Aberrant DJ-1 expression underlies L-type calcium channel hypoactivity in dendrites in tuberous sclerosis complex and Alzheimer's disease.

L-type voltage-gated calcium (Ca2+) channels (L-VGCC) dysfunction is implicated in several neurological and psychiatric diseases. While a popular therapeutic target, it is unknown whether molecular mechanisms leading to disrupted L-VGCC across neurodegenerative disorders are conserved. Importantly, L-VGCC integrate synaptic signals to facilitate a plethora of cellular mechanisms; however, mechanisms that regulate L-VGCC channel density and subcellular compartmentalization are understudied. Herein, we report that in disease models with overactive mammalian target of rapamycin complex 1 (mTORC1) signaling (or mTORopathies), deficits in dendritic L-VGCC activity are associated with increased expression of the RNA-binding protein (RBP) Parkinsonism-associated deglycase (DJ-1). DJ-1 binds the mRNA coding for the alpha and auxiliary Ca2+ channel subunits CaV1.2 and α2δ2, and represses their mRNA translation, only in the disease states, specifically preclinical models of tuberous sclerosis complex (TSC) and Alzheimer's disease (AD). In agreement, DJ-1-mediated repression of CaV1.2/α2δ2 protein synthesis in dendrites is exaggerated in mouse models of AD and TSC, resulting in deficits in dendritic L-VGCC calcium activity. Finding of DJ-1-regulated L-VGCC activity in dendrites in TSC and AD provides a unique signaling pathway that can be targeted in clinical mTORopathies.

Treatment of Blood Cholesterol to Reduce Risk for Atherosclerotic Cardiovascular Disease: Grand Rounds Discussion From the Beth Israel Deaconess Medical Center.

In November 2013, the American College of Cardiology and the American Heart Association released a clinical practice guideline on the treatment of blood cholesterol to reduce atherosclerotic cardiovascular disease (ASCVD) risk in adults. The recommendation identifies 4 patient groups with strong evidence that the benefits of reduction in ASCVD events from statin therapy exceed adverse events. For these patients, initiating statin therapy of an appropriate intensity to reduce ASCVD risk and minimize adverse effects is recommended. A new risk estimator based on a pooled cohort equation is presented for estimating 10-year ASCVD risk. There is also a recommendation to engage in a clinician-patient discussion before initiating a statin, especially for primary prevention of ASCVD. This paper summarizes a discussion between a cardiologist and an internist about how each clinician would balance these factors and what treatment they would suggest for an individual patient.

Beyond content: leadership development through a journal club.

CDC designed its Health Systems Integration Program to prepare leaders to function at the interface of public health and health care. Specific Health Systems Integration Program competencies in the areas of communication, analysis and assessment, and health systems were developed to nurture evidence-based decision-making and leadership skills crucial for future public health leaders. The program therefore designed an innovative journal club as part of its competency-based curriculum not only to meet the standard goals for a journal club-critical reading, interpretation, and acquiring content knowledge-but also to foster leadership development. This report describes the Health Systems Integration Program journal club format, its implementation, challenges, and key elements of success. Other programs using a journal club model as a learning format might consider using the Health Systems Integration Program's innovative approach that focuses on leadership development.

Should the hemoglobin A1c diagnostic cutoff differ between blacks and whites? A cross-sectional study.

