Engagement of the inhibitory receptor CD158a interrupts TCR signaling,preventing dynamic membrane reorganization in CTL/tumor cell interaction

Renal cell carcinoma (RCC) infiltrating lymphocytes (TILs) express killer cell immunoglobulinlike receptors (KIRs) that inhibit the antitumor CD8(+) T-cell lysis. In the present study, to better examine the functional consequences of KIR engagement on cytotoxic T lymphocyte (CTL)/tumor interaction, we have investigated the influence of KIR CD158a on early steps of T-cell activation. We show that coengagement of T-cell receptor (TCR) and CD158a by tumor cells inhibited tyrosine phosphorylation of early signaling proteins ZAP-70 and LAT, lipid raft coalescence, and TCR/CD3 accumulation at the CTL/tumor cell interface. In addition, the guanine exchange factor Vav was not phosphorylated, and no actin cytoskeleton rearrangement was observed. Our data indicate a role of KIR CD158a in the dynamic events induced by TCR triggering, preventing CTL membrane reorganization, and subsequent completion of CTL activation program. Accordingly, the expression of CD158 by TILs may favor tumor cell escape to the immune response.     

Diurnal Fluctuations in HPA and Neuropeptide Y-ergic Systems Underlie Differences in Vulnerability to Traumatic Stress Responses at Different Zeitgeber Times

The hypothalamic–pituitary–adrenal (HPA) axis displays a characteristic circadian pattern of corticosterone release, with higher levels at the onset of the active phase and lower levels at the onset of the inactive phase. As corticosterone levels modify the response to stress and influence the susceptibility to and/or severity of stress-related sequelae, we examined the effects of an acute psychological trauma applied at different zeitgeber times (ZTs) on behavioral stress responses. Rats were exposed to stress either at the onset of the inactive-(light) phase (ZT=0) or at the onset of the active-(dark) phase (ZT=12). Their behavior in the elevated plus-maze and acoustic startle response paradigms were assessed 7 days post exposure for retrospective classification into behavioral response groups. Serum corticosterone levels and the dexamethasone suppression test were used to assess the stress response and feedback inhibition of the HPA axis. Immunoreactivity for neuropeptide Y (NPY) and NPY-Y1 receptor (Y1R) in the paraventricular (PVN) and arcuate (ARC) hypothalamic nuclei, hippocampus, and basolateral amygdala were measured. The behavioral effects of NPY/Y1R antagonist microinfused into the PVN 30 min before stress exposure during the inactive or active phase, respectively, were evaluated. PVN immunoreactivity for NPY and Y1R was measured 1 day after the behavioral tests. The time of day of the traumatic exposure markedly affected the pattern of the behavioral stress response and the prevalence of rats showing an extreme behavioral response. Rats exposed to the stressor at the onset of their inactive phase displayed a more traumatic behavioral response, faster post-exposure corticosterone decay, and a more pronounced stress-induced decline in NPY and Y1R expression in the PVN and arcuate hypothalamic nuclei. Blocking PVN Y1R before stress applied in the active phase, or administering NPY to the PVN before stress applied in the inactive phase, had a resounding behavioral effect. The time at which stress occurred significantly affected the behavioral stress response. Diurnal variations in HPA and NPY/Y1R significantly affect the behavioral response, conferring more resilience at the onset of the active phase and more vulnerability at the onset of the inactive phase, implying that NPY has a significant role in conferring resilience to stress-related psychopathology.     

Diabetes mellitus: subclinical cardiovascular disease and risk of incident cardiovascular disease and all-cause mortality

Previously diagnosed diabetes mellitus, newly diagnosed diabetes mellitus, and impaired glucose tolerance are important determinants of the risk of clinical cardiovascular disease (CVD). We have evaluated the relation of patients with subclinical CVD, diabetes, and impaired glucose tolerance and "normal" subjects and the risk of clinical CVD in the Cardiovascular Health Study. Diabetes (1343), impaired glucose tolerance (1433), and normal (2421) were defined by World Health Organization criteria at baseline in 1989 to 1990. The average follow-up was 6.4 years (mean age 73 years). Diabetics had a higher prevalence of clinical and subclinical CVD at baseline. Compared with diabetes in the absence of subclinical disease, the presence of subclinical CVD and diabetes was associated with significant increased adjusted relative risk of death (1.5, CI 0.93 to 2.41), relative risk of incident coronary heart disease (1.99, CI 1.25 to 3.19), and incident myocardial infarction (1.93, CI 0.96 to 3.91). The risk of clinical events was greater for participants with a history of diabetes compared with newly diagnosed diabetics at baseline. Compared with nondiabetic nonhypertensive subjects without subclinical disease, patients with a combination of diabetes, hypertension, and subclinical disease had a 12-fold increased risk of stroke. Fasting blood glucose levels were a weak predictor of incident coronary heart disease as were most other risk factors. Subclinical CVD was the primary determinant of clinical CVD among diabetics in the Cardiovascular Health Study.     

