A diagnostically‐challenging case of melanoma ex blue nevus with comprehensive molecular analysis,including the 23‐gene expression signature (myPath melanoma)

Melanoma ex blue nevus (MEBN) is a rare, aggressive, and potentially lethal neoplasm. Distinguishing MEBN from an atypical cellular blue nevus can be very challenging. We report a diagnostically difficult case of MEBN with lymph node metastases, in which single nucleotide polymorphism array and fluorescence in situ hybridization were used to arrive at the correct diagnosis. It was also analyzed by the recently‐introduced proprietary 23‐gene expression signature test. To the best of our knowledge, this is the second reported case of MEBN analyzed by the 23‐gene expression signature, which provided a false‐negative result. More studies are needed to assess the sensitivity and specificity of this test in various melanocytic proliferations.     

Ten-year trends and differences in alcohol consumption among black and white female undergraduates

Background: Few studies have explored changing patterns of alcohol consumption among young females and differences based on race/ethnicity. Objective: This study examined differences in alcohol consumption between black and white undergraduate females and compared trends in three different measures of alcohol consumption over a 10-year period from 2004 to 2014. Methods: The CORE Alcohol and Drug Survey was used to collect data from female undergraduates attending a public university in the northeastern USA. Classes were randomly selected into the sample; class acceptance was 68% and student participation was 96%. The chi-square test examined differences between groups and the Cochrane Armitage Test for Trend assessed changes over time. Results: In 2014, for every measure of alcohol consumption examined, a significantly larger percentage of white females engaged in the behavior compared to black females. Trend analysis from 2004 to 2014 demonstrated a narrowing of this gap. Controlling for age, any alcohol use in past 30 days and binge drinking in the past 2 weeks increased significantly for black females 21 years or older. Any alcohol use in the past 30 days decreased significantly for white females under 21 years. Conclusion: These findings introduce many questions which should be explored through additional research.     

Gene Deletions in Mycobacterium bovis BCG Stimulate Increased CD8+ T Cell Responses

Mycobacteria, the etiological agents of tuberculosis and leprosy, have coevolved with mammals for millions of years and have numerous ways of suppressing their host''s immune response. It has been suggested that mycobacteria may contain genes that reduce the host''s ability to elicit CD8⁺ T cell responses. We screened 3,290 mutant Mycobacterium bovis bacillus Calmette Guerin (BCG) strains to identify genes that decrease major histocompatibility complex (MHC) class I presentation of mycobacterium-encoded epitope peptides. Through our analysis, we identified 16 mutant BCG strains that generated increased transgene product-specific CD8⁺ T cell responses. The genes disrupted in these mutant strains had disparate predicted functions. Reconstruction of strains via targeted deletion of genes identified in the screen recapitulated the enhanced immunogenicity phenotype of the original mutant strains. When we introduced the simian immunodeficiency virus (SIV) gag gene into several of these novel BCG strains, we observed enhanced SIV Gag-specific CD8⁺ T cell responses in vivo. This study demonstrates that mycobacteria carry numerous genes that act to dampen CD8⁺ T cell responses and suggests that genetic modification of these genes may generate a novel group of recombinant BCG strains capable of serving as more effective and immunogenic vaccine vectors.     

Viral Infection of Engrafted Human Islets Leads to Diabetes

Type 1 diabetes (T1D) is characterized by the destruction of the insulin-producing β-cells of pancreatic islets. Genetic and environmental factors both contribute to T1D development. Viral infection with enteroviruses is a suspected trigger for T1D, but a causal role remains unproven and controversial. Studies in animals are problematic because of species-specific differences in host cell susceptibility and immune responses to candidate viral pathogens such as coxsackievirus B (CVB). In order to resolve the controversial role of viruses in human T1D, we developed a viral infection model in immunodeficient mice bearing human islet grafts. Hyperglycemia was induced in mice by specific ablation of native β-cells. Human islets, which are naturally susceptible to CVB infection, were transplanted to restore normoglycemia. Transplanted mice were infected with CVB4 and monitored for hyperglycemia. Forty-seven percent of CVB4-infected mice developed hyperglycemia. Human islet grafts from infected mice contained viral RNA, expressed viral protein, and had reduced insulin levels compared with grafts from uninfected mice. Human-specific gene expression profiles in grafts from infected mice revealed the induction of multiple interferon-stimulated genes. Thus, human islets can become severely dysfunctional with diminished insulin production after CVB infection of β-cells, resulting in diabetes.     

