Two novel human cytomegalovirus NK cell evasion functions target MICA for lysosomal degradation

NKG2D plays a major role in controlling immune responses through the regulation of natural killer (NK) cells, αβ and γδ T-cell function. This activating receptor recognizes eight distinct ligands (the MHC Class I polypeptide-related sequences (MIC) A andB, and UL16-binding proteins (ULBP)1–6) induced by cellular stress to promote recognition cells perturbed by malignant transformation or microbial infection. Studies into human cytomegalovirus (HCMV) have aided both the identification and characterization of NKG2D ligands (NKG2DLs). HCMV immediate early (IE) gene up regulates NKGDLs, and we now describe the differential activation of ULBP2 and MICA/B by IE1 and IE2 respectively. Despite activation by IE functions, HCMV effectively suppressed cell surface expression of NKGDLs through both the early and late phases of infection. The immune evasion functions UL16, UL142, and microRNA(miR)-UL112 are known to target NKG2DLs. While infection with a UL16 deletion mutant caused the expected increase in MICB and ULBP2 cell surface expression, deletion of UL142 did not have a similar impact on its target, MICA. We therefore performed a systematic screen of the viral genome to search of addition functions that targeted MICA. US18 and US20 were identified as novel NK cell evasion functions capable of acting independently to promote MICA degradation by lysosomal degradation. The most dramatic effect on MICA expression was achieved when US18 and US20 acted in concert. US18 and US20 are the first members of the US12 gene family to have been assigned a function. The US12 family has 10 members encoded sequentially through US12–US21; a genetic arrangement, which is suggestive of an ‘accordion’ expansion of an ancestral gene in response to a selective pressure. This expansion must have be an ancient event as the whole family is conserved across simian cytomegaloviruses from old world monkeys. The evolutionary benefit bestowed by the combinatorial effect of US18 and US20 on MICA may have contributed to sustaining the US12 gene family

Alcohol use among university students in Sweden measured by an electronic screening instrument

<p>Abstract</p> <p>Background</p> <p>Electronic-based alcohol screening and brief interventions for university students with problem drinking behaviours forms an important means by which to identify risky drinkers.</p> <p>Methods</p> <p>In this study an e-SBI project was implemented to assess drinking patterns, and to provide personalised feedback about alcohol consumption and related health problems, to students in a Swedish university. In this study, third semester university students (n = 2858) from all faculties (colleges) at the University were invited to participate in e-SBI screenings. This study employed a randomised controlled trial, with respondents having a equal chance of being assigned to a limited, or full-feedback response.</p> <p>Results</p> <p>The study shows that high risk drinkers tend to underestimate their own consumption compared to others, and that these high risk drinkers experience more negative consequences after alcohol intake, than other respondents. There was a strong belief, for both high- and low-risk drinkers, that alcohol helped celebrations be more festive. This study also confirms findings from other study locations that while males drank more than females in our study population; females reached the same peak alcohol blood concentrations as males.</p> <p>Conclusion</p> <p>Obtaining clear and current information on drinking patterns demonstrated by university students can help public health officials, university administration, and local health care providers develop appropriate prevention and treatment strategies.</p

Obstructive sleep apnea in Treacher Collins syndrome

The aim of the present study was to investigate the prevalence of obstructive sleep apnea syndrome (OSAS) among the Norwegian population with Treacher Collins syndrome (TCS). A secondary aim was to establish whether TCS phenotype severity is associated with OSAS severity. A prospective case study design was used. Individuals who were 5 years old and above with a known diagnosis of TCS in Norway were invited to participate in a study. The study included genetic testing, medical and dental examinations and polysomnography. All participants demonstrated disturbed respiration during sleep; 18/19 met the diagnostic criteria for OSAS. Subjectively evaluated snoring was not a reliable predictor of OSAS. We found no significant association between TCS phenotype severity and the severity of OSAS. OSAS is common in TCS, but there is no association with the phenotype severity. Individuals diagnosed with TCS must undergo sleep studies to identify the presence of OSAS

