Low medical morbidity and mortality after acute courses of electroconvulsive therapy in a population-based sample.

BACKGROUND: To determine event rates for specific medical events and mortality among individuals receiving electroconvulsive therapy (ECT). METHOD: Population-based cohort study using health administrative data of acute ECT treatments delivered in Ontario, Canada, from 2003 to 2011. We measured the following medical event rates, per 10 000 ECT treatments, up to 7 and 30 days post-treatment: stroke, seizure, acute myocardial infarction, arrhythmia, pneumonia, pulmonary embolus, deep vein thrombosis, gastrointestinal bleeding, falls, hip fracture, and mortality. RESULTS: A total of 135 831 ECT treatments were delivered to 8810 unique patients. Overall medical event rates were 9.1 and 16.8 per 10 000 ECT treatments respectively. The most common medical events were falls (2.7 and 5.5 per 10 000 ECT treatments) and pneumonia (1.8 and 3.8 per 10 000 ECT treatments). Fewer than six deaths occurred on the day of an ECT treatment. This corresponded to a mortality rate of less than 0.4 per 10 000 treatments. Deaths within 7 and 30 days of an ECT treatment, excluding deaths due to external causes (e.g., accidental and intentional causes of death), were 1.0 and 2.4 per 10 000 ECT treatments respectively. CONCLUSION: Morbidity and mortality events after ECT treatments were relatively low, supporting ECT as a low-risk medical procedure.

Neuropsychological follow-up at school age of children with asymmetric ventricles or unilateral ventriculomegaly identified in utero.

OBJECTIVE: To examine the long-term neuropsychological outcome of children with a prenatal diagnosis of asymmetric ventricles or unilateral ventriculomegaly. DESIGN: A clinic-based neuropsychological study. SETTING: Paediatric neurology clinic. POPULATION: Thirty-three of 41 children, previously assessed at kindergarten age, with asymmetric ventricles or unilateral ventriculomegaly identified in utero, were recruited at school age for a neuropsychological follow-up. METHODS: All children, 9-11 years of age, underwent a battery of neuropsychological tests and the parents completed behavioural rating questionnaires. MAIN OUTCOME MEASURES: Results of the neuropsychological assessment and parents' questionnaires. RESULTS: There were no significant differences between children diagnosed with either asymmetric ventricles or unilateral ventriculomegaly in most parameters relative to the general population; the full-scale IQ scores were 103.13 ± 12.43 and 103.56 ± 10.5, respectively. A significantly lower performance was found only on one measure of attention among the unilateral ventriculomegaly group and on writing speed tasks among the asymmetric ventricles group. Both study groups showed significantly higher scores than expected in the normal population on a verbal fluency test. Comparison of both groups combined with the normative population yielded significantly lower scores only in attention tests. Yet, the clinical population showed significantly higher scores on writing accuracy, processing speed and verbal fluency and lower rates of executive dysfunction. CONCLUSIONS: Asymmetric ventricles or unilateral ventriculomegaly identified in utero does not appear to affect long-term mental development and school achievements. Further prospective research on a larger sample is needed in order to confirm our findings.

Constitutive abnormal expression of RasGRP-1 isoforms and low expression of PARP-1 in patients with systemic lupus erythematosus.

OBJECTIVE: Defective expression of Ras guanil releasing protein-1 (RasGRP-1) and increased apoptosis have been reported in lymphocytes from SLE patients. Whether these aberrations are correlated and linked to disease activity has not been elucidated. METHODS: Expression of normal 90 kDa RasGRP-1, its most prevalent 86 kDa isoform and full PARP-1 116 kDa and its cleavage fragment 84 kDa were determined in whole protein lysates of peripheral blood mononuclear cells (PBMC) in correlation with mitogen activated protein kinase (MAPK) activity and SLE clinical status in a large group of SLE patients during 1 year follow-up. RESULTS: Expression of normal 90 kDa RasGRP-1 was comparable in patients and controls. However, SLE patients demonstrated a constitutively increased 86 kDa/90 kDA ratio (p < 0.01) and decreased full poly (ADP-ribose) polymerase protein-1 (PARP-1) expression (p < 0.002) compared with controls who were disease-independent. A remission in disease activity was associated with decreased RasGRP-1 expression. Expression of 84 kDa PARP-1 cleavage fragment was found in 15% of patients but in none of the controls. In addition, expression of PARP-1 correlated positively with normal 90 kDa RasGRP-1 expression and negatively with the RasGRP-1 86 kDa/90 kDA ratio. CONCLUSIONS: These data suggest that constitutive aberrant expression of PARP-1 and RasGRP-1 ratio may act in concert to impair survival of lymphocytes in SLE patients.

