RyR1 Deficiency in Congenital Myopathies Disrupts Excitation–Contraction Coupling

In skeletal muscle, excitation–contraction (EC) coupling is the process whereby the voltage‐gated dihydropyridine receptor (DHPR) located on the transverse tubules activates calcium release from the sarcoplasmic reticulum by activating ryanodine receptor (RyR1) Ca²⁺ channels located on the terminal cisternae. This subcellular membrane specialization is necessary for proper intracellular signaling and any alterations in its architecture may lead to neuromuscular disorders. In this study, we present evidence that patients with recessive RYR1‐related congenital myopathies due to primary RyR1 deficiency also exhibit downregulation of the alfa 1 subunit of the DHPR and show disruption of the spatial organization of the EC coupling machinery. We created a cellular RyR1 knockdown model using immortalized human myoblasts transfected with RyR1 siRNA and confirm that knocking down RyR1 concomitantly downregulates not only the DHPR but also the expression of other proteins involved in EC coupling. Unexpectedly, this was paralleled by the upregulation of inositol‐1,4,5‐triphosphate receptors; functionally however, upregulation of the latter Ca²⁺ channels did not compensate for the lack of RyR1‐mediated Ca²⁺ release. These results indicate that in some patients, RyR1 deficiency concomitantly alters the expression pattern of several proteins involved in calcium homeostasis and that this may influence the manifestation of these diseases.     

Castleman's disease and retroviral therapy.

The escalating pandemic of the acquired immunodeficiency disease in sub-Saharan Africa is associated with an increasing incidence of the lymphoproliferative disorders where evidence shows that highly active retroviral therapy can reconstitute immunologic competence and, at least in some groups exemplified by Kaposi's sarcoma, result in an outcome comparable to uninfected controls. Paradoxically other subtypes are less responsive exemplified by Burkitt lymphoma and multicentric Castleman's disease, where they are localised and may present after starting treatment. This association provides a model to test the concept that pathogenesis may reflect an aberrant response to antigens including human herpesvirus-8 thereby renewing focus on proactive inclusion of anti-herpes drugs with conventional treatment for retrovirus particularly prior to initiating chemotherapy.     

Manual small incision cataract surgery: a viable option for cataract with pseudoexfoliation

International Ophthalmology - The aim of the study was to assess the spectrum of clinical presentation, intraoperative challenges and immediate surgical outcome of cataract patients with...     

Systemic amyloidosis complicating multidrug-resistant tuberculosis in childhood

Multidrug-resistant tuberculosis is increasingly common and is associated with long diagnostic delay and high morbidity. We present a 7-year-old child who developed steroid-resistant nephrotic syndrome while receiving treatment for tuberculosis. Renal biopsy results showed systemic amyloidosis; culture of peritoneal tissue confirmed disseminated multidrug-resistant tuberculosis.     

Increased availability of angiotensin AT 1 receptors leads to sustained arterial constriction to angiotensin II in diabetes - role for Rho-kinase activation

BACKGROUND AND PURPOSE

Antagonists of angiotensin AT₁ receptors elicit beneficial vascular effects in diabetes mellitus. We hypothesized that diabetes induces sustained availability of AT₁ receptors, causing enhanced arterial constriction to angiotensin II.

EXPERIMENTAL APPROACH

To assess functional availability of AT₁ receptors, constrictions to successive applications of angiotensin II were measured in isolated skeletal muscle resistance arteries (∼150 µm) of Zucker diabetic fatty (ZDF) rats and of their controls (+/Fa), exposed acutely to high glucose concentrations (HG, 25 mM, 1 h). AT₁ receptors on cell membrane surface were measured by immunofluorescence.

KEY RESULTS

Angiotensin II-induced constrictions to first applications were greater in arteries of ZDF rats (maximum: 82 ± 3% original diameter) than in those from +/Fa rats (61 ± 5%). Constrictions to repeated angiotensin II administration were decreased in +/Fa arteries (20 ± 6%), but were maintained in ZDF arteries (67 ± 4%) and in +/Fa arteries vessels exposed to HG (65 ± 6%). In ZDF arteries and in HG-exposed +/Fa arteries, Rho-kinase activities were enhanced. The Rho-kinase inhibitor, Y27632 inhibited sustained constrictions to angiotensin II in ZDF arteries and in +/Fa arteries exposed to HG. Levels of surface AT₁ receptors on cultured vascular smooth muscle cells (VSMCs) were decreased by angiotensin II but were maintained in VSMCs exposed to HG. In VSMCs exposed to HG and treated with Y27632, angiotensin II decreased surface AT₁ receptors.

CONCLUSIONS AND IMPLICATIONS

In diabetes, elevated glucose concentrations activate Rho-kinase which inhibits internalization or facilitates recycling of AT₁ receptors, leading to increased functional availability of AT₁ receptors and sustained angiotensin II-induced arterial constriction.     

Neuroschistosomiasis due to Schistosoma haematobium presenting as spinal cord tumor

Schistosomiasis is rarely encountered in the United States, but immigration and travel to endemic areas make it important to know its various presentations to improve diagnosis and treatment. We present our experience with a child with Schistosoma haematobium pseudotumor, initially diagnosed as a cord neoplasm.