Altered neuronal excitability in cerebellar granule cells of mice lacking calretinin

Calcium-binding proteins such as calretinin are abundantly expressed in distinctive patterns in the CNS, but their physiological function remains poorly understood. Calretinin is expressed in cerebellar granule cells, which provide the major excitatory input to Purkinje cells through parallel fibers. Calretinin-deficient mice exhibit dramatic alterations in motor coordination and Purkinje cell firing recorded in vivo through unknown mechanisms. In the present study, we used patch-clamp recording techniques in acute slice preparation to investigate the effect of a null mutation of the calretinin gene on the intrinsic electroresponsiveness of cerebellar granule cells at a mature developmental stage. Calretinin-deficient granule cells exhibit faster action potentials and generate repetitive spike discharge showing an enhanced frequency increase with injected currents. These alterations disappear when 0.15 mm of the exogenous fast-calcium buffer BAPTA is infused in the cytosol to restore the calcium-buffering capacity. A proposed mathematical model demonstrates that the observed alterations of granule cell excitability can be explained by a decreased cytosolic calcium-buffering capacity resulting from the absence of calretinin. This result suggests that calcium-binding proteins modulate intrinsic neuronal excitability and may therefore play a role in information processing in the CNS.     

Risk of early or severe pre-eclampsia related to pre-existing conditions

BACKGROUND: Preeclampsia (PE), especially severe or early PE, is a leading cause of morbidity and mortality among mothers and infants. We estimated the population attributable fractions of severe or early PE associated with pre-existing conditions among nulliparous and multiparous women. METHODS: Among 70 924 women in the Danish National Birth Cohort, we used hospital discharge data to identify 2117 cases of PE, of which 449 were early (<37 weeks), 426 were severe (clinically diagnosed) and 228 were both early and severe. Prospective interview data were supplemented with hospital registry data to identify women with pre-existing conditions. Generalized estimating equations were utilized to estimate adjusted relative risks, and population attributable fractions were calculated with 95% CI. RESULTS: Pre-existing hypertension, diabetes, obesity or multiple gestation were associated with 22.3% (19.8-24.9) of all PE cases among nulliparous women. These conditions, or a prior preeclamptic pregnancy, were associated with 52.2% (46.4-57.9) of PE among multiparous women. Early PE was preceded by these pre-existing conditions among 34% (28.3-40.0) of affected nulliparous women and among 50% (37.5-63.4) of multiparous women. The fraction of severe PE associated with these conditions was 23% among nulliparas and 59% among multiparas. Being obese or overweight was associated with 15-17% of the population risk of early PE among nulliparous and multiparous women. CONCLUSIONS: Pre-existing maternal and obstetric conditions are associated with a high proportion of severe or early cases of PE. Obesity and overweight contributed independently to the risk of pre-term PE, a finding with potentially profound public health implications.     

Rapid Akt activation by nicotine and a tobacco carcinogen modulates the phenotype of normal human airway epithelial cells

Tobacco-related diseases such as lung cancer cause over 4.2 million deaths annually, with approximately 400,000 deaths per year occurring in the US. Genotoxic effects of tobacco components have been described, but effects on signaling pathways in normal cells have not been described. Here, we show activation of the serine/threonine kinase Akt in nonimmortalized human airway epithelial cells in vitro by two components of cigarette smoke, nicotine and the tobacco-specific carcinogen 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK). Activation of Akt by nicotine or NNK occurred within minutes at concentrations achievable by smokers and depended upon alpha(3)-/alpha(4)-containing or alpha(7)-containing nicotinic acetylcholine receptors, respectively. Activated Akt increased phosphorylation of downstream substrates such as GSK-3, p70(S6K), 4EBP-1, and FKHR. Treatment with nicotine or NNK attenuated apoptosis caused by etoposide, ultraviolet irradiation, or hydrogen peroxide and partially induced a transformed phenotype manifest as loss of contact inhibition and loss of dependence on exogenous growth factors or adherence to ECM. In vivo, active Akt was detected in airway epithelial cells and lung tumors from NNK-treated A/J mice, and in human lung cancers derived from smokers. Redundant Akt activation by nicotine and NNK could contribute to tobacco-related carcinogenesis by regulating two processes critical for tumorigenesis, cell growth and apoptosis.     

