Melatonin protects against alterations in hippocampal cholinergic system, trace metals and oxidative stress induced by gestational and lactational exposure to cadmium

Dietary exposure to cadmium, even at lower doses, can lead to free radical induced neurotoxicity, neurobehavioral changes and alteration in neurotransmitters. Such changes are likely to be more pronounced in the developing brain due to incompleteness of blood brain barrier (BBB). Hippocampus being the seat of intelligence has a role in learning and cognitive behavior and any damage to hippocampus during developmental stage is likely to result in neurodegenerative changes in later life. To this end, fetal and neonatal exposure to cadmium was induced by exposing pregnant dams of Swiss albino strain throughout the period of gestation and following parturition up till 5th day post partum (pp) through drinking water (3ppm/animal/day). The neonates were sacrificed on day 6 pp and indices of oxidative stress, levels of trace elements and changes in cholinergic system were evaluated in the hippocampus. Increased lipid peroxidation, surge in reactive oxygen species (ROS), depressed antioxidant defense, increased accumulation of cadmium, differential alterations in trace elements and decreased activity of AChE were the features of cadmium toxicity. Simultaneous administration of melatonin to cadmium challenged animals offset these detrimental changes. The results suggest that melatonin co-administration can effectively protect against the adverse effects of cadmium on endogenous antioxidant status, changes in trace metal concentrations and compromised hippocampal cholinergic system

DOCK8 Functions as an Adaptor that Links TLR–MyD88 Signaling to B Cell Activation

DOCK8 and MyD88 have been implicated in serologic memory. Here we report antibody responses were impaired and $CD27^+$ memory B cells were severely reduced in DOCK8-deficient patients. Toll-like receptor 9 (TLR9)- but not CD40-driven B cell proliferation and immunoglobulin production were severely reduced in DOCK8-deficient B cells. In contrast, TLR9-driven expression of AICDA, CD23 and CD86, and activation of NF-κB, p38 and Rac1 were intact. DOCK8 associated constitutively with MyD88 and the tyrosine kinase Pyk2 in normal B cells. Following TLR9 ligation, DOCK8 became tyrosine phosphorylated by Pyk2, bound the Src family kinase Lyn and linked TLR9 to a Src-Syk-STAT3 cascade essential for TLR9-driven B cell proliferation and differentiation. Thus, DOCK8 functions as an adaptor in a TLR9-MyD88 signaling pathway in B cells

Factors contributing to delayed diagnosis of cancer among Aboriginal people in Australia: a qualitative study.

BACKGROUND/OBJECTIVES: Delayed presentation of symptomatic cancer is associated with poorer survival. Aboriginal patients with cancer have higher rates of distant metastases at diagnosis compared with non-Aboriginal Australians. This paper examined factors contributing to delayed diagnosis of cancer among Aboriginal Australians from patient and service providers' perspectives. METHODS: In-depth, open-ended interviews were conducted in two stages (2006-2007 and 2011). Inductive thematic analysis was assisted by use of NVivo looking around delays in presentation, diagnosis and referral for cancer. PARTICIPANTS: Aboriginal patients with cancer/family members (n=30) and health service providers (n=62) were recruited from metropolitan Perth and six rural/remote regions of Western Australia. RESULTS: Three broad themes of factors were identified: (1) Contextual factors such as intergenerational impact of colonisation and racism and socioeconomic deprivation have negatively impacted on Aboriginal Australians' trust of the healthcare professionals; (2) health service-related factors included low accessibility to health services, long waiting periods, inadequate numbers of Aboriginal professionals and high staff turnover; (3) patient appraisal of symptoms and decision-making, fear of cancer and denial of symptoms were key reasons patients procrastinated in seeking help. Elements of shame, embarrassment, shyness of seeing the doctor, psychological 'fear of the whole health system', attachment to the land and 'fear of leaving home' for cancer treatment in metropolitan cities were other deterrents for Aboriginal people. Manifestation of masculinity and the belief that 'health is women's domain' emerged as a reason why Aboriginal men were reluctant to receive health checks. CONCLUSIONS: Solutions to improved Aboriginal cancer outcomes include focusing on the primary care sector encouraging general practitioners to be proactive to suspicion of symptoms with appropriate investigations to facilitate earlier diagnosis and the need to improve Aboriginal health literacy regarding cancer. Access to health services remains a critical problem affecting timely diagnosis

