SLC6A3 polymorphism predisposes to dopamine overdose in Parkinson\u27s disease

In Parkinson\u27s disease (PD), cognitive functions mediated by brain regions innervated by ventral tegmental area (VTA) worsen with dopamine replacement therapy, whereas processes relying on regions innervated by the substantia nigra pars compacta (SNc) improve. The SLC6A3 gene encodes the dopamine transporter (DAT). The common 9R polymorphism produces higher DAT concentrations and consequently lower baseline dopamine than SLC6A3 wildtype. Whether SLC6A3 genotype modulates the effect of dopaminergic therapy on cognition in PD is not known. We investigated the effect of dopaminergic therapy and SLC6A3 genotype on encoding and recall of abstract images using the Aggie Figures Learning Test in PD patients. Encoding depends upon brain regions innervated by the VTA, whereas recall is mediated by widespread brain regions, a number innervated by the SNc. We found that dopaminergic therapy worsened encoding of abstract images in 9R carriers only. In contrast, dopaminergic therapy improved recall of abstract images in all PD patients, irrespective of SLC6A3 genotype. Our findings suggest that 9R-carrier PD patients are more predisposed to dopamine overdose and medication-induced impairment of cognitive functions mediated by VTA-innervated brain regions. Interestingly, PD patients without the 9R polymorphism did not show such an impairment. SLC6A3 genotype does not modulate the dopaminergic therapy-induced improvement of functions mediated by SNc-innervated regions in PD patients

Fast Evaluation of Interlace Polynomials on Graphs of Bounded Treewidth

We consider the multivariate interlace polynomial introduced by Courcelle (2008), which generalizes several interlace polynomials defined by Arratia, Bollobas, and Sorkin (2004) and by Aigner and van der Holst (2004). We present an algorithm to evaluate the multivariate interlace polynomial of a graph with n vertices given a tree decomposition of the graph of width k. The best previously known result (Courcelle 2008) employs a general logical framework and leads to an algorithm with running time f(k)*n, where f(k) is doubly exponential in k. Analyzing the GF(2)-rank of adjacency matrices in the context of tree decompositions, we give a faster and more direct algorithm. Our algorithm uses 2^{3k^2+O(k)}*n arithmetic operations and can be efficiently implemented in parallel.Comment: v4: Minor error in Lemma 5.5 fixed, Section 6.6 added, minor improvements. 44 pages, 14 figure

SLC6A3 Polymorphism Predisposes to Dopamine Overdose in Parkinson's Disease

In Parkinson's disease (PD), cognitive functions mediated by brain regions innervated by ventral tegmental area (VTA) worsen with dopamine replacement therapy, whereas processes relying on regions innervated by the substantia nigra pars compacta (SNc) improve. The SLC6A3 gene encodes the dopamine transporter (DAT). The common 9R polymorphism produces higher DAT concentrations and consequently lower baseline dopamine than SLC6A3 wildtype. Whether SLC6A3 genotype modulates the effect of dopaminergic therapy on cognition in PD is not known. We investigated the effect of dopaminergic therapy and SLC6A3 genotype on encoding and recall of abstract images using the Aggie Figures Learning Test in PD patients. Encoding depends upon brain regions innervated by the VTA, whereas recall is mediated by widespread brain regions, a number innervated by the SNc. We found that dopaminergic therapy worsened encoding of abstract images in 9R carriers only. In contrast, dopaminergic therapy improved recall of abstract images in all PD patients, irrespective of SLC6A3 genotype. Our findings suggest that 9R-carrier PD patients are more predisposed to dopamine overdose and medication-induced impairment of cognitive functions mediated by VTA-innervated brain regions. Interestingly, PD patients without the 9R polymorphism did not show such an impairment. SLC6A3 genotype does not modulate the dopaminergic therapy-induced improvement of functions mediated by SNc-innervated regions in PD patients

Peak Expiratory Flow Rate in Normal Hausa-Fulani Children and Adolescents of Northern Nigeria

