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

A Upf3b-mutant mouse model with behavioral and neurogenesis defects.

Nonsense-mediated RNA decay (NMD) is a highly conserved and selective RNA degradation pathway that acts on RNAs terminating their reading frames in specific contexts. NMD is regulated in a tissue-specific and developmentally controlled manner, raising the possibility that it influences developmental events. Indeed, loss or depletion of NMD factors have been shown to disrupt developmental events in organisms spanning the phylogenetic scale. In humans, mutations in the NMD factor gene, UPF3B, cause intellectual disability (ID) and are strongly associated with autism spectrum disorder (ASD), attention deficit hyperactivity disorder (ADHD) and schizophrenia (SCZ). Here, we report the generation and characterization of mice harboring a null Upf3b allele. These Upf3b-null mice exhibit deficits in fear-conditioned learning, but not spatial learning. Upf3b-null mice also have a profound defect in prepulse inhibition (PPI), a measure of sensorimotor gating commonly deficient in individuals with SCZ and other brain disorders. Consistent with both their PPI and learning defects, cortical pyramidal neurons from Upf3b-null mice display deficient dendritic spine maturation in vivo. In addition, neural stem cells from Upf3b-null mice have impaired ability to undergo differentiation and require prolonged culture to give rise to functional neurons with electrical activity. RNA sequencing (RNAseq) analysis of the frontal cortex identified UPF3B-regulated RNAs, including direct NMD target transcripts encoding proteins with known functions in neural differentiation, maturation and disease. We suggest Upf3b-null mice serve as a novel model system to decipher cellular and molecular defects underlying ID and neurodevelopmental disorders

The Hospitality Gap: Bridging Russia into the 21st Century

The new intemationalization of the field of hospitality management has led to increased opportunities in the Russian Federation. At the same time, there are major challenges to be overcome. This article describes what needs to be accomplished to be successful at business in this New World Order

Timing of pubertal stages and breast cancer risk : the Breakthrough Generations Study

Introduction: Breast development and hormonal changes at puberty might affect breast cancer risk, but epidemiological analyses have focussed largely on age at menarche and not at other pubertal stages. Methods: We investigated associations between the timing of pubertal stages and breast cancer risk using data from a cohort study of 104,931 women (Breakthrough Generations Study, UK, 2003–2013). Pubertal variables were reported retrospectively at baseline. Breast cancer risk was analysed using Cox regression models with breast cancer diagnosis as the outcome of interest, attained age as the underlying time variable, and adjustment for potentially confounding variables. Results: During follow-up (mean = 4.1 years), 1094 breast cancers (including ductal carcinoma in situ) occurred. An increased breast cancer risk was associated with earlier thelarche (age when breast growth begins; HR [95% CI] = 1.23 [1.02, 1.48], 1 [referent] and 0.80 [0.69, 0.93] for ≤10, 11–12 and ≥13 years respectively), menarche (initiation of menses; 1.06 [0.93, 1.21], 1 [referent] and 0.78 [0.62, 0.99] for ≤12, 13–14 and ≥15 years), regular periods (0.99 [0.83, 1.18], 1 [referent] and 0.74 [0.59, 0.92] for ≤12, 13–14 and ≥15 years) and age reached adult height (1.25 [1.03, 1.52], 1 [referent] and 1.07 [0.87, 1.32] for ≤14, 15–16 and ≥17 years), and with increased time between thelarche and menarche (0.87 [0.65, 1.15], 1 [referent], 1.14 [0.96, 1.34] and 1.27 [1.04, 1.55] for <0, 0, 1 and ≥2 years), and shorter time between menarche and regular periods (1 [referent], 0.87 [0.73, 1.04] and 0.66 [0.50, 0.88] for 0, 1 and ≥2 years). These associations were generally similar when considered separately for premenopausal and postmenopausal breast cancer. Conclusions: Breast duct development may be a time of heightened susceptibility to risk of carcinogenesis, and greater attention needs to be given to the relation of breast cancer risk to the different stages of puberty

Timing of pubertal stages and breast cancer risk : the Breakthrough Generations Study

Introduction: Breast development and hormonal changes at puberty might affect breast cancer risk, but epidemiological analyses have focussed largely on age at menarche and not at other pubertal stages. Methods: We investigated associations between the timing of pubertal stages and breast cancer risk using data from a cohort study of 104,931 women (Breakthrough Generations Study, UK, 2003–2013). Pubertal variables were reported retrospectively at baseline. Breast cancer risk was analysed using Cox regression models with breast cancer diagnosis as the outcome of interest, attained age as the underlying time variable, and adjustment for potentially confounding variables. Results: During follow-up (mean = 4.1 years), 1094 breast cancers (including ductal carcinoma in situ) occurred. An increased breast cancer risk was associated with earlier thelarche (age when breast growth begins; HR [95% CI] = 1.23 [1.02, 1.48], 1 [referent] and 0.80 [0.69, 0.93] for ≤10, 11–12 and ≥13 years respectively), menarche (initiation of menses; 1.06 [0.93, 1.21], 1 [referent] and 0.78 [0.62, 0.99] for ≤12, 13–14 and ≥15 years), regular periods (0.99 [0.83, 1.18], 1 [referent] and 0.74 [0.59, 0.92] for ≤12, 13–14 and ≥15 years) and age reached adult height (1.25 [1.03, 1.52], 1 [referent] and 1.07 [0.87, 1.32] for ≤14, 15–16 and ≥17 years), and with increased time between thelarche and menarche (0.87 [0.65, 1.15], 1 [referent], 1.14 [0.96, 1.34] and 1.27 [1.04, 1.55] for <0, 0, 1 and ≥2 years), and shorter time between menarche and regular periods (1 [referent], 0.87 [0.73, 1.04] and 0.66 [0.50, 0.88] for 0, 1 and ≥2 years). These associations were generally similar when considered separately for premenopausal and postmenopausal breast cancer. Conclusions: Breast duct development may be a time of heightened susceptibility to risk of carcinogenesis, and greater attention needs to be given to the relation of breast cancer risk to the different stages of puberty

