Long-term sertraline treatment increases expression and decreases phosphorylation of glycogen synthase kinase-3B in platelets of patients with late-life major depression

BackgroundAbnormal regulation of glycogen synthase kinase 3-beta (GSK3B) activity has been implicated in the pathophysiology of mood disorders. Many pharmacological agents, including antidepressants, can modulate GSK3B. The aim of the present study was to investigate the effect of short-and long-term sertraline treatment on the expression and phosphorylation of GSK3B in platelets of patients with late-life major depression.MethodsThirty-nine unmedicated elderly adults with major depressive disorder (MDD) were initially included in this study. The comparison group comprised 18 age-matched, healthy individuals. The expression of total and Ser-9 phosphorylated GSK3B (pGSK3B) was determined by Enzyme Immunometric Assay (EIA) in platelets of patients and controls at baseline, and after 3 and 12 months of sertraline treatments for patients only. During this period, patients were continuously treated with therapeutic doses of sertraline. GSK3B activity was indirectly estimated by calculating the proportion of inactive (phosphorylated) forms (pGSK3B) in relation to the total expression of the enzyme (i.e., GSK3B ratio).ResultsDepressed patients had significantly higher levels of pGSK3B as compared to controls (p < 0.001). Within the MDD group, after 3 months of sertraline treatment no significant changes were observed in GSK3B expression and phosphorylation state, as compared to baseline levels. However, after 12 months of treatment we found a significant increase in the expression of total GSK3B (p = 0.05), in the absence of any significant changes in pGSK3B (p = 0.12), leading to a significant reduction in GSK3B ratio (p = 0.001).ConclusionsOur findings indicate that GSK3B expression was upregulated by the continuous treatment with sertraline, along with an increment in the proportion of active forms of the enzyme. This is compatible with an increase in overall GSK3B activity, which may have been induced by the long-term treatment of late-life depression with sertraline.     

Serum gamma-glutamyltransferase fractions in Myotonic Dystrophy type I: Differences with healthy subjects and patients with liver disease

ObjectivesElevation of serum gamma-glutamyltransferase (GGT), in absence of a clinically significant liver damage, is often found in Myotonic Dystrophy type-1 (DM1).In this study we investigated if a specific GGT fraction pattern is present in DM1.Designs and methodsWe compared total and fractional GGT values (b-, m-, s-, f-GGT) among patients with DM1 or liver disease (LD) and healthy subjects (HS).ResultsThe increase of GGT in DM1 and LD, vs HS, was mainly due to s-GGT (median: 32.7; 66.7; and 7.9 U/L, respectively), and b-GGT (8.5; 18.9; and 2.1 U/L). The subset of DM1 patients matched with HS with corresponding serum GGT showed higher b-GGT (6.0 vs 4.2 U/L).ConclusionsDM1 patients with normal total GGT values showed an alteration of the production and release in the blood of GGT fractions. Since increased s-GGT is also found in LD, a sub-clinical liver damage likely occurs in DM1 subjects apparently free of liver disease.     

Can race be erased? Coalitional computation and social categorization

Previous studies have established that people encode the race of each individual they encounter, and do so via computational processes that appear to be both automatic and mandatory. If true, this conclusion would be important, because categorizing others by their race is a precondition for treating them differently according to race. Here we report experiments, using unobtrusive measures, showing that categorizing individuals by race is not inevitable, and supporting an alternative hypothesis: that encoding by race is instead a reversible byproduct of cognitive machinery that evolved to detect coalitional alliances. The results show that subjects encode coalitional affiliations as a normal part of person representation. More importantly, when cues of coalitional affiliation no longer track or correspond to race, subjects markedly reduce the extent to which they categorize others by race, and indeed may cease doing so entirely. Despite a lifetime's experience of race as a predictor of social alliance, less than 4 min of exposure to an alternate social world was enough to deflate the tendency to categorize by race. These results suggest that racism may be a volatile and eradicable construct that persists only so long as it is actively maintained through being linked to parallel systems of social alliance.     

Distribution of Streptococcus pneumoniae serotypes in nasopharyngeal carriage and in invasive pneumococcal disease in Sao Paulo, Brazil

To determine whether serotypes of S. pneumoniae isolated from the nasopharynx (NP) are representative of data from patients with invasive disease, we collected NP swab specimens from children, between 3 months and 5 years and obtained data from 105 children hospitalized with invasive disease. The prevalence of penicillin nonsusceptible strains in the NP carriage and invasive disease group was 16.4% and 17%, respectively, in the first period and 42% and 45% in the second period. The serotypes 23F, 6A, 14 and 19F were the most common in the NP study and 14, 1, 5 and 6B were the most common in invasive infections.     

