Circadian regulation of renal function.

Urinary excretion of water and all major electrolytes exhibit robust circadian oscillations. The 24-h periodicity has been well documented for several important determinants of urine formation, including renal blood flow, glomerular filtration, tubular reabsorption, and tubular secretion. Disturbance of the renal circadian rhythms is increasingly recognized as a risk factor for hypertension, polyuria, and other diseases and may contribute to renal fibrosis. The origin of these rhythms has been attributed to the reactive response of the kidney to circadian changes in volume and/or in the composition of extracellular fluids that are entrained by rest/activity and feeding/fasting cycles. However, numerous studies have shown that most of the renal excretory rhythms persist for long periods of time, even in the absence of periodic environmental cues. These observations led to the hypothesis of the existence of a self-sustained mechanism, enabling the kidney to anticipate various predictable circadian challenges to homeostasis. The molecular basis of this mechanism remained unknown until the recent discovery of the mammalian circadian clock made of a system of autoregulatory transcriptional/translational feedback loops, which have been found in all tissues studied, including the kidney. Here, we present a review of the growing evidence showing the involvement of the molecular clock in the generation of renal excretory rhythms.

Adjuvant or radical fractionated stereotactic radiotherapy for patients with pituitary functional and nonfunctional macroadenoma.

Purpose: To evaluate the efficacy and toxicity of stereotactic fractionated radiotherapy (SFRT) for patients with pituitary macroadenoma (PMA).Methods and Materials: Between March 2000 and March 2009, 27 patients (male to female ratio, 1.25) with PMA underwent SFRT (median dose, 50.4 Gy). Mean age of the patients was 56.5 years (range, 20.3 - 77.4). In all but one patient, SFRT was administered for salvage treatment after surgical resection (transphenoidal resection in 23, transphenoidal resection followed by craniotomy in 2 and multiple transphenoidal resections in another patient). In 10 (37%) patients, the PMAs were functional (3 ACTH-secreting, 3 prolactinomas, 2 growth hormone-secreting and 2 multiple hormone-secretion). Three (11.1%) and 9 (33.3%) patients had PMA abutting and compressing the optic chiasm, respectively. Mean tumor volume was 2.9 +/- 4.6 cm(3). Eighteen (66.7%) patients had hypopituitarism prior to SFRT. The mean follow-up period after SFRT was 72.4 +/- 37.2 months.Results: Tumor size decreased for 6 (22.2%) patients and remained unchanged for 19 (70.4%) other patients. Two (7.4%) patients had tumor growth inside the prescribed treatment volume. The estimated 5-year tumor growth control was 95.5% after SFRT. Biochemical remission occurred in 3 (30%) patients with functional PMA. Two patients with normal anterior pituitary function before SFRT developed new deficits 25 and 65 months after treatment. The 5-year survival without new anterior pituitary deficit was thus 95.8%. Five patients with visual field defect had improved visual function and 1 patient with no visual defect prior to SFRT, but an optic chiasm abutting tumor, had a decline in visual function. The estimated 5-year vision and pituitary function preservation rates were 93.2% and 95.8%, respectively.Conclusions: SFRT is a safe and effective treatment for patients with PMA, although longer follow-up is needed to evaluate long-term outcomes. In this study, approximately 1 patient with visual field defect out of two had an improved visual.

Partial cricotracheal resection for pediatric subglottic stenosis: long-term outcome in 57 patients.