Outbreak of Middle East Respiratory Syndrome at Tertiary Care Hospital, Jeddah, Saudi Arabia, 2014

During March–May 2014, a Middle East respiratory syndrome (MERS) outbreak occurred in Jeddah, Saudi Arabia, that included many persons who worked or received medical treatment at King Fahd General Hospital. We investigated 78 persons who had laboratory-confirmed MERS during March 2–May 10 and documented contact at this hospital. The 78 persons with MERS comprised 53 patients, 16 healthcare workers, and 9 visitors. Among the 53 patients, the most probable sites of acquisition were the emergency department (22 patients), inpatient areas (17), dialysis unit (11), and outpatient areas (3). Infection control deficiencies included limited separation of suspected MERS patients, patient crowding, and inconsistent use of infection control precautions; aggressive improvements in these deficiencies preceded a decline in cases. MERS coronavirus transmission probably was multifocal, occurring in multiple hospital settings. Continued vigilance and strict application of infection control precautions are necessary to prevent future MERS outbreaks

Harnessing publicly available genetic data to prioritize lipid modifying therapeutic targets for prevention of coronary heart disease based on dysglycemic risk

Therapeutic interventions that lower LDL-cholesterol effectively reduce the risk of coronary artery disease (CAD). However, statins, the most widely prescribed LDL-cholesterol lowering drugs, increase diabetes risk. We used genome-wide association study (GWAS) data in the public domain to investigate the relationship of LDL-C and diabetes and identify loci encoding potential drug targets for LDL-cholesterol modification without causing dysglycemia. We obtained summary-level GWAS data for LDL-C from GLGC, glycemic traits from MAGIC, diabetes from DIAGRAM and CAD from CARDIoGRAMplusC4D consortia. Mendelian randomization analyses identified a one standard deviation (SD) increase in LDL-C caused an increased risk of CAD (odds ratio [OR] 1.63 (95 % confidence interval [CI] 1.55, 1.71), which was not influenced by removing SNPs associated with diabetes. LDL-C/CAD-associated SNPs showed consistent effect directions (binomial P = 6.85 × 10−5). Conversely, a 1-SD increase in LDL-C was causally protective of diabetes (OR 0.86; 95 % CI 0.81, 0.91), however LDL-cholesterol/diabetes-associated SNPs did not show consistent effect directions (binomial P = 0.15). HMGCR, our positive control, associated with LDL-C, CAD and a glycemic composite (derived from GWAS meta-analysis of four glycemic traits and diabetes). In contrast, PCSK9, APOB, LPA, CETP, PLG, NPC1L1 and ALDH2 were identified as “druggable” loci that alter LDL-C and risk of CAD without displaying associations with dysglycemia. In conclusion, LDL-C increases the risk of CAD and the relationship is independent of any association of LDL-C with diabetes. Loci that encode targets of emerging LDL-C lowering drugs do not associate with dysglycemia, and this provides provisional evidence that new LDL-C lowering drugs (such as PCSK9 inhibitors) may not influence risk of diabetes

Burden of Illness in UK Subjects with Reported Respiratory Infections Vaccinated or Unvaccinated against Influenza: A Retrospective Observational Study

<div><p>Objective</p><p>Detailed data are lacking on influenza burden in the United Kingdom (UK). The objective of this study was to estimate the disease burden associated with influenza-like illness (ILI) in the United Kingdom stratified by age, risk and influenza vaccination status.</p><p>Methods</p><p>This retrospective, cross-sectional, exploratory, observational study used linked data from the General Practice Research Database and the Hospital Episode Statistics databases to estimate resource use and cost associated with ILI in the UK.</p><p>Results</p><p>Data were included from 156,193 patients with ≥1 general practitioner visit with ILI. There were 21,518 high-risk patients, of whom 12,514 (58.2%) were vaccinated and 9,004 (41.8%) were not vaccinated, and 134,675 low-risk patients, of whom 17,482 (13.0%) were vaccinated and 117,193 (87.0%) were not vaccinated. High-risk vaccinated patients were older (p<0.001) and had more risk conditions (p<0.001). High-risk (odds ratio [OR] 2.16) or vaccinated (OR 1.19) patients had a higher probability of >1 general practitioner visit compared with low-risk and unvaccinated patients. Patients who were high-risk and vaccinated had a reduced risk of >1 general practitioner visit (OR 0.82; p<0.001). High-risk individuals who were also vaccinated had a lower probability of ILI-related hospitalisation than individuals who were high-risk or vaccinated alone (OR 0.59). In people aged ≥65 years, the mortality rate was lower in vaccinated than unvaccinated individuals (OR 0.75). The cost of ILI-related GP visits and hospital admissions in the UK over the study period in low-risk vaccinated patients was £27,391,142 and £141,932,471, respectively. In low-risk unvaccinated patients the corresponding values were £168,318,709 and £112,534,130, respectively.</p><p>Conclusions</p><p>Although vaccination rates in target groups have increased, many people are still not receiving influenza vaccination, and the burden of ILI in the United Kingdom remains substantial. Improving influenza vaccination uptake may have the potential to reduce this burden.</p></div