Maternal heterodisomy/isodisomy and paternal supernumerary ring of chromosome 7 in a child with Silver-Russell syndrome

Silver-Russell syndrome (SRS) is clinically variable although most cases have several common signs. Different chromosomes and chromosomal regions have been associated with SRS. Maternal uniparental disomy (UPD) of chromosome 7 is responsible for 5-10% of cases, probably because of an imbalance between maternal and paternal imprinted genes and more recently maternal duplication or epimutations in the 11p15 imprinted region have been described. To date, only two patients with maternal UPD7 and a mosaic condition for a supernumerary ring 7 marker have been reported, and we here report a further case. Standard QFQ banding of lymphocytes as well as fluorescence in-situ hybridization analyses were performed to identify and characterize the supernumerary marker. UPD testing was performed on both the patient's and parents' DNA using chromosome 7 microsatellite markers. The patient demonstrated a ring in about 4% of the analysed cells. On the basis of cytogenetic and molecular results, break points were tentatively identified as 7p11.2 and 7q21. Maternal hetero-/iso-UPD and a paternal origin for the supernumerary ring were demonstrated. Clinical data comparison between our patient who has a SRS phenotype and cases with hetero-/iso-UPD7 mat and mosaicism for a paternally derived chromosome 7 ring and previously reported ring 7 cases suggest that the SRS phenotype is probably because of the UPD rather than to the partial trisomy.     

肿瘤外泌体来源的miR-126-5p通过抑制NLRC3促进口腔鳞癌细胞的增殖和迁移

目的 探索口腔鳞癌外泌体中miR-126-5p对肿瘤细胞生物学功能的影响.方法 qPCR分析口腔鳞癌组织芯片、临床样本及口腔鳞癌外泌体中miR-126-5p的表达情况;荧光素酶报告基因法确定与miR-126-5p相互作用的分子,qPCR检测外泌体与共孵育后的肿瘤细胞中NOD样受体家族蛋白3(NLRC3)的表达情况;通过体外细胞增殖及划痕实验,以及体内肿瘤生长反映含有miR-126-5p外泌体对肿瘤细胞生物学功能的影响.结果 芯片分析表明口腔鳞癌组织中miR-126-5p高表达,患者组织(P<0.05)及口腔鳞癌细胞系中miR-126-5p同样高表达(P<0.001),荧光素酶报告实验表明miR-126-5p与NLRC3相互作用,且miR-126-5p对NLRC3存在负性调控关系(P<0.01);此外,含有miR-126-5p的外泌体与细胞共孵育或沉默NLRC3可以促进肿瘤细胞增殖(P<0.001)及迁移(P<0.0001),且含有miR-126-5p的外泌体可以抑制NLRC3的体内表达(P<0.001),促进肿瘤的生长(P<0.001).结论 肿瘤细胞分泌的外泌体miR-126-5p可以抑制NLRC3的表达从而促进口腔鳞癌的进展.     

Initial assessment data from a 43-site program for homeless chronic mentally ill veterans

In May 1987 the Veterans Administration established the Homeless Chronically Mentally Ill Veterans Program at 43 sites to provide outreach, health care, and residential rehabilitation services. Intake assessment data on 10,529 homeless veterans screened as potential candidates for clinical services during the program's first 11 months are presented. With a median age of 40, the homeless veterans were considerably younger than veterans in the general U.S. population. More had served in the Vietnam era than in other military eras. Almost three-fifths were white, and a third were black; more than 40 percent were receiving some form of public support. Almost half manifested one or more severe psychiatric symptoms at screening, and almost two-thirds had previously been hospitalized for either a psychiatric or a substance abuse problem.     

Clinical traits and molecular findings in 46,XX males

46,XX maleness is characterized by the presence of testicular development in subjects who lack a Y chromosome. The majority of affected persons have normal external genitalia, but 10–15% show various degrees of hypospadias. Several hypotheses have been proposed to explain the etiology of this constitution: translocation of the testis-determining factor ( TDF ) from the Y to the X chromosome, mutation in an autosomal or X chromosomal gene which permits testicular determination in the absence of TDF , and undetected mosaicism with a Y-bearing cell line. We report the pheno-typic data and results of molecular analyses performed in six sporadic Mexican males with 46,XX karyotype. Molecular studies revealed Yp sequences in two individuals ( ZFY + SRY +) with different phenotypes, a third one presented with a smaller segment of Yp ( ZFY – SRY +) and complete virilization, while the remaining three were Y-negative and showed hypospadias. In all subjects a hidden mosaicism with a Y-bearing cell line was ruled out due to the absence of Y-centromeric sequences. Our data demonstrate that the phenotype does not always correlate with the presence or absence of Y-sequences in the genome, and confirm that 46,XX maleness is a genetically heterogeneous condition.     

