Genome-wide Study Identifies Association between HLA-B*55 : 01 and Self-Reported Penicillin Allergy

Hypersensitivity reactions to drugs are often unpredictable and can be life threatening, underscoring a need for understanding their underlying mechanisms and risk factors. The extent to which germline genetic variation influences the risk of commonly reported drug allergies such as penicillin allergy remains largely unknown. We extracted data from the electronic health records of more than 600,000 participants from the UK, Estonian, and Vanderbilt University Medical Center's BioVU biobanks to study the role of genetic variation in the occurrence of self-reported penicillin hypersensitivity reactions. We used imputed SNP to HLA typing data from these cohorts to further fine map the human leukocyte antigen (HLA) association and replicated our results in 23andMe's research cohort involving a total of 1.12 million individuals. Genome-wide meta-analysis of penicillin allergy revealed two loci, including one located in the HLA region on chromosome 6. This signal was further fine-mapped to the HLA-B*55:01 allele (OR 1.41 95% CI 1.33-1.49, p value 2.04 x 10(-31)) and confirmed by independent replication in 23andMe's research cohort (OR 1.30 95% CI 1.25-1.34, p value 1.00 x 10(-47)). The lead SNP was also associated with lower lymphocyte counts and in silico follow-up suggests a potential effect on T-lymphocytes at HLA-B*55:01. We also observed a significant hit in PTPN22 and the GWAS results correlated with the genetics of rheumatoid arthritis and psoriasis. We present robust evidence for the role of an allele of the major histocompatibility complex (MHC) I gene HLA-B in the occurrence of penicillin allergy.Peer reviewe

A Genetic Analysis of the Relationship Between Life-history Variation and Heat-shock Tolerance in Drosophila buzzatii

Although exposure to environmental stress is common in most populations, and the physiological effects of stress on individuals are well studied, the evolutionary importance of stress to populations is not well understood. To address multitrait responses to environmental change and potential constraints on character evolution, we analysed, in 100 isofemale lines of Drosophila buzzatii, the genetic relationships between resistance to a short heat shock and several life-history traits: survival in benign conditions, larval developmental time, fecundity and longevity. Estimates of heritability of larval thermotolerance were low, but significant, and all life-history traits varied significantly among isofemale lines. Several of these traits covaried significantly. Most correlations indicated positive life-history relationships, but males and females from lines where female fecundity was higher developed more slowly in the absence of stress, which is a negative life-history relationship. The stress reduced or negated many trait associations, and showed one additional relationship; more larvae from lines that developed fast at 25°C survived to adult after stress than did larvae from slow developing lines. These shifts in fitness relationships, when a single stress bout is applied, suggest that even small increases in environmental stress can have profound effects on evolutionary relationships among life-history traits

Cardiac Arrest Caused by Torsades de Pointes Tachycardia after Successful Atrial Flutter Radiofrequency Catheter Ablation

A 66-year-old woman underwent successful radiofrequency catheter ablation for long-lasting, drug refractory fast atrial flutter. Two days later she had a cardiac arrest due to torsades de pointes (TdP) tachycardia attributed to relative sinus bradycardia and QT interval prolongation. After successful resuscitation further episodes of TdP occurred, which were treated with temporary pacing. Because of concomitant systolic dysfunction due to ischemic and valvular heart disease she was finally treated with an implantable defibrillator. In conclusion we strongly advise prolonged monitoring for 2 or more days for patients with structural heart disease following successful catheter ablation for long lasting tachyarrhythmias

Garden and landscape-scale correlates of moths of differing conservation status: significant effects of urbanization and habitat diversity

Moths are abundant and ubiquitous in vegetated terrestrial environments and are pollinators, important herbivores of wild plants, and food for birds, bats and rodents. In recent years, many once abundant and widespread species have shown sharp declines that have been cited by some as indicative of a widespread insect biodiversity crisis. Likely causes of these declines include agricultural intensification, light pollution, climate change, and urbanization; however, the real underlying cause(s) is still open to conjecture. We used data collected from the citizen science Garden Moth Scheme (GMS) to explore the spatial association between the abundance of 195 widespread British species of moth, and garden habitat and landscape features, to see if spatial habitat and landscape associations varied for species of differing conservation status. We found that associations with habitat and landscape composition were species-specific, but that there were consistent trends in species richness and total moth abundance. Gardens with more diverse and extensive microhabitats were associated with higher species richness and moth abundance; gardens near to the coast were associated with higher richness and moth abundance; and gardens in more urbanized locations were associated with lower species richness and moth abundance. The same trends were also found for species classified as increasing, declining and vulnerable under IUCN (World Conservation Union) criteria

