Genetic variation in CC chemokine receptor 5 (CCR5), the major HIV-1 coreceptor, has been shown to influence HIV-1 transmission and disease progression. However, it is generally assumed that the same CCR5 genotype (or haplotype) has similar phenotypic effects in different populations. To test this assumption, we used an evolutionary-based classification of CCR5 haplotypes to determine their associated HIV-1 disease-modifying effects in a large wellcharacterized racially mixed cohort of HIV-1-seropositive individuals. We demonstrate that the spectrum of CCR5 haplotypes associated with disease acceleration or retardation differs between African Americans and Caucasians. Also, we show that there is a strong interactive effect between CCR5 haplotypes with different evolutionary histories. The striking population-specific phenotypic effects associated with CCR5 haplotypes emphasize the importance of understanding the evolutionary context in which disease susceptibility genes are expressed.

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SummaryTo determine whether maximum bite force (MBF), an objective measure of oral function, is associated with development of frailty in community-dwelling older adults. This prospective cohort study included community-dwelling Japanese adults aged 75 years at baseline (n = 322). Baseline MBF was measured using an electronic recording device (Occlusal Force-Meter GM10). Follow-up examinations, including physical fitness and anthropometric evaluation and structured questionnaires, were administered annually over a 5-year period to determine the incidence of frailty, which was defined by the presence of 3 or more of the following 5 components derived from the Cardiovascular Health Study: low level of mobility, low physical activity level, weakness, shrinking and poor endurance and energy. Adjusted hazard ratios (HRs) of incidence of frailty according to sex-stratified tertiles of baseline MBF were calculated using Cox proportional hazards regression models. During the follow-up, 49 participants (15.2%) developed frailty. Participants in the lower tertile of MBF exhibited a significantly greater risk of frailty than those in the upper tertile. After adjustment for sex, depression, diabetes and Eichner index, the adjusted HRs for frailty in the upper through lower tertiles of MBF were 1.00 (reference), 1.27 (95% confidence interval [CI]: 0.50-3.20) and 2.78 (95% CI: 1.15-6.72), respectively (P for trend = .01). Poor oral function, as indicated by low MBF, increases the risk of development of frailty among elderly men and women. K E Y W O R D Scohort studies, dental occlusion, epidemiology, frail elderly, muscle strength, oral health | BACKGROUNDFrailty is a state of increased vulnerability to stressors, which develops as a consequence of age-related decline in multiple physiological systems.

There is growing evidence that chemokines and their receptors regulate the movement and interaction of antigen-presenting cells such as dendritic cells (DCs) and T cells. We tested the hypothesis that the CC chemokine receptor (CCR)2 and CCR5 and the chemokine macrophage inflammatory protein (MIP)-1α, a ligand for CCR5, influence DC migration and localization. We found that deficiency of CCR2 but not CCR5 or MIP-1α led to distinct defects in DC biology. Langerhans cell (skin DC) density in CCR2-null mice was normal, and their ability to migrate into the dermis was intact; however, their migration to the draining lymph nodes was markedly impaired. CCR2-null mice had lower numbers of DCs in the spleen, and this was primarily due to a reduction in the CD8α1 T helper cell type 1 (Th1)-inducing subset of DCs. Additionally, there was a block in the Leishmania major infection–induced relocalization of splenic DCs from the marginal zone to the T cell areas. We propose that these DC defects, in conjunction with increased expression of B lymphocyte chemoattractant, a B cell–specific chemokine, may collectively contribute to the striking B cell outgrowth and Th2 cytokine–biased nonhealing phenotype that we observed in CCR2-deficient mice infected with L. major. This disease phenotype in mice with an L. major–resistant genetic background but lacking CCR2 is strikingly reminiscent of that observed typically in mice with an L. major–susceptible genetic background. Thus, CCR2 is an important determinant of not only DC migration and localization but also the development of protective cell-mediated immune responses to L. major.

IDH1 mutations alter glutamate metabolism. Combining glutamate levels optimizes the 2HG-based monitoring of IDH1 mutations via MRS and represents a reliable clinical application for diagnosing IDH1 mutant gliomas.

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A 66‐year‐old man was admitted to our department due to cholestatic liver injury. He had received five cycles of pembrolizumab for small‐cell lung cancer. Imaging showed the possibility of sclerosing cholangitis (SC) with hemobilia. Histologically, CD8+ T cells had infiltrated the biliary epithelium of the extrahepatic bile duct. We reached the diagnosis of secondary SC induced by pembrolizumab. Although we treated him with high‐dose corticosteroids, laboratory data showed only a moderate response. Clinicians should recognize that immune checkpoint inhibitors can sometimes cause severe and irreversible SC.

These results suggest that acute stress modifies the allergic airway responses distinctively depending on the genetic background, and MOR is involved in the chronic psychological stress-induced exacerbation of allergic airway inflammation.