Development of a versatile laboratory experiment to teach the metabolic transformation of hydrolysis

In this paper we describe an easy, reliable, versatile and inexpensive laboratory experiment to teach the metabolic transformation of hydrolysis to Pharmacy students. The experiment does not require the sacrifice of any experimental animal, or any work with organs or tissues, and so can be implemented in a typical university chemistry laboratory. We used acetylsalicylic acid (ASA), hexyl salicylate (HS) and two enzymes, a lipase and an esterase. Since both ASS and HS liberate salicylic acid (SA) upon hydrolysis, students can evaluate the different enzymatic transformations by monitoring the amount of SA liberated. The learning outcomes are an enhanced student understanding of: (1) the process of hydrolysis; (2) the application of enzymatic transformations of molecules from food to xenobiotics; (3) the differences between the general specificity of substrate of both enzymes; (4) the concepts of the lipophilic pocket; (5) the catalytic triad and its regioselectivity in relation to the ester bond. A questionnaire was administered to participating students at three points in time: at the beginning of the module, after enzymatic hydrolysis was taught in class, and after the laboratory experiment. From an analysis of the questionnaire data we conclude that this practical helped Pharmacy students to understand these concepts

Two Types of Planning in Neighborhoods

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/68338/2/10.1177_0739456X8400300209.pd

Genetic Drivers of Kidney Defects in the DiGeorge Syndrome

Background The DiGeorge syndrome, the most common of the microdeletion syndromes, affects multiple organs, including the heart, the nervous system, and the kidney. It is caused by deletions on chromosome 22q11.2; the genetic driver of the kidney defects is unknown. Methods We conducted a genomewide search for structural variants in two cohorts: 2080 patients with congenital kidney and urinary tract anomalies and 22,094 controls. We performed exome and targeted resequencing in samples obtained from 586 additional patients with congenital kidney anomalies. We also carried out functional studies using zebrafish and mice. Results We identified heterozygous deletions of 22q11.2 in 1.1% of the patients with congenital kidney anomalies and in 0.01% of population controls (odds ratio, 81.5; P=4.5×10(-14)). We localized the main drivers of renal disease in the DiGeorge syndrome to a 370-kb region containing nine genes. In zebrafish embryos, an induced loss of function in snap29, aifm3, and crkl resulted in renal defects; the loss of crkl alone was sufficient to induce defects. Five of 586 patients with congenital urinary anomalies had newly identified, heterozygous protein-altering variants, including a premature termination codon, in CRKL. The inactivation of Crkl in the mouse model induced developmental defects similar to those observed in patients with congenital urinary anomalies. Conclusions We identified a recurrent 370-kb deletion at the 22q11.2 locus as a driver of kidney defects in the DiGeorge syndrome and in sporadic congenital kidney and urinary tract anomalies. Of the nine genes at this locus, SNAP29, AIFM3, and CRKL appear to be critical to the phenotype, with haploinsufficiency of CRKL emerging as the main genetic driver. (Funded by the National Institutes of Health and others.)