Antigen-induced B lymphocyte activation involves the p21ras and ras.GAP signaling pathway.

Ligation of a B lymphocyte surface immunoglobulin (sIg) antigen receptor (AgR) by its specific Ag ligand initiates a signaling pathway that culminates in B cell activation. However, many events of this pathway have not been elucidated. Here we present three novel findings that demonstrate directly that AgR-mediated signaling in B cells functions by the p21ras/ras.GAP-dependent pathway. First, stimulation of TA3 7.9 Ag-specific murine B lymphoma cells for 2 min with either Ag or F(ab')2 anti-IgM induces p21ras activation as measured by an increase in the GTP/GDP ratio of its bound nucleotides. This activation of p21ras does not occur via a change in its guanine nucleotide exchange rate. Second, Ag stimulation results in the inhibition of activity of p120 ras.GAP, a protein that regulates p21ras activation. Tyrosine phosphorylation of ras.GAP occurs within 1 min after Ag stimulation but is no longer detectable at 20 min after stimulation, at which time ras.GAP activity remains inhibited. Thus, tyrosine phosphorylation of ras.GAP is not required for the inhibition of its activity. Third, despite the role proposed for a ras.GAP-associated p190 protein in the control of ras.GAP activity in B cells, p190 was not detectable either in anti-ras.GAP immunoprecipitates of [35S]methionine labeled lysates of Ag-stimulated or -unstimulated 7.9 cells or as a tyrosine phosphoprotein in Western blots of anti-ras.GAP immunoprecipitates of Ag-stimulated 7.9 cell lysates. Inasmuch as the TA3 7.9 B lymphoma is representative of a mature, sIgM-bearing B cell, our observations raise the intriguing possibility that the capacity of p190 to associate with ras.GAP and regulate the activities of ras.GAP and p21ras in a B cell is dependent on the stage of differentiation of the B cell.

Thymic T cell anergy in autoimmune nonobese diabetic mice is mediated by deficient T cell receptor regulation of the pathway of p21ras activation.

Thymic T cell anergy, as manifested by thymocyte proliferative unresponsiveness to antigens expressed in the thymic environment, is commonly believed to mediate the acquisition of immunological self-tolerance. However, we previously found that thymic T cell anergy may lead to the breakdown of tolerance and predispose to autoimmunity in nonobese diabetic (NOD) mice. Here, we show that NOD thymic T cell anergy, as revealed by proliferative unresponsiveness in vitro after stimulation through the T cell receptor (TCR), is associated with defective TCR-mediated signal transduction along the PKC/p21ras/p42mapk pathway of T cell activation. PKC activity is reduced in NOD thymocytes. Activation of p21ras is deficient in quiescent and stimulated NOD T cells, and this is correlated with a significant reduction in the tyrosine phosphorylation of p42mapk, a serine/threonine kinase active downstream of p21ras. Treatment of NOD T cells with a phorbol ester not only enhances their p21ras activity and p42mapk tyrosine phosphorylation but also restores their proliferative responsiveness. Since p42mapk activity is required for progression through to S phase of the cell cycle, our data suggest that reduced tyrosine phosphorylation of p42mapk in stimulated NOD T cells may abrogate its activity and elicit the proliferative unresponsiveness of these cells.

Interleukin 4 reverses T cell proliferative unresponsiveness and prevents the onset of diabetes in nonobese diabetic mice.

