The influence of genetic variation on innate immune activation in an environment with high infectious pressure.

Interleukin-10 (IL-10) production is under tight genetic control in populations living in affluent environments. However, little is known about the role of IL10 genetics on cytokine production in populations living in environments with high infectious pressure. We have previously reported that, in a rural Ghanaian population, the most common IL10 haplotype associates with a pro-inflammatory response. Here, we aim to replicate these findings in an independent sample of the same population 2 years later. IL-10 and tumour necrosis factor-α (TNF-α) protein concentrations were determined in whole-blood samples ex vivo stimulated with lipopolysaccharide and zymosan in 2006 (n=615) and 2008 (n=647). The association between IL10 single nucleotide polymorphisms and Z-scores of IL-10 and TNF-α levels was analysed in each population subset. The most common IL10 haplotype was associated with a significantly lower IL-10 production and nonsignificantly increased TNF-α levels. The correlation between repeated cytokine assays, based on 111 individuals with measurements in both 2006 and 2008, was r=0.53 (P<0.001) for IL-10 and r=0.36 (P<0.001) for TNF-α. The replication of our previously found effect of variation in the IL10 gene on IL-10 production and the correlation between repeated cytokine stimulation assays provide evidence that IL10 genetics have an important role in regulating the host response under high infectious pressure.

Performance of the whole-blood stimulation assay for assessing innate immune activation under field conditions.

Innate propensity of immune activation is reflected in production of pro- and anti-inflammatory cytokines upon stimulation of Toll-like receptors (TLR) in whole-blood stimulation assays. The validity of the whole-blood stimulation assay under field conditions has not been evaluated extensively. Here, we have determined correlation of individually repeated whole-blood stimulation assays in a field-study in Ghana and compared it with that of two Dutch populations performed under optimal conditions. We also examined cytokine production to various TLR-agonists in order to create an assay that would mimic general innate immune responses. Under field conditions repeated assessments of lipopolysaccharide-induced Tumor Necrosis Factor-alpha (TNFalpha) production were poorly correlated (r=0.15, p=0.087). Correlation was relatively high for production of Interleukin-10 (IL10) (r=0.48, p<0.001) and comparable to that observed in the Dutch population under optimal conditions. Combined stimulation with lipopolysaccharide and zymosan resulted in cytokine production profiles that were similar to that attained after stimulation with a mixed culture of bacteria. Here, we conclude that variation of a whole-blood assay performed in field setting is large in general but that production of IL10 seems to better reflect an innate pro- or anti-inflammatory tendency whereas production of TNFalpha may predominantly reflect recent immunological challenges. Furthermore, simultaneous stimulation of several Toll-like receptors may mimic general innate immune activation.

Quality-quantity trade-off of human offspring under adverse environmental conditions.

A central paradigm in life-history theory is the trade-off between offspring number and quality. Several studies have investigated this trade-off in humans, but data are inconclusive, perhaps because prosperous socio-cultural factors mask the trade-off. Therefore, we studied 2461 offspring groups in an area under adverse conditions in northern Ghana with high fertility and mortality rates. In a linear mixed model controlling for differences in age and tribe of the mother and socioeconomic status, each additional child in the offspring group resulted in a 2.3% (95% CI 1.9-2.6%, P < 0.001) lower proportional survival of the offspring. Furthermore, we made use of the polygamous population structure and compared offspring of co-wives in 388 households, thus controlling for variation in resources between compounds. Here, offspring survival decreased 2.8% (95% CI 2.3-4.0%, P < 0.001) for each increase in offspring number. We interpret these data as an apparent quality-quantity trade-off in human offspring.

[Diagnostic image (356). A man with a painfully distended abdomen and a mass on the plain abdominal radiograph]. / Diagnose in beeld (356). Een man met een gezwollen, pijnlijke buik en een massa op de buikoverzichtsfoto.

A 44-year-old man had abdominal pain, abdominal swelling and constipation. A plain abdominal radiograph showed signs of an ileus and as an unrelated finding an extensively calcified former renal transplant.

p53 regulates a non-apoptotic death induced by ROS.

