Natural killer T (NKT) cells are distinct glycolipid reactive innate lymphocytes that are implicated in the resistance to pathogens and tumors. Earlier attempts to mobilize NKT cells, specifically, in vivo in humans met with limited success. Here, we evaluated intravenous injection of monocyte-derived mature DCs that were loaded with a synthetic NKT cell ligand, α-galactosyl-ceramide (α-GalCer; KRN-7000) in five patients who had advanced cancer. Injection of α-GalCer–pulsed, but not unpulsed, dendritic cells (DCs) led to >100-fold expansion of several subsets of NKT cells in all patients; these could be detected for up to 6 mo after vaccination. NKT activation was associated with an increase in serum levels of interleukin-12 p40 and IFN-γ inducible protein-10. In addition, there was an increase in memory CD8+ T cells specific for cytomegalovirus in vivo in response to α-GalCer–loaded DCs, but not unpulsed DCs. These data demonstrate the feasibility of sustained expansion of NKT cells in vivo in humans, including patients who have advanced cancer, and suggest that NKT activation might help to boost adaptive T cell immunity in vivo.

Background Early menopause is linked to an increased risk of cardiovascular disease mortality; however, the association between early menopause and incidence and timing of cardiovascular disease is unclear. We aimed to assess the associations between age at natural menopause and incidence and timing of cardiovascular disease. MethodsWe harmonised and pooled individual-level data from 15 observational studies done across five countries and regions (Australia, Scandinavia, the USA, Japan, and the UK) between 1946 and 2013. Women who had reported their menopause status, age at natural menopause (if postmenopausal), and cardiovascular disease status (including coronary heart disease and stroke) were included. We excluded women who had hysterectomy or oophorectomy and women who did not report their age at menopause. The primary endpoint of this study was the occurrence of first non-fatal cardiovascular disease, defined as a composite outcome of incident coronary heart disease (including heart attack and angina) or stroke (including ischaemic stroke or haemorrhagic stroke). We used Cox proportional hazards models to estimate multivariate hazard ratios (HRs) and 95% CIs for the associations between age at menopause and incident cardiovascular disease event. We also adjusted the model to account for smoking status, menopausal hormone therapy status, body-mass index, and education levels. Age at natural menopause was categorised as premenopausal or perimenopausal, younger than 40 years (premature menopause), 40-44 years (early menopause), 45-49 years (relatively early), 50-51 years (reference category), 52-54 years (relatively late), and 55 years or older (late menopause). FindingsOverall, 301 438 women were included in our analysis. Of these 301 438 women, 12 962 (4•3%) had a first nonfatal cardiovascular disease event after menopause, of whom 9369 (3•1%) had coronary heart disease and 4338 (1•4%) had strokes. Compared with women who had menopause at age 50-51 years, the risk of cardiovascular disease was higher in women who had premature menopause (age <40 years; HR 1•55, 95% CI 1•38-1•73; p<0•0001), early menopause (age 40-44 years; 1•30, 1•22-1•39; p<0•0001), and relatively early menopause (age 45-49 years; 1•12, 1•07-1•18; p<0•0001), with a significantly reduced risk of cardiovascular disease following menopause after age 51 years (p<0•0001 for trend). The associations persisted in never smokers, and were strongest before age 60 years for women with premature menopause (HR 1•88, 1•62-2•20; p<0•0001) and early menopause (1•40, 1•27-1•54; p<0•0001), but were attenuated at age 60-69 years, with no significant association observed at age 70 years and older.Interpretation Compared with women who had menopause at age 50-51 years, women with premature and early menopause had a substantially increased risk of a non-fatal cardiovascular disease event before the age of 60 years, but not after age 70 years. Women with earlier menopause need close monitoring in clinical practice, and age at menopause might also be considered as ...

