Sheep α-globin gene sequences: Implications for their concerted evolution and for the down-regulation of the 3' genes

In sheep as in man and most other mammals, there are two α-globin genes (Iα and IIα), which are expressed at different levels, the upstream gene being the most efficient. In α-globin gene triplication and quadruplication, this trend is confirmed, i.e., the α-chain output of the downstream genes progressively decreases. In this study, we have determined the complete sequence of the cDNAs and of both the introns in a triple-α haplotype in which each gene could be recognized for the presence of distinct alleles. The sequence analysis reveals that the bodies of the three α-globin genes are essentially identical (99.9% homology) and moreover indicates that the down-regulation of additional α-globin genes in sheep is not the effect of sequence variation from the Cap to the Poly(A) addition sites. This striking similarity among α-genes is higher than that seen in other mammals and is probably sustained by particularly efficient mechanisms of gene conversion and cross-over fixation

A study on serum calcium and phosphate in dialysis patients via a mixed effects latent markov model with two outcomes.

In pres

Delayed Effect of Active Pressure Treatment on Endolymphatic Hydrops

OBJECTIVE: To identify eventual correlations between the effect of low-pressure treatment and endolymphatic hydrops in Ménière patients. MATERIAL AND METHODS: The study group consisted of subjects affected by definite Ménière disease (2015) and a severe degree of disability, who received a ventilation tube with or without a low-pressure treatment before undergoing a surgical procedure (vestibular neurectomy). After the placement of the ventilation tube, the subjects were either left alone with the tube or received 1 month of self-administered low-pressure therapy with a portable device. In all subjects, an electrocochleography (ECochG) was performed and specific questionnaires - Dizziness Handicap Inventory (DHI) and Functional Scale Level (FSL) - were completed before starting either arm of treatment, at the end of treatment, and then 3 and 6 months later. RESULTS: All selected subjects presented with an ECochG pattern that was indicative of endolymphatic hydrops before starting either treatment. At the end of pressure treatment, 80% showed symptomatic improvement while maintaining the hydropic ECochG pattern. At the 3-month control stage, the hydropic pattern resulted normalized (<0.5) in all the improved subjects. CONCLUSIONS: Although 1 month of low-pressure treatment provided a positive symptomatological outcome, normalization of the hydropic ECochG parameters occurred only at a later time. Therefore, it is possible to assume that endolymphatic hydrops could be concurrent with a non-symptomatic stage of Ménière disease, and that the anti-hydropic effect of the low-pressure treatment, if any, would present with a certain delay after its completion

Probiotic administration in patients with ileal pouch-anal anastomosis for ulcerative colitis is associated with expansion of mucosal regulatory cells.

BACKGROUND: Probiotics have anti-inflammatory effects in patients with inflammatory bowel disease and appear to regulate mucosal immune response through reductions in proinflammatory cytokines. The probiotic VSL#3 prevents pouchitis if started within a week of ileostomy closure and maintains remission following antibacterial treatment in patients with refractory or recurrent pouchitis. However, the efficacy of probiotics and their effects on regulatory cells if started at a greater time after surgery in patients undergoing ileal pouch anal anastomosis (IPAA) for ulcerative colitis are unknown. METHODS: We conducted an open-label study in which 31 patients at different periods from surgery without signs and symptoms of pouchitis were randomized to 2 sachets of VSL#3 once daily or no treatment for 12 months. Pouchitis disease activity index (PDAI) was evaluated at baseline and after 3, 6, and 12 months. The percentage of CD4+ T lymphocytes expressing CD25 and the inactive form of transforming growth factor-beta [latency-associated peptide (LAP)] were evaluated at baseline and after 3 and 6 months in peripheral-blood mononuclear cells and mucosal biopsies. Variation in tissue interleukin-1beta and Foxp3 mRNA expression was also evaluated. RESULTS: During the study period, VSL#3-treated patients showed a significant reduction in PDAI score and a significant increase in the percentage of mucosal CD4+CD25(high) and CD4+ LAP-positive cells compared with baseline values. Tissue samples at different points showed a significant reduction in IL-1beta mRNA expression, and a significant increase in Foxp3 mRNA expression. CONCLUSIONS: We conclude that VSL#3 administration in patients with IPAA modulates the PDAI and expands the number of mucosal regulatory T cells

Regulatory T cells with multiple suppressive and potentially pro-tumor activities accumulate in human colorectal cancer

