Mendelian randomization and type 2 diabetes

Type 2 diabetes (T2DM) is a common, complex disease that poses a substantial burden on individual and population health, but we have relatively limited understanding of its underlying pathophysiology. Observational studies have highlighted large numbers of risk factors for T2DM, some of which are modifiable through behavioural or pharmacological intervention. Determining which of these risk factors plays a causal role in the development of T2DM has been a challenge, but Mendelian randomisation (MR) studies are harnessing genetic data in population studies to offer new insights. Using evolving analytical methods, MR studies continue to address questions of causality related to T2DM, including exploring the roles of adiposity, blood lipids and inflammation. The causal roles of a number of important modifiable risk factors have been confirmed by MR studies, while the relevance of others has been called into question. As more MR studies are conducted, methods are developed and refined in order to make the most efficient and reliable use of available genetic and phenotypic data. In this review, the design and findings of some important MR studies related to T2DM are explored and their relevance for translation to clinical practice considered

The effects of memantine on prepulse inhibition.

Reduced prepulse inhibition (PPI) of startle provides evidence of deficient sensorimotor gating in several disorders, including schizophrenia. The role of NMDA neurotransmission in the regulation of PPI is unclear, due to cross-species differences in the effects of NMDA antagonists on PPI. Recent reports suggest that drug effects on PPI differ in subgroups of normal humans that differ in the levels of baseline PPI or specific personality domains; here, we tested the effects of these variables on the sensitivity of PPI to the NMDA antagonist, memantine. PPI was measured in male Sprague-Dawley rats, after treatment with memantine (0, 10 or 20 mg/kg, s.c.). Baseline PPI was then measured in 37 healthy adult men. Next, subjects were tested twice, in a double-blind crossover design, comparing either (1) placebo vs 20 mg of the NMDA antagonist memantine (n=19) or (2) placebo vs 30 mg memantine (n=18). Tests included measures of acoustic startle amplitude, PPI, autonomic indices and subjective self-rating scales. Memantine had dose- and interval-dependent effects on PPI in rats. Compared with vehicle, 10 mg/kg increased short-interval (10-20 ms) PPI, and 20 mg/kg decreased long-interval (120 ms) PPI. In humans, memantine caused dose-dependent effects on psychological and somatic measures: 20 mg was associated with increased ratings of happiness, and 30 mg was associated with increased ratings of dizziness. PPI at the 120 ms prepulse interval was increased by 20 mg, but not 30 mg of memantine. Subgroups most sensitive to the PPI-enhancing effects of memantine were those with low baseline PPI, or with personality scale scores suggestive of high novelty seeking, high sensation seeking, or high disinhibition. NMDA blockade with memantine appears to have dose- and interval-dependent effects on sensorimotor gating in rats and humans, particularly among specific subgroups of normal human subjects. These findings are discussed as they relate to consistencies across other studies in humans, as well as apparent inconsistencies in the NMDA regulation of PPI across species

A Vibratory Acoustic Gyroscope

No abstract availabl

Maladaptive behavior and affect regulation: A functionalist perspective.

Clinical science has benefited tremendously from taking seriously the proposition that putatively maladaptive behaviors serve psychological functions, prominently among these affect regulation (AR). These functionalist accounts have not only advanced basic clinical science, but also formed the bedrock for the development of effective treatments. Drawing heavily on reinforcement learning theory, we aim to elucidate functional relationships between maladaptive behavior and AR. Specifically, we take the view that maladaptive behaviors are frequently motivated and reinforced by hedonic AR functions (i.e., decreasing negative affect and increasing positive affect) but are also susceptible to becoming stimulus-bound habits. We review empirical evidence related to one such behavior, nonsuicidal self-injury. We close with a brief reflection on future directions. (PsycINFO Database Record (c) 2020 APA, all rights reserved)

Of Mice and Men and the Search for an Alzheimer's Disease Treatment

Translational Vision and Neuroscience Research PanelAlzheimer's disease is a common affliction that disrupts the lives of millions and costs the country hundreds of millions of dollars. The federal government, state governments, philanthropic foundations, and industry have all committed resources to solving the Alzheimer's disease problem. Clinical and basic science investigators with a wide range of backgrounds have dedicated themselves to this disease. This talk will review the current state of Alzheimer's disease research and discuss where we stand in terms of a cure. This talk will try to predict where Alzheimer's disease research will go in the near future by considering where it's been in the recent past

Variations in the management of acute illness in children with congenital adrenal hyperplasia: An audit of three paediatric hospitals

