Association of long QT syndrome loci and cardiac events among patients treated with beta-blockers

Context  Data on the efficacy of -blockers in the 3 most common genetic long QT syndrome (LQTS) loci are limited. Objective  To describe and assess outcome in a large systematically genotyped population of -blocker–treated LQTS patients. Design, Setting, and Patients  Consecutive LQTS-genotyped patients (n = 335) in Italy treated with -blockers for an average of 5 years. Main Outcome Measures  Cardiac events (syncope, ventricular tachycardia/torsades de pointes, cardiac arrest, and sudden cardiac death) while patients received -blocker therapy according to genotype. Results  Cardiac events among patients receiving -blocker therapy occurred in 19 of 187 (10%) LQT1 patients, 27 of 120 (23%) LQT2 patients, and 9 of 28 (32%) LQT3 patients (P<.001). The risk of cardiac events was higher among LQT2 (adjusted relative risk, 2.81; 95% confidence interval [CI], 1.50-5.27; P = .001) and LQT3 (adjusted relative risk, 4.00; 95% CI, 2.45-8.03; P<.001) patients than among LQT1 patients, suggesting inadequate protection from -blocker therapy. Other important predictors of risk were a QT interval corrected for heart rate that was more than 500 ms in patients receiving therapy (adjusted relative risk, 2.01; 95% CI, 1.16-3.51; P = .01) and occurrence of a first cardiac event before the age of 7 years (adjusted RR, 4.34; 95% CI, 2.35-8.03; P<.001). Conclusion  Among patients with genetic LQTS treated with -blockers, there is a high rate of cardiac events, particularly among patients with LQT2 and LQT3 genotypes.      

Volar plate arthroplasty for osteoarthritis of the proximal interphalangeal joint: a preliminary report

Osteoarthritis of the hand, including involvement of the proximal interphalangeal joint, is common in the aging population. The purpose of this study is to provide a preliminary retrospective report on 12 volar plate arthroplasties in 9 patients who had volar plate advancement arthroplasty for osteoarthritis of the proximal interphalangeal joint. The average age of the patients was 67.6 years. All of the patients' data were obtained from office notes and hand therapy assessment sheets. The average time from surgery to follow-up evaluation was 36.5 months. All patients had significant pain relief. Range of motion was maintained; there was no significant difference between preoperative and final arc of motion values. Preoperative pinch and grip strengths did not differ significantly from the final values. Postoperative position was similar to preoperative angulation, with recognized lateral stability. Our results suggest that volar plate advancement arthroplasty represents a good primary surgical therapeutic option for the osteoarthritic proximal interphalangeal joint, providing pain relief while preserving motion, strength, and stability.     

Inhibitory effects of monoacylated 2-O-beta-galactosylglycerols on Epstein-Barr virus activation: the significant role of the hexanoyl chain.

Three series of monoacyl-2-O-beta-D-galactosylglycerols bearing an acyl chain of varying length, from C4 to C10, were studied due to their antitumor promoting effects on the activation of the Epstein-Barr virus early antigen (EBV-EA), such activation being induced by the tumor promoter 12-O-tetradecanoylphorbol-13-acetate (TPA). This study indicates that it is more the length of the acyl chain that is important for the activity, six carbon atoms resulting in maximum effect, rather than the position of the ester function and the nature of the sugar (galactose or glucose).     

Extracutaneous ultrastructural alterations in pseudoxanthoma elasticum

Pseudoxanthoma elasticum (PXE) is caused by mutations in the ABCC6 gene, encoding for the membrane transporter MRP6, whose physiological role is still unknown. PXE is characterized by skin, eye, and cardiovascular alterations mainly due to mineralization of elastic fibers. The ultrastructural alterations of a large number of tissues obtained at autopsy from 2 PXE patients were analyzed and compared to clarify the involvement of the various organs in PXE and to identify cell types responsible for clinical manifestations. Ultrastructural alterations typical of PXE were present in all organs examined and consisted mostly of fragmentation and mineralization of a number of elastic fibers, abnormalities of collagen fibril shape and size, and, less frequently, deposition of aggregates of matrix constituents in the extracellular space. The severity of alterations was more pronounced in the organs affected by the clinical manifestations of PXE. Interestingly, veins and arteries were similarly damaged, the adventitia and the perivascular connective tissue being the most affected areas. Therefore, alterations in PXE are systemic and affect all soft connective tissues, even in the absence of specific clinical manifestations. The localization of alterations suggests that fibroblasts and/or smooth muscle cells are very likely involved in the pathogenesis of the disorder. These findings may help in the diagnosis of PXE when clinical manifestations affect internal organs.     

