Roscoe Reid Graham (1890 to 1948): a Canadian pioneer in general surgery.

Roscoe Reid Graham, a Canadian surgeon trained at the University of Toronto, was a true pioneer in the field of general surgery. Although he may be best known for his omental patch repair of perforated duodenal ulcers-often referred to as the Graham patch -he had a number of other significant accomplishments that decorated his surgical career. Dr. Graham is credited with being the first surgeon to successfully enucleate an insulinoma. He ventured to do an essentially brand new operation based solely on his patient\u27s symptoms and physical findings, a courageous move that even some of the most talented surgeons would shy away from. He also spent a large portion of his career dedicated to the study of rectal prolapse, working tirelessly to rid his patients of this awful affliction. He was recognized by a number of different surgical associations for his operative successes and was awarded membership to those both in Canada and the United States. Despite all of these accolades, Dr. Graham remained grounded and always fervent in his dedication to the patient and their presenting symptom(s), reminding us that to do anything more would be meddlesome. In an age when medical professionals are often all too eager to make unnecessary interventions, it is imperative that we look back at our predecessors such as Roscoe Reid Graham, for they will continually redirect us toward our one and only obligation: the patient

Sex-specific transcriptomic responses to changes in the nutritional environment

Males and females typically pursue divergent reproductive strategies and accordingly require different dietary compositions to maximise their fitness. Here we move from identifying sex-specific optimal diets to understanding the molecular mechanisms that underlie male and female responses to dietary variation in Drosophila melanogaster. We examine male and female gene expression on male-optimal (carbohydrate-rich) and female-optimal (protein-rich) diets. We find that the sexes share a large core of metabolic genes that are concordantly regulated in response to dietary composition. However, we also observe smaller sets of genes with divergent and opposing regulation, most notably in reproductive genes which are over-expressed on each sex's optimal diet. Our results suggest that nutrient sensing output emanating from a shared metabolic machinery are reversed in males and females, leading to opposing diet-dependent regulation of reproduction in males and females. Further analysis and experiments suggest that this reverse regulation occurs within the IIS/TOR network

Using Doubly-Labeled Water to Measure Energy Expenditure in an Important Small Ectotherm Drosophila melanogaster

Energy expenditure is a key variable in the study of ageing, and the fruit fly Drosophila melanogaster is a model organism that has been used to make step changes in our understanding of the ageing process. Standard methods for measurement of energy expenditure involve placing individuals in metabolic chambers where their oxygen consumption and CO2 production can be quantified. These measurements require separating individuals from any social context, and may only poorly reflect the environment in which the animals normally live. The doubly-labeled water (DLW) method is an isotope-based technique for measuring energy expenditure which overcomes these problems. However, technical challenges mean that the smallest animals this method has been previously applied to weighed 50-200 mg. We overcame these technical challenges to measure energy demands in Drosophila weighing 0.78 mg. Mass-specific energy expenditure varied between 43 and 65 mW·g(-1). These estimates are considerably higher than estimates using indirect calorimetry of Drosophila in small metabolic chambers (around 18 mW·g(-1)). The methodology we have established extends downwards by three orders of magnitude the size of animals that can be measured using DLW. This approach may be of considerable value in future ageing research attempting to understand the genetic and genomic basis of ageing