Tregs can contribute to tumor progression by suppressing antitumor immunity. Exceptionally, in human colorectal cancer (CRC), Tregs are thought to exert beneficial roles in controlling pro-tumor chronic inflammation. The goal of our study was to characterize CRC-infiltrating Tregs at multiple levels, by phenotypical, molecular and functional evaluation of Tregs from the tumor site, compared to non-tumoral mucosa and peripheral blood of CRC patients. The frequency of Tregs was higher in mucosa than in blood, and further significantly increased in tumor. Ex vivo, those Tregs suppressed the proliferation of tumor-infiltrating CD8(+) and CD4(+) T cells. A differential compartmentalization was detected between Helioshigh and Helios(low) Treg subsets (thymus-derived versus peripherally induced): while Helios(low) Tregs were enriched in both sites, only Helios(high) Tregs accumulated significantly and specifically in tumors, displayed a highly demethylated TSDR region and contained high proportions of cells expressing CD39 and OX40, markers of activation and suppression. Besides the suppression of T cells, Tregs may contribute to CRC progression also through releasing IL-17, or differentiating into Tfr cells that potentially antagonize a protective Tfh response, events that were both detected in tumor-associated Tregs. Overall, our data indicate that Treg accumulation may contribute through multiple mechanisms to CRC establishment and progression

Etude d'un épisode photochimique à l'alde d'un modèle méso-échelle et de mesures intensives sur la région de Grenoble

La ville de Grenob le, située au carrefour de trois vallées, est systématiquement soumise à des périodes de smog estival avec de fortes concentrations en ozone (0 3), Au cours de l'été 1999, l'Association pour le contrôle et la préservation de l'air dans la région grenobloise (ASCOPARG) et l'École Polytechnique Fédérale de Lausanne (EPFL) ont mené conjointement -une campagne de mesures en déployant, durant un mois, un réseau de mesures au sol renforcé par des moyens de mesures à la vertical e. Deux périodes d'observations intensives (POl) ont eu lieu, la première fin juillet, et la deuxième dé but août. Les simulations ont été réa lisées pour la première POl (24-27 juill et) avec le modèle METeorological PHOtochem istry MODel (METPHOMOD) utilisant le mécanisme chimique Regional Atmospheric Chemistry Mechanism (RACM). Une technique de nesting one-way est utilisée avec une grande grille de 198 km de côté et une résolution de 6 x 6 km et une petite grille de 78 x 68 km avec une résolution de 2 x 2 km. À la verticale, 24 niveaux sont pris en compte jusqu'à 8 000 m. Au sol, les champs de vents, les concentrations d'03 et de dioxyde d'azote (NOx) sont bien reproduits par le modèle et mettent en évidence le déplacement horizontal du panache d'03 vers le sud avec un maximum d'03 de 95 ppb. Pour la verticale, les mesures et les simulations montrent une couche de mélange convective (CMC) supérieure à 2 000 rn, le transport horizontal du panache dans la CMC et la formation de la couche réservoir d'03' La CMC est donc plus haute en terrain de montagne qu'en plaine. Une stratification verticale spécifique de l'atmosphère, suivant trois couches, a été mise en évidence lors de cet épisode photoch imique sur Grenoble. Une simulation sans émissions sur le petit domaine de calcul a permis d'évaluer la production locale d'03de la ville à 32 ppb, soit un tiers de la concentration maximale mesurée et simulée dans le sud de l'agglomération

Effect of Canagliflozin on Renal Threshold for Glucose, Glycemia, and Body Weight in Normal and Diabetic Animal Models

Background: Canagliflozin is a sodium glucose co-transporter (SGLT) 2 inhibitor in clinical development for the treatment of type 2 diabetes mellitus (T2DM). Methods: 14 C-alpha-methylglucoside uptake in Chinese hamster ovary-K cells expressing human, rat, or mouse SGLT2 or SGLT1; 3 H-2-deoxy-D-glucose uptake in L6 myoblasts; and 2-electrode voltage clamp recording of oocytes expressing human SGLT3 were analyzed. Graded glucose infusions were performed to determine rate of urinary glucose excretion (UGE) at different blood glucose (BG) concentrations and the renal threshold for glucose excretion (RTG) in vehicle or canagliflozin-treated Zucker diabetic fatty (ZDF) rats. This study aimed to characterize the pharmacodynamic effects of canagliflozin in vitro and in preclinical models of T2DM and obesity. Results: Treatment with canagliflozin 1 mg/kg lowered RT G from 415612 mg/dl to 94610 mg/dl in ZDF rats while maintaining a threshold relationship between BG and UGE with virtually no UGE observed when BG was below RTG. Canagliflozin dose-dependently decreased BG concentrations in db/db mice treated acutely. In ZDF rats treated for 4 weeks, canagliflozin decreased glycated hemoglobin (HbA1c) and improved measures of insulin secretion. In obese animal models, canagliflozin increased UGE and decreased BG, body weight gain, epididymal fat, liver weight, and the respiratory exchange ratio