OBJECTIVE: We sought to assess the long-term outcome of 57 pediatric patients who underwent partial cricotracheal resection for subglottic stenosis. METHODS: Eighty-one pediatric partial cricotracheal resections were performed in our tertiary care institution between 1978 and 2004. Fifty-seven patients had a minimal follow-up time of 1 year and were included in this study. Evaluation was based on the last laryngotracheal endoscopy, the responses to a questionnaire, and a retrospective review of the patient's data. The following parameters were analyzed: decannulation rates, breathing, voice quality, and deglutition. RESULTS: A single-stage partial cricotracheal resection was performed in 38 patients, and a double-stage procedure was performed in 19 patients. Sixteen patients underwent an extended partial cricotracheal resection (ie, partial cricotracheal resection combined with another open procedure). At a median follow-up time of 5.1 years, the decannulation rates after a single- or double-stage procedure were 97.4% and 95%, respectively. Two patients remained tracheotomy dependent. One patient had moderate exertional dyspnea, and all other patients had no exertional dyspnea. Voice quality was found to improve after surgical intervention for 1 +/- 1.34 grade dysphonia (P < .0001) according to the adapted GRBAS grading system (Grade, Roughness, Breathiness, Asthenia, and Strain). CONCLUSIONS: Partial cricotracheal resection provides good results for grades III and IV subglottic stenosis as primary or salvage operations. The procedure has no deleterious effects on laryngeal growth and function. The quality of voice significantly improves after surgical intervention but largely depends on the preoperative condition.

TNFα in synaptic function: switching gears.

Pathological brain states are known to induce massive production of proinflammatory cytokines, including tumor necrosis factor alpha (TNFα). At much lower levels, these cytokines are also present in the healthy brain, where it is increasingly being recognized that they exert regulatory influences. Recent studies suggest that TNFα plays important roles in controlling synaptic transmission and plasticity. Here, we discuss the evidence in support of synaptic regulation by TNFα and the underlying cellular mechanisms, including control of AMPA receptor trafficking and glutamate release from astrocytes. These findings suggest that increases in TNFα levels (caused by nervous system infection, injury, or disease) transform the physiological actions of the cytokine into deleterious ones. This functional switch may contribute to cognitive alterations in several brain pathologies.

Extracellular matrix and platelet function in patients with musculocontractural Ehlers-Danlos syndrome caused by mutations in the CHST14 gene.

We report on a consanguineous, Afghani family with two sisters affected with characteristic facial features, multiple contractures, progressive joint and skin laxity, hemorrhagic diathesis following minor trauma and multisystem fragility-related manifestations suggestive of a diagnosis of musculocontractural Ehlers-Danlos syndrome (EDS). This novel form of connective tissue disorder was recently reported in patients of Japanese, Turkish, and Indian descent who were formerly classified as having EDS type VIB and has now been recognized to be a part of spectrum including patients previously classified as having adducted thumb-clubfoot syndrome. We identified a previously unreported mutation in the CHST14 gene, which codes for the enzyme dermatan 4-O-sulfotransferase. We discuss the prenatal presentation, detailed clinical manifestations, and neurological findings in two sisters with this newly described musculocontractural EDS-CHST14 type. We demonstrate that fibroblasts from one of our patients produce more chondroitin sulfate than normal and show lower than normal deposition of collagens I and II and fibrillin 1-containing microfibrills. These findings suggest that the imbalance in the glycosaminoglycan content in developing tissues might interfere with normal deposition of other extracellular matrix components and ultimately contribute to the development of the phenotype observed in these patients. Furthermore, we ruled out the contribution of intrinsic platelet factors to the bleeding diathesis observed in some affected individuals. © 2012 Wiley Periodicals, Inc.

Subaortic ventricular septal defect closure: is the principle of harmony for a longer function no longer valid?

Comment on : Results of two different approaches to closure of subaortic ventricular septal defects in children. [Eur J Cardiothorac Surg. 2014]

Plasma ionized magnesium during acute hyperventilation in humans.