Variation in the HTR1A and HTR2A genes and social adjustment in depressed patients

Background

Social adjustment is impaired in depressed patients. The difficulty to adjust to social circumstances has been hypothesized to be one of the causes of depression, as well as a consequence of the disorder. Genetic variation in the serotonin transporter gene has been previously associated with social adjustment levels in patients with mood disorders.

Methods

We investigated whether variations on the HTR1A (rs6295) and HTR2A (rs7997012) genes were associated with levels of social adjustment using the Social Adjustment Scale in two samples of depressed patients (total n=156).

Results

Patients carrying the GG genotype of the HTR2A-rs7997012 showed better social adjustment in areas of work and family unit bonding.

Limitations

These findings did not survive correction for multiple testing and should be interpreted with caution.

Conclusion

Our finding is in line with previous observations that have associated the G allele of the HTR2A-rs7997012 with higher rate of antidepressant response. The HTR2A-rs7997012 is worthy of further investigation in studies examining factors that are related to depression course and outcome.     

Assessing the predictive ability of the Suicide Crisis Inventory for near‐term suicidal behavior using machine learning approaches

ObjectiveThis study explores the prediction of near‐term suicidal behavior using machine learning (ML) analyses of the Suicide Crisis Inventory (SCI), which measures the Suicide Crisis Syndrome, a presuicidal mental state.MethodsSCI data were collected from high‐risk psychiatric inpatients (N = 591) grouped based on their short‐term suicidal behavior, that is, those who attempted suicide between intake and 1‐month follow‐up dates (N = 20) and those who did not (N = 571). Data were analyzed using three predictive algorithms (logistic regression, random forest, and gradient boosting) and three sampling approaches (split sample, Synthetic minority oversampling technique, and enhanced bootstrap).ResultsThe enhanced bootstrap approach considerably outperformed the other sampling approaches, with random forest (98.0% precision; 33.9% recall; 71.0% Area under the precision‐recall curve [AUPRC]; and 87.8% Area under the receiver operating characteristic [AUROC]) and gradient boosting (94.0% precision; 48.9% recall; 70.5% AUPRC; and 89.4% AUROC) algorithms performing best in predicting positive cases of near‐term suicidal behavior using this dataset.ConclusionsML can be useful in analyzing data from psychometric scales, such as the SCI, and for predicting near‐term suicidal behavior. However, in cases such as the current analysis where the data are highly imbalanced, the optimal method of measuring performance must be carefully considered and selected.     

Maternal psychological growth following childbirth

Although maternal postpartum mental health has been extensively studied, rather little is known regarding the factors that may facilitate psychological growth following childbirth. The present study set forth to examine various pre-birth, birth, and post-birth correlates of overall psychological growth and growth domains in postpartum women, assessed within the first months following childbirth. A sample of 428 women completed self-report measures pertaining to psychological growth, mental health, maternal attachment, and childbirth characteristics. We found that the majority of women reported psychological growth following childbirth, with those experiencing stressors in childbirth reporting the highest levels of appreciation for life. In regression analyses, postpartum factors were significantly associated with overall growth and growth domains, taking into account other factors. The more the childbirth was perceived as central to the mothers’ identity and the better the maternal attachment was to the child, the higher levels of growth. Growth was also negatively related to endorsement of childbirth PTSD. Background factors, such as maternal age, education, and prior mental health, were associated with specific growth domains, although the association was small and there was no association with overall growth. Post-birth factors are important in ensuing psychological growth in the first months following birth. Attention to opportunities of growth following childbirth is warranted in clinical care, in particular following traumatic childbirth.

     

Higher gastric mucin secretion and lower gastric acid output in first-degree relatives of gastric cancer patients

BACKGROUND: Patients infected by Helicobacter pylori who have first-degree relatives with gastric cancer have an 8-fold increased risk of developing gastric cancer themselves. Mucins are high-molecular-weight glycoproteins that play a cardinal role in the protective mechanism of the gastric epithelium. AIM: To study gastric acid and mucin secretion in dyspeptic patients with and without a family history of gastric cancer and H. pylori infection. MATERIALS AND METHODS: Twenty-six dyspeptic patients underwent esophago-gastro-duodenoscopy, gastric biopsies, and acid and mucin secretory tests. The sample was divided by family history of gastric cancer and H. pylori status. RESULTS: Patients who were infected by H. pylori had a significantly higher degree of inflammation than those who were not. H. pylori-positive patients with a positive family history had a lower basal and maximal gastric acid output than infected patients with no family history and noninfected controls, and a higher basal and maximal mucin output than infected patients with no family history. MUC5AC was the major mucin species expressed in gastric juice. CONCLUSIONS: In patients with relatives with gastric cancer, H. pylori infection is associated with a more severe inflammatory reaction consisting of decreased gastric acid secretion and increased mucin secretion.