Recent Publications by CFE Educators

OBJECTIVE

Resistin causes insulin resistance and diabetes in mice whereas in humans it is linked to inflammation and atherosclerosis. Few human genetic studies of resistin in inflammation and atherosclerosis have been performed. We hypothesized that the -420C>G putative gain-of-function resistin variant would be associated with inflammatory markers and atherosclerosis but not with metabolic syndrome or adipokines in humans.

DESIGN AND METHODS

We examined the association of three resistin polymorphisms, -852A>G, -420C>G and +157C>T, and related haplotypes with plasma resistin, cytokines, C-reactive protein (CRP), adipokines, plasma lipoproteins, metabolic syndrome and coronary artery calcification (CAC) in nondiabetic Caucasians (n = 851).

RESULTS

Resistin levels were higher, dose-dependently, with the -420G allele (CC 5.9 +/- 2.7 ng/ml, GC 6.5 +/- 4.0 ng/ml and GG 7.2 +/- 4.8 ng/ml, trend P = 0.04) after age and gender adjustment [fold higher for GC + GG vs. CC; 1.07 (1.00-1.15), P 0.05)]. The -852A>G single nucleotide polymorphism (SNP) was associated with higher soluble tumour necrosis factor-receptor 2 (sol-TNFR2) levels in fully adjusted models [1.06 (95% CI 1.01-1.11), P = 0.01)]. The estimated resistin haplotype (GGT) was associated with sol-TNFR2 (P = 0.04) and the AGT haplotype was related to CRP (P = 0.04) in the fully adjusted models. Resistin SNPs and haplotypes were not associated with body mass index (BMI), fasting glucose, insulin resistance, metabolic syndrome, adipokines or CAC scores.

CONCLUSIONS

Despite modest associations with plasma resistin and inflammatory biomarkers, resistin 5' variants were not associated with metabolic parameters or coronary calcification. This suggests that resistin is an inflammatory cytokine in humans but has little influence on adiposity, metabolic syndrome or atherosclerosis.

Protein kinase C gamma (PKCgamma), which is concentrated in interneurons of the inner part of lamina II of the dorsal horn, has been implicated in injury-induced allodynia, a condition wherein pain is produced by innocuous stimuli. Although it is generally assumed that these interneurons receive input from the nonpeptidergic, IB4-positive subset of nociceptors, the fact that PKCgamma cells do not express Fos in response to noxious stimulation suggests otherwise. Here, we demonstrate that the terminal field of the nonpeptidergic population of nociceptors, in fact, lies dorsal to that of PKCgamma interneurons. There was also no overlap between the PKCgamma-expressing interneurons and the transganglionic tracer wheat germ agglutinin which, after sciatic nerve injection, labels all unmyelinated nociceptors. However, transganglionic transport of the beta-subunit of cholera toxin, which marks the medium-diameter and large-diameter myelinated afferents that transmit non-noxious information, revealed extensive overlap with the layer of PKCgamma interneurons. Furthermore, expression of a transneuronal tracer in myelinated afferents resulted in labeling of PKCgamma interneurons. Light and electron microscopic double labeling further showed that the VGLUT1 subtype of vesicular glutamate transmitter, which is expressed in myelinated afferents, marks synapses that are presynaptic to the PKCgamma interneurons. Finally, we demonstrate that a continuous non-noxious input, generated by walking on a rotarod, induces Fos in the PKCgamma interneurons. These results establish that PKCgamma interneurons are activated by myelinated afferents that respond to innocuous stimuli, which suggests that injury-induced mechanical allodynia is transmitted through a circuit that involves PKCgamma interneurons and non-nociceptive, VGLUT1-expressing myelinated primary afferents.

BACKGROUND

An estimated 25-40 million of the 127 million people of Bangladesh have been exposed to high levels of naturally occurring arsenic from drinking groundwater. The mitigating effects of diet on arsenic-related premalignant skin lesions are largely unknown.

OBJECTIVES

The purpose of this study was to clarify the effects of the vitamin B group (thiamin, riboflavin, niacin, pyridoxine, and cobalamin) and antioxidants (vitamins A, C, and E) on arsenic-related skin lesions.

METHODS

We performed a cross-sectional study using baseline data from the Health Effects of Arsenic Longitudinal Study (HEALS), 2000-2002, with individual-level, time-weighted measures of arsenic exposure from drinking water. A total of 14,828 individuals meeting a set of eligibility criteria were identified among 65,876 users of all 5,996 tube wells in the 25-km(2) area of Araihazar, Bangladesh; 11,746 were recruited into the study. This analysis is based on 10,628 subjects (90.5%) with nonmissing dietary data. Skin lesions were identified according to a structured clinical protocol during screening and confirmed with further clinical review.

RESULTS

Riboflavin, pyridoxine, folic acid, and vitamins A, C, and E significantly modified risk of arsenic-related skin lesions. The deleterious effect of ingested arsenic, at a given exposure level, was significantly reduced (ranging from 46% reduction for pyridoxine to 68% for vitamin C) for persons in the highest quintiles of vitamin intake.

CONCLUSIONS

Intakes of B-vitamins and antioxidants, at doses greater than the current recommended daily amounts for the country, may reduce the risk of arsenic-related skin lesions in Bangladesh.

