Skeletal muscle delimited myopathy and verapamil toxicity in SUR2 mutant mouse models of AIMS

ABCC9-related intellectual disability and myopathy syndrome (AIMS) arises from loss-of-function (LoF) mutations in the ABCC9 gene, which encodes the SUR2 subunit of ATP-sensitive potassium (

The Mechanism Underlying Transient Weakness in Myotonia Congenita

In addition to the hallmark muscle stiffness, patients with recessive myotonia congenita (Becker disease) experience debilitating bouts of transient weakness that remain poorly understood despite years of study. We performed intracellular recordings from muscle of both genetic and pharmacologic mouse models of Becker disease to identify the mechanism underlying transient weakness. Our recordings reveal transient depolarizations (plateau potentials) of the membrane potential to -25 to -35 mV in the genetic and pharmacologic models of Becker disease. Both Na + and Ca 2+ currents contribute to plateau potentials. Na + persistent inward current (NaPIC) through Na V 1.4 channels is the key trigger of plateau potentials and current through Ca V 1.1 Ca 2+ channels contributes to the duration of the plateau. Inhibiting NaPIC with ranolazine prevents the development of plateau potentials and eliminates transient weakness in vivo. These data suggest that targeting NaPIC may be an effective treatment to prevent transient weakness in myotonia congenita

Extravasational side effects of cytotoxic drugs: A preventable catastrophe

In addition to their therapeutic effects on malignant cells, cytotoxic agents have the potential of causing destruction of healthy, normal cells. Extravasation of the drug can produce extensive necrosis of the skin and subcutaneous tissue. Management of these extravasational effects differs from one centre to another and prevention is usually strongly emphasized. We analyzed our management of 12 patients referred to us over five years with extravasation of cytotoxic drugs and reviewed the literature for different approaches with regard to prophylaxis and management of extravasational effects. Materials and Methods: This study was done in the department of plastic surgery of a medical college. Five years of retrospective data were studied of patients referred to our department with extravasation of cytotoxic drugs. Results: We managed 12 cases referred to our department with extravasation of cytotoxic drugs. Mitomycin C was used in seven cases (58.33%), vincristine in two cases (16.66%), 5-Florouracil in another two cases while doxorubicin was responsible for extravasational side effects in one case (8.33%). The size of necrosis ranged from 3.75 cm 2 to 25 cm 2 with average size of 9.6 cm 2 . In terms of the area involved, the dorsum of the hand was involved in five cases (41.66%), the wrist in another five cases (41.66%), and the cubital fossa in the remaining two cases (16.66%). All cases were treated with daily debridement of necrotic tissue, saline dressing, and split skin grafting. Conclusion: Extravasation of cytotoxic drugs further increases the suffering of cancer patients. This catastrophe can only be avoided by vigilance and immediate application of antidotes. Once the local toxicity of the drugs takes effect, morbidity is unavoidabl

Pore mutation N617D in the skeletal muscle DHPR blocks Ca2+ influx due to atypical high-affinity Ca2+ binding

Skeletal muscle excitation-contraction (EC) coupling roots in Ca2+-influx-independent inter-channel signaling between the sarcolemmal dihydropyridine receptor (DHPR) and the ryanodine receptor (RyR1) in the sarcoplasmic reticulum. Although DHPR Ca2+ influx is irrelevant for EC coupling, its putative role in other muscle-physiological and developmental pathways was recently examined using two distinct genetically engineered mouse models carrying Ca2+ non-conducting DHPRs: DHPR(N617D) (Dayal et al., 2017) and DHPR(E1014K) (Lee et al., 2015). Surprisingly, despite complete block of DHPR Ca2+-conductance, histological, biochemical, and physiological results obtained from these two models were contradictory. Here, we characterize the permeability and selectivity properties and henceforth the mechanism of Ca2+ non-conductance of DHPR(N617). Our results reveal that only mutant DHPR(N617D) with atypical high-affinity Ca2+ pore-binding is tight for physiologically relevant monovalent cations like Na+ and K+. Consequently, we propose a molecular model of cooperativity between two ion selectivity rings formed by negatively charged residues in the DHPR pore region

Substitution of Asn by Asp at entrance of the pore region conditions ion selectivity of voltage-gated Ca2+ channels in skeletal muscle from a non-Ca2+ conducting dihydropyridine receptor mouse

International audienc

Perineal burn contractures: An experience in tertiary hospital of a Himalayan state

Perineal burn contracture is a rare burn sequel. We conducted a retrospective analysis of cases with perineal burn contractures managed in a tertiary care centre of a Himalayan state. We found that all cases sustained burn injury from burning firewood and the time of presentation was two to six years after the burn injury. We analyzed our treatment method and have classified these contractures into two types