Coronary artery aneurysms

There is no consensus on the best management of coronary artery aneurysms (CAA) in adults. We describe two patients with CAA and review transcatheter approaches to exclude them from the circulation. © 2013 Wiley Periodicals, Inc.     

Interprofessional education in palliative care: A pilot project using popular literature

Summary

A need to introduce the concepts of death and dying to the medical and health sciences undergraduate curriculum was identified at the University of Ottawa, Ontario, Canada. As care of the terminally ill is complex and requires the collaborative involvement of a diverse group of health care professionals, an interprofessional educational approach was utilized to address this need. A seminar course was developed using popular literature as the basis for learning, and offered to first and second year medical students, fourth year nursing students and graduate students in spiritual care. The discussion of roles and the provision of care within the context of works of selected literature provided a focus that enabled the students to transcend their disciplinary barriers, and to better understand the perspectives and contributions that other team members bring to patient care. Evaluation findings suggest that meaningful interprofessional education can be introduced effectively to students either prior to or while they are maturing in their professional roles.     

General approach to reversing ketol-acid reductoisomerase cofactor dependence from NADPH to NADH

To date, efforts to switch the cofactor specificity of oxidoreductases from nicotinamide adenine dinucleotide phosphate (NADPH) to nicotinamide adenine dinucleotide (NADH) have been made on a case-by-case basis with varying degrees of success. Here we present a straightforward recipe for altering the cofactor specificity of a class of NADPH-dependent oxidoreductases, the ketol-acid reductoisomerases (KARIs). Combining previous results for an engineered NADH-dependent variant of Escherichia coli KARI with available KARI crystal structures and a comprehensive KARI-sequence alignment, we identified key cofactor specificity determinants and used this information to construct five KARIs with reversed cofactor preference. Additional directed evolution generated two enzymes having NADH-dependent catalytic efficiencies that are greater than the wild-type enzymes with NADPH. High-resolution structures of a wild-type/variant pair reveal the molecular basis of the cofactor switch.     

Elevated plasma fractalkine levels are associated with higher levels of IL-6, Apo-B,LDL-C and insulin,but not with body composition in a large female twin sample

Objective

Plasma fractalkine (FRACT) is involved in the development of numerous inflammatory conditions including atherosclerosis. It is associated with type 2 diabetes mellitus and adipose inflammation. However, whether FRACT is associated with major risk factors for cardiovascular disease, in particular obesity, metabolic syndrome and blood lipids, is virtually unknown.

Methods

The study included a large community-based sample of 3306 middle-aged women drawn from the general UK population. Blood samples were analyzed for circulating levels of FRACT, leptin, insulin, glucose, LDL-C, HDL-C, Apo-A, ApoB and IL-6. Obesity was assessed by fat body mass (FBM) using dual-energy x-ray absorptiometry and by body mass index (BMI).

Results

We found no association between FRACT and body composition, in particular adiposity. Obese and non obese subjects with metabolic syndrome tended to have higher levels of FRACT compared with non-obese subjects without metabolic syndrome but this did not reach statistical significance. Most importantly we report significant correlations between FRACT and circulating IL-6, Apo-B, LDL-C and insulin. The associations with IL-6 and Apo-B were particularly significant (P-value < 0.001), and survived correction for multiple testing and adjustment for age and other covariates.

Conclusion

Higher FRACT levels correlated with elevated levels of IL-6, Apo-B, LDL-C and insulin, all known risk factors for several clinical related diseases suggesting a potential role of FRACT in inflammation and tissue injury. Variations of FRACT levels are not influenced by body composition and are not correlated with leptin indicating that fat mass alone is not responsible for elevation of FRACT seen in obese individuals.     

Sex-specific epigenetic disruption and behavioral changes following low-dose in utero bisphenol A exposure

Bisphenol A (BPA) is an estrogenic endocrine disruptor widely used in the production of plastics. Increasing evidence indicates that in utero BPA exposure affects sexual differentiation and behavior; however, the mechanisms underlying these effects are unknown. We hypothesized that BPA may disrupt epigenetic programming of gene expression in the brain. Here, we provide evidence that maternal exposure during pregnancy to environmentally relevant doses of BPA (2, 20, and 200 µg/kg/d) in mice induces sex-specific, dose-dependent (linear and curvilinear), and brain region-specific changes in expression of genes encoding estrogen receptors (ERs; ERα and ERβ) and estrogen-related receptor-γ in juvenile offspring. Concomitantly, BPA altered mRNA levels of epigenetic regulators DNA methyltransferase (DNMT) 1 and DNMT3A in the juvenile cortex and hypothalamus, paralleling changes in estrogen-related receptors. Importantly, changes in ERα and DNMT expression in the cortex (males) and hypothalamus (females) were associated with DNA methylation changes in the ERα gene. BPA exposure induced persistent, largely sex-specific effects on social and anxiety-like behavior, leading to disruption of sexually dimorphic behaviors. Although postnatal maternal care was altered in mothers treated with BPA during pregnancy, the effects of in utero BPA were not found to be mediated by maternal care. However, our data suggest that increased maternal care may partially attenuate the effects of in utero BPA on DNA methylation. Overall, we demonstrate that low-dose prenatal BPA exposure induces lasting epigenetic disruption in the brain that possibly underlie enduring effects of BPA on brain function and behavior, especially regarding sexually dimorphic phenotypes.     