Calcium,cyclic AMP and protein kinase C — partners in mitogenesis

Summary Evidence is steadily mounting that the proto-oncogenes, whose products organize and start the programs that drive normal eukaryotic cells through their chromosome replication/mitosis cycles, are transiently stimulated by sequential signals from a multi-purpose, receptor-operated mechanism (consisting of internal surges of Ca²⁺ and bursts of protein kinase C activity resulting from phosphatidylinositol 4,5-bisphosphate breakdown and the opening of membrane Ca²⁺ channels induced by receptor-associated tyrosine-protein kinase activity) and bursts of cyclic AMP-dependent kinase activity. The bypassing or subversion of the receptor-operated Ca²⁺/phospholipid breakdown/protein kinase C signalling mechanism is probably the basis of the freeing of cell proliferation from external controls that characterizes all neoplastic transformations.Abbreviations aatRNA synth aminoacyl t-RNA synthase - AC adenylate cyclase - ADR activator of DNA replication - AP antiporter - AP ₄ A diadenosine 5,5'-p¹,p⁴-tetraphosphate - Arach _ext external arachidonic acid - BK bradykinin - C subunit the common catalytic subunit of the cyclic AMP · PKs - Ca ²⁺ · CaM calcicalmodulin complex - CaM calmodulin; Ca²⁺ · CaM · PK, calcicalmodulin-dependent protein kinase - Ca ²⁺ _seq or CaER calcium sequestered in ER - cAMP · PK or cyclic AMP · PK cyclic AMP-dependent protein kinases - CDC gene a gene functioning specifically during the cell division cycle - Dex dexamethasone, a synthetic glucocorticosteroid - DG diacylglycerol - DG-K diacylglycerol kinase - DG-L diacylglycerol lipase - EGF epidermal growth factor - Enz Transloc replication enzyme translocation - ER endoplasmic reticulum - ET energy transducing mechanisms - G-GTP GTP-activated G(or N)-protein - G _i inhibitory G (or N) protein - G _s stimulatory G (or N)-protein - Glucose _ext external glucose - Glucose _i internal glucose - HPX partial (70%) hepatectomy - IBMX 3-isobutyl-1-methyl xanthine, a cyclic nucleotide PDE inhibitor - IL-2 interleukin-2, a lymphocyte progression factor - Ins insulin - IP _act protein kinase which activates MPFs - [IP · PO ₄ ]_inact inactive phosphoform of IP - IP ₃ inositol 1,4,5-triphosphate - K kinetochore - LM lipomodulin or lipocortin, a - PLA ₂ inhibitor - MF microfilaments - MLCK myosin light chain kinase - MPF maturation- or mitosispromotin - MTOC microtubule-organizing center - Musc Chol muscarinic cholinergic agent - OAG 1-oleolyl-2-acetyl glycerol, a DG - ORI chromosome replication origin - PA phosphatidic acid(s) - PAKII protease-activated protein kinase II - PDE cyclic nucleotide phosphodiesterase - PDGE platelet-derived growth factor - PG prostaglandin(s) - pH _i internal pH - PIC phosphoinositidase C - PIP-K phosphatidylinositol kinase(s) - PIP ₂ phosphatidylinositol-4,5- bisphosphate - PK protein kinase - PLA ₂ phospholipase A₃ - PrP Ca²⁺/Ca²⁺ · CaM-activatable phosphoprotein phosphatase - PTX parathyroidectomy - R receptor - Replic enz replication enzyme(s) - R.R. ribonucleotide reductase - RI, RII cyclic AMP-binding regulatory subunits of types I and II cyclic AMP · PKs - Sacch saccharin, a tumorpromoting, protein kinase C- stimulating artificial sweetener - SmC somatomedin C - T _A amino acid transporter - T _G glucose transporter - TM transponding mechanism - TopoII topoisomerase II - TopoII-PK topoisomerase II protein kinase - TPA 12-0-tetradecanoyl phorbol-13-acetate - TPTX thyroparathyroidectomy - Transglut transglutaminase - Transf transferrin - Tyr · PK tyrosine-phosphorylating protein kinase - VP vasopressin