Background: Peak expiratory flow rate (PEFR) is a useful parameter for assessing respiratory function in health and disease. However there are few studies reporting normal values of this parameter in Northern Nigeria in general and the North western zone in particular. Also prediction formulae for predicting PEFR from anthropometric parameters are not available for this population. The present study was therefore designed to measure Peak expiratory flow rate (PEFR) in normal Hausa-Fulani children and adolescents in Sokoto and to derive prediction formulae for this population. Methods: Apparently healthy boys (n=376) and girls (n=240) aged between 6 and 18 years were randomly selected and their height, weight and chest circumference determined. PEFR was measured at ambient temperature and pressure saturated with water vapour (ATPS) in the erect position. Regression analyses were carried out on the relationship between PEFR and each anthropometric parameter and prediction formulae with the least standard error of estimates chosen. Data obtained in this study were also subjected to prediction formulae derived from Nigerian populations elsewhere. Results: PEFR (L/min) was significantly (P<0.001) higher in boys (382.5 \ub1 118.3) than in girls (332.6 \ub1 88.3). It correlated positively and significantly with age, height, weight and chest circumference in both sexes. The prediction formulae derived from the present data in boys and girls respectively are: PEFR (L/min) = 85.83 + 8.25 x weight (kg) (\ub1 3.15) and PEFR (L/min) = 3.67 + 28.15 x age (years) (\ub1 3.51). The predicted PEFR values obtained using earlier formulae were generally lower than the observed values. Conclusion: PEFR has been obtained in normal healthy Hausa-Fulani children and adolescents in Sokoto and prediction formulae derived for use in this population. The results of this study suggest that the usefulness of prediction formulae may be limited to the ethnic group or locality from which they were derived.Fond : Le d\ue9bit expiratoire maximal (DEM) est un param\ue8tre utile pour \ue9valuer la fonction respiratoire dans la sant\ue9 et la maladie. Cependant, il y a peu d'\ue9tudes indiquant des valeurs normales de ce param\ue8tre au nord du Nig\ue9ria en g\ue9n\ue9ral et la zone occidentale du nord en particulier. En outre les formules de pr\ue9vision pour pr\ue9voir le DEM des param\ue8tres anthropom\ue9triques ne sont pas disponibles pour cette population. La pr\ue9sente \ue9tude a \ue9t\ue9 donc con\ue7ue pour mesurer le d\ue9bit expiratoire maximal (DEM) dans les enfants et les adolescents normaux de hausa-Fulani-Fulani \ue0 Sokoto et pour d\ue9river des formules de pr\ue9vision \ue0 cette population. M\ue9thodes : Les gar\ue7ons apparent en bonne sant\ue9 (n=376) et les filles (n=240) \ue2g\ue9s entre 6 et 18 ans ont \ue9t\ue9 al\ue9atoirement choisis et leur circonf\ue9rence de taille, de poids et de coffre ont \ue9t\ue9 d\ue9termin\ue9es. Le DEM a \ue9t\ue9 mesur\ue9 \ue0 la temp\ue9rature ambiante et \ue0 la pression satur\ue9es avec la vapeur d'eau (TAPS) en position droite. Des analyses de r\ue9gression ont \ue9t\ue9 effectu\ue9es sur le rapport entre le DEM et chaque param\ue8tre anthropom\ue9trique et formules de pr\ue9vision avec la moindre erreur type des \ue9valuations choisies. Des donn\ue9es obtenues dans cette \ue9tude ont \ue9t\ue9 \ue9galement soumises aux formules de pr\ue9vision d\ue9riv\ue9es des populations nig\ue9rianes ailleurs. R\ue9sultats : Le DEM (L/min) \ue9tait de mani\ue8re significative (P<0.001) plus haut dans les gar\ue7ons (382,5 \ub1 118,3) que dans les filles (332,6 \ub1 88,3). Il s'est corr\ue9l\ue9 positivment et de mani\ue8re significative avec l'\ue2ge, la taille, et la circonf\ue9rence de poids et de coffre dans les deux sexes. Les formules de pr\ue9vision d\ue9riv\ue9es des donn\ue9es actuelles dans les gar\ue7ons et dans les filles respectivement sont : DEM (L/min) = 85,83 + 8,25 x poid (kilogramme) (\ub1 3,15) et DEM (L/min) = 3,67 + 28,15 x \ue2ge (ann\ue9es) (\ub1 3,51). Les valeurs du DEM pr\ue9vues obtenues en utilisant des premi\ue8res formules \ue9taient g\ue9n\ue9ralement inf\ue9rieures aux valeurs observ\ue9es. Conclusion : Le DEM a \ue9t\ue9 obtenu dans les enfants et les adolescents de sant\ue9 normale d' Hausa-Fulani \ue0 Sokoto et les formules de pr\ue9vision d\ue9riv\ue9es pour l'usage dans cette population. Les r\ue9sultats de cette \ue9tude sugg\ue8rent que l'utilit\ue9 des formules de pr\ue9vision puisse \ueatre limit\ue9e au groupe ou \ue0 la localit\ue9 ethnique desquels ils ont \ue9t\ue9 d\ue9riv\ue9s

