Better renal function with enhanced immunosuppression and protocol biopsies after kidney transplantation in children

Subclinical rejection may be associated with decreased graft function after renal transplantation (Tx). Detection by protocol biopsies and treatment could thus be important for the long-term prognosis. We have earlier discovered that glomerular filtration rate (GFR) declined in young children during the first 18 months. Consequently, we slightly enhanced and individualized each patient's immunosuppression. This was a retrospective study of 59 pediatric renal Tx patients between 1995 and 2001. The 35 historical controls received triple-therapy of azathioprine, methylprednisolone and cyclosporine. GFR was measured by protocol at discharge, 6 and 18 months, and a core biopsy was obtained at 18 months. The 24 study patients in addition received basiliximab, had GFR measured at 3 and 12 months, and a biopsy taken at 3 months. Based on histology and function, immunosuppression was individually adjusted. The groups were compared for GFR and histology at 18 months after Tx. There were less acute rejection episodes in the study group (0.38 vs. 1.23 per patient) and serum creatinine concentrations were lower. Subclinical rejection was detected and treated in 39% at 3 months. There were more chronic changes in the control (47%) than in the study group (29%) at 18 months. GFR was significantly higher in the study group at 18 months (87 vs. 68 mL/min/1.73 m(2)), most remarkably in patients < or =2 yr of age (99 vs. 68 mL/min/1.73 m(2)). Detection of subclinical rejection and slightly enhanced and individualized immunosuppression improved GFR 18 months after renal Tx, especially in the youngest patients.     

Association between chronic undernutrition and hypertension

In developing countries nutritional deficit during prenatal and continuing in post‐natal life is very common. This condition leads to stunting and important metabolic changes. Over 30% of children in the world are stunted. The metabolic resultants of nutritional deficit during growth are classically known to aim at energy conservation. This review summarizes data from Brazil, a developing country undergoing the double burden of obesity and undernutrition, especially among the poor, and suggests that stunting or chronic undernutrition increases the risk of obesity and hypertension later in life. Around 60 million people are under the poverty line in Brazil. In São Paulo, the richest city of the country, 20% of the population live in slums and in Maceió, the capital of one of the poorest states, this percentage reaches 50%. Undernutrition in this population is around 20% among children, with high frequency of infections, anemia, and parasitic infestations, associated with poor sanitation. Among stunted adolescents, we found a high prevalence of hypertension (21%) that is a considerably higher estimate compared to non‐stunted adolescents (less than 10%). The prevalence of hypertension in undernourished pre‐school children, or in those who recovered from undernutrition, was higher than that in controls (29%, 20% and 2%, respectively, P < 0.001). Among stunted adults eating no more than 66% of the requirements (adjusted for stature), overweight/obesity was 35% in women and 25% in men. The prevalence of hypertension was 44% among stunted women and 18% among stunted men. Fifty per cent of stunted and obese women had hypertension. These data reinforce the important association between undernutrition and hypertension from childhood through adulthood. Health policies for preventing and combating childhood undernutrition should have an impact on the morbidity and mortality related to hypertension during adulthood.     

Mortality of multiple sclerosis in Spain: demonstration of a north-South gradient

OBJECTIVE: To analyse the geographical distribution of multiple sclerosis in Spain from 1975 to 1998. METHODS: Age-adjusted mortality rates by province were obtained by the indirect method using the whole Spanish population as the reference. Then, standardised mortality ratios (SMRs) and their 95% confidence intervals were estimated. RESULTS: For both men and women, provinces with SMRs higher than the mean tended to be in the northern third of Spain, whilst those with SMRs lower than the mean were mostly located in the southern half. A linear regression analysis showed a significant positive association between mortality and latitude. CONCLUSION: A north-south gradient in age-adjusted multiple sclerosis mortality exists in Spain.     

Culturing primary brain astrocytes under a fully controlled environment in a novel bioreactor

We report the first approach for growth and maintenance of primary astrocytes on a fully controlled environment. For this purpose, cells were immobilized in Cytodex microcarriers and grown in a stirred tank bioreactor. The distribution of astrocytes at the microcarrier surface was visualized using confocal microscopy and glial fibrillary acidic protein (GFAP) labeling, a specific glial probe. Crucial bioreaction parameters such as agitation rate, microcarrier type, and concentration, as well as cell inoculum concentration were assessed. Cytodex 3 proved the best microcarrier for astrocyte growth, with the highest cell densities obtained for 6 g/l of Cytodex 3 using an inoculum of approx. 0.15 x 10(6) cells/ml in vessels operated at 60 rpm, using a refeed operational mode consisting of complete medium replacement every 5 days. Using such optimized conditions, cells were maintained in steady-state for approximately 24 days, allowing online monitoring and control of environmental variables such as temperature, pH, and O(2). To test further the advantages of this fully controlled system, astrocytes were also subjected to hypoxic stress for 5 hr; the cell number was not affected by hypoxia but the glycolytic flux was enhanced during the stress imposed. The culture system described is a novel tool to study brain cell metabolism, allowing sampling over time and the monitoring of cellular behavior through stressful conditions and during recovery.     

