Does in utero exposure to synthetic glucocorticoids influence birthweight,head circumference and birth length? A systematic review of current evidence in humans

Synthetic glucocorticoids are the mainstay treatment for stimulating lung maturation in threatened preterm delivery. Animal studies suggest that in utero exposure to glucocorticoids leads to a reduction in birth size. Smaller birthweight has been associated with higher risk of many chronic diseases. Therefore, the authors undertook a systematic review of human studies examining the association between synthetic glucocorticoid treatment and birth size. Medline, EMBASE, PubMed, Cochrane, Google scholar and Institute of Life Science databases were searched for studies published between 1978 and 2009 investigating the association between synthetic glucocorticoids and birthweight, head circumference, birth length and ponderal index. All studies controlling for gestational age were examined. Seventeen studies were included in the analysis. Nine out of 17 studies reported a reduction in birthweight (range 12-332 g), five of nine a reduction of head circumference (range 0.31-1.02 cm) and two of four a reduction of 0.8 cm in birth length. Despite methodological inconsistencies and limitations that impede clear conclusions, the evidence suggests an association between in utero exposure to synthetic glucocorticoids and reduced birth size.     

Combined effects of MC4R and FTO common genetic variants on obesity in European general populations

Genome-wide association scans recently identified common polymorphisms, in intron 1 of FTO and 188 kb downstream MC4R, that modulate body mass index (BMI) and associate with increased risk of obesity. Although their individual contribution to obesity phenotype is modest, their combined effects and their interactions with environmental factors remained to be evaluated in large general populations from birth to adulthood. In the present study, we analyzed independent and combined effects of the FTO rs1421085 and MC4R rs17782313 risk alleles on BMI, fat mass, prevalence and incidence of obesity and subsequent type 2 diabetes (T2D) as well as their interactions with physical activity levels and gender in two European prospective population-based cohorts of 4,762 Finnish adolescents (NFBC 1986) and 3,167 French adults (D.E.S.I.R.). Compared to participants carrying neither FTO nor MC4R risk allele (20–24% of the populations), subjects with three or four risk alleles (7–10% of the populations) had a 3-fold increased susceptibility of developing obesity during childhood. In adults, their combined effects were more modest (~1.8-fold increased risk) and associated with a 1.27% increase in fat mass (P?=?0.001). Prospectively, we demonstrated that each FTO and MC4R risk allele increased obesity and T2D incidences by 24% (P?=?0.02) and 21% (P?=?0.02), respectively. However, the effect on T2D disappeared after adjustment for BMI. The Z-BMI and ponderal index of newborns homozygous for the rs1421085 C allele were 0.1 units (P?=?0.02) and 0.27 g/cm³ (P?=?0.005) higher, respectively, than in those without FTO risk allele. The MC4R rs17782313 C allele was more associated with obesity and fat mass deposition in males than in females (P?=?0.003 and P?=?0.03, respectively) and low physical activity accentuated the effect of the FTO polymorphism on BMI increase and obesity prevalence (P?=?0.008 and P?=?0.01, respectively). In European general populations, the combined effects of common polymorphisms in FTO and MC4R are therefore additive, predictive of obesity and T2D, and may be influenced by interactions with physical activity levels and gender, respectively.     

An official ATS statement: hepatotoxicity of antituberculosis therapy

Drug-induced liver injury (DILI) is a problem of increasing significance, but has been a long-standing concern in the treatment of tuberculosis (TB) infection. The liver has a central role in drug metabolism and detoxification, and is consequently vulnerable to injury. The pathogenesis and types of DILI are presented, ranging from hepatic adaptation to hepatocellular injury. Knowledge of the metabolism of anti-TB medications and of the mechanisms of TB DILI is incomplete. Understanding of TB DILI has been hampered by differences in study populations, definitions of hepatotoxicity, and monitoring and reporting practices. Available data regarding the incidence and severity of TB DILI overall, in selected demographic groups, and in those coinfected with HIV or hepatitis B or C virus are presented. Systematic steps for prevention and management of TB DILI are recommended. These include patient and regimen selection to optimize benefits over risks, effective staff and patient education, ready access to care for patients, good communication among providers, and judicious use of clinical and biochemical monitoring. During treatment of latent TB infection (LTBI) alanine aminotransferase (ALT) monitoring is recommended for those who chronically consume alcohol, take concomitant hepatotoxic drugs, have viral hepatitis or other preexisting liver disease or abnormal baseline ALT, have experienced prior isoniazid hepatitis, are pregnant or are within 3 months postpartum. During treatment of TB disease, in addition to these individuals, patients with HIV infection should have ALT monitoring. Some experts recommend biochemical monitoring for those older than 35 years. Treatment should be interrupted and, generally, a modified or alternative regimen used for those with ALT elevation more than three times the upper limit of normal (ULN) in the presence of hepatitis symptoms and/or jaundice, or five times the ULN in the absence of symptoms. Priorities for future studies to develop safer treatments for LTBI and for TB disease are presented.     