NUDT2 Disruption Elevates Diadenosine Tetraphosphate (Ap4A) and Down-Regulates Immune Response and Cancer Promotion Genes.

Regulation of gene expression is one of several roles proposed for the stress-induced nucleotide diadenosine tetraphosphate (Ap4A). We have examined this directly by a comparative RNA-Seq analysis of KBM-7 chronic myelogenous leukemia cells and KBM-7 cells in which the NUDT2 Ap4A hydrolase gene had been disrupted (NuKO cells), causing a 175-fold increase in intracellular Ap4A. 6,288 differentially expressed genes were identified with P < 0.05. Of these, 980 were up-regulated and 705 down-regulated in NuKO cells with a fold-change ≥ 2. Ingenuity® Pathway Analysis (IPA®) was used to assign these genes to known canonical pathways and functional networks. Pathways associated with interferon responses, pattern recognition receptors and inflammation scored highly in the down-regulated set of genes while functions associated with MHC class II antigens were prominent among the up-regulated genes, which otherwise showed little organization into major functional gene sets. Tryptophan catabolism was also strongly down-regulated as were numerous genes known to be involved in tumor promotion in other systems, with roles in the epithelial-mesenchymal transition, proliferation, invasion and metastasis. Conversely, some pro-apoptotic genes were up-regulated. Major upstream factors predicted by IPA® for gene down-regulation included NFκB, STAT1/2, IRF3/4 and SP1 but no major factors controlling gene up-regulation were identified. Potential mechanisms for gene regulation mediated by Ap4A and/or NUDT2 disruption include binding of Ap4A to the HINT1 co-repressor, autocrine activation of purinoceptors by Ap4A, chromatin remodeling, effects of NUDT2 loss on transcript stability, and inhibition of ATP-dependent regulatory factors such as protein kinases by Ap4A. Existing evidence favors the last of these as the most probable mechanism. Regardless, our results suggest that the NUDT2 protein could be a novel cancer chemotherapeutic target, with its inhibition potentially exerting strong anti-tumor effects via multiple pathways involving metastasis, invasion, immunosuppression and apoptosis

First trimester fetal heart rate as a predictor of newborn sex

OBJECTIVE: To predict the sex of newborns using first trimester fetal heart rate (FHR). METHODS: This was a retrospective review of medical records and ultrasounds performed between 8 and 13 weeks of gestation. Continuous variables were compared using Student\u27s t-tests while categorical variables were compared using Chi-square test. RESULTS: We found no significant differences between 332 (50.7%) female and 323 (49.3%) male FHRs during the first trimester. The mean FHR for female fetuses was 167.0 +/- 9.1 bpm and for male fetuses 167.3 +/- 10.1 bpm (p = 0.62). There was no significant difference in crown rump length between female and male fetuses (4.01 +/- 1.7 versus 3.98 +/- 1.7 cm; p = 0.78) or in gestational age at birth (38.01 +/- 2.1 versus 38.08 +/- 2.1 weeks; p = 0.67). The males were significantly heavier than females (3305.3 +/- 568.3 versus 3127.5 +/- 579.8 g; p \u3c 0.0001) but there were no differences in the proportion of small for gestational age (SGA), average for gestational age (AGA) and large for gestational age (LGA) infants. CONCLUSIONS: We found no significant difference between the female and male FHR during the first trimester in contrast to the prevailing lay view of females having a faster FHR. The only statistically significant difference was that males weighed more than female newborns

