Manifesting carriers of Xp21 muscular dystrophy; lack of correlation between dystrophin expression and clinical weakness.

Ten females presenting with muscle weakness and a raised serum creatine kinase revealed abnormalities in the expression of dystrophin in their muscle biopsies and were diagnosed as manifesting carriers of Xp21 Duchenne/Becker muscular dystrophy. Seven cases, aged 3-22 yr at the time of biopsy, had a variable proportion of dystrophin-deficient fibres and an abnormal expression on immunoblot. These were confidently diagnosed as manifesting carriers. Results in the remaining three cases, aged 8-10 yr, were less clear-cut. Dystrophin expression on immunoblots was slightly reduced and some unevenness and reduction of immunolabelling was seen on sections, but dystrophin-deficient fibres were not a feature of these cases. The weakness in the ten carriers ranged from minimal to severe and there was no correlation between the degree of weakness and the number of dystrophin-deficient fibres. Two minimally weak girls had a high proportion of dystrophin-deficient fibres. Our results show that analysis of dystrophin expression is useful for the differential diagnosis of carriers of Xp21 dystrophy and autosomal muscular dystrophy, but that dystrophin expression does not correlate directly with the degree of clinical weakness.

Interannual-decadal variability of wintertime mixed layer depths in the North Pacific detected by an ensemble of ocean syntheses

The interannual-decadal variability of the wintertime mixed layer depths (MLDs) over the North Pacific is investigated from an empirical orthogonal function (EOF) analysis of an ensemble of global ocean reanalyses. The first leading EOF mode represents the interannual MLD anomalies centered in the eastern part of the central mode water formation region in phase opposition with those in the eastern subtropics and the central Alaskan Gyre. This first EOF mode is highly correlated with the Pacific decadal oscillation index on both the interannual and decadal time scales. The second leading EOF mode represents the MLD variability in the subtropical mode water (STMW) formation region and has a good correlation with the wintertime West Pacific (WP) index with time lag of 3 years, suggesting the importance of the oceanic dynamical response to the change in the surface wind field associated with the meridional shifts of the Aleutian Low. The above MLD variabilities are in basic agreement with previous observational and modeling findings. Moreover the reanalysis ensemble provides uncertainty estimates. The interannual MLD anomalies in the first and second EOF modes are consistently represented by the individual reanalyses and the amplitudes of the variabilities generally exceed the ensemble spread of the reanalyses. Besides, the resulting MLD variability indices, spanning the 1948–2012 period, should be helpful for characterizing the North Pacific climate variability. In particular, a 6-year oscillation including the WP teleconnection pattern in the atmosphere and the oceanic MLD variability in the STMW formation region is first detected.

Nuclear accumulation of myocyte muscle LIM protein is regulated by heme oxygenase 1 and correlates with cardiac function in the transition to failure

Impaired mechanosensing leads to heart failure and we have previously shown that a decreased ratio of cytoplasmic to nuclear CSRP3/Muscle LIM protein (MLP ratio) is associated with a loss of mechanosensitivity. Here we tested whether passive or active stress/strain was important in modulating the MLP ratio and determined whether this correlated with heart function during the transition to failure. We exposed cultured neonatal rat myocytes to 10% cyclic mechanical stretch at 1 Hz, or electrically paced myocytes at 6.8 V (1 Hz) for 48 h. The MLP ratio decreased 50% (P < 0.05, n = 4) only in response to electrical pacing, suggesting impaired mechanosensitivity. Inhibition of contractility with 10 μM blebbistatin resulted in a ∼3 fold increase in the MLP ratio (n = 8, P < 0.05), indicating that myocyte contractility regulates nuclear MLP. Inhibition of histone deacetylase (HDAC) signaling with trichostatin A increased nuclear MLP following passive stretch, suggesting that HDACs block MLP nuclear accumulation. Inhibition of heme-oxygenase1 (HO-1) activity with PPZII blocked MLP nuclear accumulation. To examine how mechanosensitivity changes during the transition to heart failure, we studied a guinea pig model of angiotensin II infusion (400 ng/kg/min) over 12 weeks. Using subcellular fractionation we showed that the MLP ratio increased 88% (n = 4, P < 0.01) during compensated hypertrophy, but decreased significantly during heart failure (P < 0.001, n = 4). The MLP ratio correlated significantly with the E/A ratio (r = 0.71, P < 0.01 n = 12), a clinical measure of diastolic function. These data indicate for the first time that myocyte mechanosensitivity as indicated by the MLP ratio is regulated primarily by myocyte contractility via HO-1 and HDAC signaling.