Promotion of plasma membrane repair by vitamin E

Severe vitamin E deficiency results in lethal myopathy in animal models. Membrane repair is an important myocyte response to plasma membrane disruption injury as when repair fails, myocytes die and muscular dystrophy ensues. Here we show that supplementation of cultured cells with α-tocopherol, the most common form of vitamin E, promotes plasma membrane repair. Conversely, in the absence of α-tocopherol supplementation, exposure of cultured cells to an oxidant challenge strikingly inhibits repair. Comparative measurements reveal that, to promote repair, an anti-oxidant must associate with membranes, as α-tocopherol does, or be capable of α-tocopherol regeneration. Finally, we show that myocytes in intact muscle cannot repair membranes when exposed to an oxidant challenge, but show enhanced repair when supplemented with vitamin E. Our work suggests a novel biological function for vitamin E in promoting myocyte plasma membrane repair. We propose that this function is essential for maintenance of skeletal muscle homeostasis

Development and validation of outcome prediction models for aneurysmal subarachnoid haemorrhage:the SAHIT multinational cohort study

Objective To develop and validate a set of practical prediction tools that reliably estimate the outcome of subarachnoid haemorrhage from ruptured intracranial aneurysms (SAH). Design Cohort study with logistic regression analysis to combine predictors and treatment modality. Setting Subarachnoid Haemorrhage International Trialists' (SAHIT) data repository, including randomised clinical trials, prospective observational studies, and hospital registries. Participants Researchers collaborated to pool datasets of prospective observational studies, hospital registries, and randomised clinical trials of SAH from multiple geographical regions to develop and validate clinical predicti

Global age-sex-specific mortality, life expectancy, and population estimates in 204 countries and territories and 811 subnational locations, 1950–2021, and the impact of the COVID-19 pandemic: a comprehensive demographic analysis for the Global Burden of Disease Study 2021