Knowledge,attitude and behaviour regarding dietary salt intake among medical students in Angola

High salt (sodium chloride) consumption is an important determinant of high blood pressure and cardiovascular risk. According to World Health Organisation (WHO) statistics, over 80% of cardiovascular disease (CVD) deaths take place in low-and middle-income countries, and elevated blood pressure levels were a major cause of these CVD deaths in those countries.1 Lifestyle factors such as unhealthy diet, physical inactivity, tobacco use and harmful use of alcohol have been considered the most important behavioural risk factors for heart disease and stroke.2Among dietary factors, high salt intake has been the most strongly associated with raised blood pressure and increased risk of stroke and CVD.3 Therefore dietary sodium restriction has been recommended as a non-pharmacological approach to blood pressure lowering,4-6 and for the prevention and control of non-communicable diseases at the population level.7,8Cumulative evidence has shown that even a modest reduction in salt intake was associated with blood pressure lowering and therefore with a significant reduction in incidence of cardiovascular events.9-12 Furthermore, data from the most recent systematic review and meta-analyses has shown the benefit of lowering sodium intake in apparently healthy adults and children,13 and in both hypertensive and normotensive individuals, irrespective of gender and ethnic group.9Since hypertension is associated with CVD worldwide, a public health intervention to reduce high blood pressure must target the role of lifestyle, particularly reduced sodium intake.7 Therefore, several countries have initiated strategies to reduce dietary salt intake in the general population by a combination of various procedures such as public education, food labelling, and collaboration with the food industry to reduce the salt content of processed food.14Among sub-Saharan African countries, only Nigeria and South Africa have developed dietary guidelines regarding salt intake.15 Recently, the South African government implemented important specific legislation towards decreasing salt intake in the population by reducing sodium content of processed foods by industries.16 Therefore, the current public health recommendation is that countries should launch national initiatives to reduce the over-consumption of salt as part of non-communicable disease prevention and healthy nutrition policies for limiting salt intake to less than 5 g/day for the general population including children.7 Despite of this guideline, however, high sodium intake remains prevalent around the world, with average daily salt intake varying from 5 to 18 g/day per person.17Although processed foods have been found to be the principal source of excessive dietary salt intake,18 sources of dietary sodium vary largely worldwide and may be influenced by cultural context and dietary habits of the population.19 In sub-Saharan African countries experiencing demographic and epidemiological transition, the rapid rise in prevalence of CVD (chiefly hypertension) has been attributed to lifestyle change, including high dietary sodium intake.20,21 However, consistent data from studies on risk factors are lacking for the majority of these countries.With regard to Angola, available data from a cross-sectional study reported a high prevalence of multiple cardiovascular risk factors, such as hypertension, sedentary lifestyle, electrocardiographic left ventricular hypertrophy,22 and high rate of the metabolic syndrome23 in an apparently healthy middle-aged population of university public employees living in urban and peri-urban areas.Determining the level of sodium intake in the population is crucial to establish intervention strategies and policy on reduction of sodium intake. For medical students in particular, it is very important to assess their awareness regarding dietary salt intake, since they are the future providers of healthcare information for the counselling of people about the need to reduce salt consumption. The aim of this study was to determine salt intake and to assess the knowledge, attitude and behaviour regarding dietary salt among medical students.     

Treatment of progressive Hodgkin's disease with intensive chemoradiotherapy and autologous bone marrow transplantation

Twenty-six patients with progressive Hodgkin's disease after conventional chemotherapy received intensive chemoradiotherapy and autologous bone marrow transplantation (ABMT); 19 also received additional involved-field radiotherapy. Twenty-one patients [81%, 95% confidence intervals (CI) 61% to 94%] attained complete (n = 18) or partial responses. Ten patients (38%, 95% CI 20% to 59%) are disease- free a median of 4.5 years later (range 3.5 to 7.0 years), including seven patients with continuous complete responses. The likelihood of overall response was not significantly influenced by any clinical or treatment variable examined. However, there was a trend favoring patients with higher Karnofsky scores, and higher scores were associated with attainment of complete responses (P = .06 and P = .02, respectively, Mann-Whitney U test). Both higher Karnofsky scores and shorter durations of disease before transplantation were associated with improved survival in a stepwise Cox multivariate analysis. The chief cause of failure was progression at sites previously involved with Hodgkin's disease. No patient relapsed in the marrow, and two of three patients with a history of marrow involvement with Hodgkin's disease achieved durable complete responses after transplantation. These data suggest that inadequate pretransplant conditioning, and not the reinoculation of occult tumor cells in the autologous marrow, caused most relapses. Fatal treatment-related toxicity occurred in six patients. Three patients died of idiopathic interstitial pneumonitis; each had previously received local mediastinal irradiation before intensive chemoradiotherapy. Intensive chemoradiotherapy and ABMT produces durable responses in some patients with Hodgkin's disease incurable with conventional therapy. Use of such therapies at the first sign of failure with conventional chemotherapy and development of more effective conditioning regimens should further improve results.     

Syringocystadenocarcinoma papilliferum of the eyelid

An 86-year-old man presented with an ulcerated, painless right lower eyelid lesion of unknown duration. Excisional biopsy was performed to rule out suspected basal cell carcinoma. Pathologic evaluation demonstrated syringocystadenocarcinoma papilliferum. Three months after complete excision of the tumor, the patient remains well with no evidence of local recurrence or metastases. Review of the literature identified 20 cases of syringocystadenocarcinoma papilliferum, none of which presented in the skin of the ocular adnexa. The authors review the typical presentation, clinical course, and outcome of patients with syringocystadenocarcinoma papilliferum and compare these data to the case presented here.