deployed service members, and both mental and physical health can be affected by military operations.</p> <p>Methods:</p> <p>Baseline data were collected from 77,047 US service members during 2001–2003 as part of a large, longitudinal, population-based military health study (the Millennium Cohort Study). The authors calculated unadjusted, adjusted, and weighted means for the Medical Outcomes Study Short Form 36-item Survey for Veterans physical (PCS) and mental component summary (MCS) scores over a variety of demographic and military characteristics at baseline.</p> <p>Results:</p> <p>The unadjusted mean PCS and MCS scores for this study were 53.4 (95% confidence interval: 53.3–53.4) and 52.8 (95% confidence interval: 52.7–52.9). Average PCS and MCS scores were slightly more favorable in this military sample compared to those of the US general population of the same age and sex. Factors independently associated with more favorable health status included male gender, being married, higher educational attainment, higher military rank, and Air Force service. Combat specialists had similar health status compared to other military occupations. Having been deployed to Southwest Asia, Bosnia, or Kosovo between 1998 and 2000 was not associated with diminished health status.</p> <p>Conclusion:</p> <p>The baseline health status of this large population-based military cohort is better than that of the US general population of the same age and sex distribution over the same time period, especially in older age groups. Deployment experiences during the period of 1998–2001 were not associated with decreased health status. These data will serve as a useful reference for other military health studies and for future longitudinal analyses.</p

Re-examination of the Controversial Coexistence of Traumatic Brain Injury and Posttraumatic Stress Disorder: Misdiagnosis and Self-Report Measures

The coexistence of traumatic brain injury (TBI) and posttraumatic stress disorder (PTSD) remains a controversial issue in the literature. To address this controversy, we focused primarily on the civilian-related literature of TBI and PTSD. Some investigators have argued that individuals who had been rendered unconscious or suffered amnesia due to a TBI are unable to develop PTSD because they would be unable to consciously experience the symptoms of fear, helplessness, and horror associated with the development of PTSD. Other investigators have reported that individuals who sustain TBI, regardless of its severity, can develop PTSD even in the context of prolonged unconsciousness. A careful review of the methodologies employed in these studies reveals that investigators who relied on clinical interviews of TBI patients to diagnose PTSD found little or no evidence of PTSD. In contrast, investigators who relied on PTSD questionnaires to diagnose PTSD found considerable evidence of PTSD. Further analysis revealed that many of the TBI patients who were initially diagnosed with PTSD according to self-report questionnaires did not meet the diagnostic criteria for PTSD upon completion of a clinical interview. In particular, patients with severe TBI were often misdiagnosed with PTSD. A number of investigators found that many of the severe TBI patients failed to follow the questionnaire instructions and erroneously endorsed PTSD symptoms because of their cognitive difficulties. Because PTSD questionnaires are not designed to discriminate between PTSD and TBI symptoms or determine whether a patient's responses are accurate or exaggerated, studies that rely on self-report questionnaires to evaluate PTSD in TBI patients are at risk of misdiagnosing PTSD. Further research should evaluate the degree to which misdiagnosis of PTSD occurs in individuals who have sustained mild TBI

Insomnia symptoms and repressive coping in a sample of older Black and White women

BACKGROUND: This study examined whether ethnic differences in insomnia symptoms are mediated by differences in repressive coping styles. METHODS: A total of 1274 women (average age = 59.36 ± 6.53 years) participated in the study; 28% were White and 72% were Black. Older women in Brooklyn, NY were recruited using a stratified, cluster-sampling technique. Trained staff conducted face-to-face interviews lasting 1.5 hours acquiring sociodemographic data, health characteristics, and risk factors. A sleep questionnaire was administered and individual repressive coping styles were assessed. Fisher's exact test and Spearman and Pearson analyses were used to analyze the data. RESULTS: The rate of insomnia symptoms was greater among White women [74% vs. 46%; χ(2 )= 87.67, p < 0.0001]. Black women scored higher on the repressive coping scale than did White women [Black = 37.52 ± 6.99, White = 29.78 ± 7.38, F(1,1272 )= 304.75, p < 0.0001]. We observed stronger correlations between repressive coping and insomnia symptoms for Black [r(s )= -0.43, p < 0.0001] than for White women [r(s )= -0.18, p < 0.0001]. Controlling for variation in repressive coping, the magnitude of the correlation between ethnicity and insomnia symptoms was substantially reduced. Multivariate adjustment for differences in sociodemographics, health risk factors, physical health, and health beliefs and attitudes had little effect on the relationships. CONCLUSION: Relationships between ethnicity and insomnia symptoms are jointly dependent on the degree of repressive coping, suggesting that Black women may be reporting fewer insomnia symptoms because of a greater ability to route negative emotions from consciousness. It may be that Blacks cope with sleep problems within a positive self-regulatory framework, which allows them to deal more effectively with sleep-interfering psychological processes to stressful life events and to curtail dysfunctional sleep-interpreting processes