Cooperative activation of Src family kinases by SH3 and SH2 ligands

Src family nonreceptor tyrosine kinases are kept in a repressed state by intramolecular interactions involving the SH3 and SH2 domains of the enzymes. Ligands for these domains can displace the intramolecular associations and activate the kinases. Here, we carried out in vitro activation experiments with purified, down-regulated hematopoietic cell kinase (Hck), a Src family kinase. We show that SH3 and SH2 ligands act cooperatively to activate Src family kinases: the presence of one ligand lowers the concentration of the second ligand necessary for activation. To confirm the findings in intact cells, we studied Cas, a Src substrate that possesses SH2 and SH3 ligands. In contrast to wild-type Cas, mutant forms of Cas lacking the SH3 or SH2 ligands were unable to stimulate Src autophosphorylation when expressed in Cas-deficient fibroblasts. Cells expressing the Cas mutants also showed decreased amounts of activated Src at focal adhesions. The results suggest that proteins containing ligands for both SH3 and SH2 domains can produce a synergistic activation of Src family kinases.     

Study of Prevalence, Awareness,and control of Hypertension in a Suburban Area of Kathmandu, Nepal

BACKGROUND, In the context of rapidly raising occurrence of cardiovascular diseases in the developing countries, it becomes imperative to study the scenario in its various aspects. The present study in Nepal deals with the hypertension as it is one of the major risk factors of cardiovascular diseases. METHODS AND RESULTS, A house-to-house survey was conducted in a suburban area of Kathmandu valley from February to June 2005 in adult population (age >/=18 years) to estimate the prevalence, awareness, treatment, and control rates of hypertension. Blood pressure was measured twice using standardized mercury sphygmomanometer, and an average of the two readings was taken. Total number of subjects were 1114 (men:541; women: 573; mean age: 37.8 -/+ 16.3 years). Overall prevalence of hypertension was 19.7% (22.2% in men and 17.3% in women, p < 0.05).Prevalence of hypertension in age group of >/=40 years was 36%.Awareness, treatment, and control rates were 41.1%, 26%, and 6%, respectively. CONCLUSION, Our study indicates that prevalence of hypertension is significant in Nepal and is comparable with other developing countries of this region. Awareness, treatment, and control rates are poor.     

Study of serum phosphohexose isomerase (PHI) levels in the management of head and neck malignancies

The enzyme phosphohexose isomerase PHI was estimated in 43 patients of head and neck malignancy. The serum level of this enzyme was found to be raised in all the cancer patients. It was found that there were significantly higher levels of serum PHI in cases with metastatic lesions. The rise in PHI values was proportionate with the clinical stage of tumor. 29 Patients, out of 43 who had taken complete treatment weresubjected to post therapeutic PHI level estimations and the response to treatment was evaluated. Study showed that estimation of serum PHI levels have significant role in diagnosis of cancer, early detection of residual growth, recurrent growth and secondaries.     

Temporal alterations in brain water diffusivity in neonatal meningitis

Aim:  To compare changes in apparent diffusion coefficient (ADC) in neonatal meningitis using serial diffusion-weighted imaging (DWI).
Method:  Thirty neonates with meningitis and 12 age/sex-matched controls were studied using DWI. ADC was quantified by placing region of interest(s) on periventricular white matter during acute illness and again at 21 days. Three groups of patients were studied: those with normal findings on both conventional MRI and DWI, those with abnormal DWI only and those with abnormal conventional MRI as well as DWI. Neurodevelopment assessment was performed in controls and patients at 3 months using Indian adaptation of Bayley scales of infant development (BSID) kit.
Results:  Patients with neonatal meningitis with normal imaging (n = 8) showed no significant difference in ADC compared to controls. Patients showing abnormality only on DWI (n = 10) and on both conventional magnetic resonance imaging (MRI) as well as DWI (n = 12) had significantly reduced ADC (p = 0.001) than controls at baseline study. Follow-up study showed no significant differences in ADC in controls compared to any patient group. Significantly reduced neurodevelopmental scores were observed in patient groups compared to controls.
Conclusion:  We conclude that quantitative ADC may detect meningitis-induced hypoxia early in brain parenchyma, which may be associated with abnormal motor and mental development.     

