Actin mutations are one cause of congenital fibre type disproportion

We report three heterozygous missense mutations of the skeletal muscle alpha actin gene (ACTA1) in three unrelated cases of congenital fiber type disproportion (CFTD) from Japan and Australia. This represents the first genetic cause of CFTD to be identified and confirms that CFTD is genetically heterogeneous. The three mutations we have identified Leucine221Proline, Aspartate292Valine, and Proline332Serine are novel. They have not been found previously in any cases of nemaline, actin, intranuclear rod, or rod-core myopathy caused by mutations in ACTA1. It remains unclear why these mutations cause type 1 fiber hypotrophy but no nemaline bodies. The three mutations all lie on one face of the actin monomer on the surface swept by tropomyosin during muscle activity, which may suggest a common pathological mechanism. All three CFTD cases with ACTA1 mutations had severe congenital weakness and respiratory failure without ophthalmoplegia. There were no clinical features specific to CFTD cases with ACTA1 mutations, but the presence of normal eye movements in a severe CFTD patient may be an important clue for the presence of a mutation in ACTA1.     

Weight development over time in parous women--the SPAWN study--15 years follow-up

BACKGROUND: Weight gain is common after pregnancy. Most studies suggest that weight gain associated with a pregnancy is between 0.5 and 3.8 kg up to 2.5 y of follow-up. However, 73% of the female patients at our obesity clinic identified pregnancy as an important trigger for marked weight retention. The majority retained more than 10 kg after each pregnancy. The aim of this study was to examine long-term weight development after pregnancy in a 15 y follow-up of women who took part in the Stockholm Pregnancy And Women's Nutrition (SPAWN) study. METHOD AND SUBJECTS: The SPAWN study is a long-term follow-up study of women who delivered children in 1984-85 in Stockholm (n=2342). A total of 1423 participants (response rate=61%) completed questionnaires, which covered eating behaviour and exercise, demographic information including social situation and status and details of the pregnancy before, during and up to 1 y after pregnancy. After 15 y, these women were invited to take part in the follow-up study. Anthropometric measurements and the same questionnaire data were collected from the 563 women who participated (response rate=40%). The sample was divided into two main groups: those who were normal weight before pregnancy and remained normal weight, and those who were normal weight before pregnancy and had become overweight at 15 y follow-up. RESULTS: Those women who became overweight had a higher pre-pregnant body mass index (BMI) (22.3+/-1.5 vs 20.5+/-1.6 kg/m(2), P<0.001), gained more weight during pregnancy (16.3+/-4.3 vs 13.6+/-3.7 kg, P<0.001) and had retained more at 1 y follow-up. The women who became overweight had a steeper weight trajectory gaining more from 1 y follow-up to 15 y follow-up (11.1+/-6.5 vs 4.5+/-6.5 kg, P<0.001), with a higher BMI at 15 y follow-up of 27.5+/-2.6 vs 22.5+/-2.3 5 kg/m(2) (P<0.001). However, differences between those who became overweight and those who did not could not be explained by age, number of children and various socioeconomic factors. Features of pregnancy that did differ between the two groups were breastfeeding and smoking cessation. However, women who became overweight had lower lactation scores than women who remained normal weight. Relatively more subjects of the group that became overweight stopped smoking during pregnancy. DISCUSSION: Pregnancy is a vulnerability factor for some women to become overweight. This study attempted to identify those factors that place initially normal weight women on a steeper weight trajectory as a result of pregnancy. Demographic, behavioural, physical and psychological characteristics only partly explain the weight gain observed at 15 y follow-up. Further research is required to investigate the relative role of these characteristics in predicting postpregnancy weight development.     

