Differential regulation of ceramide in lipid-rich microdomains (rafts): antagonistic role of palmitoyl:protein thioesterase and neutral sphingomyelinase 2

Cell differentiation and myelination involve a fine balance between stasis and programmed cell death, yet the genes that regulate this have not been clearly defined. We therefore studied two key gene products involved in oligodendrocyte plasma membrane lipid metabolism and their antagonistic role in ceramide-mediated cell death signaling. Overexpression of palmitoyl:protein thioesterase (PPT1; verified by Western blot of the V5-tagged protein and increased enzyme activity) resulted in decreased ceramide in the detergent-resistant microdomain (DRM, or raft) relative to cholesterol and sphingomyelin (SM). This PPT1 overexpression also resulted in protection against cell death induced by either staurosporine or C(2)-ceramide. In contrast, overexpression of neutral sphingomyelinase 2 (NSMase2; verified by Western blot of the FLAG-tagged protein and increased enzyme activity) resulted in increased membrane NSMase and increased ceramide in rafts relative to cholesterol and SM. The difference in SM and ceramide turnover was quantitated by [(3)H]palmitate pulse-chase labeling. Furthermore, when NBD-SM was added to cells, it was hydrolyzed by NSMase-transfected cells at more than twofold the rate in untransfected cells. NSMase2 overexpression enhanced cell death induced by staurosporine or C(2)-ceramide, in contrast to the protective effect of PPT1 overexpression. The presence of a fraction of both PPT1 and NSMase2 in rafts together with their substrates (palmitoylated proteins and SM, respectively) suggests a mechanism for dynamic palmitoylation/depalmitoylation of certain proteins in controlling cell death via NSMase activation.     

Community based trials and informed consent in rural north India

Disease control has increasingly shifted towards large scale, disease specific, public health interventions. The emerging problems of HIV, hepatitis, malaria, typhoid, tuberculosis, childhood pneumonia, and meningitis have made community based trials of interventions a cost effective long term investment for the health of a population. The authors conducted this study to explore the complexities involved in obtaining informed consent to participation in rural north India, and how people there make decisions related to participation in clinical research.     

Wear mechanisms in ceramic hip implants

The wear in hip implants is one of the main causes for premature hip replacements. The wear affects the potential life of the prosthesis and subsequent removals of in vivo implants. Therefore, the objective of this article is to review various joints that show lower wear rates and consequently higher life. Ceramics are used in hip implants and have been found to produce lower wear rates. This article discusses the advantages and disadvantages of ceramics compared to other implant materials. Different types of ceramics that are being used are reviewed in terms of the wear characteristics, debris released, and their size together with other biological factors. In general, the wear rates in ceramics were lower than that of metal-on-metal and metal-on-polyethylene combinations.     

A comparative study of cardiovascular stress during different swimming strokes

The study was aimed: (i) to compare maximum heart rate during exhaustive running (HRmasr) and swimming (HRmaxs), (ii) to compare heart rate (HR) in various modes of swimming-front crawl (FC), butterfly (BF), breast stroke (BRS) and back stroke (BS). HRmaxr (192.3 +/- 4.9 beats/min) of the swimmers (N = 7) was higher, although not significantly (P < 0.05), than their HRmaxs (183.7 +/- 3.8). Peak HR of the swimmers in FC, BF, BRS and BS (each of 100 m distance) were 179.9 +/- 7.2, 180.3 +/- 7, 178.6 +/- 6.2 and 177.3 +/- 5.4 beats/min respectively. Average HR in the respective events were 167.3 +/- 15.8, 166.6 +/- 14.1, 163.3 +/- 13.5 and 165.8 +/- 14.6 beats/min. Differences were not significant between any two modes, either in peak HR or mean HR. The results conclude that: (i) maximum HR in swimming is approximately 8 beats/min lower than maximal running and (ii) when the effort is maximum, cardiovascular stress remains unaltered in different swimming modes.     

Basic auditory processing skills and specific language impairment: a new look at an old hypothesis.

PURPOSE: To explore the sensitivity of children with specific language impairment (SLI) to amplitude-modulated and durational cues that are important for perceiving suprasegmental speech rhythm and stress patterns. METHOD: Sixty-three children between 7 and 11 years of age were tested, 21 of whom had a diagnosis of SLI, 21 of whom were matched for chronological age to the SLI sample, and 21 of whom were matched for language age to the SLI sample. All children received a battery of nonspeech auditory processing tasks along with standardized measures of phonology and language. RESULTS: As many as 70%-80% of children diagnosed with SLI were found to perform below the 5th percentile of age-matched controls in auditory processing tasks measuring sensitivity to amplitude envelope rise time and sound duration. Furthermore, individual differences in sensitivity to these cues predicted unique variance in language and literacy attainment, even when age, nonverbal IQ, and task-related (attentional) factors were controlled. CONCLUSION: Many children with SLI have auditory processing difficulties, but for most children, these are not specific to brief, rapidly successive acoustic cues. Instead, sensitivity to durational and amplitude envelope cues appear to predict language and literacy outcomes more strongly. This finding now requires replication and exploration in languages other than English.     

