Individual Variation in Adaptive Immune Responses and Risk of Hip Fracture—A NOREPOS Population-Based Cohort Study

Immune-mediated bone loss significantly impacts fracture risk in patients with autoimmune disease, but to what extent individual variations in immune responses affect fracture risk on a population level is unknown. To examine how immune responses relate to risk of hip fracture, we looked at the individual variation in a post-vaccination skin test response that involves some of the immune pathways that also drive bone loss. From 1963 to 1975, the vast majority of the Norwegian adult population was examined as part of the compulsory nationwide Norwegian mass tuberculosis screening. These examinations included standardized tuberculin skin tests (TSTs). Our study population included young individuals (born 1940 to 1960 and aged 14 to 30 years at examination) who had all received Bacille Calmette-Guerin (BCG) vaccination after a negative TST at least 1 year prior and had no signs of tuberculosis upon clinical examination. The study population ultimately included 244,607 individuals, whose data were linked with a national database of all hospitalized hip fractures in Norway from 1994 to 2013. There were 3517 incident hip fractures during follow-up. Using a predefined Cox model, we found that men with a positive or a strong positive TST result had a 20% (hazard ratio [HR] = 1.20, 95% confidence interval [CI] 1.01–1.44) and 24% (HR = 1.24, 95% CI 1.03–1.49) increased risk of hip fracture, respectively, compared with men with a negative TST. This association was strengthened in sensitivity analyses. Total hip bone mineral density (BMD) was available for a limited subsample and similarly revealed a non-significantly reduced BMD among men with a positive TST. Interestingly, no such clear association was observed in women. An increased immune response after vaccination is associated with an increased risk of hip fracture decades later among men, possibly because of increased immune-mediated bone loss. © 2020 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR).     

Marijuana and Alcohol Use and Attempted Smoking Cessation in Adolescent Boys and Girls

ABSTRACT. Background: This study sought to determine the relationship between the frequency of current marijuana and alcohol use and cigarette quit attempts in male and female adolescent smokers. Methods: Data from a cross-sectional survey of health behaviors in high-school-aged adolescents were analyzed. Current cigarette smokers (n = 804) who reported use of at least 1 cigarette in the past month were divided into those with and without a history of at least 1 quit attempt (a self-reported episode of trying to “stop smoking”). Logistic regression models were fit to describe the association between the frequency of marijuana/alcohol use and a history of cigarette quit attempts. Results: Among the total sample, higher-frequency marijuana use (more than 6 times in the past 30 days) and frequent binge drinking (more than 5 days of binge drinking in the past 30 days) decreased the odds of having a past cigarette quit attempt (higher-frequency marijuana: adjusted odds ratio [AOR] = 0.56, 95% confidence interval [CI] = 0.36–0.86; frequent binge drinking: AOR = 0.49, 95% CI = 0.29–0.83). A significant gender interaction was observed for the relationship between higher-frequency marijuana use and a history of cigarette quit attempts (P = .03), with decreased odds in boys (AOR = 0.41, 95% CI = 0.22–0.77) but not in girls (AOR = 0.71, 95% CI = 0.37–1.33). Conclusions: Adolescent smokers who report higher-frequency marijuana use or frequent binge drinking have a decreased likelihood of a history of a cigarette quit attempt. The gender-related association between higher-frequency marijuana use and a history of quit attempts suggests that boys with greater substance use may need particularly intensive support to initiate quit attempts.     

RET proto-oncogene: a review and update of genotype-phenotype correlations in hereditary medullary thyroid cancer and associated endocrine tumors.

Hereditary medullary thyroid carcinoma (MTC) is caused by autosomal dominant gain-of-function mutations in the RET proto-oncogene. Associations between specific RET mutations (genotype) and the aggressiveness of MTC and presence or absence of other endocrine neoplasms (phenotype) are well documented. Mutations in six exons (10, 11, 13, 14, 15, and 16) located in either cysteine-rich or tyrosine kinase domains cause one of three distinctive clinical subtypes: familial MTC, multiple endocrine neoplasia (MEN) type 2A (including variants with Hirschsprung's disease and cutaneous lichen amyloidosis), and MEN 2B. Hallmarks of MEN 2A include MTC, pheochromocytoma, and hyperparathyroidism. MEN 2B is associated with an earlier onset of MTC and pheochromocytoma, the absence of hyperparathyroidism, and the presence of striking physical stigmata (e.g., coarse facies, ganglioneuromatosis, and marfanoid habitus). Familial MTC is not associated with other endocrine neoplasms; however, the accurate distinction between familial MTC and MEN 2A may be difficult in kindreds with small size, incomplete histories, or a predominance of young individuals who may not have yet fully manifested the syndrome. Genetic testing detects greater than 95% of mutation carriers and is considered the standard of care for all first-degree relatives of patients with newly diagnosed MTC. Recommendations on the timing of prophylactic thyroidectomy and the extent of surgery are based upon a model that utilizes genotype- phenotype correlations to stratify mutations into three risk levels.     

Amplified human MYC oncogenes localized to replicating submicroscopic circular DNA molecules.

