Dermatomyositis And Polymyositis

Idiopathic inflammatory myositis (IIM) is classified into 4 subtypes based on clinical and histopathological features. Polymyositis and dermatomyositis (PM/DM) are 2 of those subtypes in addition to immune-mediated necrotizing myopathy and inclusion body myositis. The presence of autoantibodies and inflammatory infiltration in the muscles suggests that idiopathic inflammatory myositis is an autoimmune condition, but the target autoantigens have not yet been identified. Apart from symmetric proximal muscle weakness, polymyositis and dermatomyositis have several clinical manifestations in common when compared to inclusion body myositis and necrotizing myopathy and can be grouped for discussion. The most commonly used criteria for PM/DM are Peter/Bohan Criteria.[1]: 1. Symmetric proximal muscle weakness. 2. Elevated serum muscle enzymes. 3. Myopathic changes in electromyography (EMG). 4. Characteristic muscle biopsy abnormalities. 5. Typical rash of dermatomyositis for diabetes mellitus

Influence of tetrahydrobiopterin supplementation on rate pressure product

Augmentation of tetrahydrobiopterin (BH4) could potentially improve eNOS uncoupling by increasing Nitric oxide (NO) bioavailability to improve endothelial health in cardiovascular diseases. With age, the bioactivity of eNOS decreases resulting in a decrease in concentration and bioavailability of NO. Elevated levels of eNOS cofactor BH4 helps in synthesizing NO, whereas limited concentrations of BH4 production potentiallyleads to uncoupling of eNOS and the production of superoxides. A study conducted by Pierce et al., 2012 on young and old men showed that limited BH4 bioavailability contributed to impaired arterial compliance, elasticity and other hemodynamics of vascular tissue. Experiments on sedentary and aerobically trained men by Eskurza et al., (2005) indicated that flow mediated dilation (FMD) increased by approximately 45% in old sedentary men but did not affect FMD in young sedentary or old aerobically trained individuals. Thus BH4 supplementation is a potential therapeutic target in regulation of eNOS and NO generation in vascular diseases. We hypothesize that acute oral tetrahydrobiopterin (BH4) supplementation can influence the heart work through rate pressure product that would negatively affect with age among male and female participants. Methods: A double-blinded study conducted on young men and women (21-45yrs), old men and women (60-75yrs), who were asked to consume an acute dose of BH4 supplements (10mg/kg) or equal dose of placebo supplementation (cellulose) on two separate visits. Single leg knee kick exercise with increase in resistance (0watt, 7watt, 15watt and 20 watt) was performed and measurements of heart rate (ECG) , beat-to-beat blood pressure (CNAP finger plethysmography), leg blood flow (Doppler ultrasound) were recorded. Work of heart was calculated as the Rate Pressure Product (RPP), which is a product of Heart rate (HR) and Systolic blood pressure (SBP). Results: RPP is generally higher in sedentary old men and women, with treatment RPP decreased in older participants (P\u3c 0.05) when compared to young men and women. Conclusion: Low RPP may be due to an increase in compliance of arteries and a decrease in the vascular tone of the resistance vessels and workload conducted by heart. Thus lowering heart rate and systolic blood pressure with BH4 therapy would be beneficial to patients with systemic hypertension and cardiovascular disease

The Effects of Metabolic Syndrome on the Increased Prevalence of Cognitive Decline in Minority Groups.

Alzheimer’s disease is one of the leading causes of dementia, affecting over five million people in the United States. It is clinically diagnosed by the presence of amyloid plaques and hyperphosphoryated tau. Alzheimer’s disease patients present with memory and cognitive decline. The cumulative effects of an increasing elderly population and the elevation in the number of persons with diseases such as hypertension, diabetes and obesity, which are risk factors for Alzheimer’s disease elevated the interest in understanding the interrelatedness between factors of metabolic syndrome and Alzheimer’s disease. The disparity between the incidences of Alzheimer’s disease among racial groups in the United States also correlates with the differences in the incidence of metabolic syndrome (MetSyn) among these groups. We hypothesized that persons who are classified as MetSyn will also show deficits in cognition, carotid blood flow and above normal levels of IL-6 and C-reactive protein. We believe that the amalgamation of risk factors associated with MetSyn might offer an explanation for the differential occurrence of Alzheimer’s disease in ethnic minority populations in the United States. The study has enrolled 15 participants from the community. Of the 15 participants there are 5 males and 10 females between the ages of 19 and 62, 5 of the participants have two or three risk factors for MetSyn and 7 are members of a minority population. The study is divided into 2 visits; during the first visit, anthropometric measurements and a blood draw for the plasma analysis of interleukin-6 and C-reactive protein are taken. The second visit consisted of the imaging of the carotid artery and the administration of the Penn CNP neurocognitive battery. The battery included measures of working memory, attention, executive function and verbal learning and memory. The data did not show any significant difference between persons that are metabolically compromised and normal controls in the areas of cognitive ability and inflammatory marker concentration. There were gender and racial difference in response times in the cognitive area of working memory with males having lower response times than females and Caucasian having lower response times than minorities, however the differences are not currently significant. The study continues to enroll participants, we believe that with a greater sample size the trends seen in gender and racial population differences will become significant; particularly if we are able to increase the number of persons with metabolic syndrome

