Heritability and Expression of C-Reactive Protein in Type 2 Diabetes in the Diabetes Heart Study

Elevated C-reactive protein (CRP) levels are associated with both prevalent and incident cardiovascular disease. In this study, familial aggregation was estimated, and we tested for association between serum CRP levels and polymorphisms within the CRP and APOE genes in sib-ships with type 2 diabetes mellitus, a population at increased risk for cardiovascular disease. CRP levels were determined in 461 diabetes-affected subjects from 224 sibships from the Diabetes Heart Study (DHS). Heritability estimates of CRP levels were obtained using variance component models. Genetic influence on serum CRP levels by single nucleotide polymorphisms (SNPs) in the CRP and APOE genes was evaluated by association analysis using mixed models. Subjects were Caucasian American (84%) and African-American (16%), 53% female, and had an average age of 62.2 ± 9.2 years. The median CRP level was 3.3 mg/L (range 0 to 59.3 mg/L), and estimated heritability for CRP was approximately 40%. Estimates of heritability were significantly greater than zero (P < 0.0001) and relatively constant, despite adjustments for important modifiers (age, sex, ethnicity, diabetes duration, statin-use and anti-inflammatory use) of CRP. There was no significant evidence for association of CRP levels with CRP gene SNPs; however, consistent with previous reports, there was significant evidence of association of CRP levels with polymorphisms within the APOE gene. These data indicate CRP levels are significantly influenced by genetic (and/or environmental) factors that are shared within DHS families. While the APOE locus shows evidence of contributing to CRP levels, no evidence of CRP gene polymorphism association with CRP levels was observed.     

Tunicamycin resistant glycosylation of a coronavirus glycoprotein: Demonstration of a novel type of viral glycoprotein

Tunicamycin has different effects on the glycosylation of the two envelope glycoproteins of mouse hepatitis virus (MHV), a coronavirus. Unlike envelope glycoproteins of other viruses, the transmembrane glycoprotein El is glycosylated normally in the presence of tunicamycin. This suggests that glycosylation of El does not involve transfer of core oligosaccharides from dolichol pyrophosphate intermediates to asparagine residues, but may occur by 0-linked glycosylation of serine or threonine residues. Synthesis of the peplomeric glycoprotein E2 is not readily detectable in the presence of tunicamycin. Inhibition of N-linked glycosylation of E2 by tunicamycin either prevents synthesis or facilitates degradation of the protein moiety of E2. Radiolabeling with carbohydrate precursors and borate gel electrophoresis of glycopeptides show that different oligcsaccharide side chains are attached to El and E2. The two coronavirus envelope glycoproteins thus appear to be glycosylated by different mechanisms. In tunicamycin-treated cells, noninfectious virions lacking peplomers are formed at intracytoplasmic membranes and released from the cells. These virions contain normal amounts of nucleocapsid protein and glycosylated El, but lack E2. Thus the transmembrane glycoprotein El is the only viral glycoprotein required for the formation of the viral envelope or for virus maturation and release. The peplomeric glycoprotein E2 appears to be required for attachment to virus receptors on the plasma membrane. The coronavirus envelope envelope glycoprotein E1 appears to be a novel type of viral glycoprotein which is post-translationally glycosylated by a tunicamycin-resistant process that yields oligosaccharide side chains different from those of N-linked glycoproteins. These findings suggest that El may be particularly useful as a model for studying the biosynthesis, glycosylation, and intracellular transport of 0-linked glycoproteins.     

Executive function in Tourette's syndrome and obsessive-compulsive disorder

BACKGROUND: Cognitive performance was compared in the genetically and neurobiologically related disorders of Tourette's syndrome (TS) and obsessive-compulsive disorder (OCD), in three domains of executive function: planning, decision-making and inhibitory response control. METHOD: Twenty TS patients, twenty OCD patients and a group of age- and IQ-matched normal controls completed psychometric and computerized cognitive tests and psychiatric rating scales. The cognitive tests were well-characterized in terms of their sensitivity to other fronto-striatal disorders, and included pattern and spatial recognition memory, attentional set-shifting, and a Go/No-go set-shifting task, planning, and decision-making. RESULTS: Compared to controls, OCD patients showed selective deficits in pattern recognition memory and slower responding in both pattern and spatial recognition, impaired extra-dimensional shifting on the set-shifting test and impaired reversal of response set on the Go/No-go test. In contrast, TS patients were impaired in spatial recognition memory, extra-dimensional set-shifting, and decision-making. Neither group was impaired in planning. Direct comparisons between the TS and OCD groups revealed significantly different greater deficits for recognition memory latency and Go/No-go reversal for the OCD group, and quality of decision-making for the TS group. CONCLUSIONS: TS and OCD show both differences (recognition memory, decision-making) and similarities (set-shifting) in selective profiles of cognitive function. Specific set-shifting deficits in the OCD group contrasted with their intact performance on other tests of executive function, such as planning and decision-making, and suggested only limited involvement of frontal lobe dysfunction, possibly consistent with OCD symptomatology.     