Hypoaldosteronism in three sibs due to 18-dehydrogenase deficiency

Three sibs all presented in the early neonatal period with a salt-losing syndrome. The salt-losing form of congenital adrenal hyperplasia was diagnosed and appropriate treatment with glucocorticosteroids, mineralocorticosteroids, and additional dietary salt started. Although early life was maintained with difficulty, with age all 3 children required decreasing amounts of replacement steroids to maintain normal plasma electrolyte balance. They were reinvestigated at the ages of 15 years and 8 years (twins), when cortisol synthesis and metabolism proved normal, but aldosterone synthesis was blocked by deficiency of 18-dehydrogenase. Rational treatment of these cases of a salt-losing syndrome in which aldosterone synthesis alone is blocked due to lack of the enzyme 18-dehydrogenase requires the administration of a mineralocorticosteroid drug only. Since deoxycorticosterone (acetate or pivalate) requires intramuscular administration, as life-long therapy oral fludrocortisone is preferable. Although fludrocortisone has glucocorticoid activity, the "hydrocortisone equivalent" effect of the small dosage used was unlikely to inhibit either pituitary corticotrophin or growth hormone production.     

Influence of clinical status on the association between plasma total and unbound bilirubin and death or adverse neurodevelopmental outcomes in extremely low birth weight infants

Objectives: To assess the influence of clinical status on the association between total plasma bilirubin and unbound bilirubin on death or adverse neurodevelopmental outcomes at 18–22 months corrected age in extremely low birth weight infants. Method: Total plasma bilirubin and unbound bilirubin were measured in 1101 extremely low birth weight infants at 5 ± 1 days of age. Clinical criteria were used to classify infants as clinically stable or unstable. Survivors were examined at 18–22 months corrected age by certified examiners. Outcome variables were death or neurodevelopmental impairment, death or cerebral palsy, death or hearing loss, and death prior to follow‐up. For all outcomes, the interaction between bilirubin variables and clinical status was assessed in logistic regression analyses adjusted for multiple risk factors. Results: Regardless of clinical status, an increasing level of unbound bilirubin was associated with higher rates of death or neurodevelopmental impairment, death or cerebral palsy, death or hearing loss and death before follow‐up. Total plasma bilirubin values were directly associated with death or neurodevelopmental impairment, death or cerebral palsy, death or hearing loss, and death before follow‐up in unstable infants, but not in stable infants. An inverse association between total plasma bilirubin and death or cerebral palsy was found in stable infants. Conclusions: In extremely low birth weight infants, clinical status at 5 days of age affects the association between total plasma bilirubin and death or adverse neurodevelopmental outcomes at 18–22 months of corrected age. An increasing level of UB is associated a higher risk of death or adverse neurodevelopmental outcomes regardless of clinical status. Increasing levels of total plasma bilirubin are directly associated with increasing risk of death or adverse neurodevelopmental outcomes in unstable, but not in stable infants.     

Acute inhalation of ozone induces DNA methylation of apelin in lungs of Long-Evans rats

Apelin has cardiopulmonary protective properties that promote vasodilation and maintenance of the endothelial barrier. While reductions in apelin have been identified as a contributor to various lung diseases, including pulmonary edema, its role in the effect of air pollutants has not been examined. Thus, in the current study, we sought to investigate if apelin is a downstream target of inhaled ozone and if such change in expression is related to altered DNA methylation in the lung. Male, Long-Evans rats were exposed to filtered air or 1.0?ppm ozone for 4?h. Ventilation changes were assessed using whole-body plethysmography immediately following exposure, and markers of pulmonary edema and inflammation were assessed in the bronchoaveolar lavage (BAL) fluid. The enzymatic regulators of DNA methylation were measured in the lung, along with methylation and hydroxymethylation of the apelin promoter. Data showed that ozone exposure was associated with increased enhanced pause and protein leakage in the BAL fluid. Ozone exposure reduced DNA cytosine-5-methyltransferase (DNMT) activity and Dnmt3a/b gene expression. Exposure-induced upregulation of proliferating cell nuclear antigen, indicative of DNA damage, repair, and maintenance methylation. Increased methylation and reduced hydroxymethylation were measured on the apelin promoter. These epigenetic modifications accompanied ozone-induced reduction of apelin expression and development of pulmonary edema. In conclusion, epigenetic regulation, specifically increased methylation of the apelin promoter downstream of DNA damage, may lead to reductions in protective signaling of the apelinergic system, contributing to the pulmonary edema observed following the exposure to oxidant air pollution.