Beginning at the time of insulitis (7 wk of age), CD4+ and CD8+ mature thymocytes from nonobese diabetic (NOD) mice exhibit a proliferative unresponsiveness in vitro after T cell receptor (TCR) crosslinking. This unresponsiveness does not result from either insulitis or thymic involution and is long lasting, i.e., persists until diabetes onset (24 wk of age). We previously proposed that it represents a form of thymic T cell anergy that predisposes to diabetes onset. This hypothesis was tested in the present study by further investigating the mechanism responsible for NOD thymic T cell proliferative unresponsiveness and determining whether reversal of this unresponsiveness protects NOD mice from diabetes. Interleukin 4 (IL-4) secretion by thymocytes from > 7-wk-old NOD mice was virtually undetectable after treatment with either anti-TCR alpha/beta, anti-CD3, or Concanavalin A (Con A) compared with those by thymocytes from age- and sex-matched control BALB/c mice stimulated under identical conditions. NOD thymocytes stimulated by anti-TCR alpha/beta or anti-CD3 secreted less IL-2 than did similarly activated BALB/c thymocytes. However, since equivalent levels of IL-3 were secreted by Con A-activated NOD and BALB/c thymocytes, the unresponsiveness of NOD thymic T cells does not appear to be dependent on reduced IL-2 secretion. The surface density and dissociation constant of the high affinity IL-2 receptor of Con A-activated thymocytes from both strains are also similar. The patterns of unresponsiveness and lymphokine secretion seen in anti-TCR/CD3-activated NOD thymic T cells were also observed in activated NOD peripheral spleen T cells. Exogenous recombinant (r)IL-2 only partially reverses NOD thymocyte proliferative unresponsiveness to anti-CD3, and this is mediated by the inability of IL-2 to stimulate a complete IL-4 secretion response. In contrast, exogenous IL-4 reverses the unresponsiveness of both NOD thymic and peripheral T cells completely, and this is associated with the complete restoration of an IL-2 secretion response. Furthermore, the in vivo administration of rIL-4 to prediabetic NOD mice protects them from diabetes. Thus, the ability of rIL-4 to reverse completely the NOD thymic and peripheral T cell proliferative defect in vitro and protect against diabetes in vivo provides further support for a causal relationship between this T cell proliferative unresponsiveness and susceptibility to diabetes in NOD mice.

Increased ERK and JNK activities correlate with disease activity in patients with systemic lupus erythematosus.

BACKGROUND: Aberrant signalling along the p21ras/MAP kinase pathway has been demonstrated in systemic lupus erythematosus (SLE). OBJECTIVE: To determine whether expression and activity of the MAP kinases ERK and JNK reflect disease activity in patients with SLE. METHODS: Blood samples of 42 outpatients with SLE were prospectively collected during four consecutive visits. The control group included 20 healthy subjects. Disease activity was assessed using the SLE Disease Activity Index (SLEDAI). Expression of total ERK and JNK kinases and their active forms (pERK and pJNK) was determined in whole protein lysates of peripheral blood mononuclear cells. RESULTS: The mean levels of the active kinases pERK and pJNK were significantly increased in patients with active disease (SLEDAI 4-20) as compared with patients with inactive disease (SLEDAI 0-3), p = 0.04, as well as with healthy controls, p = 0.03 and p = 0.003 for pERK and pJNK, respectively. The percentage of activated forms of ERK and JNK of the total expression of these MAP kinases was also gradually increased, reaching 50% for pERK and >40% for pJNK in patients with SLE with moderate-to-severe disease (SLEDAI 7-20), p = 0.005, p = 0.005 and p = 0.02, p = 0.05 as compared with controls and inactive patients, respectively. A decrease of more than three SLEDAI points was associated with a significant reduction in the expression of both total and activated forms of ERK and JNK, p = 0.03, p = 0.01, respectively. CONCLUSIONS: The results show that ERK and JNK activity reflects disease activity in patients with SLE. These MAP kinases may serve as additional tools for the evaluation of disease activity and management of these patients.

Comparison of modified preadmission glucose-lowering regimen with basal/bolus regimen for glucose control on outcome in general medicine wards.

