Warfarin-related nephropathy modeled by nephron reduction and excessive anticoagulation

An acute increase in international normalized ratio (INR) to >3.0 in patients with chronic kidney disease (CKD) can associate with an unexplained acute increase in serum creatinine and accelerated progression of CKD. A subset of these patients have renal tubular obstruction by casts of red blood cells, presumably the dominant mechanism of the acute kidney injury described as warfarin-related nephropathy. Here, we developed an animal model of this acute kidney injury that is based on the 5/6-nephrectomy model to aid future investigation of the pathogenesis of this condition. We found that acute excessive anticoagulation with brodifacoum ("superwarfarin") increased serum creatinine levels and hematuria in 5/6-nephrectomized rats but not in controls. In addition, morphologic findings in 5/6-nephrectomized rats included glomerular hemorrhage, occlusive red blood cell casts, and acute tubular injury, similar to the biopsy findings among affected patients. Furthermore, in the rat model, we observed an increase in apoptosis of glomerular endothelial cells. In summary, the 5/6-nephrectomy model combined with excessive anticoagulation may be a useful tool to study the pathogenesis of warfarin-related nephropathy.     

Spider venom peptides for gene therapy of Chlamydia infection

Spider venoms are vast natural pharmacopoeias selected by evolution. The venom of the ant spider Lachesana tarabaevi contains a wide variety of antimicrobial peptides. We tested six of them (latarcins 1, 2a, 3a, 4b, 5, and cytoinsectotoxin 1a) for their ability to suppress Chlamydia trachomatis infection. HEK293 cells were transfected with plasmid vectors harboring the genes of the selected peptides. Controlled expression of the transgenes led to a significant decrease of C. trachomatis viability inside the infected cells.     

Critical thinking about adverse drug effects: lessons from the psychology of risk and medical decision-making for clinical psychopharmacology

Systematic biases in decision-making have been well characterized in medical and nonmedical fields but mostly ignored in clinical psychopharmacology. The purpose of this paper is to sensitize clinicians who prescribe psychiatric drugs to the issues of the psychology of risk, especially as they pertain to the risk of side effects. Specifically, the present analysis focuses on heuristic organization and framing effects that create cognitive biases in medical practice. Our purpose is to increase the awareness of how pharmaceutical companies may influence physicians by framing the risk of medication side effects to favor their products.     

GSK3β mediates muscle pathology in myotonic dystrophy

Myotonic dystrophy type 1 (DM1) is a complex neuromuscular disease characterized by skeletal muscle wasting, weakness, and myotonia. DM1 is caused by the accumulation of CUG repeats, which alter the biological activities of RNA-binding proteins, including CUG-binding protein 1 (CUGBP1). CUGBP1 is an important skeletal muscle translational regulator that is activated by cyclin D3–dependent kinase 4 (CDK4). Here we show that mutant CUG repeats suppress Cdk4 signaling by increasing the stability and activity of glycogen synthase kinase 3β (GSK3β). Using a mouse model of DM1 (HSA^LR), we found that CUG repeats in the 3′ untranslated region (UTR) of human skeletal actin increase active GSK3β in skeletal muscle of mice, prior to the development of skeletal muscle weakness. Inhibition of GSK3β in both DM1 cell culture and mouse models corrected cyclin D3 levels and reduced muscle weakness and myotonia in DM1 mice. Our data predict that compounds normalizing GSK3β activity might be beneficial for improvement of muscle function in patients with DM1.     

Effects of a Supratherapeutic Dose of Investigational Orally Inhaled Dihydroergotamine (MAP0004) on QT Interval: A Randomized, Double-Blind, Active- and Placebo-Controlled Crossover Study in Healthy Volunteers

BackgroundMAP0004 is an orally inhaled investigational drug containing dihydroergotamine (DHE). Although DHE has been used for 60 years with no reported cardiac arrhythmias, a thorough QT study had not previously been performed with DHE.ObjectiveThe objective of this study was to assess the effects of MAP0004 on the QT interval as required for regulatory approval of a new product.MethodsThis randomized, double-blind, placebo-controlled, 3-period crossover study enrolled healthy volunteers. Subjects were assigned to receive, in randomized sequence, MAP0004 at a supratherapeutic dose (3-fold the clinically effective dose) (3.0 mg), moxifloxacin 400 mg, or inactive vehicle, each administered with 1 placebo capsule. Triplicate ECGs were performed continuously at baseline (day 0), before dosing, and over 24 hours after dosing in each treatment period. The effect on the QT interval was assessed using the Fridericia (QTcF) and individualized (QTcI) correction formulas.ResultsFifty-four healthy adults (20 men, 34 women; mean age, 28 years) completed the trial and had measurable plasma levels of DHE after MAP0004 administration. The largest observed mean difference in QTcI between MAP0004 and placebo was 0.08 msec, and the largest 1-sided 95% upper confidence bound was 2.24 msec, both at 30 minutes after dosing. In contrast, moxifloxacin increased the mean QTcI between 9.57 and 11.28 msec relative to placebo, with a 1-sided lower 95% CL between 7.23 and 8.96 msec, confirming that the assay sensitivity was sufficient to detect MAP0004-related effects. Nausea (27.8%) was common following MAP0004 administration but apparently did not influence the QTc interval.ConclusionsA supratherapeutic dose of MAP0004 was not associated with prolonged QTc intervals. At the proposed clinical dose (1.0 mg), MAP0004 is unlikely to affect the QT interval. MAP0004 and its primary metabolite showed no evidence for prolongation of the QTc interval in healthy subjects according to the criteria required from regulatory agencies. ClinicalTrials.gov identifier: NCT01191723.     

