Somatostatin in the rat periventricular nucleus: sex differences and effect of gonadal steroids

In the rat, the sexual dimorphism in growth hormone release is driven by sex steroids, and is suggested to result mainly from differences in somatostatin (SOM) release patterns from the median eminence. We studied the effect of gonadal steroids on SOM peptide-containing cells in the periventricular nucleus (PeVN) of ovariectomized (OVX) female rats, and compared these data with data from intact male rats. Adult female rats were treated with estradiol (E2) and/or progesterone (P), 3 months (long-term) or 2 weeks (short-term) after ovariectomy (OVX). Perfusion-fixed brains were sliced and stained, and the number of SOM-immunoreactive (-ir) cells and total SOM-ir area (in μm2) were determined using computer assisted analysis. SOM-ir cells in the PeVN showed a very characteristic rostro-caudal distribution and localization in relation to the third ventricle. Both the number of SOM-ir cells and total SOM-ir area in the PeVN were higher in male compared to OVX female rats. Neither the number of SOM-ir cells, nor the total SOM-ir area in the PeVN was affected by E2 or P treatment alone. Treatment with both gonadal steroids, however, did increase total SOM-immunoreactivity. This study is the first to describe SOM cell distribution within the rat PeVN in great detail. A clear sex difference exists in SOM peptide content in the rat PeVN. In addition, E2 and P may act synergistically to affect SOM cells in the female PeVN, suggesting that both gonadal steroids may be involved in the generation of the typical feminine SOM release pattern

Deposition Bias of Chromatin Proteins Inverts under DNA Replication Stress Conditions

Following DNA replication, equal amounts of chromatin proteins are distributed over sister chromatids by re-deposition of parental chromatin proteins and deposition of newly synthesized chromatin proteins. Molecular mechanisms balancing the allocation of new and old chromatin proteins remain largely unknown. Here, we studied the genome-wide distribution of new chromatin proteins relative to parental DNA template strands and replication initiation zones using the double-click-seq. Under control conditions, new chromatin proteins were preferentially found on DNA replicated by the lagging strand machinery. Strikingly, replication stress induced by hydroxyurea or curaxin treatment and inhibition of ataxia telangiectasia and Rad3-related protein (ATR) or p53 inactivation inverted the observed chromatin protein deposition bias to the strand replicated by the leading strand polymerase in line with previously reported effects on replication protein A occupancy. We propose that asymmetric deposition of replication protein occupancy. propose asymmetric deposition newly synthesized chromatin proteins onto sister chromatids reflects differences in the processivity of leading and lagging strand synthesis

The General Age of Leadership: Older-Looking Presidential Candidates Win Elections during War

As nation-state leaders age they increasingly engage in inter-state militarized disputes yet in industrialized societies a steady decrease in testosterone associated with aging is observed – which suggests a decrease in dominance behavior. The current paper points out that from modern societies to Old World monkeys increasing both in age and social status encourages dominant strategies to maintain acquired rank. Moreover, it is argued this consistency has shaped an implicit prototype causing followers to associate older age with dominance leadership. It is shown that (i) faces of older leaders are preferred during intergroup conflict and (ii) morphing U.S. Presidential candidates to appear older or younger has an overriding effect on actual election outcomes. This indicates that democratic voting can be systematically adjusted by activating innate biases. These findings appear to create a new line of research regarding the biology of leadership and contextual cues of age

Influence of routine computed tomography on predicted survival from blunt thoracoabdominal trauma

Item does not contain fulltextINTRODUCTION: Many scoring systems have been proposed to predict the survival of trauma patients. This study was performed to evaluate the influence of routine thoracoabdominal computed tomography (CT) on the predicted survival according to the trauma injury severity score (TRISS). PATIENTS AND METHODS: 1,047 patients who had sustained a high-energy blunt trauma over a 3-year period were prospectively included in the study. All patients underwent physical examination, conventional radiography of the chest, thoracolumbar spine and pelvis, abdominal sonography, and routine thoracoabdominal CT. From this group with routine CT, we prospectively defined a selective CT (sub)group for cases with abnormal physical examination and/or conventional radiography and/or sonography. Type and extent of injuries were recorded for both the selective and the routine CT groups. Based on the injuries found by the two different CT algorithms, we calculated the injury severity scores (ISS) and predicted survivals according to the TRISS methodology for the routine and the selective CT algorithms. RESULTS: Based on injuries detected by the selective CT algorithm, the mean ISS was 14.6, resulting in a predicted mortality of 12.5%. Because additional injuries were found by the routine CT algorithm, the mean ISS increased to 16.9, resulting in a predicted mortality of 13.7%. The actual observed mortality was 5.4%. CONCLUSION: Routine thoracoabdominal CT in high-energy blunt trauma patients reveals more injuries than a selective CT algorithm, resulting in a higher ISS. According to the TRISS, this results in higher predicted mortalities. Observed mortality, however, was significantly lower than predicted. The predicted survival according to MTOS seems to underestimate the actual survival when routine CT is used