Acute and repeated restraint stress influences cellular damage in rat hippocampal slices exposed to oxygen and glucose deprivation

Several studies have shown that high corticosteroid hormone levels increase neuronal vulnerability. Here we evaluate the consequences of in vivo acute or repeated restraint stress on cellular viability in rat hippocampal slices suffering an in vitro model of ischemia. Cellular injury was quantified by measuring lactate dehydrogenase (LDH) and neuron-specific enolase released into the medium. Acute stress did not affect cellular death when oxygen and glucose deprivation (OGD) was applied both immediately or 24h after restraint. The exposure to OGD, followed by reoxygenation, resulted in increased LDH in the medium. Repeated stress potentiated the effect of OGD both, on LDH and neuron-specific enolase released to the medium. There was no effect of repeated stress on the release of S100B, an astrocytic protein. Additionally, no effect of repeated stress was observed on glutamate uptake by the tissue. These results suggest that repeated stress increases the vulnerability of hippocampal cells to an in vitro model of ischemia, potentiating cellular damage, and that the cells damaged by the exposure to repeated stress+OGD are mostly neurons. The uptake of glutamate was not observed to participate in the mechanisms responsible for rendering the neurons more susceptible to ischemic damage after repeated stress.     

CINRG randomized controlled trial of creatine and glutamine in Duchenne muscular dystrophy

We tested the efficacy and safety of glutamine (0.6 gm/kg/day) and creatine (5 gm/day) in 50 ambulant boys with Duchenne muscular dystrophy in a 6-month, double-blind, placebo-controlled clinical trial. Drug efficacy was tested by measuring muscle strength manually (34 muscle groups) and quantitatively (10 muscle groups). Timed functional tests, functional parameters, and pulmonary function tests were secondary outcome measures. Although there was no statistically significant effect of either therapy based on manual and quantitative measurements of muscle strength, a disease-modifying effect of creatine in older Duchenne muscular dystrophy and creatine and glutamine in younger Duchenne muscular dystrophy cannot be excluded. Creatine and glutamine were well tolerated.     

Mutation analysis of B-RAF gene in human gliomas

The RAS/RAF/MEK/ERK kinase pathway is pivotal in the transduction of mitogenic stimuli from activated growth factor receptors, which regulates cell proliferation, survival, and differentiation. Up-regulation of this pathway due to RAS mutations is found in approximately 30% of human tumors. Recently, activating mutations of B-RAF were identified in a large proportion of human cancers. Gliomas are the most frequent primary central nervous system tumors and the molecular mechanisms that underlie the development and progression of these tumors are far from being completely understood. The purpose of this study was to clarify the incidence of B-RAF mutations and their possible relation with tumor progression in a series of 82 human gliomas, including 49 astrocytic and 33 oligodendroglial tumors. The analysis of B-RAF hotspot regions, exons 11 and 15, showed presence of B-RAF mutations in only 2 out of 34 (6%) glioblastomas, and absence in the remaining histological types. Both mutations were located in the hotspot residue 600 (V600E) at exon 15, which leads to constitutive B-RAF kinase activity. These data suggest that activating mutations of B-RAF are not a frequent event in gliomas; nevertheless, when present they are associated with high-grade malignant lesions.The first two authors contributed equally to the present study     

Cognitive therapy vs medications in the treatment of moderate to severe depression

BACKGROUND: There is substantial evidence that antidepressant medications treat moderate to severe depression effectively, but there is less data on cognitive therapy's effects in this population. OBJECTIVE: To compare the efficacy in moderate to severe depression of antidepressant medications with cognitive therapy in a placebo-controlled trial. DESIGN: Random assignment to one of the following: 16 weeks of medications (n = 120), 16 weeks of cognitive therapy (n = 60), or 8 weeks of pill placebo (n = 60). SETTING: Research clinics at the University of Pennsylvania, Philadelphia, and Vanderbilt University, Nashville, Tenn. PATIENTS: Two hundred forty outpatients, aged 18 to 70 years, with moderate to severe major depressive disorder. INTERVENTIONS: Some study subjects received paroxetine, up to 50 mg daily, augmented by lithium carbonate or desipramine hydrochloride if necessary; others received individual cognitive therapy. MAIN OUTCOME MEASURE: The Hamilton Depression Rating Scale provided continuous severity scores and allowed for designations of response and remission. RESULTS: At 8 weeks, response rates in medications (50%) and cognitive therapy (43%) groups were both superior to the placebo (25%) group. Analyses based on continuous scores at 8 weeks indicated an advantage for each of the active treatments over placebo, each with a medium effect size. The advantage was significant for medication relative to placebo, and at the level of a nonsignificant trend for cognitive therapy relative to placebo. At 16 weeks, response rates were 58% in each of the active conditions; remission rates were 46% for medication, 40% for cognitive therapy. Follow-up tests of a site x treatment interaction indicated a significant difference only at Vanderbilt University, where medications were superior to cognitive therapy. Site differences in patient characteristics and in the relative experience levels of the cognitive therapists each appear to have contributed to this interaction. CONCLUSION: Cognitive therapy can be as effective as medications for the initial treatment of moderate to severe major depression, but this degree of effectiveness may depend on a high level of therapist experience or expertise.