BACKGROUND: Hemoglobin A1c (HbA1c) levels are known to be consistently higher in black persons than in white persons at any given glycemic level. Whether the optimal diagnostic threshold of HbA1c should differ between blacks and whites is unclear. OBJECTIVE: To compare the relationships between HbA1c level and the prevalence of retinopathy in black and white U.S. adults. DESIGN: Cross-sectional study. SETTING: A nationally representative sample of the National Health and Nutrition Examination Survey from 2005 through 2008. PATIENTS: 2804 white persons and 1008 black persons aged 40 years or older in the United States. MEASUREMENTS: Prevalence of retinopathy. Logistic regression models and restricted cubic spline models were constructed separately for white and black populations to test the HbA1c levels at which risk for retinopathy begins to increase. RESULTS: After adjustment for age, sex, hypertension, body mass index, family history of diabetes, and use of antidiabetes medications or insulin, the lowest HbA1c category for which the prevalence of retinopathy was significantly higher than the reference category (<5.5%) was 6.0% to 6.4% for white persons (risk difference, 4.8% [95% CI, 0.5% to 9.1%]) and 5.5% to 5.9% for black persons (risk difference, 5.3% [CI, 1.0% to 9.5%]). The restricted cubic spline models indicated that the risk for retinopathy increased at lower HbA1c levels in black persons than in white persons. LIMITATION: The cross-sectional design of the study precluded examining the effect of the duration at each HbA1c level. CONCLUSION: The prevalence of retinopathy begins to increase at a lower HbA1c level in black Americans than in white Americans. The findings do not support increasing the diagnostic threshold of HbA1c in black persons. PRIMARY FUNDING SOURCE: None.

New diabetes diagnostic threshold of hemoglobin A(1c) and the 3-year incidence of retinopathy.

The new diagnostic threshold of hemoglobin A(1c) was made based on evidence from cross-sectional studies, and no longitudinal study supports its validity. To examine whether hemoglobin A(1c) of 6.5% or higher defines a threshold for elevated risk of incident retinopathy, we analyzed longitudinal data of 19,897 Japanese adults who underwent a health checkup in 2006 and were followed up 3 years later. We used logistic regression models and restricted cubic spline models to examine the relationship between baseline hemoglobin A(1c) levels and the prevalence and the 3-year incidence of retinopathy. The restricted cubic spline model indicated a possible threshold for the risk of incident retinopathy at hemoglobin A(1c) levels of 6.0-7.0%. Logistic regression analysis found that individuals with hemoglobin A(1c) levels of 6.5-6.9% were at significantly higher risk of developing retinopathy at 3 years compared with those with hemoglobin A(1c) levels of 5.0-5.4% (adjusted odds ratio, 2.35 [95% CI 1.08-5.11]). Those with hemoglobin A(1c) levels between 5.5 and 6.4% exhibited no evidence of elevated risks. We did not observe a threshold in the analysis of prevalent retinopathy. Our longitudinal results support the validity of the new hemoglobin A(1c) threshold of 6.5% or higher for diagnosing diabetes.

Designing and implementing a cultural competence OSCE: lessons learned from interviews with medical students.

PURPOSE: Objective structured clinical examinations (OSCEs) use standardized patients (SPs) to teach and evaluate medical students' skills. Few studies describe using OSCEs for cultural competence education, now a Liaison Committee on Medical Education accreditation standard for medical schools. We designed an OSCE station emphasizing cross-cultural communication skills (ccOSCE) and interviewed students to better understand and improve upon this tool. METHOD: Two investigators conducted semistructured interviews with 22 second-year Harvard medical students who completed the ccOSCE. Three investigators coded and analyzed the interview transcripts by using qualitative methods to explore students' perspectives on the station and its focus on cultural competence. RESULTS: Themes that emerged pertinent to design and implementation of the station were grouped into four categories: learning goals, logistical issues, faculty feedback, and SPs. Students were positive about the overall experience. They appreciated the practical focus on nonadherence. Some found the learning goals complex, and others felt the format promoted stereotypes. Logistical issues included concerns about marginalizing cross-cultural care by creating a separate station. Faculty feedback was helpful when specific about sociocultural issues students did or did not explore well. Students found SPs realistic but inconsistent in how easily they revealed information. CONCLUSION: Designing a ccOSCE experience is challenging but feasible. Students' perspectives highlight a tension between presenting cultural competence in a dedicated station (potentially marginalizing the topic and promoting stereotypes) and spreading it across stations (limiting opportunity for focused teaching). Learning goals should be clear, concise, and effectively communicated to faculty and SPs so their feedback can be standardized and specific.

Mentoring matters. Mentoring and career preparation in internal medicine residency training.

