Cocaine Induces Cytoskeletal Changes in Cardiac Myocytes: Implications for Cardiac Morphology

Cocaine is one of the most widely abused illicit drugs worldwide and has long been recognised as an agent of cardiac dysfunction in numerous cases of drug overdose. Cocaine has previously been shown to up-regulate cytoskeletal rearrangements and morphological changes in numerous tissues; however, previous literature observes such changes primarily in clinical case reports and addiction studies. An investigation into the fundamental cytoskeletal parameters of migration, adhesion and proliferation were studied to determine the cytoskeletal and cytotoxic basis of cocaine in cardiac cells. Treatment of cardiac myocytes with cocaine increased cell migration and adhesion (p < 0.05), with no effect on cell proliferation, except with higher doses eliciting (1–10 μg/mL) its diminution and increase in cell death. Cocaine downregulated phosphorylation of cofilin, decreased expression of adhesion modulators (integrin-β3) and increased expression of ezirin within three hours of 1 μg/mL treatments. These functional responses were associated with changes in cellular morphology, including alterations in membrane stability and a stellate-like phenotype with less compaction between cells. Higher dose treatments of cocaine (5–10 μg/mL) were associated with significant cardiomyocyte cell death (p < 0.05) and loss of cellular architecture. These results highlight the importance of cocaine in mediating cardiomyocyte function and cytotoxicity associated with the possible loss of intercellular contacts required to maintain normal cell viability, with implications for cardiotoxicity relating to hypertrophy and fibrogenesis.     

A real-time approach to detect seal defects in food packages using ultrasonic imaging

The microbial integrity of many types of flexible food packages depends on a zero defect level in the fused seam seal. Human inspection for defects in these seals is marginal at best, and secondary incubation protocols are often used to spot packages with compromised integrity before releasing product for sale. A new type of inspection method has been developed and is being evaluated for robustness. The purpose of the study was to evaluate a new raster scanning geometry to simulate continuous motion, online ultrasonic inspection of the seal region in flexible food package seals. A principal engineering tradeoff of scanning inspection systems is between increased line speed that results from decreased spatial sampling (less acquired data to process) and decreased image quality. The previously developed pulse-echo Backscattered Amplitude Integral (BAI) mode imaging technique is used to form ultrasound images using the new scanning geometry. At an ultrasonic frequency of 22.9 MHz, 38- and 50-microm-diameter air-filled channel defects in all-plastic transparent trilaminate are evaluated. The contrast-to-noise ratio (CNR) of the processed BAI-mode image is used to quantify image quality as a function of spatial sampling. Results show seal defects (38- and 50-microm diameter) are still detectable for undersampled conditions, although image quality degrades as spatial sampling decreases. Further, it is concluded that the raster scanning geometry is feasible for online inspection.     

Disrupted temporal control in the R6/2 mouse model of Huntington’s disease.

Huntington’s disease is characterized by corticostriatal dysfunction and degeneration of the striatum with progressive loss of the medium spiny neurons. These circuits are important for instrumental responding, interval timing, and temporal control over motor output. We investigated the acquisition of timed operant responding in two R6/2 Huntington’s Disease models, differing in CAG repeat length and genetic background (115 and 250 CAG repeats, and a mixed CBAxC57 or pure C57 background) and their corresponding wild type controls using the peak procedure. Both mouse lines exhibited similar response control deficits. In unreinforced peak trials, mice either did not learn to terminate an ongoing response past reinforcement time or required more trials to acquisition compared to the wild type mice. While transgenic and wild type mice did not exhibit differences in temporal accuracy, response curves were flatter in transgenic mice, suggesting decreased temporal control over operant responding. The results are discussed in terms of the neurobiology of interval timing, instrumental responding, and the neuropathology of HD and R6/2 mice. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Germ-line mutations in the neurofibromatosis 2 gene: correlations with disease severity and retinal abnormalities

Neurofibromatosis 2 (NF2) features bilateral vestibular schwannomas, other benign neural tumors, and cataracts. Patients in some families develop many tumors at an early age and have rapid clinical progression, whereas in other families, patients may not have symptoms until much later and vestibular schwannomas may be the only tumors. The NF2 gene has been cloned from chromosome 22q; most identified germ-line mutations result in a truncated protein and severe NF2. To look for additional mutations and clinical correlations, we used SSCP analysis to screen DNA from 32 unrelated patients. We identified 20 different mutations in 21 patients (66%): 10 nonsense mutations, 2 frameshifts, 7 splice-site mutations, and 1 large in-frame deletion. Clinical information on 47 patients from the 21 families included ages at onset and at diagnosis, numbers of meningiomas, spinal and skin tumors, and presence of cataracts and retinal abnormalities. We compared clinical findings in patients with nonsense or frameshift mutations to those with splice-site mutations. When each patient was considered as an independent random event, the two groups differed (P < or = .05) for nearly every variable. Patients with nonsense or frameshift mutations were younger at onset and at diagnosis and had a higher frequency and mean number of tumors, supporting the correlation between nonsense and frameshift mutations and severe NF2. When each family was considered as an independent random event, statistically significant differences between the two groups were observed only for mean ages at onset and at diagnosis. A larger data set is needed to resolve these discrepancies. We observed retinal hamartomas and/or epiretinal membranes in nine patients from five families with four different nonsense mutations. This finding, which may represent a new genotype-phenotype correlation, merits further study.     

