Clonidine augmentation in patients with schizophrenia:A double-blind, randomized placebo-controlled trial

Introduction: Noradrenergic imbalance in the brain of schizophrenia patients may underlie both symptomatology and deficits in basic information processing. The current study investigated whether augmentation with the noradrenergic α2-agonist clonidine might alleviate these symptoms. Methods: In a double-blind placebo-controlled randomized clinical trial, 32 chronic schizophrenia patients were randomly assigned to six-weeks augmentation with either 50 μg clonidine or placebo to their current medication. Effects on symptom severity and both sensory- and sensorimotor gating were assessed at baseline, 3- and 6-weeks. Results were compared with 21 age- and sex-matched healthy controls (HC) who received no treatment. Results: Only patients treated with clonidine showed significantly reduced PANSS negative, general and total scores at follow-up compared to baseline. On average, also patients treated with placebo showed minor (non-significant) reductions in these scores, likely indicating a placebo effect. Sensorimotor gating of patients was significantly lower at baseline compared to controls. It increased in patients treated with clonidine over the treatment period, whereas it decreased in both the HC and patients treated with placebo. However, neither treatment nor group effects were found in sensory gating. Clonidine treatment was very well tolerated. Conclusion: Only patients treated with clonidine showed a significant decrease on two out of the three PANSS subscales, while additionally retained their levels of sensorimotor gating. Given that there are only a few reports on effective treatment for negative symptoms in particular, our current results support augmentation of antipsychotics with clonidine as a promising, low-cost and safe treatment strategy for schizophrenia

Clonidine augmentation in patients with schizophrenia: A double-blind, randomized placebo-controlled trial

Introduction: Noradrenergic imbalance in the brain of schizophrenia patients may underlie both symptomatology and deficits in basic information processing. The current study investigated whether augmentation with the noradrenergic α2-agonist clonidine might alleviate these symptoms. Methods: In a double-blind placebo-controlled randomized clinical trial, 32 chronic schizophrenia patients were randomly assigned to six-weeks augmentation with either 50 μg clonidine or placebo to their current medication. Effects on symptom severity and both sensory- and sensorimotor gating were assessed at baseline, 3- and 6-weeks. Results were compared with 21 age- and sex-matched healthy controls (HC) who received no treatment. Results: Only patients treated with clonidine showed significantly reduced PANSS negative, general and total scores at follow-up compared to baseline. On average, also patients treated with placebo showed minor (non-significant) reductions in these scores, likely indicating a placebo effect. Sensorimotor gating of patients was significantly lower at baseline compared to controls. It increased in patients treated with clonidine over the treatment period, whereas it decreased in both the HC and patients treated with placebo. However, neither treatment nor group effects were found in sensory gating. Clonidine treatment was very well tolerated. Conclusion: Only patients treated with clonidine showed a significant decrease on two out of the three PANSS subscales, while additionally retained their levels of sensorimotor gating. Given that there are only a few reports on effective treatment for negative symptoms in particular, our current results support augmentation of antipsychotics with clonidine as a promising, low-cost and safe treatment strategy for schizophrenia

The type II secretion system (Xcp) of Pseudomonas putida is active and involved in the secretion of phosphatases.

The genome of the Gram-negative bacterium Pseudomonas putida harbours a complete set of xcp genes for a type II protein secretion system (T2SS). This study shows that expression of these genes is induced under inorganic phosphate (Pi ) limitation and that the system enables the utilization of various organic phosphate sources. A phosphatase of the PhoX family, previously designated UxpB, was identified, which was produced under low Pi conditions and transported across the cell envelope in an Xcp-dependent manner demonstrating that the xcp genes encode an active T2SS. The signal sequence of UxpB contains a twin-arginine translocation (Tat) motif as well as a lipobox, and both processing by leader peptidase II and Tat dependency were experimentally confirmed. Two different tat gene clusters were detected in the P.?putida genome, of which one, named tat-1, is located adjacent to the uxpB and xcp genes. Both Tat systems appeared to be capable of transporting the UxpB protein. However, expression of the tat-1 genes was strongly induced by low Pi levels, indicating a function of this system in survival during Pi starvation

Glycerophosphodiesterase GDE2 Promotes Neuroblastoma Differentiation through Glypican Release and Is a Marker of Clinical Outcome