1. Respiratory alkalosis accompanies the clinical syndrome of tetany, precipitates cardiac arrhythmias and predisposes to coronary vasoconstriction. Magnesium plays a critical role in the maintenance of membrane function, and magnesium depletion is often associated with cardiac arrhythmias or vasoconstriction. 2. As technology for detecting circulating ionized magnesium (the most interesting form with respect to physiological and biological properties) is now available in the form of new magnesium-selective electrodes, the effect of respiratory alkalosis induced by voluntary overbreathing for 30 min on circulating ionized magnesium was studied in eight healthy subjects. 3. The total plasma magnesium concentration was not modified by hyperventilation. On the contrary, hyperventilation was associated with a significant reduction in the ionized magnesium concentration of 0.05 (0.02-0.15) mmol/l (median and range) and in the free magnesium fraction of 0.06 (0.01-0.19). During hyperventilation the relative intravascular magnesium mass, calculated from changes in total plasma magnesium concentration and haematocrit, decreased significantly. 4. It is concluded that acute overbreathing reduces the circulating ionized magnesium concentration and the intravascular magnesium mass. It is therefore conceivable that extracellular magnesium deficiency is at least a subsidiary cause of the syndrome of tetany and the cardiac complications that are precipitated by hyperventilation.

Autotransplant of spleen tissue in children with schistosomiasis: evaluation of splenic function after splenosis

Autotransplantation of spleen tissue has been done, in the past ten years, in children with schistosomiasis mansoni with bleeding varices. The purposes of this investigation were: (1) to study the morphology and function of the remnant spleen tissue; (2) to quantify the production of tuftsin; and (3) to assess the immune response to pneomococcal vaccine of these patients. Twenty three children, who underwent splenectomy and autologous implantation of spleen tissue into the greater omentum were included in this investigation. The average postoperative follow-up is five years. Splenosis was proved by colloid liver-spleen scans. Search for Howell-Jolly bodies assessed the filtration function. Tuftsin and the titer of pneumococcal antibodies were quantified by ELISA. Splenosis was evident in all children; however, it was insufficient in two. Howell-Jolly bodies were found only in these two patients. The mean tuftsin serum concentration (335.0 ± 29.8 ng/ml) was inside the normal range. The immune response to pneumococcal vaccination was adequate in 15 patients; intermediate in four; and inadequate in four. From the results the following conclusions can be drawn: splenosis was efficient in maintaining the filtration splenic function in more than 90% and produced tuftsin inside the range of normality. It also provided the immunologic splenic response to pneumococcal vaccination in 65% of the patients of this series.

Prevalence and clinical significance of small joint synovitis detected by ultrasonography in axial SpA

Objectives:¦The aim of this study was to estimate the prevalence of subclinical small joint synovitis detected by ultrasonography in patients with axial SpA, and to evaluate their relevance in terms of function or and disease activity.¦Methods:¦Forty axial SpA patients, 40 RA and 20 healthy subjects were evaluated by ultrasonography, using a reproducible semi-quantitative score by B-mode and Doppler, for synovitis, while disease activity and function were assessed using validated instruments (DAS28, BASDAI, BASFI, m-SACRAH and HAQ).¦Results:¦Median B-mode score were respectively 8.2 for axial SpA, 11.5 for RA and 6.0 for healthy subjects, corresponding to a prevalence of clinical significant synovitis of respectively 37.5%, 60% and 11% for a level of significance at > 8 chosen to¦classify as active > 75% of RA patient with DAS28 >2.6 and < 10% of controls. Addtionally, Doppler was positive in 8% of SpA, 30 % of RA and none of the healthy subjects. Echographic synovitis correlated with disease activity (DAS28) and function¦(HAQ, mSACRAH) in RA patients, but no correlation were found for SpA patients with disease activity (BASDAI) or function (BASFI, HAQ, mSACRAH). Cases of synovitis using classification by Doppler positivity were insufficient to allow any¦statistical analysis.¦Conclusions:¦B-mode ultrasonographic evaluation can demonstrate subclinical synovitis in almost 40% of SpA patients, but they do not appear to correlate with disease activity or function on the contrary to what is observed in RA patients, representing potentially different processes

Distinct profiles of cytotoxic granules in memory CD8 T cells correlate with function, differentiation stage, and antigen exposure.