Acute Vitamin D Toxicity in an Infant

We report vitamin D toxicity in an infant following consecutive administration use of a large dose of vitamin D, causing symptomatic hypercalcemia, which was successfully managed with injectable calcitonin. However, the child developed bilateral medullary nephrocalcinosis which persisted 42 mon after the initial episode.     

Cyclooxygenase-2 Expression Increases with the Stage and Grade in Transitional Cell Carcinoma of the Urinary Bladder

Objectives: Experimental models of carcinogenesis show that non-steroidal anti-inflammatory drugs (NSAIDs) increase apoptosis, inhibit angiogenesis and reduce metastases. A linkage between the activity of prostaglandin synthase enzyme cyclooxygenase-2 (COX-2), a known mediator of inflammation, and cancer angiogenesis is implicated. We investigated the expression of COX-2 in bladder cancer tissue specimens using immunohistochemistry. Methods: The immunohistochemical expression of COX-2 in bladder cancer was evaluated by scoring the intensity of immunoreactivity from 0 to 3. Further, the degree of COX-2 expression was correlated with the tumor grade and depth of invasion (T stage). Result: Fifty eight percent patients (n=22) had superficial bladder tumors, while 42% (n=16) were invasive bladder cancers. Overall, COX-2 immuno-positivity was seen in 84.2% (32/38) patients. COX-2 expression was positive in 76.4% (13/17) cases with pTa tumors, 100% (5/5) of pT1 tumors, 86.6% (13/15) of pT2 tumors and in 100% (1/1) of pT3 tumor. The higher stage tumors stained more intensely; this correlation wassignificant(p=0.01987; χ2=19.6977). With reference to the grade of tumors, a positive expression was seen in 81.25% (13/16) of the low-grade tumors and 89% (17/19) of the high-grade tumors. The differential COX-2 expression relative to the grade of tumor was found to be statistically significant (p=0.05; χ2=15.8612). Conclusion: The degree of COX-2 expression is significantly increased with advancing grade and T stage of disease (p < 0.05).     

Prevalence of urinary tract infection and renal scars in patients with diabetes mellitus

Insulin resistance is known as an important risk factor for coronary artery disease (CAD). However, CAD-related mortality in Japanese type 2 diabetics is lower than in Caucasians. To investigate whether insulin resistance is related to CAD in Japanese type 2 diabetics, we measured insulin sensitivity and several coronary risk factors in Japanese patients with type 2 diabetes with and without CAD. Thirty-three patients with definite CAD and 33 age- and sex-matched patients without CAD (control) were studied. Insulin sensitivity was assessed by the K index of insulin tolerance test (KITT). Clinical characteristics, classical risk factors, lipoprotein (a), and insulin sensitivity were compared between the two groups. Patients with CAD had a significantly longer duration of diabetes (9.0 +/- 1.4 vs. 5.5 +/- 0.9 years, P < 0.05, respectively), were mostly hypertensive (69.7 vs. 39.4%, P < 0.05), and more likely to be treated with insulin (45.5 vs. 18.2%, P < 0.05) compared with the control. Concerning the metabolic parameters, patients with CAD had a significantly higher insulin resistance than control (2.40 +/- 0.15 vs. 3.23 +/- 0.17%/min, P < 0.01, respectively), higher triglyceride (1.39 +/- 0.10 vs. 1.05 +/- 0.05 mmol/l, P < 0.05), lower HDL cholesterol (1.05 +/- 0.05 vs. 1.28 +/- 0.06 mmol/l, P < 0.05), and higher lipoprotein (a) (27.5 +/- 4.3 vs. 17.4 +/- 2.0 mg/dl, P < 0.05). Multiple logistic regression analysis indicated that hypertension, insulin resistance, high lipoprotein (a) and triglyceride, and low HDL cholesterol were independently related to CAD. Our results suggest that insulin resistance per se is a significant risk factor for CAD in Japanese patients with type 2 diabetes.     

Risk factors for development of dehydration in young children with acute watery diarrhoea: a case-control study

In a case-control study to understand the risk factors for development of life-threatening dehydration, a total of 379 children comprising 243 cases (moderate or severe dehydration) and 136 controls (non or mild dehydration) up to 2 years of age suffering from acute watery diarrhoea were studied. By univariate analysis, the presence of vibrios in stool, withdrawal of breast feeding during diarrhoea, not giving fluids, including oral rehydration solution (ORS), during diarrhoea, frequent purging (> 8/ day), vomiting (> 2/day) and undernutrition were identified as risk factors. However, by multivariate analysis after controlling for confounders, withdrawal of breast feeding during diarrhoea (odds ratio (OR) = 6.8, p < 0.00001) and not giving ORS during diarrhoea (OR = 2.1, p < 0.006) were identified as significant risk factors. The confounding variables which also contributed significantly to increasing the risk were age (≤ 12 months; OR = 2.7, p = 0.001), frequent purging (> 8/day; OR = 4.1, p < 0.00001), vomiting (> 2/day; OR = 2.4, p = 0.001) and severe undernutrition (%median <60 weight-for-age of Indian Academy of Paediatrics classification; OR = 3.1, p = 0.001). We feel that these findings will be useful for Global and National Diarrhoeal Diseases Control Programmes for formulating intervention strategies for preventing death due to diarrhoeal dehydration.