Neuroblastoma is a pediatric embryonal malignancy characterized by impaired neuronal differentiation. A better understanding of neuroblastoma differentiation is essential for developing new therapeutic approaches. GDE2 (encoded by GDPD5) is a six-transmembrane-domain glycerophosphodiesterase that promotes embryonic neurogenesis. We find that high GDPD5 expression is strongly associated with favorable outcome in neuroblastoma. GDE2 induces differentiation of neuroblastoma cells, suppresses cell motility, and opposes RhoA-driven neurite retraction. GDE2 alters the Rac-RhoA activity balance and the expression of multiple differentiation-associated genes. Mechanistically, GDE2 acts by cleaving (in cis) and releasing glycosylphosphatidylinositol-anchored glypican-6, a putative co-receptor. A single point mutation in the ectodomain abolishes GDE2 function. Our results reveal GDE2 as a cell-autonomous inducer of neuroblastoma differentiation with prognostic significance and potential therapeutic value.</p

Comprehensive evaluation of methods to assess overall and cell-specific immune infiltrates in breast cancer

Background: Breast cancer (BC) immune infiltrates play a critical role in tumor progression and response to treatment. Besides stromal tumor infiltrating lymphocytes (sTILs) which have recently reached level 1B evidence as a prognostic marker in triple negative BC, a plethora of methods to assess immune infiltration exists, and it is unclear how these compare to each other and if they can be used interchangeably. Methods: Two experienced pathologists scored sTIL, intra-tumoral TIL (itTIL), and 6 immune cell types (CD3+, CD4+, CD8+, CD20+, CD68+, FOXP3+) in the International Cancer Genomics Consortium breast cancer cohort using hematoxylin and eosin-stained (n = 243) and immunohistochemistry-stained tissue microarrays (n = 254) and whole slides (n = 82). The same traits were evaluated using transcriptomic- and methylomic-based deconvolution methods or signatures. Results: The concordance correlation coefficient (CCC) between pathologists for sTIL was very good (0.84) and for cell-specific immune infiltrates slightly lower (0.63-0.66). Comparison between tissue microarray and whole slide pathology scores revealed systematically higher values in whole slides (ratio 2.60-5.98). The Spearman correlations between microscopic sTIL and transcriptomic- or methylomic-based assessment of immune infilt

Association of beta-blockers and first-registered heart rhythm in out-of-hospital cardiac arrest: real-world data from population-based cohorts across two European countries

AIMS: Conflicting results have been reported regarding the effect of beta-blockers on first-registered heart rhythm in out-of-hospital cardiac arrest (OHCA). We aimed to establish whether the use of beta-blockers influences first-registered rhythm in OHCA. METHODS AND RESULTS: We included patients with OHCA of presumed cardiac cause from two large independent OHCA-registries from Denmark and the Netherlands. Beta-blocker use was defined as exposure to either non-selective beta-blockers, β1-selective beta-blockers, or α-β-dual-receptor blockers within 90 days prior to OHCA. We calculated odds ratios (ORs) for the association of beta-blockers with first-registered heart rhythm using multivariable logistic regression. We identified 23 834 OHCA-patients in Denmark and 1584 in the Netherlands: 7022 (29.5%) and 519 (32.8%) were treated with beta-blockers, respectively. Use of non-selective beta-blockers, but not β1-selective blockers, was more often associated with non-shockable rhythm than no use of beta-blockers [Denmark: OR 1.93, 95% confidence interval (CI) 1.48-2.52; the Netherlands: OR 2.52, 95% CI 1.15-5.49]. Non-selective beta-blocker use was associated with higher proportion of pulseless electrical activity (PEA) than of shockable rhythm (OR 2.38, 95% CI 1.01-5.65); the association with asystole was of similar magnitude, although not statistically significant compared with shockable rhythm (OR 2.34, 95% CI 0.89-6.18; data on PEA and asystole were only available in the Netherlands). Use of α-β-dual-receptor blockers was significantly associated with non-shockable rhythm in Denmark (OR 1.21; 95% CI 1.03-1.42) and not significantly in the Netherlands (OR 1.37; 95% CI 0.61-3.07). CONCLUSION: Non-selective beta-blockers, but not β1-selective beta-blockers, are associated with non-shockable rhythm in OHCA