Reliability of videotaped observational gait analysis in patients with orthopedic impairments

BACKGROUND: In clinical practice, visual gait observation is often used to determine gait disorders and to evaluate treatment. Several reliability studies on observational gait analysis have been described in the literature and generally showed moderate reliability. However, patients with orthopedic disorders have received little attention. The objective of this study is to determine the reliability levels of visual observation of gait in patients with orthopedic disorders. METHODS: The gait of thirty patients referred to a physical therapist for gait treatment was videotaped. Ten raters, 4 experienced, 4 inexperienced and 2 experts, individually evaluated these videotaped gait patterns of the patients twice, by using a structured gait analysis form. Reliability levels were established by calculating the Intraclass Correlation Coefficient (ICC), using a two-way random design and based on absolute agreement. RESULTS: The inter-rater reliability among experienced raters (ICC = 0.42; 95%CI: 0.38–0.46) was comparable to that of the inexperienced raters (ICC = 0.40; 95%CI: 0.36–0.44). The expert raters reached a higher inter-rater reliability level (ICC = 0.54; 95%CI: 0.48–0.60). The average intra-rater reliability of the experienced raters was 0.63 (ICCs ranging from 0.57 to 0.70). The inexperienced raters reached an average intra-rater reliability of 0.57 (ICCs ranging from 0.52 to 0.62). The two expert raters attained ICC values of 0.70 and 0.74 respectively. CONCLUSION: Structured visual gait observation by use of a gait analysis form as described in this study was found to be moderately reliable. Clinical experience appears to increase the reliability of visual gait analysis

Inducible and constitutive heat shock gene expression responds to modification of Hsp70 copy number in Drosophila melanogaster but does not compensate for loss of thermotolerance in Hsp70 null flies

<p>Abstract</p> <p>Background</p> <p>The heat shock protein Hsp70 promotes inducible thermotolerance in nearly every organism examined to date. Hsp70 interacts with a network of other stress-response proteins, and dissecting the relative roles of these interactions in causing thermotolerance remains difficult. Here we examine the effect of <it>Hsp70 </it>gene copy number modification on thermotolerance and the expression of multiple stress-response genes in <it>Drosophila melanogaster</it>, to determine which genes may represent mechanisms of stress tolerance independent of Hsp70.</p> <p>Results</p> <p><it>Hsp70 </it>copy number in four strains is positively associated with <it>Hsp70 </it>expression and inducible thermotolerance of severe heat shock. When assayed at carefully chosen temperatures, <it>Hsp70 </it>null flies are almost entirely deficient in thermotolerance. In contrast to expectations, increasing <it>Hsp70 </it>expression levels induced by thermal pretreatment are associated with increasing levels of seven other inducible <it>Hsps </it>across strains. In addition, complete <it>Hsp70 </it>loss causes upregulation of the inducible <it>Hsps </it>and six constitutive stress-response genes following severe heat shocks.</p> <p>Conclusion</p> <p>Modification of <it>Hsp70 </it>copy number quantitatively and qualitatively affects the expression of multiple other stress-response genes. A positive association between absolute expression levels of <it>Hsp70 </it>and other <it>Hsps </it>after thermal pretreatment suggests novel regulatory mechanisms. Severe heat shocks induce both novel gene expression patterns and almost total mortality in the <it>Hsp70 </it>null strain: alteration of gene expression in this strain does not compensate for <it>Hsp70 </it>loss but suggests candidates for overexpression studies.</p

Breech presentation at term and associated obstetric risks factors-a nationwide population based cohort study