Cough quality in children: a comparison of subjective vs. bronchoscopic findings

BACKGROUND: Cough is the most common symptom presenting to doctors. The quality of cough (productive or wet vs dry) is used clinically as well as in epidemiology and clinical research. There is however no data on the validity of cough quality descriptors. The study aims were to compare (1) cough quality (wet/dry and brassy/non-brassy) to bronchoscopic findings of secretions and tracheomalacia respectively and, (2) parent's vs clinician's evaluation of the cough quality (wet/dry). METHODS: Cough quality of children (without a known underlying respiratory disease) undergoing elective bronchoscopy was independently evaluated by clinicians and parents. A 'blinded' clinician scored the secretions seen at bronchoscopy on pre-determined criteria and graded (1 to 6). Kappa (K) statistics was used for agreement, and inter-rater and intra-rater agreement examined on digitally recorded cough. A receiver operating characteristic (ROC) curve was used to determine if cough quality related to amount of airway secretions present at bronchoscopy. RESULTS: Median age of the 106 children (62 boys, 44 girls) enrolled was 2.6 years (IQR 5.7). Parent's assessment of cough quality (wet/dry) agreed with clinicians' (K = 0.75, 95%CI 0.58–0.93). When compared to bronchoscopy (bronchoscopic secretion grade 4), clinicians' cough assessment had the highest sensitivity (0.75) and specificity (0.79) and were marginally better than parent(s). The area under the ROC curve was 0.85 (95%CI 0.77–0.92). Intra-observer (K = 1.0) and inter-clinician agreement for wet/dry cough (K = 0.88, 95%CI 0.82–0.94) was very good. Weighted K for inter-rater agreement for bronchoscopic secretion grades was 0.95 (95%CI 0.87–1). Sensitivity and specificity for brassy cough (for tracheomalacia) were 0.57 and 0.81 respectively. K for both intra and inter-observer clinician agreement for brassy cough was 0.79 (95%CI 0.73–0.86). CONCLUSIONS: Dry and wet cough in children, as determined by clinicians and parents has good clinical validity. Clinicians should however be cognisant that children with dry cough may have minimal to mild airway secretions. Brassy cough determined by respiratory physicians is highly specific for tracheomalacia

The association between intimate partner violence, alcohol and depression in family practice

Background: Depressive symptoms, intimate partner violence and hazardous drinking are common among patients attending general practice. Despite the high prevalence of these three problems; the relationship between them remains relatively unexplored. Methods: This paper explores the association between depressive symptoms, ever being afraid of a partner and hazardous drinking using cross-sectional screening data from 7667 randomly selected patients from a large primary care cohort study of 30 metropolitan and rural general practices in Victoria, Australia. The screening postal survey included the Center for Epidemiological Studies Depression Scale, the Fast Alcohol Screening Test and a screening question from the Composite Abuse Scale on ever being afraid of any intimate partner. Results: 23.9% met criteria for depressive symptoms. A higher proportion of females than males (20.8% vs. 7.6%) reported ever being afraid of a partner during their lifetime (OR 3.2, 95%CI 2.5 to 4.0) and a lower proportion of females (12%) than males (25%) were hazardous drinkers (OR 0.4; 95%CI 0.4 to 0.5); and a higher proportion of females than males (20.8% vs. 7.6%) reported ever being afraid of a partner during their lifetime (OR 3.2, 95%CI 2.5 to 4.0). Men and women who had ever been afraid of a partner or who were hazardous drinkers had on average higher depressive symptom scores than those who had never been afraid or who were not hazardous drinkers. There was a stronger association between depressive symptoms and ever been afraid of a partner compared to hazardous drinking for both males (ever afraid of partner; Diff 6.87; 95% CI 5.42, 8.33; p < 0.001 vs. hazardous drinking in last year; Diff 1.07, 95% CI 0.21, 1.94; p = 0.015) and females (ever afraid of partner; Diff 5.26; 95% CI 4.55, 5.97; p < 0.001 vs. hazardous drinking in last year; Diff 2.23, 95% CI 1.35, 3.11; p < 0.001), even after adjusting for age group, income, employment status, marital status, living alone and education level. Conclusions: Strategies to assist primary care doctors to recognise and manage intimate partner violence and hazardous drinking in patients with depression may lead to better outcomes from management of depression in primary care

New Specimens of Nemegtomaia from the Baruungoyot and Nemegt Formations (Late Cretaceous) of Mongolia

Two new specimens of the oviraptorid theropod Nemegtomaia barsboldi from the Nemegt Basin of southern Mongolia are described. Specimen MPC-D 107/15 was collected from the upper beds of the Baruungoyot Formation (Campanian-Maastrichtian), and is a nest of eggs with the skeleton of the assumed parent of Nemegtomaia on top in brooding position. Much of the skeleton was damaged by colonies of dermestid coleopterans prior to its complete burial. However, diagnostic characters are recovered from the parts preserved, including the skull, partial forelimbs (including the left hand), legs, and distal portions of both feet. Nemegtomaia represents the fourth known genus of oviraptorid for which individuals have been found on nests of eggs. The second new specimen, MPC-D 107/16, was collected a few kilometers to the east in basal deposits of the Nemegt Formation, and includes both hands and femora of a smaller Nemegtomaia individual. The two formations and their diverse fossil assemblages have been considered to represent sequential time periods and different environments, but data presented here indicate partial overlap across the Baruungoyot-Nemegt transition. All other known oviraptorids from Mongolia and China are known exclusively from xeric or semi-arid environments. However, this study documents that Nemegtomaia is found in both arid/aeolian (Baruungoyot Formation) and more humid/fluvial (Nemegt Formation) facies

