Aberrant Function of the C-Terminal Tail of HIST1H1E Accelerates Cellular Senescence and Causes Premature Aging.

Histones mediate dynamic packaging of nuclear DNA in chromatin, a process that is precisely controlled to guarantee efficient compaction of the genome and proper chromosomal segregation during cell division and to accomplish DNA replication, transcription, and repair. Due to the important structural and regulatory roles played by histones, it is not surprising that histone functional dysregulation or aberrant levels of histones can have severe consequences for multiple cellular processes and ultimately might affect development or contribute to cell transformation. Recently, germline frameshift mutations involving the C-terminal tail of HIST1H1E, which is a widely expressed member of the linker histone family and facilitates higher-order chromatin folding, have been causally linked to an as-yet poorly defined syndrome that includes intellectual disability. We report that these mutations result in stable proteins that reside in the nucleus, bind to chromatin, disrupt proper compaction of DNA, and are associated with a specific methylation pattern. Cells expressing these mutant proteins have a dramatically reduced proliferation rate and competence, hardly enter into the S phase, and undergo accelerated senescence. Remarkably, clinical assessment of a relatively large cohort of subjects sharing these mutations revealed a premature aging phenotype as a previously unrecognized feature of the disorder. Our findings identify a direct link between aberrant chromatin remodeling, cellular senescence, and accelerated aging.

First two unrelated cases of isolated sedoheptulokinase deficiency: A benign disorder?

We present the first two reported unrelated patients with an isolated sedoheptulokinase (SHPK) deficiency. The first patient presented with neonatal cholestasis, hypoglycemia, and anemia, while the second patient presented with congenital arthrogryposis multiplex, multiple contractures, and dysmorphisms. Both patients had elevated excretion of erythritol and sedoheptulose, and each had a homozygous nonsense mutation in SHPK. SHPK is an enzyme that phosphorylates sedoheptulose to sedoheptulose-7-phosphate, which is an important intermediate of the pentose phosphate pathway. It is questionable whether SHPK deficiency is a causal factor for the clinical phenotypes of our patients. This study illustrates the necessity of extensive functional and clinical workup for interpreting a novel variant, including nonsense variants.

Young adolescent with trisomy 13.

A young adolescent girl with trisomy 13 was admitted twice to the paediatric department: the first time because of haematocolpos due to uterus didelphys and unilateral transverse vaginal septum, and the second time because of heart failure due to ruptured sinus of Valsalva aneurysm. As a consequence of the historical early high mortality rate in trisomy 13, we are not aware of known complications in older patients. With better survival nowadays through childhood, we advise structural ultrasonographic cardiac and female genital screening in trisomy 13 patients reaching adolescent age.

[A boy with abdominal pain and a hypertympanic abdomen]. / Een jongen met buikpijn en hypertympanie.

A 6-year-old boy, known with Potocki-Lupski syndrome (17p11.2 duplication), mild intellectual disability and constipation, presented with episodes of abdominal pain. His defecation pattern was normal with polyethylene glycol. Physical examination showed a hypertympanic distended abdomen. Extreme dilatation and elongation of the colon was seen on abdominal x-ray, corresponding with aerophagia.

[A toddler with a rare complication of scarlet fever]. / Een peuter met een zeldzame complicatie van roodvonk.

BACKGROUND: Haemolytic group A streptococci (GAS) are the most common bacterial cause of infection in the Netherlands. These bacteria can cause many different non-invasive infections, including scarlet fever. CASE DESCRIPTION: A two-year-old girl presented with fever, tachycardia, exanthema and swelling in the neck. On suspicion of scarlet fever with neck phlegmon we treated her with antibiotics and supportive therapy. Blood and throat cultures revealed growth of haemolytic GAS. Lab tests revealed mild hyperthyroidism and neck ultrasound revealed an inhomogeneous appearance of the thyroid. We diagnosed her with 'infectious thyroiditis', a rare complication of infection with haemolytic GAS. A fistula from the pyriform sinus could not be demonstrated. CONCLUSION: Although GAS infections are common, complications such as thyroiditis are rare. When a paediatric patient is diagnosed with infectious thyroiditis, a fistula from the pyriform sinus should be considered. Patients with such a congenital malformation have an increased risk of recurrent infectious thyroiditis and thyroid abscess formation.

[Anorectal pain in children: rare or rarely recognised?]. / Anuskrampen bij kinderen: Zeldzaam of zelden herkend?