Purpose The aim of this study was to estimate whether breech presentation at term was associated with known individual obstetric risk factors for adverse fetal outcome. Methods This was a retrospective, nationwide Finnish population-based cohort study. Obstetric risks in all breech and vertex singleton deliveries at term were compared between the years 2005 and 2014. A multivariable logistic regression model was used to determine significant risk factors. Results The breech presentation rate at term for singleton pregnancies was 2.4%. The stillbirth rate in term breech presentation was significantly higher compared to cephalic presentation (0.2 vs 0.1%). The odds ratios (95% CIs) for fetal growth restriction, oligohydramnios, gestational diabetes, a history of cesarean section and congenital fetal abnormalities were 1.19 CI (1.07-1.32), 1.42 CI (1.27-1.57), 1.06 CI (1.00-1.13), 2.13 (1.98-2.29) and 2.01 CI (1.92-2.11). Conclusions The study showed that breech presentation at term on its own was significantly associated with antenatal stillbirth and a number of individual obstetric risk factors for adverse perinatal outcomes. The risk factors included oligohydramnios, fetal growth restriction, gestational diabetes, history of caesarean section and congenital anomalies.Peer reviewe

Regulation of phosphorylase kinase by low concentrations of Ca ions upon muscle contraction: the connection between metabolism and muscle contraction and the connection between muscle physiology and Ca-dependent signal transduction

It had long been one of the crucial questions in muscle physiology how glycogenolysis is regulated in connection with muscle contraction, when we found the answer to this question in the last half of the 1960s. By that time, the two principal currents of muscle physiology, namely, the metabolic flow starting from glycogen and the mechanisms of muscle contraction, had already been clarified at the molecular level thanks to our senior researchers. Thus, the final question we had to answer was how to connect these two currents. We found that low concentrations of Ca ions (10−7–10−4 M) released from the sarcoplasmic reticulum for the regulation of muscle contraction simultaneously reversibly activate phosphorylase kinase, the enzyme regulating glycogenolysis. Moreover, we found that adenosine 3′,5′-monophosphate (cyclic AMP), which is already known to activate muscle phosphorylase kinase, is not effective in the absence of such concentrations of Ca ions. Thus, cyclic AMP is not effective by itself alone and only modifies the activation process in the presence of Ca ions (at that time, cyclic AMP-dependent protein kinase had not yet been identified). After a while, it turned out that our works have not only provided the solution to the above problem on muscle physiology, but have also been considered as the first report of Ca-dependent protein phosphorylation, which is one of the central problems in current cell biology. Phosphorylase kinase is the first protein kinase to phosphorylate a protein resulting in the change in the function of the phosphorylated protein, as shown by Krebs and Fischer. Our works further showed that this protein kinase is regulated in a Ca-dependent manner. Accordingly, our works introduced the concept of low concentrations of Ca ions, which were first identified as the regulatory substance of muscle contraction, to the vast field of Ca biology including signal transduction

Validity of Thermal Ramping Assays Used to Assess Thermal Tolerance in Arthropods

Proper assessment of environmental resistance of animals is critical for the ability of researchers to understand how variation in environmental conditions influence population and species abundance. This is also the case for studies of upper thermal limits in insects, where researchers studying animals under laboratory conditions must select appropriate methodology on which conclusions can be drawn. Ideally these methods should precisely estimate the trait of interest and also be biological meaningful. In an attempt to develop such tests it has been proposed that thermal ramping assays are useful assays for small insects because they incorporate an ecologically relevant gradual temperature change. However, recent model-based papers have suggested that estimates of thermal resistance may be strongly confounded by simultaneous starvation and dehydration stress. In the present study we empirically test these model predictions using two sets of independent experiments. We clearly demonstrate that results from ramping assays of small insects (Drosophila melanogaster) are not compromised by starvation- or dehydration-stress. Firstly we show that the mild disturbance of water and energy balance of D. melanogaster experienced during the ramping tests does not confound heat tolerance estimates. Secondly we show that flies pre-exposed to starvation and dehydration have “normal” heat tolerance and that resistance to heat stress is independent of the energetic and water status of the flies. On the basis of our results we discuss the assumptions used in recent model papers and present arguments as to why the ramping assay is both a valid and ecologically relevant way to measure thermal resistance in insects