Cytotoxic CD8 T cells exert their antiviral and antitumor activity primarily through the secretion of cytotoxic granules. Degranulation activity and cytotoxic granules (perforin plus granzymes) generally define CD8 T cells with cytotoxic function. In this study, we have investigated the expression of granzyme K (GrmK) in comparison to that of GrmA, GrmB, and perforin. The expression of the cytotoxic granules was assessed in virus-specific CD8 T cells specific to influenza virus, Epstein-Barr virus (EBV), cytomegalovirus (CMV), or human immunodeficiency virus type 1 (HIV-1). We observed a dichotomy between GrmK and perforin expression in virus-specific CD8 T cells. The profile in influenza virus-specific CD8 T cells was perforin(-) GrmB(-) GrmA(+/-) GrmK(+); in CMV-specific cells, it was perforin(+) GrmB(+) GrmA(+) GrmK(-/+); and in EBV- and HIV-1-specific cells, it was perforin(-/+) GrmB(+) GrmA(+) GrmK(+). On the basis of the delineation of memory and effector CD8 T cells with CD45RA and CD127, the GrmK(+) profile was associated with early-stage memory CD8 T-cell differentiation, the perforin(+) GrmB(+) GrmA(+) profile with advanced-stage differentiation, and the GrmB(+) GrmA(+) Grmk(+) profile with intermediate-stage differentiation. Furthermore, perforin and GrmB but not GrmA and GrmK correlated with cytotoxic activity. Finally, changes in antigen exposure in vitro and in vivo during primary HIV-1 infection and vaccination modulated cytotoxic granule profiles. These results advance our understanding of the relationship between distinct profiles of cytotoxic granules in memory CD8 T cells and function, differentiation stage, and antigen exposure.

Serum anticholinergic activity and postoperative cognitive dysfunction in elderly patients.

BACKGROUND: Cerebral cholinergic transmission plays a key role in cognitive function, and anticholinergic drugs administered during the perioperative phase are a hypothetical cause of postoperative cognitive dysfunction (POCD). We hypothesized that a perioperative increase in serum anticholinergic activity (SAA) is associated with POCD in elderly patients. METHODS: Seventy-nine patients aged >65 years undergoing elective major surgery under standardized general anesthesia (thiopental, sevoflurane, fentanyl, and atracurium) were investigated. Cognitive functions were assessed preoperatively and 7 days postoperatively using the extended version of the CERAD-Neuropsychological Assessment Battery. POCD was defined as a postoperative decline >1 z-score in at least 2 test variables. SAA was measured preoperatively and 7 days postoperatively at the time of cognitive testing. Hodges-Lehmann median differences and their 95% confidence intervals were calculated for between-group comparisons. RESULTS: Of the patients who completed the study, 46% developed POCD. Patients with POCD were slightly older and less educated than patients without POCD. There were no relevant differences between patients with and without POCD regarding gender, demographically corrected baseline cognitive functions, and duration of anesthesia. There were no large differences between patients with and without POCD regarding SAA preoperatively (pmol/mL, median [interquartile range]/median difference [95% CI], P; 1.14 [0.72, 2.37] vs 1.13 [0.68, 1.68]/0.12 [-0.31, 0.57], P = 0.56), SAA 7 days postoperatively (1.32 [0.68, 2.59] vs 0.97 [0.65, 1.83]/0.25 [-0.26, 0.81], P = 0.37), or changes in SAA (0.08 [-0.50, 0.70] vs -0.02 [-0.53, 0.41]/0.1 [-0.31, 0.52], P = 0.62). There was no significant relationship between changes in SAA and changes in cognitive function (Spearman rank correlation coefficient preoperatively of 0.03 [95% CI, -0.21, 0.26] and postoperatively of -0.002 [95% CI, -0.24, 0.23]). CONCLUSIONS: In this panel of patients with low baseline SAA and clinically insignificant perioperative anticholinergic burden, although a relationship cannot be excluded in some patients, our analysis suggests that POCD is probably not a substantial consequence of anticholinergic medications administered perioperatively but rather due to other mechanisms.