Anorectal pain is a common symptom, often as part of functional gastrointestinal disorders. Children seldom present with this complaint. Proctalgia fugax and chronic proctalgia are both anorectal pain syndromes but differ in duration and frequency of episodes and in pain characteristics. No research has been conducted on anorectal pain syndromes in children. We present two patients. Firstly, an 8-year-old girl who suffered from anorectal cramps. We found no underlying cause apart from constipation. The symptoms disappeared spontaneously. The second concerned an 8-year-old boy who presented with recurrent anorectal cramps. He was diagnosed with celiac disease. Anorectal dysfunction and visceral hypersensitivity have been described in adult celiac patients. Symptoms of anorectal pain in children are rare probably because it often remains unrecognised. Noninvasive diagnostic methods and interventions are preferred in paediatric medicine. Screening for celiac disease in children with anorectal pain episodes should be considered.

Moderate alcohol consumption is associated with reduced arterial stiffness in older adults: the Rotterdam study.

BACKGROUND: Light-to-moderate alcohol consumption has been associated with a lower risk of cardiovascular disease. The protective effect of alcohol could involve arterial properties as arterial stiffness and distensibility. METHODS: The relationship between alcohol and arterial stiffness was studied within the framework of the Rotterdam Study, a population-based study in individuals aged 55 and older. The present study included 3178 participants in the third examination phase. Arterial stiffness was measured by two different methods, i.e., the carotid-femoral pulse wave velocity and the DC of the common carotid artery. Categories of alcohol consumption were defined as follows: < or =3 glasses of alcohol per week, 4-10 glasses per week, 11-20 glasses per week, and > or =21 glasses per week. Linear regression analysis was used to investigate the association between alcohol consumption and measures of arterial stiffness. RESULTS: In multivariate-adjusted models, women drinking 4-10, 11-20, and > or =21 glasses of alcoholic beverage per week had a -0.07 (0.22 to -0.38), -0.18 (0.12 to -0.49), and 0.12 (0.19 to -0.43) m/s difference in mean pulse wave velocity compared to those drinking 0-3 glasses per week (reference group). Corresponding differences in the carotid DC were 0.68 (1.21 to 0.15), 0.28 (0.82 to -0.25), and 0.36 (0.91 to -0.18) 10(-3)/kPa. In men, the estimates were not statistically significant, although a similar trend was observed. CONCLUSIONS: Moderate alcohol consumption is associated with lower arterial stiffness in women independently of cardiovascular risk factors and atherosclerosis.

Alcohol consumption and coronary calcification in a general population.

BACKGROUND: A U- or J-shaped association exists between alcohol consumption and coronary heart disease. One of the proposed mechanisms for this association involves atherogenesis, but there are no data on the association between alcohol consumption and coronary atherosclerosis in asymptomatic subjects. Coronary calcification, a measure of coronary atherosclerosis, allows for the study of the association. METHODS: This cross-sectional study was performed using data from the population-based Rotterdam Coronary Calcification Study. Data on alcohol consumption were available for 1795 individuals without coronary heart disease. Mean +/- SD age of the participants was 71 +/- 5.7 years. Coronary calcification was detected on electron beam computed tomographic scans and quantified as a calcium score by the Agatston method. Extensive coronary calcification was defined as a calcium score above 400. RESULTS: In this population, 15.8% of individuals consumed no alcohol; 46.5% consumed 1 alcoholic drink or less per day; 16.9% consumed 1 to 2 drinks per day; and 20.9% consumed more than 2 drinks per day. A U-shaped association was found between alcohol consumption and coronary calcification. Compared with nondrinkers, the odds ratio of extensive coronary calcification was 0.60 (95% confidence interval [CI], 0.44-0.82) for those who consumed 1 drink or less daily; 0.51 (95% CI, 0.35-0.76) for those who consumed 1 to 2 drinks daily; and 0.90 (95% CI, 0.62-1.29) for those who consumed more than 2 drinks. The association remained after multivariate adjustment. CONCLUSIONS: The consumption of 2 alcoholic drinks or fewer per day was inversely associated with extensive coronary calcification. The risk of extensive coronary calcification was 50% lower in individuals who consumed 1 to 2 alcoholic drinks per day than in nondrinkers.

Families and the natural history of blood pressure. A 27-year follow-up study.