Calcitonin is a sensitive tumor marker for medullary thyroid cancer (MTC) and is useful in preoperative diagnosis and postoperative surveillance for recurrent disease. Calcitonin-negative MTC is a rare occurrence. We present the case of a 68-year-old man with a 6.5 cm sporadic MTC with a 5-cm metastasis in the neck, but only minimally elevated serum calcitonin levels. He underwent total thyroidectomy, resection of internal jugular vein, and limited ipsilateral lymph node dissection. He remains disease-free 12 months after surgery. We review the literature on calcitonin-negative MTC and discuss methods of postoperative surveillance in this subset of patients.

OBJECTIVE

Recent educational reform in US medical schools has created integrated curricular structures. This study investigated how stakeholders in a newly integrated curriculum - students, course directors and curriculum leaders - define integration and perceive its successes and challenges during its first year.

METHODS

We conducted interviews with curriculum reform leaders, course directors and first year medical students. Interview transcripts were analysed for themes, which were compared within and across stakeholder groups.

RESULTS

Three curriculum leaders, four Year 1 course directors and six Year 1 medical students were interviewed. Fifteen students participated in a group interview. Four major themes emerged: interdisciplinary teaching; interdisciplinary faculty collaboration; building curricular links, and sequencing and framing curricular content. Cross-group analysis revealed participant agreement that an integrated curriculum required interdisciplinary teaching, clinical application and careful oversight. Differences among groups were also identified. Faculty (course directors and curriculum leaders) discussed faculty collaboration and the challenges of faculty buy-in and course implementation. Students highlighted the impact of integration on their learning and the challenges of sequencing and scaffolding content. Both students and course directors focused on course monitoring and conceptual links for student learning.

CONCLUSIONS

Integrating a curriculum is a complex process. It is differentially understood and experienced by students and faculty, and can refer to instructional method, content, faculty work or synthesis of knowledge in the minds of learners. It can occur at different rates and some subjects are integrated more easily than others. We point to some specific considerations as medical schools embark on curriculum reform.

OBJECTIVES

We evaluated the hypothesis that plasma levels of adiponectin and leptin are independently but oppositely associated with coronary artery calcification (CAC), a measure of subclinical atherosclerosis. In addition, we assessed which biomarkers of adiposity and insulin resistance are the strongest predictors of CAC beyond traditional risk factors, metabolic syndrome, and plasma C-reactive protein (CRP).

BACKGROUND

Adipokines are fat-secreted biomolecules with pleiotropic actions that converge in diabetes and cardiovascular disease.

METHODS

We examined the association of plasma adipocytokines with CAC in 860 asymptomatic, nondiabetic participants in the SIRCA (Study of Inherited Risk of Coronary Atherosclerosis).

RESULTS

Plasma adiponectin and leptin levels had opposite and distinct associations with adiposity, insulin resistance, and inflammation. Plasma leptin was positively (top vs. bottom quartile) associated with higher CAC after adjustment for age, gender, traditional risk factors, and Framingham risk scores (tobit regression ratio 2.42 (95% confidence interval [CI]: 1.48 to 3.95; p = 0.002) and further adjustment for metabolic syndrome and CRP (tobit regression ratio: 2.31; 95% CI: 1.36 to 3.94; p = 0.002). In contrast, adiponectin levels were not associated with CAC. Comparative analyses suggested that levels of leptin, interleukin-6, and soluble tumor necrosis factor receptor-2, as well as the homeostasis model assessment of insulin resistance (HOMA-IR) index, predicted CAC scores, but only leptin and HOMA-IR provided value beyond risk factors, metabolic syndrome, and CRP.

CONCLUSIONS

In SIRCA, although both leptin and adiponectin levels were associated with metabolic and inflammatory markers, only leptin was a significant independent predictor of CAC. Of several metabolic markers, leptin and the HOMA-IR index had the most robust, independent associations with CAC.

BACKGROUND

Percutaneous coronary intervention (PCI) is performed in many patients with stable coronary artery disease, despite evidence of little clinical benefit over optimal medical therapy.

OBJECTIVE

To examine physicians' beliefs, practices, and decision-making regarding elective PCI.

DESIGN

Six focus groups, three with primary care physicians and three with cardiologists. Participants discussed PCI using hypothetical case scenarios. Transcripts were analyzed using grounded theory, and commonly expressed themes regarding the decision-making pathway to PCI were identified.

PARTICIPANTS

Twenty-eight primary care physicians and 20 interventional and non-interventional cardiologists in Butte County, Orange County, and San Francisco Bay Area, California, in 2006.

RESULTS

A number of factors led primary care physicians to evaluate non-symptomatic or minimally symptomatic patients for coronary artery disease and refer them to a cardiologist. The use of screening tests often led to additional testing and referral, as well as fear of missing a coronary stenosis, perceived patient expectations, and medicolegal concerns. The end result was a cascade such that any positive test would generally lead to the catheterization lab, where an "oculostenotic reflex" made PCI a virtual certainty.

CONCLUSIONS

The widespread use of PCI in patients with stable coronary artery disease--despite evidence of little benefit in outcomes over medical therapy--may in part be due to psychological and emotional factors leading to a cascade effect wherein testing leads inevitably to PCI. Determining how to help physicians better incorporate evidence-based medicine into decision-making has important implications for patient outcomes and the optimal use of new technologies.