Switching to Sulphonylureas in Children With iDEND Syndrome Caused by KCNJ11 Mutations Results in Improved Cerebellar Perfusion

OBJECTIVE

Activating mutations in the KCNJ11 gene, encoding the Kir6.2 subunit of the K_ATP channel, result in permanent neonatal diabetes mellitus. They also may cause neurologic symptoms such as mental retardation and motor problems (iDEND syndrome) and epilepsy (DEND syndrome). Sulphonylurea (SU) treatment is reported to alleviate both the neurologic symptoms and diabetes in such cases. The study aimed to establish the magnitude and functional basis of the effect of SUs on the neurologic phenotype in children with iDEND using neuroimaging before and after insulin replacement with glibenclamide.

RESEARCH DESIGN AND METHODS

To localize and quantify the effect of glibenclamide administration, we performed single-photon emission computed tomography in seven patients with different mutations in KCNJ11. In five patients, measurements before and after initiation of SU treatment were performed.

RESULTS

Significant changes in single-photon emission computed tomography signal intensity after transfer to SU therapy were restricted to the cerebellum, consistent with previous data showing high Kir6.2 expression in this brain region. Cerebellar perfusion improved for both left (P = 0.006) and right (P = 0.01) hemispheres, with the mean improvement being 26.7 ± 7.1% (n = 5). No patients showed deterioration of cerebellar perfusion on SU therapy. Electrophysiological studies revealed a good correlation between the magnitude of K_ATP channel dysfunction and the clinical phenotype; mutant channels with the greatest reduction in adenosine 5′-triphosphate inhibition were associated with the most severe neurologic symptoms.

CONCLUSIONS

We conclude it is likely that at least some of the beneficial effects of SU treatment on neurodevelopment in iDEND patients result from improved cerebellar perfusion.Approximately 50% of cases of permanent neonatal diabetes mellitus are caused by mutations in the genes encoding either the pore-forming (Kir6.2, KCNJ11) or regulatory (SUR1, ABCC8) subunits of the ATP-sensitive K⁺ (K_ATP) channel (1). In some patients with these mutations, neurologic symptoms such as mental retardation, impaired motor development, and hypotonia coexist with neonatal diabetes (iDEND syndrome); if epilepsy is also present, then the condition is called DEND syndrome (2). Previous studies have shown that it is possible to alleviate diabetes and some of the neurologic symptoms by substituting insulin therapy with orally ingested sulphonylurea (SU) drugs (3). In one patient, the improvement in neurologic function was associated with enhanced perfusion of the brain, particularly of the cerebellum, as measured by single-photon emission computed tomography (SPECT). To determine if this effect is common to patients treated with SU, we performed SPECT in patients with different mutations in KCNJ11 and varying clinical phenotypes.     

Women's experiences of increasing subjective well-being in CFS/ME through leisure-based arts and crafts activities: A qualitative study

Purpose. To understand the meanings of art-making among a group of women living with the occupational constraints and stigma of CFS/ME. The study explored their initial motives for art-making, and then examined how art-making had subsequently influenced their subjective well-being.

Method. Ten women with CFS/ME were interviewed; three provided lengthy written accounts to the interview questions.

Findings. Illness had resulted in devastating occupational and role loss. Participants took many years to make positive lifestyle changes. Art-making was typically discovered once participants had accepted the long-term nature of CFS/ME, accommodated to illness, and reprioritized occupations. Several factors then attracted participants specifically to art-making. It was perceived as manageable within the constraints of ill-health. Participants also tended to be familiar with craft skills; had family members interested in arts and crafts, and some desired a means to express grief and loss. Once established as a leisure activity, art-making increased subjective well-being mainly through providing increased satisfaction in daily life, positive self-image, hope, and contact with the outside world. Participants recommended provision of occupational/recreational counselling earlier in the illness trajectory.

Conclusions. Creative art-making occurred as part of a broader acceptance and adjustment process to CFS/ME, and allowed some psychological escape from a circumscribed lifeworld.