J.A. de Wilde

A serine protease is involved in the initiation of DNA damage-induced apoptosis.

AbstractCaspases are considered to be the key effector proteases of apoptosis. Initiator caspases cleave and activate downstream executioner caspases, which are responsible for the degradation of numerous cellular substrates. We studied the role of caspases in apoptotic cell death of a human melanoma cell line. Surprisingly, the pancaspase inhibitor zVAD-fmk was unable to block cleavage of poly(ADP-ribose) polymerase (PARP) after treatment with etoposide, while it did prevent DEVDase activity. It is highly unlikely that caspase-2, which is a relatively zVAD-fmk-resistant caspase, is mediating etoposide-induced PARP cleavage, as a preferred inhibitor of this caspase could not prevent cleavage. In contrast, caspase activation and PARP degradation were blocked by pretreatment of the cells with the serine protease inhibitor 4-(2-aminoethyl)benzenesulfonyl fluoride (AEBSF). We therefore conclude that a serine protease regulates an alternative initiation mechanism that leads to caspase activation and PARP cleavage. More importantly, while zVAD-fmk could not rescue melanoma cells from etoposide-induced death, the combination with AEBSF resulted in substantial protection. This indicates that this novel pathway fulfills a critical role in the execution of etoposide-induced programmed cell death.

Height of South Asian children in the Netherlands aged 0–20 years: secular trends and comparisons with current Asian Indian, Dutch and WHO references

Abstract Background: People from Asian populations are generally shorter than other ethnic groups. It is unknown if current universal height references are suitable for affluent South Asian children in the Netherlands. Aims: To develop height-for-age charts for contemporary South Asian children aged 0–20 years living in the Netherlands, to evaluate secular trends, and to compare the charts with current Asian Indian, Dutch and WHO references. Subjects and methods: A population-based study measured 3315 South Asian children aged 0–20 years between 2007–2010. Among this cohort, 6876 measurements were taken. Another 7388 measurements were taken of a historical cohort of 1078 children born between 1974–1976 (aged 0–18 years). Results: An upward trend in height was observed for South Asian children living in the Netherlands between 1992–2010. The height-for-age charts of the South Asian historical cohort were similar to current Asian Indian charts. South Asian children in the Netherlands were shorter than their Dutch contemporaries at every age; and these differences increased further during adolescence. Compared to the WHO height-for-age references, there were considerable discrepancies in height, with curves intersecting twice. Conclusion: The discrepancies between the South Asian and Dutch and WHO height-for-age references indicate differences in growth patterns between the source populations.

Finding maximal transcriptome differences between reprotoxic and non-reprotoxic phthalate responses in rat testis

The chemical legislation of the EU, Registration, Evaluation, and Authorization of Chemicals (REACH), stipulates that about 30 000 chemical substances are to be assessed on their possible risks. Toxicological evaluation of these compounds will at least partly be based on animal testing. In particular, the assessment of reproductive toxicity is a very complicated, time‐consuming and animal‐demanding process. Introducing microarray‐based technologies can potentially refine in vivo toxicity testing. If compounds of a distinct chemical class induce reproducible gene‐expression responses with a recognizable overlap, these gene‐expression signatures may indicate intrinsic features of certain compounds, including specific toxicity. In the present study, we have set out the first steps towards this approach for the reproductive toxicity of phthalates. Male rats were treated with a single dose of either reprotoxic or non‐reprotoxic phthalates, and were analyzed 24 h afterwards. Subsequently, histopathological and gene‐expression profiling analyses were performed. Despite ambiguous histopathological observations, we were able to identify genes with differential expression profiles between the reprotoxic phthalates and the non‐reprotoxic counterparts. This shows that differences in gene‐expression profiles, indicative of the type of exposure, may be detected earlier, or at lower doses, than classical pathological endpoints. These findings are promising for ‘early warning’ biomarker analyses and for using toxicogenomics in a category approach. Ultimately, this could lead to a more cost‐effective approach for prioritizing the toxicity testing of large numbers of chemicals in a short period of time in hazard assessment of chemicals, which is one of the objectives of the REACH chemical legislation. Copyright

BMI-for-age in South Asian children of 0–20 years in the Netherlands: secular changes and misclassification by WHO growth references

Abstract Background: South Asians are prone to cardiometabolic disease at lower BMI levels than most other ethnic groups, starting in childhood. The magnitude of BMI misclassifications is unknown. Aim: To compare the BMI distribution of contemporary South Asian 0–20 year olds in the Netherlands with: (1) The South Asian norm reference (secular trends); and (2) The WHO child growth standard and reference. Subjects and methods: The BMI-for-age distribution of 6677 routine measurements of 3322 South Asian children, aged 0–20 years, was described with the LMS method and BMI z-scores. Results: The BMI distribution in South Asian 0–4 year olds was almost similar to the norm reference (mean BMI z-score = 0.11, skewness = 0.31, SD = 1.0), whereas in 5–19 year olds the distribution had shifted upwards (mean = 0.53) and widened (skewness = −0.12, SD = 1.08). Overweight (incl. obesity) and obesity peaked at 8–10 years, at 45–48% and 35–37%, respectively. Relative to the WHO references, the BMI distribution was left-shifted at ages 0–4 years (mean BMI z-score = −0.46, skewness = 0.23, SD = 0.98) and widened at ages 5–20 years (mean = 0.05; skewness = −0.02, SD = 1.40). At most ages, thinness rates were significantly higher and obesity rates lower than based on South Asian norms. Conclusions: A secular change of BMI-for-age in South Asian children mostly affected children >4 years. WHO references likely under-estimate overweight and obesity rates in South Asian children.

Tracking of thinness and overweight in children of Dutch, Turkish, Moroccan and South Asian descent from 3 through 15 years of age: a historical cohort study

BackgroundOverweight is shown to track (= to maintain a relative position in a distribution) from childhood to adulthood, but is mostly studied in preobesogenic cohorts and in single ethnic groups. Little is known about tracking of thinness by ethnicity.Objectivesto determine (differences in) tracking of BMI (class) from 3 through 15 years and the prediction of BMI class at 13–15 years of age in contemporary Dutch, Turkish, Moroccan and South Asian children living in the Netherlands.MethodsHistorical cohort of 7625 children, born 1994–1997, with 24,376 measurements of BMI. BMI z-score and BMI class was analysed using universal criteria. South Asian children were also assessed using ethnic specific BMI criteria. Diagnostic odds ratios (OR) and test properties were calculated to estimate the ability of BMI class at 3–4 years to predict BMI class at 13–15 years.ResultsTracking of thinness between 3 and 15 years was stronger than that of overweight, as indicated by a generally higher diagnostic OR. BMI trajectories between 3 and 15 years of age of thin, normal weight and overweight adolescents were, although significantly different, quite similarly shaped in children of Dutch, Turkish and Moroccan descent. The South Asian BMI trajectory deviated considerably from the other ethnic groups, but the differences disappeared when South Asian specific BMI criteria were applied. A substantial proportion of overweight developed between 5–10 years, after which less children shifted to other BMI classes. A total of 55–78% of children with overweight at 3–4 years retained their overweight at 13–15 years, and 10–20% of 3–4 year olds with thinness remained thin.ConclusionsIn all ethnic groups, overweight and especially thinness highly tracked into adolescence. South Asian children differed from the other ethnic groups when universal BMI criteria were applied, but with South Asian specific BMI criteria tracking patterns became more concordant.