Background Estimates of demographic metrics are crucial to assess levels and trends of population health outcomes. The profound impact of the COVID-19 pandemic on populations worldwide has underscored the need for timely estimates to understand this unprecedented event within the context of long-term population health trends. The Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) 2021 provides new demographic estimates for 204 countries and territories and 811 additional subnational locations from 1950 to 2021, with a particular emphasis on changes in mortality and life expectancy that occurred during the 2020–21 COVID-19 pandemic period. Methods 22 223 data sources from vital registration, sample registration, surveys, censuses, and other sources were used to estimate mortality, with a subset of these sources used exclusively to estimate excess mortality due to the COVID-19 pandemic. 2026 data sources were used for population estimation. Additional sources were used to estimate migration; the effects of the HIV epidemic; and demographic discontinuities due to conflicts, famines, natural disasters, and pandemics, which are used as inputs for estimating mortality and population. Spatiotemporal Gaussian process regression (ST-GPR) was used to generate under-5 mortality rates, which synthesised 30 763 location-years of vital registration and sample registration data, 1365 surveys and censuses, and 80 other sources. ST-GPR was also used to estimate adult mortality (between ages 15 and 59 years) based on information from 31 642 location-years of vital registration and sample registration data, 355 surveys and censuses, and 24 other sources. Estimates of child and adult mortality rates were then used to generate life tables with a relational model life table system. For countries with large HIV epidemics, life tables were adjusted using independent estimates of HIV-specific mortality generated via an epidemiological analysis of HIV prevalence surveys, antenatal clinic serosurveillance, and other data sources. Excess mortality due to the COVID-19 pandemic in 2020 and 2021 was determined by subtracting observed all-cause mortality (adjusted for late registration and mortality anomalies) from the mortality expected in the absence of the pandemic. Expected mortality was calculated based on historical trends using an ensemble of models. In location-years where all-cause mortality data were unavailable, we estimated excess mortality rates using a regression model with covariates pertaining to the pandemic. Population size was computed using a Bayesian hierarchical cohort component model. Life expectancy was calculated using age-specific mortality rates and standard demographic methods. Uncertainty intervals (UIs) were calculated for every metric using the 25th and 975th ordered values from a 1000-draw posterior distribution. Findings Global all-cause mortality followed two distinct patterns over the study period: age-standardised mortality rates declined between 1950 and 2019 (a 62·8% [95% UI 60·5–65·1] decline), and increased during the COVID-19 pandemic period (2020–21; 5·1% [0·9–9·6] increase). In contrast with the overall reverse in mortality trends during the pandemic period, child mortality continued to decline, with 4·66 million (3·98–5·50) global deaths in children younger than 5 years in 2021 compared with 5·21 million (4·50–6·01) in 2019. An estimated 131 million (126–137) people died globally from all causes in 2020 and 2021 combined, of which 15·9 million (14·7–17·2) were due to the COVID-19 pandemic (measured by excess mortality, which includes deaths directly due to SARS-CoV-2 infection and those indirectly due to other social, economic, or behavioural changes associated with the pandemic). Excess mortality rates exceeded 150 deaths per 100 000 population during at least one year of the pandemic in 80 countries and territories, whereas 20 nations had a negative excess mortality rate in 2020 or 2021, indicating that all-cause mortality in these countries was lower during the pandemic than expected based on historical trends. Between 1950 and 2021, global life expectancy at birth increased by 22·7 years (20·8–24·8), from 49·0 years (46·7–51·3) to 71·7 years (70·9–72·5). Global life expectancy at birth declined by 1·6 years (1·0–2·2) between 2019 and 2021, reversing historical trends. An increase in life expectancy was only observed in 32 (15·7%) of 204 countries and territories between 2019 and 2021. The global population reached 7·89 billion (7·67–8·13) people in 2021, by which time 56 of 204 countries and territories had peaked and subsequently populations have declined. The largest proportion of population growth between 2020 and 2021 was in sub-Saharan Africa (39·5% [28·4–52·7]) and south Asia (26·3% [9·0–44·7]). From 2000 to 2021, the ratio of the population aged 65 years and older to the population aged younger than 15 years increased in 188 (92·2%) of 204 nations. Interpretation Global adult mortality rates markedly increased during the COVID-19 pandemic in 2020 and 2021, reversing past decreasing trends, while child mortality rates continued to decline, albeit more slowly than in earlier years. Although COVID-19 had a substantial impact on many demographic indicators during the first 2 years of the pandemic, overall global health progress over the 72 years evaluated has been profound, with considerable improvements in mortality and life expectancy. Additionally, we observed a deceleration of global population growth since 2017, despite steady or increasing growth in lower-income countries, combined with a continued global shift of population age structures towards older ages. These demographic changes will likely present future challenges to health systems, economies, and societies. The comprehensive demographic estimates reported here will enable researchers, policy makers, health practitioners, and other key stakeholders to better understand and address the profound changes that have occurred in the global health landscape following the first 2 years of the COVID-19 pandemic, and longer-term trends beyond the pandemic

The burden of bacterial antimicrobial resistance in the WHO African region in 2019: a cross-country systematic analysis