Local changes in computational non-rapid eye movement sleep depth in infants

Objective

Deep NREM sleep and its hallmark EEG phenomenon slow wave activity (SWA) are under homeostatic control in adults. SWA is also locally regulated as it increases in the brain areas that have been used intensively. Moreover, in children, SWA is a marker of cortical maturation. In the present study the local properties of NREM sleep depth were evaluated using the quantitative mean frequency method. We aimed to study if age is related to NREM sleep depth in young infants. In addition, we studied if young infants have local differences in their NREM sleep.

Personality of young adults born prematurely: the Helsinki study of very low birth weight adults

Background:  Today, the first generations of very low birth weight (VLBW ≤ 1500 g) infants are entering adulthood but very little is known of their personality traits, associated with both psychopathological vulnerability and resilience.
Methods:  In this cohort study we compared personality traits among young adults (age range 18 to 27 years, mean 21.4, SD 2.19) with VLBW ( n  = 158) with those of term-born controls ( n  = 168) of same gender, age, and maternity hospital. The participants completed the Neo-Personality Inventory.
Results:  Of the five main traits, the VLBW participants scored significantly higher in conscientiousness (MD .1, 95% CI .0 to .3; p  < .03), agreeableness (MD .2, 95% CI .0 to .3; p  < .001), and lower in openness to experience (MD –.1, 95% CI –.2 to .0; p  < .02). In addition, the VLBW group differed from the controls with regard to facets of neuroticism (lower hostility and impulsivity, p s < .05) and extraversion (less assertiveness p  < .01). Furthermore, there were fewer undercontrolled personality profiles among the VLBW subjects ( p  < .01). All differences were independent of gender, age at assessment, parental education, individual school grade average, and maternal pre-eclampsia and smoking during pregnancy.
Conclusions:  Young adults born with VLBW showed markedly different personality traits compared with their controls. The VLBW group displayed less negative emotions, were more dutiful and cautious, and displayed more warmth in their social relationships than their term-born peers. We present two potential mechanisms underlying these findings. The first relates to parental influences and the other to evidence linking biological mechanisms associated with prematurity with personality characteristics in adulthood.     

Postchallenge Glucose, A1C, and Fasting Glucose as Predictors of Type 2 Diabetes and Cardiovascular Disease: A 10-year prospective cohort study

OBJECTIVE

A1C has been proposed as a new indicator for high risk of type 2 diabetes. The long-term predictive power and comparability of elevated A1C with the currently used high-risk indicators remain unclear. We assessed A1C, impaired glucose tolerance (IGT), and impaired fasting glucose (IFG) as predictors of type 2 diabetes and cardiovascular disease (CVD) at 10 years.

RESEARCH DESIGN AND METHODS

This prospective population-based study of 593 inhabitants from northern Finland, born in 1935, was conducted between 1996 and 2008. An oral glucose tolerance test (OGTT) was conducted at baseline and follow-up, and A1C was determined at baseline. Those with a history of diabetes were excluded from the study. Elevated A1C was defined as 5.7–6.4%. Incident type 2 diabetes was confirmed by two OGTTs. Cardiovascular outcome was measured as incident CVD or CVD mortality. Multivariate log-binomial regression models were used to predict diabetes, CVD, and CVD mortality at 10 years. Receiver operating characteristic curves compared predictive values of A1C, IGT, and IFG.