DNA damage induced by reactive oxygen species and several chemotherapeutic agents promotes both p53 and poly (ADP-ribose) polymerase (PARP) activation. p53 activation is well known to regulate apoptotic cell death, whereas robust activation of PARP-1 has been shown to promote a necrotic cell death associated with energetic collapse. Here we identify a novel role for p53 in modulating PARP enzymatic activity to regulate necrotic cell death. In mouse embryonic fibroblasts, human colorectal and human breast cancer cell lines, loss of p53 function promotes resistance to necrotic, PARP-mediated cell death. We therefore demonstrate that p53 can regulate both necrotic and apoptotic cell death, mutations or deletions in this tumor-suppressor protein may be selected by cancer cells to provide not only their resistance to apoptosis but also to necrosis, and explain resistance to chemotherapy and radiation even when it kills via non-apoptotic mechanisms.

Gerontology and geriatrics in Dutch medical education.

BACKGROUND: The world population is ageing and healthcare services require trained staff who can address the needs of older patients. In this study we determined how current medical education prepares Dutch students of medicine in the field of Gerontology and Geriatrics (G&G). METHODS: Using a checklist of the essentials of G&G, we assessed Dutch medical education on three levels. On the national level we analysed the latest National Blueprint for higher medical education (Raamplan artsopleiding 2009). On the faculty level we reviewed medical curricula on the basis of interviews with program directors and inspection of course materials. On the student level we assessed the topics addressed in the questions of the cross-institutional progress test (CIPT). RESULTS: The National Bluepr int contains few specific G&G objectives. Obligatory G&G courses in medical schools on average amount to 2.2% of the total curriculum measured as European Credit Transfer System units (ECTS). Only two out of eight medical schools have practical training during the Master phase in the form of a clerkship in G&G. In the CIPT, on average 1.5% of questions cover G&G. CONCLUSION: Geriatric education in the Netherlands does not seem to be in line with current demographic trends. The National Blueprint falls short of providing sufficiently detailed objectives for education on the care of older people. The geriatric content offered by medical schools is varied and incomplete, and students are only marginally tested on their knowledge of G&G in the CIPT.

Mortality in former Olympic athletes: retrospective cohort analysis.

OBJECTIVE: To assess the mortality risk in subsequent years (adjusted for year of birth, nationality, and sex) of former Olympic athletes from disciplines with different levels of exercise intensity. DESIGN: Retrospective cohort study. SETTING: Former Olympic athletes. PARTICIPANTS: 9889 athletes (with a known age at death) who participated in the Olympic Games between 1896 and 1936, representing 43 types of disciplines with different levels of cardiovascular, static, and dynamic intensity exercise; high or low risk of bodily collision; and different levels of physical contact. MAIN OUTCOME MEASURE: All cause mortality. RESULTS: Hazard ratios for mortality among athletes from disciplines with moderate cardiovascular intensity (1.01, 95% confidence interval 0.96 to 1.07) or high cardiovascular intensity (0.98, 0.92 to 1.04) were similar to those in athletes from disciplines with low cardiovascular intensity. The underlying static and dynamic components in exercise intensity showed similar non-significant results. Increased mortality was seen among athletes from disciplines with a high risk of bodily collision (hazard ratio 1.11, 1.06 to 1.15) and with high levels of physical contact (1.16, 1.11 to 1.22). In a multivariate analysis, the effect of high cardiovascular intensity remained similar (hazard ratio 1.05, 0.89 to 1.25); the increased mortality associated with high physical contact persisted (hazard ratio 1.13, 1.06 to 1.21), but that for bodily collision became non-significant (1.03, 0.98 to 1.09) as a consequence of its close relation with physical contact. CONCLUSIONS: Among former Olympic athletes, engagement in disciplines with high intensity exercise did not bring a survival benefit compared with disciplines with low intensity exercise. Those who engaged in disciplines with high levels of physical contact had higher mortality than other Olympians later in life.