The impact of generational change and retirement on psychiatry to 2025

<p>Abstract</p> <p>Background</p> <p>Australia is currently experiencing widespread shortages of psychiatrists. The changing nature of the workforce and increasing demand mean that these shortages are unlikely to ease. This study aims to identify demographic change and retirement patterns of the Australian psychiatry workforce from 1995 to 2003, and the implications of those changes for future workforce planning.</p> <p>Methods</p> <p>Data from the Australian Institute of Health and Welfare (AIHW) Medical Labour Force Survey from 1995 to 2003 is used to examine ageing of the psychiatry workforce and attrition of psychiatrists aged 50 years and over. Future attrition from the workforce is projected to 2025.</p> <p>Results</p> <p>Sixty two percent of psychiatrists practicing in the year 2000 are predicted to have retired by 2025. Most psychiatrists continue to work until late in life, with only 18 per cent retiring before age 65. The psychiatry workforce aged significantly between 1995 and 2003 (p < 0.001), with men older than women in both years. A reduction in hours worked by psychiatrists reflects both the increasing proportion of females and the older members of the profession reducing their hours in preparation for retirement.</p> <p>Conclusion</p> <p>The impact of ageing of the workforce may be more immediate for psychiatry than for some other health professions. With the growing proportion of females and their typically lower workforce participation, more than one younger psychiatrist will be required to replace each of the mostly male retirees.</p

Extensive telomere erosion is consistent with localised clonal expansions in Barrett’s metaplasia

Barrett’s oesophagus is a premalignant metaplastic condition that predisposes patients to the development of oesophageal adenocarcinoma. However, only a minor fraction of Barrett’s oesophagus patients progress to adenocarcinoma and it is thus essential to determine bio-molecular markers that can predict the progression of this condition. Telomere dysfunction is considered to drive clonal evolution in several tumour types and telomere length analysis provides clinically relevant prognostic and predictive information. The aim of this work was to use high-resolution telomere analysis to examine telomere dynamics in Barrett’s oesophagus. Telomere length analysis of XpYp, 17p, 11q and 9p, chromosome arms that contain key cancer related genes that are known to be subjected to copy number changes in Barrett’s metaplasia, revealed similar profiles at each chromosome end, indicating that no one specific telomere is likely to suffer preferential telomere erosion. Analysis of patient matched tissues (233 samples from 32 patients) sampled from normal squamous oesophagus, Z-line, and 2 cm intervals within Barrett’s metaplasia, plus oesophago-gastric junction, gastric body and antrum, revealed extensive telomere erosion in Barrett’s metaplasia to within the length ranges at which telomere fusion is detected in other tumour types. Telomere erosion was not uniform, with distinct zones displaying more extensive erosion and more homogenous telomere length profiles. These data are consistent with an extensive proliferative history of cells within Barrett’s metaplasia and are indicative of localised clonal growth. The extent of telomere erosion highlights the potential of telomere dysfunction to drive genome instability and clonal evolution in Barrett’s metaplasia

Genetic association study of QT interval highlights role for calcium signaling pathways in myocardial repolarization.

The QT interval, an electrocardiographic measure reflecting myocardial repolarization, is a heritable trait. QT prolongation is a risk factor for ventricular arrhythmias and sudden cardiac death (SCD) and could indicate the presence of the potentially lethal mendelian long-QT syndrome (LQTS). Using a genome-wide association and replication study in up to 100,000 individuals, we identified 35 common variant loci associated with QT interval that collectively explain ∼8-10% of QT-interval variation and highlight the importance of calcium regulation in myocardial repolarization. Rare variant analysis of 6 new QT interval-associated loci in 298 unrelated probands with LQTS identified coding variants not found in controls but of uncertain causality and therefore requiring validation. Several newly identified loci encode proteins that physically interact with other recognized repolarization proteins. Our integration of common variant association, expression and orthogonal protein-protein interaction screens provides new insights into cardiac electrophysiology and identifies new candidate genes for ventricular arrhythmias, LQTS and SCD