Common pediatric esophageal disorders

Esophageal disorders in children can result in significant morbidity. The most common esophageal disorder seen in children is gastroesophageal reflux. Other common disorders affecting the esophagus include peptic esophageal strictures, esophageal atresia with or without tracheoesophageal fistula, caustic and foreign body ingestions, achalasia, and cricopharyngeal achalasia. We discuss what is currently known about these common pediatric esophageal disorders with regard to pathophysiology, clinical presentation, and diagnostic and treatment strategies.     

Ratings of perceived exertion (RPE) during cycling exercises at constant power output

The purpose of the present investigation was to study the overall rating of perceived exertion (RPEov) according to the 6-20 scale proposed by Borg (1970) and muscular RPE (RPEmu) in exercises at constant load. The relationship between RPE and heart rate for three different loads was studied during exhausting exercises in 10 participants. Whether the drift of RPE during a 20 min exercise at constant load could be an index of the endurance time during long-lasting exercises at constant load was also investigated. At 1-week intervals, the participants performed cycling exercises up to exhaustion at 60, 73, and 86% maximal aerobic power (MAP) measured during an incremental test. Heart rate, RPEov, RPEmu and exhaustion time (tlim) were measured. The upward shift of the HRmax-RPE regressions was significant between 86, 73 and 60% MAP (p < 0.001) for RPEov and RPEmu. This result suggests that the equation HR = 10 x RPE proposed by Borg (1973) for incremental exercise is not valid for long-lasting exercise at constant load until exhaustion because the heart rate corresponding to a given RPE depends on load and time. Mean RPE increased linearly with time up to exhaustion. Unexpectedly, the relationships between RPEmu or RPEov and percentage of exhaustion time were similar for exercises at 60 and 73% MAP although the exhaustion times were very different (79.40 +/- 30.64 min versus 36.19 +/- 15.99 min, respectively) (p < 0.001). Consequently, it is likely that RPE was a subjective estimation of the hardness of exercise rather than the intensity of exercise. The RPE pattern at the beginning of long-lasting exercises at constant load (60 and 73% MAP) cannot be considered as a sensitive predictor of the point of self-imposed exhaustion for individuals. Indeed, the errors in the estimation of exhaustion time from extrapolation of RPE at the beginning of exercise were very large. Moreover, at 60% MAP, a steady-state in RPE was observed during 20 min in five subjects whose tlim were not longer than tlim of the other subjects. In addition, the data of the present study indicate that RPEmu could be more useful than RPEov in cycling.     

Effect of the hydrolysis method on the determination of the amino acid composition of proteins

Acetabular reconstruction in both primary and revision hip arthroplasty often requires reconstruction of deficient acetabular bone stock. The exact role of allografts remains controversial. Published results of structural allografting are presented. Recent literature supports the use of segmental allografts for reconstruction of large segmental and combined defects.     

Augmentation of human and rat lenticular glutathione in vitro by prodrugs of gamma-L-glutamyl-L-cysteine

A marked age-related decrease in glutathione (GSH) levels as well as depression of gamma-glutamylcysteine synthetase activity are factors that are believed to render the aged lens more susceptible to oxidative stress and, therefore, to cataractogenesis. Providing gamma-L-glutamyl-L-cysteine, the dipeptide precursor of GSH, would effectively bypass the compromised first step in its biosynthesis and should protect the lens from GSH depletion. Accordingly, some bioreversible sulfhydryl-, amino-, and C-terminal carboxyl-protected prodrug forms of this dipeptide were prepared. Sulfhydryl protection was in the form of an acetyl thioester, while the carboxyl group was protected as the ethyl ester. These prodrugs were evaluated for their GSH-enhancing activity in cultured human and rat lenses in vitro using an assay that measured the incorporation of [14C]glycine into lens GSH. Ethyl S-acetyl-gamma-L-glutamyl-L-cysteinate (2) raised GSH levels in human lenses by 25% and in rat lenses by >150%. These data suggest that 2 may have potential as an anticataract agent since ethyl gamma-L-glutamyl-L-cysteinate (1a), the des-S-acetyl analog of 2, had been shown (by others) to protect against experimental rodent cataracts. GSH augmentation by 1a was 2% in human lenses and 25% in rat lenses, considerably less than that shown by 2.