Design, fabrication, and testing of a helium-cooled module for the ITER divertor

The International Thermonuclear Reactor (ITER) will have a single-null divertor with total power flow of 200 MW and a peak heat flux of about 5 MW/m{sup 2}. The reference coolant for the divertor is water. However, helium is a viable alternative and offers advantages from safety considerations, such as excellent radiation stability and chemical inertness. In order to prove the feasibility of helium cooling at ITER relevant heat flux conditions, General Atomics designed, fabricated, and tested a helium-cooled divertor module. The module was made from dispersion strengthened copper, with a heat flux surface 25 mm wide and 80 mm long, designed for twice the ITER divertor heat flux. Different techniques were examined to enhance the heat transfer, which in turn reduced the flow and pumping power required to cool the module. It was concluded that an extended surface was the most practical solution. An optimization study was performed to find the best extended surface parameters. The optimum extended surface geometry consisted of fins: 10 mm high, 0.4 mm thick with a 1 mm pitch. It was estimated to require a pumping power of 150 W to remove 20 kW of power. This is more than an order of magnitude reduction in pumping power requirement, compared to smooth surface. The module was fabricated by electric discharge machining (EDM) process. The testing was carried out at SNLA during August 1993. The testing confirmed the design calculations. The peak heat flux during the test was 10 MW/m{sup 2} applied over a surface area of 20 cm{sup 2}. The pumping power calculated from flow rate and pressure drop measurement was about 160 W, which was less than 1% of the power removed. It is planned to test the module to higher temperature limits and higher heat fluxes during coming months. As a result of this effort we conclude that helium cooling of the ITER divertor is feasible without requiring a very large helium pressure or a large pumping power

LEADER 5: prevalence and cardiometabolic impact of obesity in cardiovascular high-risk patients with type 2 diabetes mellitus: baseline global data from the LEADER trial

Background: Epidemiological data on obesity are needed, particularly in patients with type 2 diabetes mellitus (T2DM) and high cardiovascular (CV) risk. We used the baseline data of liraglutide effect and action in diabetes: evaluation of CV outcome results—A long term Evaluation (LEADER) (a clinical trial to assess the CV safety of liraglutide) to investigate: (i) prevalence of overweight and obesity; (ii) relationship of the major cardiometabolic risk factors with anthropometric measures of adiposity [body mass index (BMI) and waist circumference (WC)]; and (iii) cardiometabolic treatment intensity in relation to BMI and WC. Methods: LEADER enrolled two distinct populations of high-risk patients with T2DM in 32 countries: (1) aged ≥50 years with prior CV disease; (2) aged ≥60 years with one or more CV risk factors. Associations of metabolic variables, demographic variables and treatment intensity with anthropometric measurements (BMI and WC) were explored using regression models (ClinicalTrials.gov identifier: NCT01179048). Results: Mean BMI was 32.5 ± 6.3 kg/m2 and only 9.1 % had BMI &lt;25 kg/m2. The prevalence of healthy WC was also extremely low (6.4 % according to International Joint Interim Statement for the Harmonization of the Metabolic Syndrome criteria). Obesity was associated with being younger, female, previous smoker, Caucasian, American, with shorter diabetes duration, uncontrolled blood pressure (BP), antihypertensive agents, insulin plus oral antihyperglycaemic treatment, higher levels of triglycerides and lower levels of high-density lipoprotein cholesterol. Conclusions: Overweight and obesity are prevalent in high CV risk patients with T2DM. BMI and WC are related to the major cardiometabolic risk factors. Furthermore, treatment intensity, such as insulin, statins or oral antihypertensive drugs, is higher in those who are overweight or obese; while BP and lipid control in these patients are remarkably suboptimal. LEADER confers a unique opportunity to explore the longitudinal effect of weight on CV risk factors and hard endpoints

“When treatment is more challenging than the disease” : a qualitative study of MDR-TB patient retention.

CAPRISA, 2016.Abstract available in PDF file