An RNA toolbox for single-molecule force spectroscopy studies

Precise, controllable single-molecule force spectroscopy studies of RNA and RNA-dependent processes have recently shed new light on the dynamics and pathways of RNA folding and RNA-enzyme interactions. A crucial component of this research is the design and assembly of an appropriate RNA construct. Such a construct is typically subject to several criteria. First, single-molecule force spectroscopy techniques often require an RNA construct that is longer than the RNA molecules used for bulk biochemical studies. Next, the incorporation of modified nucleotides into the RNA construct is required for its surface immobilization. In addition, RNA constructs for single-molecule studies are commonly assembled from different single-stranded RNA molecules, demanding good control of hybridization or ligation. Finally, precautions to prevent RNase- and divalent cation-dependent RNA digestion must be taken. The rather limited selection of molecular biology tools adapted to the manipulation of RNA molecules, as well as the sensitivity of RNA to degradation, make RNA construct preparation a challenging task. We briefly illustrate the types of single-molecule force spectroscopy experiments that can be performed on RNA, and then present an overview of the toolkit of molecular biology techniques at one's disposal for the assembly of such RNA constructs. Within this context, we evaluate the molecular biology protocols in terms of their effectiveness in producing long and stable RNA constructs

Sex differences in body composition in people with prediabetes and type 2 diabetes as compared with people with normal glucose metabolism: the Maastricht Study

Aims/hypothesis: Obesity is a major risk factor for type 2 diabetes. However, body composition differs between women and men. In this study we investigate the association between diabetes status and body composition and whether this association is moderated by sex. Methods: In a population-based cohort study (n=7639; age 40–75 years, 50% women, 25% type 2 diabetes), we estimated the sex-specific associations, and differences therein, of prediabetes (i.e. impaired fasting glucose and/or impaired glucose tolerance) and type 2 diabetes (reference: normal glucose metabolism [NGM]) with dual-energy x-ray absorptiometry (DEXA)- and MRI-derived measures of body composition and with hip circumference. Sex differences were analysed using adjusted regression models with interaction terms of sex-by-diabetes status. Results: Compared with their NGM counterparts, both women and men with prediabetes and type 2 diabetes had more fat and lean mass and a greater hip circumference. The differences in subcutaneous adipose tissue, hip circumference and total and peripheral lean mass between type 2 diabetes and NGM were greater in women than men (women minus men [W–M] mean difference [95% CI]: 15.0 cm2 [1.5, 28.5], 3.2 cm [2.2, 4.1], 690 g [8, 1372] and 443 g [142, 744], respectively). The difference in visceral adipose tissue between type 2 diabetes and NGM was greater in men than women (W–M mean difference [95% CI]: −14.8 cm2 [−26.4, −3.1]). There was no sex difference in the percentage of liver fat between type 2 diabetes and NGM. The differences in measures of body composition between prediabetes and NGM were generally in the same direction, but were not significantly different between women and men. Conclusions/interpretation: This study indicates that there are sex differences in body composition associated with type 2 diabetes. The pathophysiological significance of these sex-associated differences requires further study. Graphical abstract: [Figure not available: see fulltext.]

Particulate matter exposure during pregnancy is associated with birth weight, but not gestational age, 1962-1992: a cohort study

<p>Abstract</p> <p>Background</p> <p>Exposure to air pollutants is suggested to adversely affect fetal growth, but the evidence remains inconsistent in relation to specific outcomes and exposure windows.</p> <p>Methods</p> <p>Using birth records from the two major maternity hospitals in Newcastle upon Tyne in northern England between 1961 and 1992, we constructed a database of all births to mothers resident within the city. Weekly black smoke exposure levels from routine data recorded at 20 air pollution monitoring stations were obtained and individual exposures were estimated via a two-stage modeling strategy, incorporating temporally and spatially varying covariates. Regression analyses, including 88,679 births, assessed potential associations between exposure to black smoke and birth weight, gestational age and birth weight standardized for gestational age and sex.</p> <p>Results</p> <p>Significant associations were seen between black smoke and both standardized and unstandardized birth weight, but not for gestational age when adjusted for potential confounders. Not all associations were linear. For an increase in whole pregnancy black smoke exposure, from the 1^st(7.4 μg/m³) to the 25^th(17.2 μg/m³), 50^th(33.8 μg/m³), 75^th(108.3 μg/m³), and 90^th(180.8 μg/m³) percentiles, the adjusted estimated decreases in birth weight were 33 g (SE 1.05), 62 g (1.63), 98 g (2.26) and 109 g (2.44) respectively. A significant interaction was observed between socio-economic deprivation and black smoke on both standardized and unstandardized birth weight with increasing effects of black smoke in reducing birth weight seen with increasing socio-economic disadvantage.</p> <p>Conclusions</p> <p>The findings of this study progress the hypothesis that the association between black smoke and birth weight may be mediated through intrauterine growth restriction. The associations between black smoke and birth weight were of the same order of magnitude as those reported for passive smoking. These findings add to the growing evidence of the harmful effects of air pollution on birth outcomes.</p