1,418 research outputs found
Safety and efficacy of an engineered hepatotropic AAV gene therapy for ornithine transcarbamylase deficiency in cynomolgus monkeys
X-linked inherited ornithine transcarbamylase deficiency (OTCD) is the most common disorder affecting the liver-based urea cycle, a pathway enabling detoxification of nitrogen waste and endogenous arginine biosynthesis. Patients develop acute hyperammonemia leading to neurological sequelae or death despite the best-accepted therapy based on ammonia scavengers and protein-restricted diet. Liver transplantation is curative but associated with procedure-related complications and lifelong immunosuppression. Adeno-associated viral (AAV) vectors have demonstrated safety and clinical benefits in a rapidly growing number of clinical trials for inherited metabolic liver diseases. Engineered AAV capsids have shown promising enhanced liver tropism. Here, we conducted a good-laboratory practice-compliant investigational new drug-enabling study to assess the safety of intravenous liver-tropic AAVLK03 gene transfer of a human codon-optimized OTC gene. Juvenile cynomolgus monkeys received vehicle and a low and high dose of vector (2 × 1012 and 2 × 1013 vector genome (vg)/kg, respectively) and were monitored for 26 weeks for in-life safety with sequential liver biopsies at 1 and 13 weeks post-vector administration. Upon completion of monitoring, animals were euthanized to study vector biodistribution, immune responses, and histopathology. The product was well tolerated with no adverse clinical events, predominant hepatic biodistribution, and sustained supra-physiological OTC overexpression. This study supports the clinical deployment of intravenous AAVLK03 for severe OTCD
Cirsium species show disparity in patterns of genetic variation at their range-edge, despite similar patterns of reproduction and isolation
Genetic variation was assessed across the UK geographical range of Cirsium acaule and Cirsium heterophyllum. A decline in genetic diversity and increase in population divergence approaching the range edge of these species was predicted based on parallel declines in population density and seed production reported seperately. Patterns were compared with UK populations of the widespread Cirsium arvense.Populations were sampled along a latitudinal transect in the UK and genetic variation
assessed using microsatellite markers. Cirsium acaule
shows strong isolation by distance, a significant decline in diversity and an increase in divergence among range-edge populations. Geographical structure is also evident in
C. arvense, whereas no such patterns are seen in C.heterophyllum. There is a major disparity between patterns of genetic variation in C. acaule and
C. heterophyllum despite very similar patterns in seed production and population isolation in these species. This suggests it may be misleading to make assumptions
about the geographical structure of genetic variation within species based solely on the present-day reproduction and distribution of populations
Effect of a Web-Based Behavior Change Program on Weight Loss and Cardiovascular Risk Factors in Overweight and Obese Adults at High Risk of Developing Cardiovascular Disease: Randomized Controlled Trial.
Web-based programs are a potential medium for supporting weight loss because of their accessibility and wide reach. Research is warranted to determine the shorter- and longer-term effects of these programs in relation to weight loss and other health outcomes
Acute Pancreatitis in the Emergency Department
Introduction: Acute pancreatitis (AP) is a common emergency department (ED) presentation with a variety of outcomes. Stratifying AP severity with scoring systems can allow physicians to effectively manage patient disposition.
Objective: To identify ED pancreatitis patients who will likely be admitted to the ICU or be discharged within 48 hours, and to validate existing pancreatitis severity scores.
Methods: Patients with a final ED diagnosis of AP and/or lipase ≥ 3 times the upper limit of normal were enrolled in a prospective, observational chart review study. Parametric and non-parametric descriptive statistics were used to describe the patient population. Area under receiver operating curve (AUC) was used to determine the predictive accuracy of existing pancreatitis scores.
Results: Ranson criteria, Glasgow-Imrie (GI) criteria, Bedside Index of Severity in Acute Pancreatitis (BISAP), and Harmless Acute Pancreatitis Score (HAPS) were assessed. GI criteria (AUC = 0.77) had the highest predictive accuracy for ICU admission, while Ranson criteria (AUC = 0.62) had the highest predictive accuracy for early discharge. Mean scores of ICU patients were significantly (p \u3c 0.05) higher than those of non-ICU patients in all four scoring systems; however, mean scores in ICU patients failed to meet the severe case threshold for all four scoring systems.
Discussion: Existing pancreatitis scoring systems cannot consistently predict AP severity in ED patients. The small difference in mean ICU and non-ICU patient scores illustrates the difficulty of using scoring systems to stratify AP severity in the ED. Further efforts to develop an ED-specific scoring system could allow physicians to more efficiently admit patients
The Neurotoxicity of DOPAL: Behavioral and Stereological Evidence for Its Role in Parkinson Disease Pathogenesis
BACKGROUND: The etiology of Parkinson disease (PD) has yet to be fully elucidated. We examined the consequences of injections of 3,4-dihydroxyphenylacetaldehyde (DOPAL), a toxic metabolite of dopamine, into the substantia nigra of rats on motor behavior and neuronal survival. METHODS/PRINCIPAL FINDINGS: A total of 800 nl/rat of DOPAL (1 µg/200 nl) was injected stereotaxically into the substantia nigra over three sites while control animals received similar injections of phosphate buffered saline. Rotational behavior of these rats was analyzed, optical density of striatal tyrosine hydroxylase was calculated, and unbiased stereological counts of the substantia nigra were made. The rats showed significant rotational asymmetry ipsilateral to the lesion, supporting disruption of dopaminergic nigrostriatal projections. Such disruption was verified since the density of striatal tyrosine hydroxylase decreased significantly (p<0.001) on the side ipsilateral to the DOPAL injections when compared to the non-injected side. Stereological counts of neurons stained for Nissl in pars compacta of the substantia nigra significantly decreased (p<0.001) from control values, while counts of those in pars reticulata were unchanged after DOPAL injections. Counts of neurons immunostained for tyrosine hydroxylase also showed a significant (p=0.032) loss of dopaminergic neurons. In spite of significant loss of dopaminergic neurons, DOPAL injections did not induce significant glial reaction in the substantia nigra. CONCLUSIONS: The present study provides the first in vivo quantification of substantia nigra pars compacta neuronal loss after injection of the endogenous toxin DOPAL. The results demonstrate that injections of DOPAL selectively kills SN DA neurons, suggests loss of striatal DA terminals, spares non-dopaminergic neurons of the pars reticulata, and triggers a behavioral phenotype (rotational asymmetry) consistent with other PD animal models. This study supports the "catecholaldehyde hypothesis" as an important link for the etiology of sporadic PD
Appointing Women to Boards: Is There a Cultural Bias?