Extra thoracic Castleman’s disease associated with myasthenia gravis

Castleman’s disease is an uncommon lymphoproliferative disorder. Amongst known associations with Castleman’s disease, myasthenia gravis is very rare and only four cases have been reported in the literature. We report a patient with Castleman’s disease with myasthenia gravis who successfully underwent thymectomy for control of his symptoms.     

Comparative thermodynamic and spectroscopic properties of water interaction with human stratum corneum

Background/purpose: The water content of skin has a significant impact on skin properties; sufficient hydration is necessary to keep the skin supple, flexible, and smooth. To understand more completely the water retention properties of the human skin barrier, physical macroscopic properties must be related to the structural organization of the stratum corneum (SC). Water, lipids, and natural moisturizing factor (NMF) influence the molecular structures that affect the properties of SC, including water sorption and binding enthalpy. In the research reported here, isothermal microcalorimetry was used to study the interaction of water vapor with isolated human SC in intact, delipidized, and water‐washed delipidized forms to identify the influences of the principal components of SC on water sorption. The calorimetric data are interpreted in conjunction with spectroscopic results to identify the conformational changes in keratins induced by lipid and NMF removal and to assess the influence of these changes on water binding in SC. Methods: Isothermal calorimetry was used to measure the integral heat of water vapor sorption on intact, delipidized, and water‐washed delipidized human SC at 32 °C as a function of relative humidity using back and thigh skin from three donors. Calorimetric measurements were combined with water vapor sorption measurements to determine the differential thermodynamic properties of these systems. Attenuated total reflection–Fourier transform infrared spectroscopy was used to investigate effects of extraction on protein secondary structure. Results: The magnitudes of the differential enthalpy, entropy, and free energy were greatest for intact SC and least for water‐washed delipidized SC. Water sorption followed a similar trend. Delipidization led to a significantly reduced binding enthalpy at low water content; water washing the delipidized SC had only a small additional effect on binding enthalpy. Delipidization converts a fraction of keratin α‐helixes to turns and random coils, while water sorption converts a fraction of keratin α‐helixes to β‐sheets, turns, and random coils. Conclusions: The results of this study are consistent with a water sorption model in which keratin–keratin hydrogen bonds are replaced by keratin–water hydrogen bonds. Delipidization reduces the fraction of dry keratin that is in the α‐helix conformation, suggesting that lipids hold the keratins in a conformation conducive to optimal hydration.     

Hirschsprung''s disease: Is there a relationship between mast cells and nerve fibers?

AIM:To define the topography of mast cells and their numbers in cases of Hirschsprung's disease (HD) and non-HD, assess neural hypertrophy using imaging software and to study the relationship between mast cells and nerve fibers. METHODS:HE stained sections of 32 cases of chronic constipation in the age group of 0-14 years were reviewed for ganglion cells. AChE staining was performed on frozen sections of colonic and rectal biopsies. Based on their findings cases were divided into HD and non-HD and mast cells stained by toluidine blue were evaluated. Image analysis by computerized software was applied to S-100 stained sections for assessment of neural hypertrophy. RESULTS:Difference between number of mast cells in HD group (mean = 36.44) and in non-HD group (mean = 14.79) was statistically significant. Image analysis morphometry on S-100 stained sections served as a useful adjunct. The difference between number, size, and perimeter of the nerve fibers between HD and non-HD group was statistically significant. CONCLUSION:Mast cells are significantly increased in HD and their base line values are much higher in Indian children than that reported in Western literature. Their role in HD needs further research. Morphometry of S-100 stained nerve fibers is a useful adjunct to conventional methods for diagnosis of HD.