Alterations of elastin fibrogenesis by inhibition of the formation of desmosine crosslinks. Comparison between the effect of beta-aminopropionitrile (beta-APN) and penicillamine

Experimental lathyrism was induced by feeding newborn chicks a diet containing 0.2 and 0.4% DL-Penicillamine, with or without CuSO4 (10 mg/Kg diet) and Vitamin B6 (100 mg/Kg diet), or 0.015 and 0.1% beta-aminopropionitrile fumarate (beta-APN). After 7, 15, 25 and 55 days of treatment the animals were killed, the aortas removed and processed for electron microscopy in the presence of markers for proteoglycans, and the elastic fibers were carefully examined. Penicillamine, which prevents the formation of desmosine crosslinks by binding to precursors, induced the production of numerous new elastin fibers which appeared normal from the ultrastructural point of view. It seems, therefore, that at least in chick aortas, desmosine crosslinks are not necessary for the aggregation of tropoelastin molecules into structurally normal fibers. On the contrary, beta-APN, a classical inhibitor of lysyl oxidase, induced the tropoelastin molecules to aggregate into abnormal protuberances on the old fibers. Moreover, the elastin deposited during beta-APN treatment was always permeated by cytochemically revealed proteoglycans, which were never observed after penicillamine treatment. It is speculated that, at least in the system under study, the epsilon-amino groups of tropoelastin molecules may offer the binding sites for matrix proteoglycans until they are removed by lysyl oxidase, and that matrix proteoglycans might play a role in elastin fibrogenesis by preventing spontaneous tropoelastin aggregation in areas far from growing elastin fibers.     

Elastofibroma: An in Vivo Model of Abnormal Neoelastogenesis

Thirteen cases of elastofibroma have been studied by conventional light and electron microscopy, as well as by histochemistry and immunohisto-chemistry. By light microscopy elastinophilic material appeared as huge fibers crossing collagen bundles. Immunohistochemistry demonstrated a strong positivity for elastin in numerous and circumscribed areas of the extracellular matrix. By electron microscopy, collagen consisted of 40-50-nm wide fibrils, and elastin was made of large aggregates of moderately electron-dense material surrounding a very thin, apparently normal, elastin core. At high magnification these aggregates consisted of short tubules, often in regular arrays, surrounded by microfibrils and microfilaments. These data, associated with selective digestions on thin sections with elastase, purified collagenase, hyaluronidase, and chondroitinase ABC, revealed that elastic fibers in elastofibroma seem to be made of true elastin surrounded by an enormous amount of hydrophilic material, in which some elastin, chondroitin sulfates, and collagenase type-VII sensitive material are aggregated forming a rather ordered array of short tubules.     

Skin reactivity to histamine and codeine in unselected 9-year-old children from Italy, Poland and Libya

BACKGROUND: Previous studies have shown that histamine skin reactivity (the dimensions of a skin wheal elicited by a prick with histamine 10 mg/ml) in unselected school children has increased in Italy during the past two decades and is higher in Italy than in Poland. Hence this variable can probably be influenced by a changing or different lifestyle. The aim of this study was to compare skin reactivity to histamine and codeine (a marker of histamine releasability from mast cells) in schoolchildren from countries with different lifestyles. METHODS: Six previously unstudied unselected populations of 9-year-old schoolchildren (two each from Poland, Italy, and Libya; n = 863 subjects; 49.0% males) were pricked with two concentrations of histamine (10 and 1 mg/ml) and codeine (90 and 9 mg/ml). RESULTS: The higher concentrations of both pharmacologic agents tested yielded significantly different wheal areas in the three countries: Poland < Italy < Libya (histamine, 11.8, 16.1 and 20.7 mm2; codeine, 9.2, 13.2 and 16.2 mm2; p < 0.001 for all comparisons). The lower concentrations elicited almost matching results. Histamine wheal areas correlated closely with areas elicited by codeine in the same individual: angular coefficients of the histamine to codeine regression lines were 0.535, Italy; 0.551, Libya; 0.612, Poland; and 0.581 for the whole population. More histamine was needed to produce a wheal in Poland than in Libya: a 20-mm2 wheal required an injected histamine concentration of about 8.8 mg/ml in Libya, 29.5 mg/ml in Italy and 102.1 mg/ml in Poland. CONCLUSION: More studies are necessary to explain the observed international differences in skin histamine reactivity and their effect on the prevalence of positive allergen skin tests.