Background A critical and persistent challenge to global health and modern health care is the threat of antimicrobial resistance (AMR). Previous studies have reported a disproportionate burden of AMR in low-income and middle-income countries, but there remains an urgent need for more in-depth analyses across Africa. This study presents one of the most comprehensive sets of regional and country-level estimates of bacterial AMR burden in the WHO African region to date. Methods We estimated deaths and disability-adjusted life-years (DALYs) attributable to and associated with AMR for 23 bacterial pathogens and 88 pathogen–drug combinations for countries in the WHO African region in 2019. Our methodological approach consisted of five broad components: the number of deaths in which infection had a role, the proportion of infectious deaths attributable to a given infectious syndrome, the proportion of infectious syndrome deaths attributable to a given pathogen, the percentage of a given pathogen resistant to an antimicrobial drug of interest, and the excess risk of mortality (or duration of an infection) associated with this resistance. These components were then used to estimate the disease burden by using two counterfactual scenarios: deaths attributable to AMR (considering an alternative scenario where infections with resistant pathogens are replaced with susceptible ones) and deaths associated with AMR (considering an alternative scenario where drug-resistant infections would not occur at all). We obtained data from research hospitals, surveillance networks, and infection databases maintained by private laboratories and medical technology companies. We generated 95% uncertainty intervals (UIs) for final estimates as the 25th and 975th ordered values across 1000 posterior draws, and models were cross-validated for out-of-sample predictive validity. Findings In the WHO African region in 2019, there were an estimated 1·05 million deaths (95% UI 829 000–1 316 000) associated with bacterial AMR and 250 000 deaths (192 000–325 000) attributable to bacterial AMR. The largest fatal AMR burden was attributed to lower respiratory and thorax infections (119 000 deaths [92 000–151 000], or 48% of all estimated bacterial pathogen AMR deaths), bloodstream infections (56 000 deaths [37 000–82 000], or 22%), intra-abdominal infections (26 000 deaths [17 000–39 000], or 10%), and tuberculosis (18 000 deaths [3850–39 000], or 7%). Seven leading pathogens were collectively responsible for 821 000 deaths (636 000–1 051 000) associated with resistance in this region, with four pathogens exceeding 100 000 deaths each: Streptococcus pneumoniae, Klebsiella pneumoniae, Escherichia coli, and Staphylococcus aureus. Third-generation cephalosporin-resistant K pneumoniae and meticillin-resistant S aureus were shown to be the leading pathogen–drug combinations in 25 and 16 countries, respectively (53% and 34% of the whole region, comprising 47 countries) for deaths attributable to AMR. Interpretation This study reveals a high level of AMR burden for several bacterial pathogens and pathogen–drug combinations in the WHO African region. The high mortality rates associated with these pathogens demonstrate an urgent need to address the burden of AMR in Africa. These estimates also show that quality and access to health care and safe water and sanitation are correlated with AMR mortality, with a higher fatal burden found in lower resource settings. Our cross-country analyses within this region can help local governments to leverage domestic and global funding to create stewardship policies that target the leading pathogen–drug combinations. Funding Bill & Melinda Gates Foundation, Wellcome Trust, and Department of Health and Social Care using UK aid funding managed by the Fleming Fund

Blood Pressure and Electrocardiographic changes During Face Immersion in Water in Young Men on Regular Exercise

The cardiovascular responses in non-exercising and regularly exercising young men (22.0-32.0 yr) to breath-holding and face immersion in water at 210C or 400C is reported. The possibility of a myocardial oxygen conserving effect of face immersion in water is also investigated. Blood Pressure (BP) and electrocardiographic (ECG) measurements were made at the same time with the subject standing, neck flexed and immersed in water with the breath held. Results show that in both groups of subjects face immersion in water (at either temperature) with breath-hold significantly increased BP, QRS amplitude, PR interval, QT interval and R-R interval. Face immersion thus caused a significant reduction in heart rate (HR). However, in both groups of subjects, the changes in BP and HR due to face immersion at 210C were greater than the changes brought about by face immersion at 400C. The rate-pressure product (RPP) or myocardial oxygen demand fell by the same amount in the two groups of subjects at 400C. At 210C, the fall in myocardial oxygen demand was significantly greater in exercising subjects than in non-exercising subjects (

Using in-course assessment scores to predict sessional performance of medical students in meidcal physiology

No Abstract. NQJHM Vol. 8 (4) 1998: pp. 304-30