Moderate Multiple Parentage and Low Genetic Variation Reduces the Potential for Genetic Incompatibility Avoidance Despite High Risk of Inbreeding

Background: Polyandry is widespread throughout the animal kingdom. In the absence of direct benefits of mating with different males, the underlying basis for polyandry is enigmatic because it can carry considerable costs such as elevated exposure to sexual diseases, physical injury or other direct fitness costs. Such costs may be balanced by indirect genetic benefits to the offspring of polyandrous females. We investigated polyandry and patterns of parentage in the spider Stegodyphus lineatus. This species experiences relatively high levels of inbreeding as a result of its spatial population structure, philopatry and limited male mating dispersal. Polyandry may provide an opportunity for post mating inbreeding avoidance that reduces the risk of genetic incompatibilities arising from incestuous matings. However, multiple mating carries direct fitness costs to females suggesting that genetic benefits must be substantial to counter direct costs. Methodology/Principal Findings: Genetic parentage analyses in two populations from Israel and a Greek island, showed mixed-brood parentage in approximately 50 % of the broods. The number of fathers ranged from 1–2 indicating low levels of multiple parentage and there was no evidence for paternity bias in mixed-broods from both populations. Microsatellite loci variation suggested limited genetic variation within populations, especially in the Greek island population. Relatedness estimates among females in the maternal generation and potentially interacting individuals were substantial indicating fullsib and half-sib relationships

Lemierre’s syndrome: current perspectives on diagnosis and management

Katrine M Johannesen,1 Uffe Bodtger1–3 1Department of Lung Medicine, Naestved Hospital, Naestved, 2Institute for Regional Health Research, University of Southern Denmark, Odense, 3Department of Pulmonology, Zealand University Hospital, Roskilde, Denmark Abstract: This is a systematic review of cases with Lemierre’s syndrome (LS) in the past 5 years. LS is characterized by sepsis often evolving after a sore throat or tonsillitis and then complicated by various septic emboli and thrombosis of the internal jugular vein. Symptoms include sepsis, pain, and/or swelling in the throat or neck, as well as respiratory symptoms. Laboratory findings show elevated infectious parameters and radiological findings show thrombosis of the internal jugular vein and emboli in the lungs or other organs. The syndrome is often associated with an infection with Fusobacterium necrophorum. We found a total of 137 cases of LS, of which 47 were infected with F. necrophorum and others with Staphylococcus and Streptococcus. Complications of this rare but severe disease included osteomyelitis, meningitis, and acute respiratory distress syndrome. Mortality was extremely high in the pre-antibiotic era but has diminished with the advent of antibiotics. This review showed a mortality rate of only 2% of which none of the cases involved fusobacteria. Duration of treatment varied; a 4–6-week course of carbapenem or piperacillin/tazobactam in combination with metronidazole was optimum. Other treatment options included anticoagulants in 46% of cases, which is unwarrantedly high, as to date, no evidence of the positive effects of anticoagulants in LS exists. Only two cases had ligation of the internal jugular vein performed. This review confirms the rare, but severe aspects of LS. Mortality from LS in this day and age appears to be low, however the syndrome is difficult to recognize, and still requires the full attention of the clinician. Keywords: Lemierre’s syndrome, fusobacteria, postanginal sepsi

Electrocardiographic Biomarkers for Detection of Drug-Induced Late Sodium Current Block

Drugs that prolong the heart rate corrected QT interval (QTc) on the electrocardiogram (ECG) by blocking the hERG potassium channel and also block inward currents (late sodium or L-type calcium) are not associated with torsade de pointes (e.g. ranolazine and verapamil). Thus, identifying ECG signs of late sodium current block could aid in the determination of proarrhythmic risk for new drugs. A new cardiac safety paradigm for drug development (the "CiPA" initiative) will involve the preclinical assessment of multiple human cardiac ion channels and ECG biomarkers are needed to determine if there are unexpected ion channel effects in humans.In this study we assess the ability of eight ECG morphology biomarkers to detect late sodium current block in the presence of QTc prolongation by analyzing a clinical trial where a selective hERG potassium channel blocker (dofetilide) was administered alone and then in combination with two late sodium current blockers (lidocaine and mexiletine). We demonstrate that late sodium current block has the greatest effect on the heart-rate corrected J-Tpeak interval (J-Tpeakc), followed by QTc and then T-wave flatness. Furthermore, J-Tpeakc is the only biomarker that improves detection of the presence of late sodium current block compared to using QTc alone (AUC: 0.83 vs. 0.72 respectively, p<0.001).Analysis of the J-Tpeakc interval can differentiate drug-induced multichannel block involving the late sodium current from selective hERG potassium channel block. Future methodologies assessing drug effects on cardiac ion channel currents on the ECG should use J-Tpeakc to detect the presence of late sodium current block.NCT02308748 and NCT01873950

Deciphering the premature mortality in PIGA-CDG – An untold story

Objective: Congenital disorder of glycosylation (CDG) due to a defective phosphatidylinositol glycan anchor biosynthesis class A protein (PIGA) is a severe X-linked developmental and epileptic encephalopathy. Seizures are often treatment refractory, and patients have intellectual disability and global developmental delay. Previous reports have suggested that patients with PIGA-CDG have a high risk of premature mortality. This study aimed to evaluate the observed high mortality and the causes of death in PIGA-CDG patients. Methods: We reviewed the literature and collected additional unpublished patients through an international network. Results: In total, we reviewed the data of 88 patients of whom 30 patients born alive were deceased, and the overall mortality before the age of 20 years was 30 % (26/88). Age at death ranged from 15 days to 48 years of life. The median age at death was two years and more than half of the patients deceased in early childhood. The PIGA-specific mortality rate/1000 person-years was 44.9/1000 person-years (95 %, CI 31.4–64.3). There were no cases of definite or probable sudden unexpected death in epilepsy (SUDEP) and half of the patients died due to respiratory failure (15/30, 50 %) or possible SUDEP (3/30, 10 %). Three patients (10 %) died from severe cardiomyopathy, liver failure and gastrointestinal bleeding, respectively. The cause of death was unclassified in nine patients (30 %). Autopsies were rarely performed and the true cause of death remains unknown for the majority of patients. Significance: Our data indicate an increased risk of premature death in patients with PIGA-CDG when compared to most monogenic developmental and epileptic encephalopathies