Dual mTORC1/2 inhibition sensitizes testicular cancer models to cisplatin treatment

Testicular cancer is the most common cancer type among young men. Despite highly effective cisplatin-based chemotherapy, around 20% of patients with metastatic disease will still die from the disease. The aim of this study was to explore the use of kinase inhibitors to sensitize testicular cancer cells to cisplatin treatment. Activation of kinases, including receptor tyrosine kinases and downstream substrates, was studied in five cisplatin-sensitive or -resistant testicular cancer cell lines using phospho-kinase arrays and Western blotting. The phospho-kinase array showed AKT and S6 to be among the top phosphorylated proteins in testicular cancer cells, which are part of the PI3K/AKT/mTORC pathway. Inhibitors of most active kinases in the PI3K/AKT/mTORC pathway were tested using apoptosis assays and survival assays. Two mTORC1/2 inhibitors, AZD8055 and MLN0128, strongly enhanced cisplatin-induced apoptosis in all tested testicular cancer cell lines. Inhibition of mTORC1/2 blocked phosphorylation of the mTORC downstream proteins S6 and 4E-BP1. Combined treatment with AZD8055 and cisplatin led to reduced clonogenic survival of testicular cancer cells. Two testicular cancer patient-derived xenografts (PDX), either from a chemosensitive or -resistant patient, were treated with cisplatin in the absence or presence of kinase inhibitor. Combined AZD8055 and cisplatin treatment resulted in effective mTORC1/2 inhibition, increased caspase-3 activity, and enhanced tumor growth inhibition. In conclusion, we identified mTORC1/2 inhibition as an effective strategy to sensitize testicular cancer cell lines and PDX models to cisplatin treatment. Our results warrant further investigation of this combination therapy in the treatment of patients with testicular cancer with high-risk relapsed or refractory disease

Testing relationships: ethical arguments for screening with HbA1C

Since the 1990s, glycated haemoglobin (HbA1C) has been the gold standard for monitoring glycaemic control in people diagnosed as having either type 1 diabetes mellitus (T1DM) or type 2 diabetes mellitus (T2DM). Discussions are underway about diagnosing diabetes mellitus on the basis of HbA1C titres and using HbA1C tests to screen for T2DM. These discussions have focused on the relative benefits for individual patients, with some attention directed towards reduced costs to healthcare systems and benefits to society. We argue that there are strong ethical reasons for adopting HbA1C-based diagnosis and T2DM screening that have not yet been articulated. The rationale includes the differential impact of HbA1C-based diabetic testing on disadvantaged groups, and what we are beginning to learn about HbA1C vis-à-vis population health. Although it is arguable that screening must primarily benefit the individual, using HbA1C to diagnose and screen for T2DM may promote a more just distribution of health resources and lead to advances in investigating, monitoring and tackling the social determinants of health

Identification of novel genetic risk factors of dilated cardiomyopathy: from canine to human

BACKGROUND: Dilated cardiomyopathy (DCM) is a life-threatening heart disease and a common cause of heart failure due to systolic dysfunction and subsequent left or biventricular dilatation. A significant number of cases have a genetic etiology; however, as a complex disease, the exact genetic risk factors are largely unknown, and many patients remain without a molecular diagnosis. METHODS: We performed GWAS followed by whole-genome, transcriptome, and immunohistochemical analyses in a spontaneously occurring canine model of DCM. Canine gene discovery was followed up in three human DCM cohorts. RESULTS: Our results revealed two independent additive loci associated with the typical DCM phenotype comprising left ventricular systolic dysfunction and dilatation. We highlight two novel candidate genes, RNF207 and PRKAA2, known for their involvement in cardiac action potentials, energy homeostasis, and morphology. We further illustrate the distinct genetic etiologies underlying the typical DCM phenotype and ventricular premature contractions. Finally, we followed up on the canine discoveries in human DCM patients and discovered candidate variants in our two novel genes. CONCLUSIONS: Collectively, our study yields insight into the molecular pathophysiology of DCM and provides a large animal model for preclinical studies

A 57-year-old man who developed arthritis during R-CHOP chemotherapy for non-Hodgkin lymphoma

Rituximab is a chimeric human-mouse anti-CD20 monoclonal antibody, which is used in the treatment of both B-cell lymphomas and rheumatic diseases. We describe a case of a previously healthy 57-year-old man developing arthritis while being treated with rituximab-CHOP chemotherapy (R-CHOP) for a non-Hodgkin lymphoma. The remittant arthritis developed at successively shorter time-intervals after R-CHOP administration and only improved after rituximab was removed from the chemotherapy schedule, suggesting a rituximab-related phenomenon, as extensive diagnostic testing ruled out any other diagnosis