Physical child abuse demands increased awareness during health and socioeconomic crises like COVID-19: A review and education material

Background and purposePhysical abuse of children, i.e., nonaccidental injury (NAI) including abusive head trauma (AHT) is experienced by up to 20% of children; however, only 0.1% are diagnosed. Healthcare professionals issue less than 20% of all reports suspecting NAI to the responsible authorities. Insufficient knowledge concerning NAI may partly explain this low percentage. The risk of NAI is heightened during health and socioeconomic crises such as COVID-19 and thus demands increased awareness. This review provides an overview and educational material on NAI and its clinical presentation.MethodsWe combined a literature review with expert opinions of the senior authors into an educational paper aiming to help clinicians to recognize NAI and act appropriately by referral to multidisciplinary child protection teams and local authorities.ResultsDespite the increased risk of NAI during the current COVID-19 crisis, the number of reports suspecting NAI decreased by 42% during the lockdown of the Danish society. Healthcare professionals filed only 17% of all reports of suspected child abuse in 2016.InterpretationThe key to recognizing and suspecting NAI upon clinical presentation is to be aware of inconsistencies in the medical history and suspicious findings on physical and paraclinical examination. During health and socioeconomic crises the incidence of NAI is likely to peak. Recognition of NAI, adequate handling by referral to child protection teams, and reporting to local authorities are of paramount importance to prevent mortality and physical and mental morbidity.

Physical abuse of children, i.e., non-accidental injury (NAI) including abusive head trauma (AHT), is experienced by up to 20% of children; however, only 0.1% are diagnosed with the ICD-10 code: T74.1 physical abuse (Christoffersen 2010, Stoltenborgh et al. 2013, Oldrup et al. 2016).During the current COVID-19 crisis some European countries have reported an alarming increase in domestic violence by one-third (Delaleu 2020). Likewise, the risk of NAI is heightened during health and socioeconomic crises (Baird 2020, Peterman et al. 2020). Therefore, a Joint Leaders’ statement by the World Health Organization, UNICEF, Save the Children International, and SOS Children’s Villages International among others, highlights the acute risk of violence against children due to COVID-19 and calls for increased awareness (World Health Organization 2020).The vast majority of NAI is reported by staff working at institutions (daycares, kindergartens, schools), which are temporarily closed during the COVID-19 pandemic. Healthcare professionals issue less than 20% of reports regarding suspected maltreatment to the responsible child protection authorities (Christoffersen 2010, Oldrup et al. 2016). Failure to recognize NAI due to insufficient knowledge among healthcare professionals may partly explain this low percentage (Villadsen et al. 2015).Healthcare professionals need to be aware of the increased risk of NAI during COVID-19 and future health and socio-economic crises in order to act appropriately based on current knowledge of the issue. Only then can they begin to recognize patterns of NAI from the medical history and objective findings, and act appropriately through immediate consultation and referral to multidisciplinary child protection teams, who can clarify the suspicion and ensure child protection.     

Comparative chromosome painting defines the karyotypic relationships among the domestic dog, Chinese raccoon dog and Japanese raccoon dog

The Chinese raccoon dog (Nyctereutes procyonoides procyonoides, 2n = 54 + 2-3 B) and Japanese raccoon dog (Nyctereutes p. viverrinus, 2n = 38 + 3-4 B) are two subspecies of the same species. The genome-wide comparative chromosome map between the Japanese raccoon dog and domestic dog (Canis familiaris) has been established by fluorescence in-situ hybridization with a set of domestic dog painting probes. In this study, we established the comparative chromosome map for the Chinese raccoon dog and domestic dog. In total, dog probes specific for the 38 autosomes delineated 41 conserved chromosomal segments in the Chinese raccoon dog. Probes from dog chromosomes 1, 13 and 19 each painted two Chinese raccoon dog chromosome segments. Fifteen dog autosomal probes each hybridized to one Chinese raccoon dog chromosome, while each of the other dog autosomal probes painted to a single Chinese raccoon dog chromosomal arm. Dog X chromosome probe delineated the entire X chromosome of the Chinese raccoon dog; the dog Y chromosome probe hybridized to the pseudoautosomal region at the Xpter as well as the entire Y chromosome of the Chinese raccoon dog. Comparative analysis of the distribution patterns of conserved segments defined by dog paints in the genomes of the Chinese and Japanese raccoon dogs demonstrates that their differences in the karyotypes of these two subspecies could have resulted from eight Robertsonian translocations. The large difference in chromosome number between the Chinese and Japanese raccoon dogs suggests that they should be considered as two distinct species.