BACKGROUND: Previous studies on familial aggregation of blood pressure (BP) have reported data on family history of hypertension. Data on actual parental BP levels and the subsequent natural history of BP in their offspring are scarce. METHODS: In a population-based study with 596 children aged 5 to 19 years, cardiovascular risk factors were measured annually from 1975 through 2002. Parental data were obtained at baseline. Repeated BP measurements were studied as a function of tertiles of age-adjusted BP measured in their parents at baseline. RESULTS: Systolic BP during follow-up was higher in offspring whose parents were both in the highest tertile compared with children whose parents were not in the highest tertile (difference 2.7 mm Hg, 95% confidence interval 0.2 to 5.2). Having both parents in the highest tertile of diastolic BP resulted in a substantially higher diastolic BP ranging from 1.9 mm Hg at age 15 years to 8.5 mm Hg at age 45 years. These differences were adjusted for age, sex, body mass index, total serum cholesterol, smoking habits, and alcohol consumption. CONCLUSIONS: The results of this study indicate that actual parental BP is an important predictor of BP development from childhood into young adulthood. This is important when constituting cardiovascular risk profiles for children and young adults.

Accuracy of a screening instrument to identify potential child abuse in emergency departments.

Although screening for child abuse at emergency departments (EDs) increases the detection rate of potential child abuse, an accurate instrument is lacking. This study was designed to measure the accuracy of a screening instrument for detection of potential child abuse used in EDs. In a prospective cohort study at three Dutch EDs, a 6-item screening instrument for child abuse, Escape, was completed for each child visiting the ED. The data from the completed Escape instrument was used to calculate sensitivity, specificity, and the positive/negative predictive value per item. The clinical notes and conclusions of the screen instruments of all potentially abused children reported to the hospitals' Child Abuse Teams were collected and reviewed by an expert panel. A logistic regression model was used to evaluate the predictors of potential abuse. Completed Escape instruments were available for 18,275 ED visits. Forty-four of the 420 children with a positive screening result, and 11 of the 17,855 children with a negative result were identified as potentially abused. Sensitivity of the Escape instrument was 0.80 and specificity was 0.98. Univariate logistic regression showed that potentially abused children were significantly more likely to have had an aberrant answer to at least one of the items, OR=189.8, 95% CI [97.3, 370.4]. Most of the children at high risk for child abuse were detected through screening. The Escape instrument is a useful tool for ED staff to support the identification of those at high risk for child abuse.

Effects of systematic screening and detection of child abuse in emergency departments.

OBJECTIVE: Although systematic screening for child abuse of children presenting at emergency departments might increase the detection rate, studies to support this are scarce. This study investigates whether introducing screening, and training of emergency department nurses, increases the detection rate of child abuse. METHODS: In an intervention cohort study, children aged 0 to 18 years visiting the emergency departments of 7 hospitals between February 2008 and December 2009 were enrolled. We developed a screening checklist for child abuse (the "Escape Form") and training sessions for nurses; these were implemented by using an interrupted time-series design. Cases of suspected child abuse were determined by an expert panel using predefined criteria. The effect of the interventions on the screening rate for child abuse was calculated by interrupted time-series analyses and by the odds ratios for detection of child abuse in screened children. RESULTS: A total of 104028 children aged 18 years or younger were included. The screening rate increased from 20% in February 2008 to 67% in December 2009. Significant trend changes were observed after training the nurses and after the legal requirement of screening by the Dutch Health Care Inspectorate in 2009. The detection rate in children screened for child abuse was 5 times higher than that in children not screened (0.5% vs 0.1%, P < .001). CONCLUSIONS: These results indicate that systematic screening for child abuse in emergency departments is effective in increasing the detection of suspected child abuse. Both a legal requirement and staff training are recommended to significantly increase the extent of screening.

Maternal smoking in pregnancy is associated with cholesterol development in the offspring: A 27-years follow-up study.

OBJECTIVE: To examine the associations of maternal smoking in pregnancy with development of cholesterol levels from childhood to adulthood. METHODS: Total cholesterol, high-density lipoprotein (HDL) cholesterol and low-density lipoprotein (LDL) cholesterol were measured annually from 1975 to 1993 and in 2002 in 350 subjects aged 5-19 years at baseline who participate in a prospective cohort study. Pregnancy and birth data were obtained through questionnaires sent to the parents. RESULTS: Children of mothers who smoked in pregnancy showed a higher annual change in total cholesterol of 0.12 mmol/l per 10 years (95% confidence interval (CI): 0, 0.23) compared to children whose mothers did not smoke in pregnancy. Larger effect estimates were found in children with moderate overweight (0.39 mmol/l per 10 years (95% CI: 0.14, 0.63). HDL-cholesterol and LDL-cholesterol showed tendencies towards a decrease and increase, respectively, in children of mothers who smoked in pregnancy compared to children whose mothers did not smoke in pregnancy. Adjustment for potential confounders did not materially change the effect estimates. CONCLUSION: This study suggests for the first time that maternal smoking in pregnancy is associated with an increased rise in total cholesterol levels and a tendency towards an adverse lipoprotein profile in the offspring.