Effect of Race on the Incidence of Aortic Stenosis and Outcomes of Aortic Valve Replacement in the United States

Objective

To assess the effect of race on the incidence of aortic stenosis (AS) and utilization and outcomes of aortic valve replacement (AVR).

Is there a potential dual effect of denosumab for treatment of osteoporosis and sarcopenia?

Clinical Rheumatology - The prevalence of sarcopenia with osteoporosis results in a higher risk of falling and fractures. It was noted that patients who had completed their planned 5-year denosumab...     

Treatment of spastic esophageal motility disorders

Treatment of spastic motility disorders continues to be challenging.Therapeutic options remain limited due in part to our lack of understanding of the pathophysiology and significance of these disorders. Furthermore, most of therapeutic trials to date are hampered by the poorly designed nature of the study, including the small size of the trials and the lack of placebo arm. Most of the available information suggests that there seems to be an important dissociation between symptoms (chest pain/dysphagia) and esophageal dysmotility. Drug treatment aimed at visceral sensitivity seems more effective in relieving symptoms than spasmolytic medications. Recent trials with Botox, nitric oxide derivatives, and SSRIs offer promising results. Rigorous study design that includes large placebo-controlled trials is needed in this area.     

Left ventricular volume reduction surgery in the middle East

Heart transplantation is not yet socially acceptable in the Middle East, and left ventricular assist facilities are not generally available in this region. Therefore, left ventricular volume reduction surgery was attempted in 41 patients with end-stage heart failure (33 males; median age, 36.3 years) in 4 Middle Eastern tertiary referral centers between February 1996 and January 2001. Heart failure was due to idiopathic cardiomyopathy in 21 patients, ischemia in 11, rheumatic valvular disease in 8, and viral myocarditis in 1. Associated procedures were aortic valve replacement in 5 patients, mitral valve repair in 25, mitral valve replacement in 7, tricuspid valve repair in 6, and coronary bypass grafting in 8. Hospital mortality was 31.7%. Five patients were lost to follow-up. The survival rate of hospital survivors at 18 months was 65.2%. Three of the surviving patients did not benefit from the operation. Although our results were somewhat disappointing, this operation remains an option for surgeons working in developing areas of the world. It is hoped that better patient selection and new techniques of left ventricular volume reduction that avoid resection of viable muscle will further improve the outcome of this operation.     

Immunoglobulin D lambda multiple myeloma and amyloidosis with predominant soft tissue involvement.

Multiple myeloma (MM) is associated with amyloidosis in approximately 15% of the patients. The most frequent presenting signs of such an association are nephrotic syndrome, cardiomyopathy and peripheral neuropathy. Amyloid arthropathy is not a frequent feature. We report a patient with immunoglobulin D (IgD) lambda type MM with presenting symptoms related to mucocutaneous amyloidosis and also amyloid arthropathy. He had no clinical and laboratory involvement due to nephrotic syndrome or cardiomyopathy. IgD myeloma is a rare form of MM and therefore much of the information about the disease is derived from case reports describing patients with associated symptoms. Our case also shows an unusual organ distribution of amyloid.     

Analyzing HLA-G polymorphisms in children from women with scleroderma

Embryos during pregnancy and organs during transplantation, express high levels of soluble HLA-G (sHLA-G) molecules for successful implantation and protection against maternal immune cells or recipient’s cells. We and others have shown that women with scleroderma (SSc) carry cells/DNA arising from pregnancy, so-called fetal microchimerism (Mc) more often and in higher quantities than healthy women decades after delivery.     

New Tmc1 Deafness Mutations Impact Mechanotransduction in Auditory Hair Cells

Transmembrane channel-like protein isoform 1 (TMC1) is a major component of the mechano-electrical transducer (MET) channel in cochlear hair cells and is subject to numerous mutations causing deafness. We report a new dominant human deafness mutation, TMC1 p.T422K, and have characterized the homologous mouse mutant, Tmc1 p.T416K, which caused deafness and outer hair cell (OHC) loss by the fourth postnatal week. MET channels showed decreased Ca²⁺ permeability and resting open probability, but no change in single-channel conductance or expression. Three adjacent deafness mutations are TMC1 p.L416R, p.G417R, and p.M418K, the last homologous to the mouse Beethoven that exhibits similar channel effects. All substitute a positive for a neutral residue, which could produce charge screening in the channel pore or influence binding of an accessory subunit. Channel properties were compared in mice of both sexes between dominant (Tmc1 p.T416K, Tmc1 p.D569N) and recessive (Tmc1 p.W554L, Tmc1 p.D528N) mutations of residues near the putative pore of the channel. Tmc1 p.W554L and p.D569N exhibit reduced maximum current with no effect on single-channel conductance, implying a smaller number of channels transported to the stereociliary tips; this may stem from impaired TMC1 binding to LHFPL5. Tmc1 p.D528N, located in the pore''s narrowest region, uniquely caused large reductions in MET channel conductance and block by dihydrostreptomycin (DHS). For Tmc1 p.T416K and Tmc1 p.D528N, transduction loss occurred between P15 and P20. We propose two mechanisms linking channel mutations and deafness: decreased Ca²⁺ permeability, common to all mutants, and decreased resting open probability in low Ca²⁺, confined to dominant mutations.SIGNIFICANCE STATEMENT Transmembrane channel-like protein isoform 1 (TMC1) is thought to be a major component of the mechanotransducer channel in auditory hair cells, but the protein organization and channel structure are still uncertain. We made four mouse lines harboring Tmc1 point mutations that alter channel properties, causing hair cell degeneration and deafness. These include a mouse homolog of a new human deafness mutation pT416K that decreased channel Ca²⁺ permeability by introducing a positively-charged amino acid in the putative pore. All mutations are consistent with the channel structure predicted from modeling, but only one, p.D528N near the external face of the pore, substantially reduced channel conductance and Ca²⁺ permeability and virtually abolished block by dihydrostreptomycin (DHS), strongly endorsing its siting within the pore.