Objective: Episodes of acute adrenal insufficiency (AI)/adrenal crises (AC) are a serious consequence of congenital adrenal hyperplasia (CAH). This study aimed to assess morbidity from acute illness in CAH and identify factors associated with use of IV hydrocortisone, admission and diagnosis of an AC. Method: An audit of acute illness presentations among children with CAH to paediatric hospitals in New South Wales, Australia, between 2000 and 2015. Results: There were 321 acute presentations among 74 children with CAH. Two thirds (66.7%, n=214) of these resulted in admission and 49.2% (n=158) of the patients received intravenous (IV) hydrocortisone. An AC was diagnosed in (9.0%). Prior to presentation, 64.2% (n=206) had used oral stress dosing and 22.1% (n=71) had been given intramuscular (IM) hydrocortisone. Vomiting was recorded in 61.1% (n=196), 32.7% (n=64) of whom had used IM hydrocortisone. Admission, AC diagnosis, and use of stress dosing varied significantly between hospitals. IM use varied from 7.0% in one metropolitan hospital to 45.8% in the regional hospital. Children aged up to 12 months had the lowest levels of stress dosing and IV hydrocortisone administration. A higher number of prior hospital attendances for acute illness was associated with increased use of IM hydrocortisone. Conclusion: Pre-hospital and in-hospital management of children with CAH can vary between health services. Children under 12 months have lower levels of stress dosing prior to hospital than other age groups. Experience with acute episodes improves self-management of CAH in the context of acute illness in educated patient populations

Incidence of testicular germ-cell malignancies in England and Wales: trends in children compared with adults.

The incidence of testicular cancer has been increasing markedly in most industrialised countries. This rise is known to have affected young adults, but it is less clear whether it has affected other age groups, particularly children. We used data from the National Cancer Registry file at the Office of National Statistics (ONS) and the National Registry of Childhood Tumours to examine trends in testicular germ-cell malignancies overall in England and Wales from 1962 to 1990 and in children from 1962 to 1995. The incidence of testicular cancer at all ages rose by 3.4% (95% CI 3.3-3.6%) per annum from 1962 to 1990. A similar rise in the incidence of germ-cell malignancies occurred during the years for which histological information was available in the ONS files, 1971-1989 (3.4%; 3.1-3.6%), to which both seminomas and non-seminomas contributed equally. The incidence of non-seminomas in adults rose in men under age 55 years and declined in older men, whereas there were increases in the incidence of seminomas in both young and older men. Cohort analysis at young ages showed a marked rise in the risk of germ-cell malignancies up to the cohort born in 1955-1959 but no further rise for those born subsequently. The rise in the incidence of these tumours in young adults was paralleled by a similar trend, although less marked, in children aged under 15 years (1.3% per annum; 0.2-2.5%). The increase in risk for children in this very large data set alongside the rise in young adults is compatible with the hypothesis that childhood and adult testicular germ-cell malignancies may have some common risk factors, presumably pre-natal

Optimizing Illumina next-generation sequencing library preparation for extremely AT-biased genomes.

BAckground: Massively parallel sequencing technology is revolutionizing approaches to genomic and genetic research. Since its advent, the scale and efficiency of Next-Generation Sequencing (NGS) has rapidly improved. In spite of this success, sequencing genomes or genomic regions with extremely biased base composition is still a great challenge to the currently available NGS platforms. The genomes of some important pathogenic organisms like Plasmodium falciparum (high AT content) and Mycobacterium tuberculosis (high GC content) display extremes of base composition. The standard library preparation procedures that employ PCR amplification have been shown to cause uneven read coverage particularly across AT and GC rich regions, leading to problems in genome assembly and variation analyses. Alternative library-preparation approaches that omit PCR amplification require large quantities of starting material and hence are not suitable for small amounts of DNA/RNA such as those from clinical isolates. We have developed and optimized library-preparation procedures suitable for low quantity starting material and tolerant to extremely high AT content sequences. Results: We have used our optimized conditions in parallel with standard methods to prepare Illumina sequencing libraries from a non-clinical and a clinical isolate (containing ~53% host contamination). By analyzing and comparing the quality of sequence data generated, we show that our optimized conditions that involve a PCR additive (TMAC), produces amplified libraries with improved coverage of extremely AT-rich regions and reduced bias toward GC neutral templates. Conclusion: We have developed a robust and optimized Next-Generation Sequencing library amplification method suitable for extremely AT-rich genomes. The new amplification conditions significantly reduce bias and retain the complexity of either extremes of base composition. This development will greatly benefit sequencing clinical samples that often require amplification due to low mass of DNA starting material