Cross-domain sentiment classification using grams derived from syntax trees and an adapted naive Bayes approach

Master of ScienceDepartment of Computing and Information SciencesDoina CarageaThere is an increasing amount of user-generated information in online documents, includ- ing user opinions on various topics and products such as movies, DVDs, kitchen appliances, etc. To make use of such opinions, it is useful to identify the polarity of the opinion, in other words, to perform sentiment classification. The goal of sentiment classification is to classify a given text/document as either positive, negative or neutral based on the words present in the document. Supervised learning approaches have been successfully used for sentiment classification in domains that are rich in labeled data. Some of these approaches make use of features such as unigrams, bigrams, sentiment words, adjective words, syntax trees (or variations of trees obtained using pruning strategies), etc. However, for some domains the amount of labeled data can be relatively small and we cannot train an accurate classifier using the supervised learning approach. Therefore, it is useful to study domain adaptation techniques that can transfer knowledge from a source domain that has labeled data to a target domain that has little or no labeled data, but a large amount of unlabeled data. We address this problem in the context of product reviews, specifically reviews of movies, DVDs and kitchen appliances. Our approach uses an Adapted Naive Bayes classifier (ANB) on top of the Expectation Maximization (EM) algorithm to predict the sentiment of a sentence. We use grams derived from complete syntax trees or from syntax subtrees as features, when training the ANB classifier. More precisely, we extract grams from syntax trees correspond- ing to sentences in either the source or target domains. To be able to transfer knowledge from source to target, we identify generalized features (grams) using the frequently co-occurring entropy (FCE) method, and represent the source instances using these generalized features. The target instances are represented with all grams occurring in the target, or with a reduced grams set obtained by removing infrequent grams. We experiment with different types of grams in a supervised framework in order to identify the most predictive types of gram, and further use those grams in the domain adaptation framework. Experimental results on several cross-domains task show that domain adaptation approaches that combine source and target data (small amount of labeled and some unlabeled data) can help learn classifiers for the target that are better than those learned from the labeled target data alone

Development of a physiologically based pharmacokinetic model of actinomycin D in children with cancer

AIMS: Use of the anti‐tumour antibiotic actinomycin D is associated with development of hepatotoxicity, particularly in young children. A paucity of actinomycin D pharmacokinetic data make it challenging to develop a sound rationale for defining dosing regimens in younger patients. The study aim was to develop a physiologically based pharmacokinetic (PBPK) model using a combination of data from the literature and generated from experimental analyses. METHODS: Assays to determine actinomycin D Log P, blood:plasma partition ratio and ABCB1 kinetics were conducted. These data were combined with physiochemical properties sourced from the literature to generate a compound file for use within the modelling‐simulation software Simcyp (version 14 release 1). For simulation, information was taken from two datasets, one from 117 patients under the age of 21 and one from 20 patients aged 16–48. RESULTS: The final model incorporated clinical renal and biliary clearance data and an additional systemic clearance value. The mean AUC(0‐26h) of simulated subjects was within 1.25‐fold of the observed AUC(0‐26h) (84 ng h ml(−1) simulated vs. 93 ng h ml(−1) observed). For the younger age ranges, AUC predictions were within two‐fold of observed values, with simulated data from six of the eight age/dose ranges falling within 15% of observed data. Simulated values for actinomycin D AUC(0‐26h) and clearance in infants aged 0–12 months ranged from 104 to 115 ng h ml(−1) and 3.5–3.8 l h(−1), respectively. CONCLUSIONS: The model has potential utility for prediction of actinomycin D exposure in younger patients and may help guide future dosing. However, additional independent data from neonates and infants is needed for further validation. Physiological differences between paediatric cancer patients and healthy children also need to be further characterized and incorporated into PBPK models

Physiologically Based Pharmacokinetic Modelling of Cytochrome P450 2C9-Related Tolbutamide Drug Interactions with Sulfaphenazole and Tasisulam