Research into aerodynamic modulation of wind turbine noise:final report

The study described in this report has been commissioned by Defra, BERR (formerly DTI) and CLG. It follows on from a report by the Hayes McKenzie Partnership to DTI in 2005 in which reports of low frequency noise emission from windfarms were investigated. Their report concluded that the complaints were not caused by low frequency noise, but by amplitude modulation of aerodynamic noise (AM) from the wind turbines. The term AM indicates aerodynamic noise from wind turbines, but with a greater than normal degree of regular fluctuation at blade passing frequency, typically once per second. The aims of this current study are to ascertain the prevalence of AM on UK wind farm sites, to try to gain a better understanding of the likely causes, and to establish whether further research into AM is required. The study was carried out in four parts, a survey of local authorities with windfarms in their areas, further investigation of sites for which AM was identified as a factor, a literature review and a survey of wind turbine manufacturers.The survey of local authorities was in two parts, a scoping survey aimed at identifying problem sites, and a detailed survey to establish whether AM could have been a factor in causing complaints. The response to both parts of the survey was 100%, although full information was not available for all sites at the detailed stage. The results showed that 27 of the 133 windfarm sites operational across the UK at the time of the survey had attracted noise complaints at some point. An estimated total of 239 formal complaints have been received about UK windfarm sites since 1991, 152 of which were from a single site. The estimated total number of complainants is 81 over the same sixteen year period. This shows that in terms of the number of people affected, wind farm noise is a small-scale problem compared with other types of noise; for example the number of complaints about industrial noise exceeds those about windfarms by around three orders of magnitude. In only one case was the windfarm considered by the local authority to be causing a statutory nuisance. Again, this indicates that, despite press articles to the contrary, the incidence of windfarm noise and AM in the UK is low.AM was considered to be a factor in four of the sites, and a possible factor in another eight. Regarding the four sites, analysis of meteorological data suggests that the conditions for AM would prevail between about 7% and 15% of the time. AM would not therefore be present most days, although it could occur for several days running over some periods. Complaints have subsided for three out of these four sites, in one case as a result of remedial treatment in the form of a wind turbine control system. In the remaining case, which is a recent installation, investigations are ongoing.The literature review indicated that, although there has been much research into the general area of aerodynamic noise it is a highly complex field, and whilst general principles are understood there are still unanswered questions. Regarding the specific phenomenon of AM there has been little research and the causes are still the subject of debate. AM is not fully predictable at current state of the art. The survey of wind turbine manufacturers revealed that, although there was considerable interest, few have any experience of AM.The low incidence of AM and the low numbers of people adversely affected make it difficult to justify further research funding in preference to other more widespread noise issues. On the other hand, since AM cannot be fully predicted at present, and its causes are not fully understood we consider that it might be prudent to carry out further research to improve understanding in this area

External validation and recalibration of an incidental meningioma prognostic model – IMPACT: protocol for an international multicentre retrospective cohort study

Introduction: Due to the increased use of CT and MRI, the prevalence of incidental findings on brain scans is increasing. Meningioma, the most common primary brain tumour, is a frequently encountered incidental finding, with an estimated prevalence of 3/1000. The management of incidental meningioma varies widely with active clinical-radiological monitoring being the most accepted method by clinicians. Duration of monitoring and time intervals for assessment, however, are not well defined. To this end, we have recently developed a statistical model of progression risk based on single-centre retrospective data. The model Incidental Meningioma: Prognostic Analysis Using Patient Comorbidity and MRI Tests (IMPACT) employs baseline clinical and imaging features to categorise the patient with an incidental meningioma into one of three risk groups: low, medium and high risk with a proposed active monitoring strategy based on the risk and temporal trajectory of progression, accounting for actuarial life expectancy. The primary aim of this study is to assess the external validity of this model. Methods and analysis: IMPACT is a retrospective multicentre study which will aim to include 1500 patients with an incidental intracranial meningioma, powered to detect a 10% progression risk. Adult patients ≥16 years diagnosed with an incidental meningioma between 1 January 2009 and 31 December 2010 will be included. Clinical and radiological data will be collected longitudinally until the patient reaches one of the study endpoints: intervention (surgery, stereotactic radiosurgery or fractionated radiotherapy), mortality or last date of follow-up. Data will be uploaded to an online Research Electronic Data Capture database with no unique identifiers. External validity of IMPACT will be tested using established statistical methods. Ethics and dissemination: Local institutional approval at each participating centre will be required. Results of the study will be reported through peer-reviewed articles and conferences and disseminated to participating centres, patients and the public using social media

A Rapid-ACCE review of CYP2C9 and VKORC1 alleles testing to informwarfarin dosing in adults at elevated risk for thrombotic events to avoid serious bleeding,”