Companies that are serious about corporate governance and business ethics are turning their attention to gender diversity at the most senior levels of business (Institute of Business Ethics, Business Ethics Briefing 21:1, 2011). Board gender diversity has been the subject of several studies carried out by international organizations such as Catalyst (Increasing gender diversity on boards: Current index of formal approaches, 2012), the World Economic Forum (Hausmann et al., The global gender gap report, 2010), and the European Board Diversity Analysis (Is it getting easier to find women on European boards? 2010). They all lead to reports confirming the overall relatively low proportion of women on boards and the slow pace at which more women are being appointed. Furthermore, the proportion of women on corporate boards varies much across countries. Based on institutional theory, this study hypothesizes and tests whether this variation can be attributed to differences in cultural settings across countries. Our analysis of the representation of women on boards for 32 countries during 2010 reveals that two cultural characteristics are indeed associated with the observed differences. We use the cultural dimensions proposed by Hofstede (Culture’s consequences: International differences in work-related values, 1980) to measure this construct. Results show that countries which have the greatest tolerance for inequalities in the distribution of power and those that tend to value the role of men generally exhibit lower representations of women on boards
Calculating the energy spectra of magnetic molecules: application of real- and spin-space symmetries
The determination of the energy spectra of small spin systems as for instance
given by magnetic molecules is a demanding numerical problem. In this work we
review numerical approaches to diagonalize the Heisenberg Hamiltonian that
employ symmetries; in particular we focus on the spin-rotational symmetry SU(2)
in combination with point-group symmetries. With these methods one is able to
block-diagonalize the Hamiltonian and thus to treat spin systems of
unprecedented size. In addition it provides a spectroscopic labeling by
irreducible representations that is helpful when interpreting transitions
induced by Electron Paramagnetic Resonance (EPR), Nuclear Magnetic Resonance
(NMR) or Inelastic Neutron Scattering (INS). It is our aim to provide the
reader with detailed knowledge on how to set up such a diagonalization scheme.Comment: 29 pages, many figure
Ten years of Ana: lessons from a transdisciplinary body of literature on online pro-eating disorder websites
This paper offers a methodical review of the scientific literature of the last decade that concerns itself with online services offering supportive advocacy for anorexia nervosa and bulimia nervosa (‘pro-ana’ and ‘pro-mia’). The main question is whether these studies reproduce the traditional divide in the study of eating disorders, between clinical and social science perspectives, with limited mutual exchanges. Having first identified a specific body of literature, the authors investigate its content, methods and approaches, and analyse the network of cross-citations the components generate and share. On this basis, the authors argue that the scientific literature touching on pro-ana websites can be regarded as a single
transdisciplinary body of knowledge. What’s more, they show that the literature on computermediated sociabilities centred on eating disorders displays different structural characteristics with respect to the traditional, non-Web-related research on eating disorders. In the latter, the social sciences have usually provided a critical counterpoint to the development of a health sciences mainstream. In the case of Web-related research, however, the social sciences have taken the lead role in defining the field, with the health sciences following suit
Prevalence of suspected hypertrophic cardiomyopathy or left ventricular hypertrophy based on race and gender in teenagers using screening echocardiography
BACKGROUND:The goal of this study was to evaluate the prevalence of suspected hypertrophic cardiomyopathy (HCM) in a population of teenagers undergoing screening echocardiography for the detection of HCM.METHOD:The Anthony Bates Foundation performs screening echocardiography for the prevention of sudden death. A total of 2,066 students were studied between the ages of 13 to 19 years. Suspected HCM was defined as any wall thickness greater than or equal to] 15 mm. LVH was defined as wall thickness greater than or equal to] 13 mmRESULTS:Prevalence of suspected HCM was 0.7% (14/2066). After adjusting for hypertension (HTN), the total prevalence was 0.5% (8/1457). In a subgroup analysis, 551 teenagers with documented race and LV wall thickness were identified between the ages of 13 - 19 years. African American teenagers 6% (3/50)] had higher prevalence of suspected HCM 0.8% (4/501), OR 7.93, CI 1.72-36.49, p = 0.002]. After multivariate adjustment for age, gender, BMI and HTN (systolic BP >140 and diastolic BP of > 90), African American race remained independently associated with suspected HCM (OR 4.89, CI 1.24-39.62, p = 0.02).CONCLUSION:The prevalence of suspected HCM in young teenagers is approximately 0.2%. This prevalence appears to be higher in African Americans. However, due to small number of African Americans in our population, our result needs to be confirmed in larger trials.This item is part of the UA Faculty Publications collection. For more information this item or other items in the UA Campus Repository, contact the University of Arizona Libraries at [email protected]
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