Effects of Anacetrapib in Patients with Atherosclerotic Vascular Disease

BACKGROUND: Patients with atherosclerotic vascular disease remain at high risk for cardiovascular events despite effective statin-based treatment of low-density lipoprotein (LDL) cholesterol levels. The inhibition of cholesteryl ester transfer protein (CETP) by anacetrapib reduces LDL cholesterol levels and increases high-density lipoprotein (HDL) cholesterol levels. However, trials of other CETP inhibitors have shown neutral or adverse effects on cardiovascular outcomes. METHODS: We conducted a randomized, double-blind, placebo-controlled trial involving 30,449 adults with atherosclerotic vascular disease who were receiving intensive atorvastatin therapy and who had a mean LDL cholesterol level of 61 mg per deciliter (1.58 mmol per liter), a mean non-HDL cholesterol level of 92 mg per deciliter (2.38 mmol per liter), and a mean HDL cholesterol level of 40 mg per deciliter (1.03 mmol per liter). The patients were assigned to receive either 100 mg of anacetrapib once daily (15,225 patients) or matching placebo (15,224 patients). The primary outcome was the first major coronary event, a composite of coronary death, myocardial infarction, or coronary revascularization. RESULTS: During the median follow-up period of 4.1 years, the primary outcome occurred in significantly fewer patients in the anacetrapib group than in the placebo group (1640 of 15,225 patients [10.8%] vs. 1803 of 15,224 patients [11.8%]; rate ratio, 0.91; 95% confidence interval, 0.85 to 0.97; P=0.004). The relative difference in risk was similar across multiple prespecified subgroups. At the trial midpoint, the mean level of HDL cholesterol was higher by 43 mg per deciliter (1.12 mmol per liter) in the anacetrapib group than in the placebo group (a relative difference of 104%), and the mean level of non-HDL cholesterol was lower by 17 mg per deciliter (0.44 mmol per liter), a relative difference of -18%. There were no significant between-group differences in the risk of death, cancer, or other serious adverse events. CONCLUSIONS: Among patients with atherosclerotic vascular disease who were receiving intensive statin therapy, the use of anacetrapib resulted in a lower incidence of major coronary events than the use of placebo. (Funded by Merck and others; Current Controlled Trials number, ISRCTN48678192 ; ClinicalTrials.gov number, NCT01252953 ; and EudraCT number, 2010-023467-18 .)

Laxative Use in the Community: A Literature Review

Laxatives are widely available without prescription and, as a consequence, they are commonly used for self-management of constipation by community-dwelling adults. However, it is not clear to what extent laxatives are used. Nor is it clear how laxatives are chosen, how they are used and whether consumers are satisfied with their performance. This review of published literature in the last 30 years shows the prevalence of laxative use in community-dwelling adults varied widely from 1% to 18%. The prevalence of laxative use in adults with any constipation (including both chronic and sporadic constipation) also varied widely from 3% to 59%. Apart from any geographical differences and differences in research methodologies, this wide range of estimated prevalence may be largely attributed to different definitions used for laxatives. This review also shows that laxative choice varies, and healthcare professionals are infrequently involved in selection. Consequently, satisfaction levels with laxatives are reported to be low and this may be because the laxatives chosen may not always be appropriate for the intended use. To improve constipation management in community and primary healthcare settings, further research is required to determine the true prevalence of laxative use and to fully understand laxative utilisation

A Longitudinal study of constipation and laxative use in a community-dwelling elderly population

Background: Little is known about laxative use, the association of constipation with laxative use, risk factors for constipation and how each of these changes over time in the community-dwelling elderly. Objective: The aim was to explore the prevalence of laxative use and of self-reported constipation, and identify risk factors (including age) associated with constipation, in a cohort of community-dwelling elderly residents. Methods: Data from the Australian Longitudinal Study of Ageing (ALSA) was used to compare differences in constipation and laxative use in the community-dwelling elderly between 1992-1993 and 2003-2004. Results: Relevant data was available for 239 ALSA participants. The prevalence of self-reported constipation increased from 14% in 1992-1993 to 21% in 2003-2004. There was a corresponding increase in the prevalence of laxative use from 6% to 15% over the same period. At both time points, females reported a higher prevalence of both constipation and laxative use however the female:male prevalence ratios decreased over time indicating higher increases in the prevalence of each among males. Persistent chronic constipation occurred in 9% of the cohort. The association between laxative use and self-reported constipation was poor and laxative use was associated with self-reported constipation in less than a third of cases. Conclusion: The prevalence of both constipation and laxative use increases with age in the elderly, and these increases are greater for males than for females. Discrepancies between self-reported constipation and laxative use may suggest sub-optimal management of constipation in the community-dwelling elderly and further work is needed to fully understand this.7 page(s

Modeling the Impact of Global Climate and Regional Land use Change on Regional Climate and Air Quality Over the Northeastern United States