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characteristics, LUTS, health-related quality of life (HRQoL), and hospital attendance. RESULTSThe responses from 4570 respondents (mean age 61 years) were analysed. The estimated prevalence of OAB was 12.4% (men 14%, women 11%). Prevalence rates for OAB with and without urgency incontinence (one or more episode/week) were 6.4% and 6.0%, respectively. Prevalence rates increased with age; 5% of respondents aged 40-49 and 37% of those aged ≥ 80 years had OAB. HRQoL was compromised in 53% of respondents with OAB symptoms, specifically emotions (42%), sleep/vitality (37%), physical limitation (34%), role limitation (29%), and social limitation (22%). Among those whose HRQoL was affected, 23% (men 36%, women 8%) had visited a medical institution because of their urinary problems. CONCLUSIONThe results from this survey indicate that the prevalence of OAB was high and increased with age, but the rate of hospital attendance was low. Public awareness of OAB should be increased so that there can be optimum management of this condition. KEYWORDS urinary symptoms, epidemiology, overactive bladder OBJECTIVETo report an epidemiological survey of lower urinary tract symptoms (LUTS) to determine the prevalence of overactive bladder (OAB) symptoms (defined as a symptom complex of daily urinary frequency of eight or more times and urgency once or more per week) in Japan. SUBJECTS AND METHODSA self-administered questionnaire was mailed to 10 096 Japanese men and women aged ≥ 40 years selected by a two-stage randomized process. Survey questions, developed by members of the Japan Neurogenic Bladder Society Committee, covered four areas: demographic

STUDY QUESTIONAre parity and the timing of menarche associated with premature and early natural menopause?SUMMARY ANSWEREarly menarche (≤11 years) is a risk factor for both premature menopause (final menstrual period, FMP <40 years) and early menopause (FMP 40–44 years), a risk that is amplified for nulliparous women.WHAT IS KNOWN ALREADYWomen with either premature or early menopause face an increased risk of chronic conditions in later life and of early death. Findings from some studies suggest that early menarche and nulliparity are associated with early menopause, however overall the evidence is mixed. Much of the evidence for a direct relationship is hampered by a lack of comparability across studies, failure to adjust for confounding factors and inadequate statistical power.STUDY DESIGN, SIZE, DURATIONThis pooled study comprises 51 450 postmenopausal women from nine observational studies in the UK, Scandinavia, Australia and Japan that contribute to the International collaboration for a Life course Approach to reproductive health and Chronic disease Events (InterLACE).PARTICIPANTS/MATERIALS, SETTING, METHODSAge at menarche (categorized as ≤11, 12, 13, 14 and 15 or more years) and parity (categorized as no children, one child and two or more children) were exposures of interest. Age at FMP was confirmed by at least 12 months of cessation of menses where this was not the result of an intervention (such as surgical menopause due to bilateral oophorectomy or hysterectomy) and categorized as premature menopause (FMP before age 40), early menopause (FMP 40–44 years), 45–49 years, 50–51 years, 52–53 years and 54 or more years. We used multivariate multinomial logistic regression models to estimate relative risk ratio (RRR) and 95% CI for associations between menarche, parity and age at FMP adjusting for within-study correlation.MAIN RESULTS AND THE ROLE OF CHANCEThe median age at FMP was 50 years (interquartile range 48–53 years), with 2% of the women experiencing premature menopause and 7.6% early menopause. Women with early menarche (≤11 years, compared with 12–13 years) were at higher risk of premature menopause (RRR 1.80, 95% CI 1.53–2.12) and early menopause (1.31, 1.19–1.44). Nulliparity was associated with increased risk of premature menopause (2.26, 1.84–2.77) and early menopause (1.32, 1.09–1.59). Women having early menarche and nulliparity were at over 5-fold increased risk of premature menopause (5.64, 4.04–7.87) and 2-fold increased risk of early menopause (2.16, 1.48–3.15) compared with women who had menarche at ≥12 years and two or more children.LIMITATIONS, REASONS FOR CAUTIONMost of the studies (except the birth cohorts) relied on retrospectively reported age at menarche, which may have led to some degree of recall bias.WIDER IMPLICATIONS OF THE FINDINGSOur findings support early monitoring of women with early menarche, especially those who have no children, for preventive health interventions aimed at mitigating the risk of adverse health outcomes associated with early menopause.STUDY FUNDI...