Molecular Modeling Approaches for Determining Gene Function: application to a Putative Poly-A Binding Protein from Leishmania amazonensis (LaPABP)

The great expansion in the number of genome sequencing projects has revealed the importance of computational methods to speed up the characterization of unknown genes. These studies have been improved by the use of three dimensional information from the predicted proteins generated by molecular modeling techniques. In this work, we disclose the structure-function relationship of a gene product from Leishmania amazonensis by applying molecular modeling and bioinformatics techniques. The analyzed sequence encodes a 159 aminoacids polypeptide (estimated 18 kDa) and was denoted LaPABP for its high homology with poly-A binding proteins from trypanosomatids. The domain structure, clustering analysis and a three dimensional model of LaPABP, basically obtained by homology modeling on the structure of the human poly-A binding protein, are described. Based on the analysis of the electrostatic potential mapped on the model's surface and conservation of intramolecular contacts responsible for folding stabilization we hypothesize that this protein may have less avidity to RNA than it's L. major counterpart but still account for a significant functional activity in the parasite. The model obtained will help in the design of mutagenesis experiments aimed to elucidate the mechanism of gene expression in trypanosomatids and serve as a starting point for its exploration as a potential source of targets for a rational chemotherapy.

Thyroid function and prevalent and incident metabolic syndrome in older adults: the Health, Ageing and Body Composition Study.

OBJECTIVE: Both subclinical hypothyroidism and the metabolic syndrome have been associated with increased risk of coronary heart disease events. It is unknown whether the prevalence and incidence of metabolic syndrome is higher as TSH levels increase, or in individuals with subclinical hypothyroidism. We sought to determine the association between thyroid function and the prevalence and incidence of the metabolic syndrome in a cohort of older adults. DESIGN: Data were analysed from the Health, Ageing and Body Composition Study, a prospective cohort of 3075 community-dwelling US adults. PARTICIPANTS: Two thousand one hundred and nineteen participants with measured TSH and data on metabolic syndrome components were included in the analysis. MEASUREMENTS: TSH was measured by immunoassay. Metabolic syndrome was defined per revised ATP III criteria. RESULTS: At baseline, 684 participants met criteria for metabolic syndrome. At 6-year follow-up, incident metabolic syndrome developed in 239 individuals. In fully adjusted models, each unit increase in TSH was associated with a 3% increase in the odds of prevalent metabolic syndrome (OR, 1.03; 95% CI, 1.01-1.06; P = 0.02), and the association was stronger for TSH within the normal range (OR, 1.16; 95% CI, 1.03-1.30; P = 0.02). Subclinical hypothyroidism with a TSH > 10 mIU/l was significantly associated with increased odds of prevalent metabolic syndrome (OR, 2.3; 95% CI, 1.0-5.0; P = 0.04); the odds of incident MetS was similar (OR 2.2), but the confidence interval was wide (0.6-7.5). CONCLUSIONS: Higher TSH levels and subclinical hypothyroidism with a TSH > 10 mIU/l are associated with increased odds of prevalent but not incident metabolic syndrome.

Variation of the Oviposition Preferences of Aedes aegypti in Function of Substratum and Humidity

Two Aedes aegypti (L.) populations were studied in the laboratory regarding the preference for three types of breeding sites, i.e., flasks containing only water, flasks with a plant and flasks with a stick. Each of these breeding units was placed in one cage and the choice of the oviposition sites was determined for individual females and three females per experimental unit at two humidity levels. Preference for ovipositing on the water surface was observed and varied according to experimental unit and humidity. Mean hatching of eggs in water surface was 46.6%. Experiments with three females showed a more marked difference than when only one female was used. Inter and intrapopulation variability regarding oviposition sites was observed. The discrimination between the different oviposition substrates, hatching in water surface and its implication for mosquito control are discussed.