In recent years, the focus of global climate change research has shifted towards the assessment of regional scale consequences. This paper describes the design and initial results of a modeling study aimed at simulating the effects of global climate change and regional land use change on climate and air quality over the northeastern United States in order to project the associated public health impacts in the region. To this end, modeling tools on a variety of scales are being linked. Specifically, regional climate models are linked to both a global climate model and a regional land-use change model. Outputs from regional climate simulations are subsequently used both to assess changes in public health due to heat stress and to simulate regional and urban air quality. Finally, results from these air quality simulations are coupled to health impact models. This paper focuses on the air quality modeling aspect of the project. Global and regional climate change could conceivably alter regional and urban air quality in a variety of ways through both direct and indirect effects. Rising temperatures could have a direct effect on chemical reaction rates and mixed-layer heights, while changes in synoptic circulation patterns might influence the transport and mixing of pollutants as well as the occurrence of conditions conducive to high ozone concentrations. Additionally, anthropogenic emissions of the ozone precursors NOx and VOC are also expected to change in future decades, and it is necessary to understand whether future ozone air quality is more sensitive to changes in emissions or changes in climate. In this paper, we present initial results from regional-scale simulations for 3-months summer seasons under current and future climate conditions

Mapping the human genetic architecture of COVID-19

The genetic make-up of an individual contributes to the susceptibility and response to viral infection. Although environmental, clinical and social factors have a role in the chance of exposure to SARS-CoV-2 and the severity of COVID-191,2, host genetics may also be important. Identifying host-specific genetic factors may reveal biological mechanisms of therapeutic relevance and clarify causal relationships of modifiable environmental risk factors for SARS-CoV-2 infection and outcomes. We formed a global network of researchers to investigate the role of human genetics in SARS-CoV-2 infection and COVID-19 severity. Here we describe the results of three genome-wide association meta-analyses that consist of up to 49,562 patients with COVID-19 from 46 studies across 19 countries. We report 13 genome-wide significant loci that are associated with SARS-CoV-2 infection or severe manifestations of COVID-19. Several of these loci correspond to previously documented associations to lung or autoimmune and inflammatory diseases3–7. They also represent potentially actionable mechanisms in response to infection. Mendelian randomization analyses support a causal role for smoking and body-mass index for severe COVID-19 although not for type II diabetes. The identification of novel host genetic factors associated with COVID-19 was made possible by the community of human genetics researchers coming together to prioritize the sharing of data, results, resources and analytical frameworks. This working model of international collaboration underscores what is possible for future genetic discoveries in emerging pandemics, or indeed for any complex human disease

J Invest Dermatol

The Pemphigus Disease Area Index (PDAI) and Autoimmune Bullous Skin Disorder Intensity-Score (ABSIS) scores have been proposed to provide an objective measure of pemphigus activity. These scores have been evaluated only on already treated patients mainly with mild to moderate activity. The objective was to assess the interrater reliability of ABSIS and PDAI scores and their correlation with other severity markers in a large international study. Consecutive patients with newly diagnosed pemphigus were enrolled in 31 centers. Severity scores were recorded during a 24-month period by the same two blinded investigators. Serum was collected at each visit for ELISA measurement of anti-desmoglein antibodies. The intraclass correlation coefficient (ICC) and Spearman rank correlation coefficient were calculated. A total of 116 patients with pemphigus vulgaris (n = 84) or pemphigus foliaceus (n = 32) were included. At baseline, the ABSIS and PDAI ICCs were 0.90 (95% confidence interval [CI] = 0.85-0.93), and 0.91(95% CI = 0.87-0.94), respectively. The ICCs for PDAI were higher in moderate and extensive pemphigus (ICC = 0.82, 95% CI = 0.63-0.92 and ICC = 0.80, 95% CI = 0.62-0.90, respectively) than in patients with intermediate (significant) extent (ICC = 0.50, 95% CI = 0.27-0.68). Conversely, the ICCs for ABSIS were lower in patients with moderate extent (ICC = 0.44, 95% CI = 0.004-0.74) than in those with intermediate or extensive forms, (ICC = 0.69, 95% CI = 0.51-0.81 and ICC = 0.75, 95% CI = 0.51-0.88, respectively). During patients' follow-up, the ICCs of both ABSIS and PDAI scores remained higher than 0.70. ABSIS and PDAI skin (r = 0.71 and r = 0.75) but not mucosal (r = 0.32 and r = 0.37) subscores were correlated with the evolution of anti-DSG1 and anti-DSG3 ELISA values, respectively. ABSIS and PDAI scores are robust tools to accurately assess pemphigus activity