Background and Objectives: Cytochrome P450 2C9 (CYP2C9) is involved in the biotransformation of many commonly used drugs, and significant drug interactions have been reported for CYP2C9 substrates. Previously published physiologically based pharmacokinetic (PBPK) models of tolbutamide are based on an assumption that its metabolic clearance is exclusively through CYP2C9; however, many studies indicate that CYP2C9 metabolism is only responsible for 80–90% of the total clearance. Therefore, these models are not useful for predicting the magnitude of CYP2C9 drug–drug interactions (DDIs). This paper describes the development and verification of SimCYP-based PBPK models that accurately describe the human pharmacokinetics of tolbutamide when dosed alone or in combination with the CYP2C9 inhibitors sulfaphenazole and tasisulam. Methods: A PBPK model was optimized in SimCYP for tolbutamide as a CYP2C9 substrate, based on published in vitro and clinical data. This model was verified to replicate the magnitude of DDI reported with sulfaphenazole and was further applied to simulate the DDI with tasisulam, a small molecule investigated for the treatment of cancer. A clinical study (CT registration # NCT01185548) was conducted in patients with cancer to assess the pharmacokinetic interaction of tasisulum with tolbutamide. A PBPK model was built for tasisulam, and the clinical study design was replicated using the optimized tolbutamide model. Results: The optimized tolbutamide model accurately predicted the magnitude of tolbutamide AUC increase (5.3–6.2-fold) reported for sulfaphenazole. Furthermore, the PBPK simulations in a healthy volunteer population adequately predicted the increase in plasma exposure of tolbutamide in patients with cancer (predicted AUC ratio = 4.7–5.4; measured mean AUC ratio = 5.7). Conclusions: This optimized tolbutamide PBPK model was verified with two strong CYP2C9 inhibitors and can be applied to the prediction of CYP2C9 interactions for novel inhibitors. Furthermore, this work highlights the utility of mechanistic models in navigating the challenges in conducting clinical pharmacology studies in cancer patients

Impact of gastrointestinal tract variability on oral drug absorption and pharmacokinetics : an UNGAP review

The absorption of oral drugs is frequently plagued by significant variability with potentially serious therapeutic consequences. The source of variability can be traced back to interindividual variability in physiology, differences in special populations (age- and disease-dependent), drug and formulation properties, or food-drug interactions. Clinical evidence for the impact of some of these factors on drug pharmacokinetic variability is mounting: e.g. gastric pH and emptying time, small intestinal fluid properties, differences in pediatrics and the elderly, and surgical changes in gastrointestinal anatomy. However, the link of colonic factors variability (transit time, fluid composition, microbiome), sex differences (male vs. female) and gut-related diseases (chronic constipation, anorexia and cachexia) to drug absorption variability has not been firmly established yet. At the same time, a way to decrease oral drug pharmacokinetic variability is provided by the pharmaceutical industry: clinical evidence suggests that formulation approaches employed during drug development can decrease the variability in oral exposure. This review outlines the main drivers of oral drug exposure variability and potential approaches to overcome them, while highlighting existing knowledge gaps and guiding future studies in this area

Impacts of ozonation on the adsorption and surface characteristics of powdered activated carbon

This research reports to see the effects of simultaneous use of ozonation along with adsorption using powdered activated carbon in a drinking water treatment plant without significantly degrading the performance of one or both the treatment processes --Introduction, page 3

Study of natural convection heat transfer above a horizontal heated plate using a laser specklegram technique

Due to the character of the original source materials and the nature of batch digitization, quality control issues may be present in this document. Please report any quality issues you encounter to [email protected], referencing the URI of the item.Includes bibliographical references.Heat transfer by free convection in air from an isothermal horizontal heated flat plate facing upward has been experimentally studied by using a non intrusive and accurate optical technique, Speckle photography or a specklegram technique. The local and the average heat transfer coefficients and hence the Nusselt numbers were determined in the range of Rayleigh numbers from 9 x 10' to 4 x 10'. The nature of the free convection flow over the heated surface was inferred from the local and average Nusselt numbers and the boundary layer pictures at varying Rayleigh numbers. Measurements were compared with both experimental and theoretical results. The convective heat transfer from the horizontal flat plate showed an increase with increasing "specific perimeter per unit area" or with decreasing aspect ratio of the heated surface. The critical Rayleigh number for laminar to turbulent transition for a horizontal isothermal surface has been estimated to be 3.0 x 10'. The experimental results show that the specklegram technique has a strong potential to be a new and powerful technique for the assessment of heat transfer behaviors