BACKGROUND: It is undecided whether glucose control as advocated by the professional organisations and the glucose-lowering method by itself affects clinical outcome in patients with diabetes mellitus hospitalised in general medical wards. Our aim was to investigate whether a basal/bolus regimen and a modified prehospitalisation regimen have a different impact on the clinical diabetic patients in general medicine wards. METHODS: Glucose control of patients with diabetes hospitalised in two different wards of internal medicine was achieved according to their wards' policy: a modified preadmission regimen (conventional regime) or a basal/bolus regimen (intensive regime). Death and any adverse event were determined during hospitalisation and within 6 months after discharge to assess clinical outcome. RESULTS: Median fasting and daily glucose levels were similar in the conventional (n = 116) and intensive regime (n = 129) groups: 161 mg/dl (inter-quartile range: 138-201) and 176 mg/dl (152-215) vs. 155 mg/dl (133-208) and 173 mg/dl (146-208) respectively. Clinical outcome was not affected by the treatment modality. In the subgroup of patients hospitalised with infection, the median fasting glucose was significantly lower in the interventional compared with the conventional regime: 141 and 172 mg/dl respectively (p = 0.041). However, tighter control was associated with a significantly higher incidence of adverse events within 6 months after discharge: 48.9% and 21.4% respectively (p = 0.047). CONCLUSION: In general medicine wards, modified prehospital hypoglycaemic regimens and a basal/bolus insulin regimen achieve similar glucose control. The clinical outcome was not affected by the modality of glucose control.

Therapeutic potency of IL2-caspase 3 targeted treatment in a murine experimental model of inflammatory bowel disease.

BACKGROUND: Inflammatory bowel disease (IBD) comprises primarily the two disorders - ulcerative colitis and Crohn's disease - that involve deregulated T cell responses. The ever-increasing incidence rate of Crohn's disease and ulcerative colitis during recent decades, combined with the limited efficacy and potential adverse effects of current treatments, explain the real need for seeking more specific and selective methods for treating these diseases. AIM: To investigate the ability of interleukin 2 (IL2)-caspase 3 chimeric protein, designed to target activated T lymphocytes that express the high-affinity IL2 receptor, to ameliorate the clinical symptoms of acute murine experimental colitis, using a mouse model of dextran sodium sulfate (DSS)-induced colitis. METHODS: Mice with DSS-induced colitis were treated with IL2-caspase 3 for 7 days and disease severity was assessed in parallel to control, non-treated mice, receiving only daily injections of phosphate-buffered saline. IL2-caspase 3 was tested both for its ability to prevent the development of colitis, and for its therapeutic potential to cure on-going, active acute disease. In addition, colon tissue samples were used for myeloperoxidase assays and RNA isolation followed by polymerase chain reaction to determine mRNA expression levels of specific genes. RESULTS: Treatment with IL2-caspase 3 dose-dependently ameliorated the disease activity index (DAI) of mice colitis. We achieved up to 78% improvement in DAI with intravenous injections of 15 microg/mouse/day. Furthermore, IL2-caspase 3 decreased neutrophil and macrophage infiltration to the inflamed tissue by up to 57%. IL2-caspase 3 was proven as a therapeutic reagent in another model, where treatment begins only after disease onset. Here we demonstrated a 70% decrease in DAI when compared to non-treated sick mice. A reduction in mRNA expression levels of both IL1 beta and tumour necrosis factor alpha was found in lysates of total colon tissue of treated mice, as compared to sick, untreated mice. We also found that expression levels of Bcl2 were significantly decreased after treatment, while Bax was upregulated in comparison to non-treated mice. Moreover, the Bcl2/Bax ratio, which is elevated in both experimental colitis and in human Crohn's disease, decreased dramatically after treatment. CONCLUSIONS: IL2-caspase 3 chimeric protein may provide a novel approach to the therapy of human IBD, and a possible suggested treatment for other pathological conditions that involve uncontrolled expansion of activated T cells.

Circadian rhythm for tryptophan pyrrolase activity and its circulating substrate.

Hepatic tryptophan pyrrolase and its circulating substrate, whole blood tryptophan, have a circadian rhythmicity in mice. Intact adrenocortical function is required for the normal rhythmicity of both enzyme and substrate although an altered but less apparent rhythm persists in the adrenalectomized state.

Evidence for aberrant regulation of MAP kinase signal transduction pathway in peripheral blood mononuclear cells in patients with active celiac disease.