ALG11‐CDG syndrome: Expanding the phenotype

ALG11‐Congenital Disorder of Glycosylation (ALG11‐CDG, also known as congenital disorder of glycosylation type Ip) is an inherited inborn error of metabolism due to abnormal protein and lipid glycosylation. We describe two unrelated patients with ALG11‐CDG due to novel mutations, review the literature of previously described affected individuals, and further expand the clinical phenotype. Both affected individuals reported here had severe psychomotor disabilities and epilepsy. Their fibroblasts synthesized truncated precursor glycan structures, consistent with ALG11‐CDG, while also showing hypoglycosylation of a novel biomarker, GP130. Surprisingly, one patient presented with normal transferrin glycosylation profile, a feature that has not been reported previously in patients with ALG11‐CDG. Together, our data expand the clinical and mutational spectrum of ALG11‐CDG.     

Changing and sustaining medical students' knowledge, skills, and attitudes about patient safety and medical fallibility.

PURPOSE: To study the effects of a patient safety and medical fallibility curriculum on second-year medical students at the University of Missouri-Columbia School of Medicine in 2003-2004. METHOD: Students completed a knowledge, skills, and attitudes questionnaire before the curriculum, after the final learning experience, and one year later. A 95% confidence interval (CI) for paired differences assessed change over time. At one year, students also responded to items about their use of the curriculum, error reporting, and disclosure experiences. RESULTS: Fifty three of 92 students (55%) completed the questionnaire at all three assessment points. Students' eight items and the calculated knowledge score improved after the curriculum but only seven of these improvements were sustained one year. Responses to seven items did not change and five changed in an undesired direction after the curriculum and/or after one year. Seventy two students completed the self-reported behavior questions at one year. More than half reported using what they learned in the curriculum. Although 76% of students reported observing an error, 71% of these disclosed an error to their peers, 56% to a resident, and 46% to faculty. Only 7% reported an error using our electronic error reporting system. CONCLUSIONS: The curriculum led to changes in second-year medical students' knowledge, skills, and attitudes, but not all of the changes were sustained at one year, were in the desired direction, or were supported by their self-reported behaviors. The extent to which other informal or hidden curriculum experiences reversed the gains and affected the changes at one year is unknown.     

Antihypertensive mechanism of action of ketanserin and some ketanserin analogues in the spontaneously hypertensive rat

Summary Ketanserin is a new antihypertensive agent with affinity to serotonin (5-HT)₂ receptors and at higher concentrations also to ₁-adrenoceptors. The present study was designed to evaluate the relative functional importance of the antagonism of ₁-adrenoreceptors and 5-HT₂-receptors in the antihypertensive mechanism of action of ketanserin and analogues after acute administration. In the spontaneously hypertensive rat, ketanserin and the two ketanserin analogues, R56413 and R55667 (which have relatively weaker -adrenolytic properties) were studied with regard to their ability to reduce the blood pressure after acute administration in the conscious rat and their ability to shift the dose response curves for 5-HT and phenylephrine in the pithed rat. The agents tested reduced the blood pressure only in a dose range where they blocked ₁-adrenoceptors and there was a striking correlation between the degree of hypotension and the degree of inhibition of the phenylephrine induced pressor responses. 5-HT₂-receptor blockade alone did not influence basal blood pressure. However, following pretreatment with R55667 in a low dose the blood pressure reduction to prazosin was enhanced.It is concluded that following acute administration in the rat the major portion of the antihypertensive response to ketanserin is due to an ₁-adrenoceptor blockade but that the 5-HT₂-receptor blockade contributes.Abbreviations 5-HT 5-hydroxytryptamine - SHR spontaneously hypertensive rat - SNS sympathetic nervous stimulation     

How does a move towards a coaching approach impact the delivery of written feedback in undergraduate clinical education?

Advances in Health Sciences Education - Feedback uptake relies on interactions between learners and educators Winstone (Educ Psychol 52: 17–37, 2017). Feedback that coaches using a...