Amplification of genes can sometimes be detected by molecular hybridization but not by cytogenetic methods, suggesting that in some cases the units of amplification may be too small to be detected by light microscopy. The experiments reported here investigate whether submicroscopic amplification units are present in early passages of the human tumor cell lines HL-60 and COLO 320. The results show that such cells do contain submicroscopic, extrachromosomal, supercoiled circular molecules harboring MYC genes. The molecules in HL-60 are approximately 250 kilobase pairs (kbp), while those in COLO 320 are 120-160 kbp. The extrachromosomal molecules in HL-60 are shown to replicate semiconservatively and approximately once in one cell cycle. We propose that these submicroscopic elements are precursors of double-minute chromosomes, the usual extrachromosomal manifestation of gene amplification, since both are structurally similar and replicate autonomously.     

Elimination of extrachromosomally amplified MYC genes from human tumor cells reduces their tumorigenicity.

Oncogene amplification has been observed in a broad spectrum of human tumors and has been associated with a poor prognosis for patients with several different types of malignancies. Importantly, at biopsy, the amplified genes localize to acentric extrachromosomal elements such as double-minute chromosomes (DMs) in the vast majority of cases. We show here that treatment of several human tumor cell lines with low concentrations of hydroxyurea accelerates the loss of their extrachromosomally amplified oncogenes. The decreases in MYC copy number in a human tumor cell line correlated with a dramatic reduction in cloning efficiency in soft agar and tumorigenicity in nude mice. No effect on gene copy number or tumorigenicity was observed for a closely related cell line containing the same number of chromosomally amplified MYC genes. One step involved in the accelerated loss of extrachromosomal elements is shown to involve their preferential entrapment of DMs within micronuclei. The data suggest that agents that accelerate the loss of extrachromosomally amplified genes could provide valuable tools for moderating the growth of a large number of human neoplasms.     

Sexual Risk for HIV Among Gay Male Couples: A Longitudinal Study of the Impact of Relationship Dynamics

While the relationship context itself is increasingly being examined to understand sexual risk behavior among gay male couples, few studies have examined relationship dynamics and HIV risk longitudinally. We aimed to investigate relationship dynamics and psychosocial predictors of unprotected anal intercourse (UAI) with outside partners of serodiscordant or unknown HIV serostatus (UAIOUT) over time as well as UAI with primary partner in serodiscordant couples (UAIPP). We recruited a sample of 566 ethnically diverse, seroconcordant and serodiscordant couples and interviewed them six times over the course of 3 years. The surveys encompassed relationship dynamics between the partners and sexual behavior with primary and outside partners. We fit generalized linear mixed models for both the UAI outcomes with time and relationship dynamics as predictors while controlling for relationship length. Analyses of the longitudinal data revealed that, in both categories of couples, those with higher levels of positive relationship dynamics (e.g., commitment, satisfaction) were less likely to engage in UAIOUT. Higher investment in sexual agreement and communication were among the factors that significantly predicted less UAIOUT for seroconcordant couples, but not for the serodiscordant couples. For serodiscordant couples, greater levels of attachment and intimacy were associated with greater odds of UAIPP while increased HIV-specific social support was associated with lower odds of UAIPP. These results underscore the importance of creating and tailoring interventions for gay couples that help maintain and strengthen positive relationship dynamics as they have the potential to produce significant changes in HIV risk behavior and thereby in HIV transmission.     

Increased fasting glucose and the prevalence of arterial stiffness: a cross-sectional study in Chinese adults

Abstract

Objective:

Previous studies have shown that diabetes increases the prevalence of arterial stiffness. However, it remains controversial whether impaired fasting glucose (IFG), a key pre-diabetes condition, is associated with increased risk of arterial stiffness. This study aimed to investigate the relationship between increased fasting plasma glucose (FPG) and the prevalence of arterial stiffness in a Chinese adult population.

Methods:

A random sample of 5039 participants aged 40 years or older (40·0% female) were enrolled in this study. Information on potential risk factors for cardiovascular disease was collected, and the presence of arterial stiffness was assessed by measuring brachial-ankle pulse wave velocity (baPWV). Participants were stratified into three groups: normal fasting glucose (NFG), IFG, and diabetes mellitus (DM). The IFG group was further stratified by quartiles based on the level of FPG into Q1, Q2, Q3, and Q4.

Results:

Fasting plasma glucose level was found to be independently and positively associated with baPWV. The adjusted odds ratios (ORs) (95% confidence interval (CI)) for arterial stiffness were 1·09 (0·80–1·48), 1·33 (0·98–1·81), 1·27 (0·93–1·73), 1·82 (1·31–2·53), and 2·15 (1·66–2·79) for those in IFG Q1, Q2, Q3, Q4, and DM groups compared with NFG group (P < 0·001), respectively, after adjusting for age, sex, and other potential confounders. Moreover, male participants and participants younger than 60 years were closely associated with the presence and severity of arterial stiffness (P < 0·001).

Conclusion:

Our study reports a previously unidentified positive association between increased FPG and the prevalence of arterial stiffness, suggesting the importance of FPG control in the prevention of arterial stiffness.