BACKGROUND: Aberrant signaling via the p21/mitogen-activated proteins (MAP) kinase pathway has been described in lymphocytes of patients with various autoimmune diseases. There is little published data about the intracellular mediators and signals that regulate expression and activity of transcription factors and their effect on celiac disease induction and progression. AIM: To investigate the possible involvement of MAP kinase pathway in peripheral blood mononuclear cells (PBMC) in celiac disease and its correlation with disease activity. METHODS: Expression of the total and activated forms of two MAP kinases [extracellular response kinase (ERK) and c-Jun amino terminal kinase (JNK)] were studied by Western blots in PBMC of 17 untreated and 19 treated celiac patients, and 17 controls. Seven of these untreated celiac patients were studies before and after 6 months of gluten-free diet. RESULTS: Phosphorylated ERK of active celiac disease patients was significantly lower compared with controls (P < 0.01) and was increased towards normal after 6 month of gluten-free diet (P < 0.01). Phosphorylated JNK was increased significantly in the untreated celiac group (P < 0.01) and normalized towards the control level after 6 months of gluten-free diet (P < 0.04). CONCLUSIONS: Aberrant MAP-kinase pathway activity is associated with active celiac disease (CD). Further studies should examine the potential role of this aberration in pathogenesis of CD.

Correction: Isolation of five Enterobacteriaceae species harbouring blaNDM-1 and mcr-1 plasmids from a single paediatric patient.

[This corrects the article DOI: 10.1371/journal.pone.0221960.].

Isolation of five Enterobacteriaceae species harbouring blaNDM-1 and mcr-1 plasmids from a single paediatric patient.

In Argentina, NDM metallo-ß-lactamase was first reported in 2013. By now, it has disseminated throughout the country in diverse Gram negative bacteria. Here, we report the case of a paediatric patient that underwent a 1-year hospitalisation due to erythrodermic psoriasis in 2014 and received multiple antimicrobial treatments. During his stay, five isolates were obtained from rectal swabs (rs) or blood culture (bc) suspicious of carbapenemase production: a K. quasipneumoniae subsp. quasipneumoniae (rs), Citrobacter freundii (rs), Escherichia coli (bc), Enterobacter cloacae (rs), and a Serratia marcescens (bc). The isolates were studied with broth microdilution, biparental conjugation and plasmid and whole genome sequencing (Illumina). All isolates harboured an 138,998-bp type 1 IncC plasmid that carried blaNDM-1, bleMBL, blaCMY-6, rmtC, aac(6')-Ib, and sul1 resistance genes. Additionally, the blaNDM-plasmids contained ISKpn8 an insertion sequence previously described as associated only to blaKPC. One isolate, a colistin-resistant E. coli, also carried a mcr-1-containing an IncI2 plasmid, which did not harbour additional resistance. The whole genome of K. quasipneumoniae subsp. quasipneumoniae isolate was fully sequenced. This isolate harboured, additionally to blaNDM, three plasmid-mediated quinolone resistance genes: qnrB4, qnrB52 and aac(6')-Ib-cr1. The E. cloacae isolate also harboured qnrA1. These findings alert to the underestimated horizontal dissemination of multidrug-resistant plasmids limiting treatment options with last resort antimicrobials.

An open-label study of citalopram for major depression following traumatic brain injury.

Major depression is associated with substantial psychosocial dysfunction and post-concussive symptomatology following traumatic brain injury (TBI). Studies to date of anti-depressant treatment for major depression post-TBI have been limited by small sample size. The goal of the present study is to examine the rates of response and remission associated with citalopram treatment for major depression following traumatic brain injury. Subjects with major depression following mild-to moderate TBI were treated with open-label citalopram with a starting dose of 20 mg/day to a maximum of 50 mg/day for either 6 weeks (n = 54) or 10 weeks (n = 26). The Hamilton Depression Rating Scale (HAMD) was used to assess depression severity. Response was defined by a 50% reduction in HAMD score, and remission was defined by a HAMD score of < or =7. The mean HAMD at baseline and 6 weeks were 23.66 (SD 6.8) and 16.30 (SD 9.3), respectively (t[53] = 7.157, p < 0.0001). The mean HAMD at 10 weeks was 12.96 (SD 7.9) (t[25] = 7.323, p < 0.0001). At 6 weeks, 54 subjects were assessed and 27.7% responded with 24.1% in remission. At 10 weeks, 26 subjects were assessed and 46.2% responded with 26.9% in remission. The response rate in the present sample was substantially lower than previously reported for patients with TBI, but comparable to the results of the largest effectiveness trial of citalopram for general out-patients with major depression in the absence of TBI.

