Facial-muscle weakness, speech disorders and dysphagia are common in patients with classic infantile Pompe disease treated with enzyme therapy

Classic infantile Pompe disease is an inherited generalized glycogen storage disorder caused by deficiency of lysosomal acid α-glucosidase. If left untreated, patients die before one year of age. Although enzyme-replacement therapy (ERT) has significantly prolonged lifespan, it has also revealed new aspects of the disease. For up to 11 years, we investigated the frequency and consequences of facial-muscle weakness, speech disorders and dysphagia in long-term survivors. Sequential photographs were used to determine the timing and severity of facial-muscle weakness. Using standardized articulation tests and fibreoptic endoscopic evaluation of swallowing, we investigated speech and swallowing function in a subset of patients. This study included 11 patients with classic infantile Pompe disease. Median age at the start of ERT was 2.4 months (range 0.1-8.3 months), and median age at the end of the study was 4.3 years (range 7.7 months −12.2 years). All patients developed facial-muscle weakness before the age of 15 months. Speech was studied in four patients. Articulation was disordered, with hypernasal resonance and reduced speech intelligibility in all four. Swallowing function was studied in six patients, the most important findings being ineffective swallowing with residues of food (5/6), penetration or aspiration (3/6), and reduced pharyngeal and/or laryngeal sensibility (2/6). We conclude that facial-muscle weakness, speech disorders and dysphagia are common in long-term survivors receiving ERT for classic infantile Pompe disease. To improve speech and reduce the risk for aspiration, early treatment by a speech therapist and regular swallowing assessments are recommended

Lysosomal membrane permeabilization in cell death

18 páginas, 3 figuras, 2 tablas -- PAGS nros. 6434-6451Mitochondrial outer membrane permeabilization (MOMP) constitutes one of the major checkpoint(s) of apoptotic and necrotic cell death. Recently, the permeabilization of yet another organelle, the lysosome, has been shown to initiate a cell death pathway, in specific circumstances. Lysosomal membrane permeabilization (LMP) causes the release of cathepsins and other hydrolases from the lysosomal lumen to the cytosol. LMP is induced by a plethora of distinct stimuli including reactive oxygen species, lysosomotropic compounds with detergent activity, as well as some endogenous cell death effectors such as Bax. LMP is a potentially lethal event because the ectopic presence of lysosomal proteases in the cytosol causes digestion of vital proteins and the activation of additional hydrolases including caspases. This latter process is usually mediated indirectly, through a cascade in which LMP causes the proteolytic activation of Bid (which is cleaved by the two lysosomal cathepsins B and D), which then induces MOMP, resulting in cytochrome c release and apoptosome-dependent caspase activation. However, massive LMP often results in cell death without caspase activation; this cell death may adopt a subapoptotic or necrotic appearance. The regulation of LMP is perturbed in cancer cells, suggesting that specific strategies for LMP induction might lead to novel therapeutic avenuesResearch in our labs is supported by grants from Ministry of Science (BFU-2006-00508) and from Fundación La Caixa (BM06-125-1) to PB and Ligue Nationale contre le Cancer (Equipe labellisée), European Commission (Active p53, Apo-Sys, RIGHT, TransDeath, ChemoRes, DeathTrain), Agence Nationale pour la Recherche, Institut National contre le Cancer, Cancéropôle Ile-de-France and Fondation pour la Recherche Médicale to GKPeer reviewe

High-avidity IgA protects the intestine by enchaining growing bacteria

Vaccine-induced high-avidity IgA can protect against bacterial enteropathogens by directly neutralizing virulence factors or by poorly defined mechanisms that physically impede bacterial interactions with the gut tissues ('immune exclusion'). IgA-mediated cross-linking clumps bacteria in the gut lumen and is critical for protection against infection by non-typhoidal Salmonella enterica subspecies enterica serovar Typhimurium (S. Typhimurium). However, classical agglutination, which was thought to drive this process, is efficient only at high pathogen densities (≥10; 8; non-motile bacteria per gram). In typical infections, much lower densities (10; 0; -10; 7; colony-forming units per gram) of rapidly dividing bacteria are present in the gut lumen. Here we show that a different physical process drives formation of clumps in vivo: IgA-mediated cross-linking enchains daughter cells, preventing their separation after division, and clumping is therefore dependent on growth. Enchained growth is effective at all realistic pathogen densities, and accelerates pathogen clearance from the gut lumen. Furthermore, IgA enchains plasmid-donor and -recipient clones into separate clumps, impeding conjugative plasmid transfer in vivo. Enchained growth is therefore a mechanism by which IgA can disarm and clear potentially invasive species from the intestinal lumen without requiring high pathogen densities, inflammation or bacterial killing. Furthermore, our results reveal an untapped potential for oral vaccines in combating the spread of antimicrobial resistance

Biomarkers of aging associated with past treatments in breast cancer survivors

Therapeutics: past chemotherapy and radiation linked to cellular aging Past exposure to chemotherapy and radiation is associated with signs of cellular aging among breast cancer survivors. Zorica Scuric, Judith Carroll, and colleagues from the University of California, Los Angeles, USA, tested markers of biological aging and inflammation in blood samples taken from women 3–6 years after their initial treatment for stage 0–IIIA breast cancer. They found that women who had received chemotherapy and/or radiation were more likely to have high levels of DNA damage, lower activity of telomerase—an enzyme involved in maintaining the length of chromosomes—and elevated inflammatory activation compared to women who underwent surgery alone. The findings point to an enduring biological effect of chemotherapy and radiation, and suggest that some breast cancer survivors may be vulnerable to accelerated aging because of their prior treatment

Personality typology in relation to muscle strength

BACKGROUND: Physical inactivity plays a central role in the age-related decline in muscle strength, an important component in the process leading to disability. Personality, a significant determinant of health behaviors including physical activity, could therefore impact muscle strength throughout adulthood and affect the rate of muscle strength decline with aging. Personality typologies combining “high neuroticism” (N≥55), “low extraversion” (E<45), and “low conscientiousness” (C<45) have been associated with multiple risky health behaviors but have not been investigated with regards to muscle strength. PURPOSE: The purpose of this study is to investigate associations between individual and combined typologies consisting of high N, low E, and low C and muscle strength, and whether physical activity and body mass index act as mediators. METHOD: This cross-sectional study includes 1,220 participants from the Baltimore Longitudinal Study of Aging. RESULTS: High N was found among 18%, low E among 31%, and low C among 26% of the sample. High levels of N, particularly when combined with either low E or low C, were associated with lower muscle strength compared with having only one or none of these personality types. Facet analyses suggest an important role for the N components of depression and hostility. Physical activity level appears to partly explain some of these associations. CONCLUSION: Findings provide support for the notion that the typological approach to personality may be useful in identifying specific personality types at risk of low muscle strength and offer the possibility for more targeted prevention and intervention programs