Purpose: Summarize evidence regarding genetic testing in adults to inform warfarin dosing to reduce adverse drug events such as serious bleeding. Methods: Review published (and selected gray) literature using the Rapid-ACCE structure that addresses analytic validity, clinical validity, clinical utility, and ethical, legal, and social implications. Results: Preliminary data suggest overall analytic sensitivity and specificity will be 98% or higher for CYP2C9 genotyping, but strength of evidence for analytic validity is low, especially for VKORC1 testing. Strength of evidence is high for the clinical validity of both genes in predicting stable warfarin dose, an intermediate outcome, but is low for the association between CYP2C9 testing and severe bleeding events (clinical sensitivity 46% (95% CI 32-60%); specificity 69% (95% CI 62-75%) and absent for bleeding events associated with VKORC1 testing. No data are available to document clinical utility of genotyping before warfarin dosing. Conclusions: The most important gaps identified are: which variants should be included in a testing panel, lack of data from external proficiency testing, lack of validated dosing algorithm incorporating genetic and nongenetic factors, evidence of clinical utility, reliable economic analyses, and methods to address several ethical, legal, and social implications issues. Genet Med 2008:10(2):89 -98

Associations of Variants in CHRNA5/A3/B4 Gene Cluster with Smoking Behaviors in a Korean Population

Multiple genome-wide and targeted association studies reveal a significant association of variants in the CHRNA5-CHRNA3-CHRNB4 (CHRNA5/A3/B4) gene cluster on chromosome 15 with nicotine dependence. The subjects examined in most of these studies had a European origin. However, considering the distinct linkage disequilibrium patterns in European and other ethnic populations, it would be of tremendous interest to determine whether such associations could be replicated in populations of other ethnicities, such as Asians. In this study, we performed comprehensive association and interaction analyses for 32 single-nucleotide polymorphisms (SNPs) in CHRNA5/A3/B4 with smoking initiation (SI), smoking quantity (SQ), and smoking cessation (SC) in a Korean sample (N = 8,842). We found nominally significant associations of 7 SNPs with at least one smoking-related phenotype in the total sample (SI: P = 0.015∼0.023; SQ: P = 0.008∼0.028; SC: P = 0.018∼0.047) and the male sample (SI: P = 0.001∼0.023; SQ: P = 0.001∼0.046; SC: P = 0.01). A spectrum of haplotypes formed by three consecutive SNPs located between rs16969948 in CHRNA5 and rs6495316 in the intergenic region downstream from the 5′ end of CHRNB4 was associated with these three smoking-related phenotypes in both the total and the male sample. Notably, associations of these variants and haplotypes with SC appear to be much weaker than those with SI and SQ. In addition, we performed an interaction analysis of SNPs within the cluster using the generalized multifactor dimensionality reduction method and found a significant interaction of SNPs rs7163730 in LOC123688, rs6495308 in CHRNA3, and rs7166158, rs8043123, and rs11072793 in the intergenic region downstream from the 5′ end of CHRNB4 to be influencing SI in the male sample. Considering that fewer than 5% of the female participants were smokers, we did not perform any analysis on female subjects specifically. Together, our detected associations of variants in the CHRNA5/A3/B4 cluster with SI, SQ, and SC in the Korean smoker samples provide strong evidence for the contribution of this cluster to the etiology of SI, ND, and SC in this Asian population

In the Laboratory and during Free-Flight: Old Honey Bees Reveal Learning and Extinction Deficits that Mirror Mammalian Functional Decline

Loss of brain function is one of the most negative and feared aspects of aging. Studies of invertebrates have taught us much about the physiology of aging and how this progression may be slowed. Yet, how aging affects complex brain functions, e.g., the ability to acquire new memory when previous experience is no longer valid, is an almost exclusive question of studies in humans and mammalian models. In these systems, age related cognitive disorders are assessed through composite paradigms that test different performance tasks in the same individual. Such studies could demonstrate that afflicted individuals show the loss of several and often-diverse memory faculties, and that performance usually varies more between aged individuals, as compared to conspecifics from younger groups. No comparable composite surveying approaches are established yet for invertebrate models in aging research. Here we test whether an insect can share patterns of decline similar to those that are commonly observed during mammalian brain aging. Using honey bees, we combine restrained learning with free-flight assays. We demonstrate that reduced olfactory learning performance correlates with a reduced ability to extinguish the spatial memory of an abandoned nest location (spatial memory extinction). Adding to this, we show that learning performance is more variable in old honey bees. Taken together, our findings point to generic features of brain aging and provide the prerequisites to model individual aspects of learning dysfunction with insect models