Circadian periodicity of tryptophan metabolism.

Rhythmicity of tryptophan metabolism via the kynurenine pathway has been demonstrated in man. Normal subjects given 3 g of tryptophan at 0900 hours excreted almost three times the quantity of kynurenine, kynurenic acid, and xanthurenic acid than did subjects given the same dose at 2100 hours. Other metabolites of the kynurenine pathway varied in the same fashion but with lesser magnitude. In contrast, indican, a tryptophan metabolite not in the kynurenine pathway, varied inversely with the other metabolites measured. The data suggest that the liver enzyme tryptophan pyrrolase has a circadian rhythm in man similar to that already described in mice in a previous study. Tryptophan tolerance tests in the future should be controlled relative to time of amino acid administration.

Desensitization of the insulin receptor by antireceptor antibodies in vivo is blocked by treatment of mice with beta-adrenergic agonists.

In previous studies we reported that immunization of mice with ungulate insulins induced the development of antiinsulin antibodies, which include an idiotype that appeared to recognize the part of the insulin molecule recognized by the hormone receptor. The antiinsulin antibodies of this idiotype were replaced spontaneously by antiidiotypic antibodies. The antiidiotypic antibodies, which persisted for about 14 d, mimicked insulin and functioned as antibodies to the insulin receptor. They induced down regulation, desensitization and refractoriness of the insulin receptor and disturbances in glucose homeostasis in vivo (Shechter, Y., D. Elias, R. Maron, and I.R. Cohen., 1984; Elias, D., R. Maron, I.R. Cohen, and Y. Shechter. 1984, J. Biol. Chem. 259: 6411-6419). We now report that effects of the antiidiotypic antibodies on the insulin receptor effector system can be modified pharmacologically. Administration of the beta-adrenergic agonist isoproterenol during the period of insulin resistance (days 26-40 after primary immunization), largely restored fat cell responsiveness to insulin, and eliminated the appearance of fasting hyperglycemia. This restoration appeared to be caused by inhibition of both insulin receptor desensitization and refractoriness. In contrast, down regulation of insulin receptors was not reversed by isoproterenol treatment in vivo. The effects of treatment with isoproterenol persisted for 2-4 d after termination of treatment. The beta-antagonist, propranolol and more so, the beta 1a-antagonist metoprolol, specifically blocked the effect of isoproterenol at a molar ratio of 3-10:1. Oral administration of the cAMP phosphodiesterase inhibitor, aminophylline, was also effective in inhibiting the development of desensitization in fat cells. These results indicate that treatment with beta 1-adrenergic agonists in vivo, or other agents that elevate cellular cAMP levels, can inhibit the development of the "postbinding" defects induced by insulin-mimicking, antireceptor antibodies. These observations have both basic and clinical implications.

Neonatal activation of CD28 signaling overcomes T cell anergy and prevents autoimmune diabetes by an IL-4-dependent mechanism.

Optimal T cell responsiveness requires signaling through the T cell receptor (TCR) and CD28 costimulatory receptors. Previously, we showed that T cells from autoimmune nonobese diabetic (NOD) mice display proliferative hyporesponsiveness to TCR stimulation, which may be causal to the development of insulin-dependent diabetes mellitus (IDDM). Here, we demonstrate that anti-CD28 mAb stimulation restores complete NOD T cell proliferative responsiveness by augmentation of IL-4 production. Whereas neonatal treatment of NOD mice with anti-CD28 beginning at 2 wk of age inhibits destructive insulitis and protects against IDDM by enhancement of IL-4 production by islet-infiltrating T cells, administration of anti-CD28 beginning at 5-6 wk of age does not prevent IDDM. Simultaneous anti-IL-4 treatment abrogates the preventative effect of anti-CD28 treatment. Thus, neonatal CD28 costimulation during 2-4 wk of age is required to prevent IDDM, and is mediated by the generation of a Th2 cell-enriched nondestructive environment in the pancreatic islets of treated NOD mice. Our data support the hypothesis that a CD28 signal is requisite for activation of IL-4-producing cells and protection from IDDM.

p21ras and protein kinase C function in distinct and interdependent signaling pathways in C3H 10T1/2 fibroblasts.