RESULTS

Incidence of diabetes during the follow-up was 17.1%. Two of three of the cases of newly diagnosed diabetes were predicted by a raise in ≥1 of the markers. Elevated A1C, IGT, or IFG preceded diabetes in 32.8, 40.6, and 21.9%, respectively. CVD was predicted by an intermediate and diabetic range of 2-h glucose but only by diabetic A1C levels in women.

CONCLUSIONS

A1C predicted 10-year risk of type 2 diabetes at a range of A1C 5.7–6.4% but CVD only in women at A1C ≥6.5%.Early detection of high risk for type 2 diabetes is fundamental for prevention of diabetes and associated cardiovascular complications. Impaired fasting glucose (IFG) and impaired glucose tolerance (IGT) are currently used for diagnosis of high-risk glucose levels below the diabetic range. The International Expert Committee proposed A1C ≥6.5% as a diagnostic tool for diabetes in 2009 (1) and in January 2010 an intermediate range of A1C 5.7–6.4% (elevated A1C) was proposed by the American Diabetes Association (ADA) to detect individuals at high risk for developing type 2 diabetes (2).To date, however, limited data exist to support the use of A1C in predicting type 2 diabetes (3–8). Importantly, the long-term predictive power of elevated A1C as defined above has not yet been investigated. Previous data on the association between A1C and incident type 2 diabetes in unselected populations have relied on self-reporting, fasting glucose measurements, and use of antidiabetes medication to determine the outcomes. An oral glucose tolerance test (OGTT) has not been used to determine the outcome (3–8).Deterioration of glucose homeostasis reflects a continuum of glycemia, some of which is reversible if detected early (9,10). Importantly, the risk of cardiovascular disease is increased already before glycemia reaches the levels of diabetes, and 2-h glucose appears to be a better predictor of cardiovascular disease (CVD) than fasting glucose (11). Recently, A1C was shown to be a better predictor of CVD than fasting glucose (12).Data directly comparing 2-h glucose and A1C as long-term predictors of new-onset cardiovascular disease are scarce, and results are controversial (13,14). Therefore, we compared A1C, 2-h glucose, and fasting glucose as predictors of type 2 diabetes, CVD, and CVD mortality during a prospective population-based study with a 10-year follow-up.     

IgA bovine serum albumin antibodies are increased in newly diagnosed patients with insulin-dependent diabetes mellitus, but the increase is not an independent risk factor for diabetes

We studied the significance of antibodies to bovine serum albumin (BSA) as a risk factor for insulin-dependent diabetes mellitus (IDDM) in a case-control setting. IgA and IgG antibodies to BSA and ovalbumin were measured from sera of 104 patients with newly diagnosed IDDM and of 111 matched controls by enzyme-linked immunosorbent assay. Patients with diabetes had significantly higher levels of IgA antibodies to BSA ( p = 0.003); IgG antibodies also tended to be higher ( p = 0.08). Levels of IgA antibodies to ovalbumin were similar in the patients and controls, but IgG antibodies were higher in controls ( p = 0.02). When antibodies to BSA, β-lactoglobulin, whole cow's milk and islet cell antibodies were studied as risk determinants of IDDM in a multivariate, logistic regression analysis, IgA antibodies to β-lactoglobulin and to cow's milk were independently associated with the risk ( p = 0.037 and 0.048, respectively), while antibodies to BSA were not a significant risk factor. The results question the role of BSA as a cross-reacting antigen with pancreatic β-cell surface proteins in the aetiology of IDDM.     

From the Cover: Embryonic stem cells develop into functional dopaminergic neurons after transplantation in a Parkinson rat model

Although implantation of fetal dopamine (DA) neurons can reduce parkinsonism in patients, current methods are rudimentary, and a reliable donor cell source is lacking. We show that transplanting low doses of undifferentiated mouse embryonic stem (ES) cells into the rat striatum results in a proliferation of ES cells into fully differentiated DA neurons. ES cell-derived DA neurons caused gradual and sustained behavioral restoration of DA-mediated motor asymmetry. Behavioral recovery paralleled in vivo positron emission tomography and functional magnetic resonance imaging data demonstrating DA-mediated hemodynamic changes in the striatum and associated brain circuitry. These results demonstrate that transplanted ES cells can develop spontaneously into DA neurons. Such DA neurons can restore cerebral function and behavior in an animal model of Parkinson's disease.