New Insights Into Gestational Glucose Metabolism: Lessons Learned From 21st Century Approaches

Pregnancy presents a unique physiological challenge that requires changes coordinated by placentally and non–placentally derived hormones to prepare the mother for the metabolic stress presented by fetal development and to ensure appropriate nutrient allocation between mother and fetus. Of particular importance is the maintenance of normal glucose metabolism during pregnancy. Here, we describe physiological changes in glucose metabolism during pregnancy and highlight new insights into these adaptations that have emerged over the past decade using novel methodologies, specifically genome-wide association studies (GWAS) and metabolomics. While GWAS have identified some novel associations with metabolic traits during pregnancy, the majority of the findings overlap with those observed in nonpregnant populations and individuals with type 2 diabetes (T2D). Metabolomics studies have provided new insight into key metabolites involved in gestational diabetes mellitus (GDM). Both of these approaches have suggested that a strong link exists between GDM and T2D. Most recently, a role of the gut microbiome in pregnancy has been observed, with changes in the microbiome during the third trimester having metabolic consequences for the mother. In this Perspectives in Diabetes article, we highlight how these new data have broadened our understanding of gestational metabolism, and emphasize the importance of future studies to elucidate differences between GDM and T2D.     

Functional Impairment Is a Risk Factor for Knee Replacement in the Multicenter Osteoarthritis Study

Background

Debilitating pain associated with knee osteoarthritis (OA) often leads patients to seek and complete total knee arthroplasty (TKA). To date, few studies have evaluated the relation of functional impairment to the risk of TKA, despite the fact that OA is associated with functional impairment.

Questions/purposes

The purpose of our study was to (1) evaluate whether function as measured by WOMAC physical function subscale was associated with undergoing TKA; and (2) whether any such association varied by sex.

Methods

The National Institutes of Health-funded Multicenter Osteoarthritis Study (MOST) is an observational cohort study of persons aged 50 to 79 years with or at high risk of symptomatic knee OA who were recruited from the community. All eligible subjects with complete data were included in this analysis. Our study population sample consisted of 2946 patients with 5796 knees; 1776 (60%) of patients were women. We performed a repeated-measures analysis using baseline WOMAC physical function score to predict the risk of TKA from baseline to 30 months and WOMAC score at 30 months to predict risk of incident TKA from 30 months to 60 months. We used generalized estimating equations to account for the correlation between two knees within an individual and across the two periods. We calculated relative risk (RR) of TKA over 30 months by WOMAC function using a score of 0 to 5 as the referent in multiple binomial regressions with log link.

Results

Those with the greatest functional impairment (WOMAC scores 40–68; 62 TKAs in 462 knee periods) had 15.5 times (95% confidence interval [CI], 7.6–31.8; p < 0.001) the risk of undergoing TKA over 30 months compared with the referent group (12 TKAs in 3604 knee periods), adjusting for basic covariates, and 5.9 times (95% CI, 2.8–12.5; p < 0.001) the risk after further adjusting for knee pain severity. At every level of functional limitation, the RR for TKA for women was higher than for men, but interaction with sex did not reach significance after adjustment for covariates including ipsilateral pain (p = 0.138).

Conclusions

Baseline physical function appears to be an important element in patients considering TKA. Future studies should examine whether interventions to improve function can reduce the need for TKA.

Level of Evidence

Level III, observational cohort study.     

Pilot evaluation of paroxetine for treating hot flashes in men

OBJECTIVE: To provide prospective information on the potential utility of paroxetine for treating hot flashes In men receiving androgen ablation therapy for prostate cancer. PATIENTS AND METHODS: Men with symptomatic androgen ablation therapy-related hot flashes were entered into this clinical trial between August 2001 and October 2003. After a baseline week of documentation of the frequency of hot flashes, patients were assigned to receive paroxetine; the initial dosage was 12.5 mg/d, and it was increased to 37.5 mg/d over the ensuing 4 weeks. RESULTS: Of the 24 patients in whom medication was initiated, 18 completed the 5-week study. In these patients, the median frequency of hot flashes decreased from 6.2 per day during the baseline week to 2.5 per day during the last study week. Hot flash scores (frequency x mean severity) during the same period decreased from 10.6 per day to 3.0 per day. Overall, paroxetine was well tolerated by most patients. CONCLUSION: The results from this trial suggest that paroxetine Is an effective agent for diminishing hot flashes in men receiving androgen ablation therapy.     

Measuring health beliefs in Spanish-speaking Mexican Americans with type 2 diabetes: adapting an existing instrument

Mexican Americans bear a disproportionate burden of type 2 diabetes, and although clinicians and researchers are beginning to develop culturally competent interventions, few instruments are available for measuring variables relevant to health outcomes. The purpose of this study was to determine the psychometric properties of a diabetes-related health belief instrument translated for use with Spanish-speaking Mexican Americans. Three hundred and twenty-six Spanish-speaking Mexican Americans from Starr County, a Texas-Mexico border community, diagnosed with type 2 diabetes participated in the study. Factor analysis was used to examine the factor structure of the instrument, and reliability testing was conducted to determine the internal consistency of the resulting factors. The final instrument had 25 items with four subscales-Barriers, Social Support for Diet, Impact of Job on Therapy, and Benefits of Therapy-and one item to measure, Control. Internal consistency coefficients for these subscales were .56, .62, .86, and .90, respectively. The translated instrument needs to be tested over time with other Hispanic populations.