Both p21ras and protein kinase C (PKC) are believed to function downstream of plasma membrane-associated tyrosine kinases in cellular signal transduction pathways. However, it has remained controversial whether they function in the same pathway and, if so, what their relative position and functional relationship in such a pathway are. We investigated the possibilities that p21ras and PKC function either upstream or downstream of each other in a common linear pathway or that they function independently in colinear signal pathways. Either decreased expression of endogenous normal ras in fibroblasts transfected with an inducible antisense ras construct or overexpression of a mutant ras gene reduced the capacity of the phorbol ester tetradecanoyl phorbol acetate to trigger expression of the tetradecanoyl phorbol acetate-responsive and ras-dependent reporter gene osteopontin (OPN). PKC depletion decreased basal OPN mRNA levels, and the overexpression of ras restored OPN expression to the level of non-PKC-depleted cells. We propose a model in which ras and PKC function in distinct and interdependent signaling pathways.

Acute psychotic stress is associated with decreased adiponectin serum levels.

OBJECTIVE: To determine the effect of acute psychotic stress on adipokine secretion in non-diabetic subjects. RESEARCH DESIGN AND METHODS: Adiponectin, leptin, and cortisol serum levels were determined in 39 non-diabetic patients with acute psychotic stress reaction admitted to a psychiatric ward. The clinical global impression (CGI) score was used to evaluate the level of psychotic stress. Insulin sensitivity (IS) was determined by the homeostasis model assessment (HOMA). Patients were re-assessed 2 weeks after admission. During hospitalization patients were treated for variable times with either phenothiazines or thioxanthenes. RESULTS: The mean CGI score decreased significantly with time: 5.3+/-0.8 and 2.6+/-0.8 on admission and after 2 weeks respectively (p<0.001). On admission, the mean adiponectin level was significantly lower in patients compared to normal controls: 15.3+/-8.2 mug/ml and 26+/-12.8 mug/ml, respectively (p=0.02). It increased significantly after 2 weeks to 18.2+/-10 mug/ml (p=0.003). By contrast, the leptin and cortisol levels did not change significantly. No correlation was found between the changes in individual CGI scores and adiponectin levels. However, female patients with the highest stress on admission demonstrated the lowest adiponectin levels and insulin sensitivity: p=0.002 and 0.03 respectively. CONCLUSIONS: These data suggest a link between acute psychotic stress reaction and decreased serum adiponectin levels. Further studies are recommended to determine the strength of this association.

Novel class 1 Integrons and sequence types in VIM-2 and VIM-11-producing clinical strains of Enterobacter cloacae.

All VIM-producing Enterobacteriaceae (six Enterobacter cloacae) submitted to the Argentinian Reference Laboratory in Antimicrobial Resistance in the period 2008-13 were characterized. The isolates were referred from 6 nosocomial institutions located in 5 different cities across the country. All isolates showed carbapenem disk diffusion inhibition zones ≤22mm and synergism between a carbapenem disk and EDTA/SMA. The six isolates were PCR positive for blaVIM. Imipenem MICs were ≤1 to 8µg/ml. Typing by PFGE and MLST distinguished six pulsotypes and sequence types with blaVIM located on novel class 1 integron arrays: ECL-1: ST182, In883; ECL-2, ST90, In885; ECL-3, ST88, In346 with blaVIM-11; ECL-4, ST184, In900; ECL-5, ST749-new, In900; ECL-6, ST91 and uncharacterized In. Only ECL-2 was able to transfer blaVIM-2 to E. coli J53 by biparental conjugation. blaVIM was located in plasmids of 53-82Kb and in the chromosome (ECL-1 and ECL-5). The diversity of clones, class 1 integrons, plasmids and location of blaVIM, reveals the plasticity of the genetic elements described and highlights the importance of surveillance programs as tools to identify the transmission of these highly resistant metallo-ß-lactamase-producing Enterobacteriaceae.