PURPOSE: Mentoring during the early stages of a career has been associated with high career satisfaction and may guide development of professional expertise. Little is known about mentoring experiences during residency training. Our purpose was to describe mentoring relationships among internal medicine residents, and to examine the relationship between mentoring and perceived career preparation. SUBJECTS AND METHODS: We designed and administered a mailed survey to all interns and residents enrolled in the five independent Internal Medicine Residency Training Programs affiliated with Harvard Medical School. We examined the development of mentoring relationships during residency training, and measured satisfaction with mentoring and with perceived career preparation. RESULTS: Of the 329 respondents (65% response rate), 93% reported that it is important to have a mentor during residency, but only half identified a current or past mentor. Interns [adjusted odds ratio (AOR) 0.3 (95% confidence interval (CI) 0.2, 0.5)] and underrepresented minority residents [0.3 (0.1, 0.7)] were significantly less likely to establish a mentoring relationship than their peers. Mentored residents were nearly twice as likely to describe excellent career preparation [1.8 (1.1, 3.1)]. CONCLUSION: Our findings demonstrate the importance of mentoring to medical residents, and identify a relationship between mentoring and perceived career preparation. We also identify a relative lack of mentoring among interns and underrepresented minority residents.

Untranslated regions from C4 amaranth AhRbcS1 mRNAs confer translational enhancement and preferential bundle sheath cell expression in transgenic C4 Flaveria bidentis.

Many aspects of photosynthetic gene expression are posttranscriptionally regulated in C4 plants. To determine if RbcS mRNA untranslated regions (UTRs) in themselves could confer any characteristic C4 expression patterns, 5'- and 3'-UTRs of AhRbcS1 mRNA from the C4 dicot amaranth were linked to a gusA reporter gene. These were constitutively transcribed from a cauliflower mosaic virus promoter and assayed for posttranscriptional expression patterns in transgenic lines of the C4 dicot Flaveria bidentis. Three characteristic C4 expression patterns were conferred by heterologous AhRbcS1 UTRs in transgenic F. bidentis. First, the AhRbcS1 UTRs conferred strong translational enhancement of gusA expression, relative to control constructs lacking these UTRs. Second, while the UTRs did not appear to confer tissue-specific expression when analyzed by beta-glucuronidase activity assays, differences in gusA mRNA accumulation were observed in leaves, stems, and roots. Third, the AhRbcS1 UTRs conferred preferential gusA expression (enzyme activity and gusA mRNA accumulation) in leaf bundle sheath cells. AhRbcS1 UTR-mediated translational enhancement was also observed in transgenic C3 plants (tobacco [Nicotiana tabacum]) and in in vitro translation extracts. These mRNAs appear to be translated with different efficiencies in C4 versus C3 plants, indicating that processes determining overall translational efficiency may vary between these two categories of higher plants. Our findings suggest that the AhRbcS1 5'-UTR functions as a strong translational enhancer in leaves and other tissues, and may work synergistically with the 3'-UTR to modulate overall levels of Rubisco gene expression in different tissues and cell types of C4 plants.

When risk is low: primary care physicians' counseling about HIV prevention.

To explore the conceptualization of risk by primary care physicians about behaviors associated with a relatively low risk of HIV transmission, we performed open-ended telephone interviews with 59 primary care physicians throughout the United States. During the interviews, physicians were asked to respond to a series of clinical vignettes presenting situations where the risk of HIV transmission is relatively low or unknown. We performed a qualitative content analysis of physicians' responses to these clinical vignettes. We found that relatively few information-gathering statements were made in an effort to elicit the patient's perspective regarding risk, and that risk counseling by physicians often followed an 'all or nothing' heuristic that manifested itself as the advice to take maximum precautions under situations of any perceived risk, no matter how small. In addition, HIV testing was often incompletely explained. When combined with the all or nothing heuristic, this created advice that was potentially harmful by using testing as a means to achieve zero risk and forgo protective strategies in settings where patients may potentially be in the HIV negative 'window' phase of infection.