A future for neonatal α1‐antitrypsin screening?

A WHO expert group recommends neonatal screening for alpha1-antitrypsin deficiency (alpha1ATD). Homozygous alpha1ATD PiZZ occurs in 1 in 5000 of the U.S. Caucasian population and up to 1 in 500 individuals of the European population, with a large regional variation. It is a risk factor that predisposes mainly to liver disease in early infancy and emphysema in early adulthood. Most importantly, smoking decreases the duration of the asymptomatic phase and life expectancy by 10-20 y. The Swedish alpha1AT screening programme and subsequent information and advice prevented the majority of adolescents from starting to smoke. The involved parents and alpha1ATD adolescents retrospectively recommended neonatal screening. Potential advantages of neonatal alpha1AT screening are: early diagnosis and treatment of neonatal liver disease, optimal treatment of fever and bacterial infections theoretically preventing liver cell damage, genetic advice and information about the consequences of passive and active smoking. Potential advantages of postponing screening until age 11-12y are: identification of alpha1ATD close to the age when smoking may start, and possibility for the child to take part in the screening decision. Disadvantages of alpha1AT screening are: psychosocial reactions--the mother probably being most vulnerable in the neonatal period--and discrimination by insurance companies and employers. Important uncertainties are: lack of knowledge concerning participation in a voluntary alpha1AT screening, psychosocial reactions and the efficacy of anti-smoking advice if the information is given to school-age children and families. Thus the question whether and when to screen for alpha1ATD is still the topic of lively debate.     

Transient tachypnea of the newborn (TTN): A role for polymorphisms in the β‐adrenergic receptor (ADRB) encoding genes?

AIM: Transient tachypnea of the newborn (TTN) is a common cause of early respiratory distress in the neonatal period of term infants. Delayed resorption of foetal lung fluid after birth is considered as the main pathophysiological factor. As resorption of foetal lung fluid is a catecholamine dependent process, we aimed at investigating, whether beta1- and beta2-adrenoreceptor (ADRB1, ADRB2) polymorphisms, known to alter catecholamine activity, are operative in TTN. METHODS: DNA was collected for genotyping from 73 term newborns suffering from TTN and 55 healthy controls from a Caucasian cohort. RESULTS: TTN infants were more likely to be male (70% vs. 49%; p < 0.05), had a lower mean birthweight (3120 +/- 450 vs. 3396 +/- 504 g; p < 0.001) and gestational age (GA) (38.4 +/- 1.2 vs. 39.4 +/- 1.3 weeks; p < 0.001) and were more often delivered by caesarean section (CS) (71% vs. 26%; p < 0.001). The beta1Ser49Gly polymorphism differed significantly between cases and controls. Multivariate analysis provided beta1Gly49 homozygotes with higher risk for TTN (OR 18.5; 95%CI 1.5-229; p = 0.023) than beta1Ser49 allele carrier. Further analysis showed significant association of T-47C, A46G, C79G and C491T (TACC) haplotype in ADRB2 gene with TTN (p = 0.048). CONCLUSION: We conclude that beta1Gly49 homozygosity and TACC haplotype of ADRB2 gene, both loss-of-function genetic variations, may predispose to TTN.     

Type 2 diabetes in youth: are there racial differences in β‐cell responsiveness relative to insulin sensitivity?

Bacha F, Gungor N, Lee S, Arslanian SA. Type 2 diabetes in youth: are there racial differences in β‐cell responsiveness relative to insulin sensitivity? Objective: Non‐diabetic African American (AA) youth have an upregulated insulin secretion relative to insulin sensitivity (IS) compared with their American White (AW) peers. We investigated if similar racial differences exist in youth with T2DM. Research Design and Methods: Fourteen AAs and 14 AWs T2DM adolescents underwent evaluation of IS and clearance (hyperinsulinemic–euglycemic clamp), first‐ and second‐phase insulin and C‐peptide secretion (hyperglycemic clamp); body composition (DEXA); and abdominal adiposity (CT). Results: AA and AW T2DM had similar HbA1c, diabetes duration, BMI, and % body fat, with lower visceral fat in AAs (p = 0.013). While insulin‐stimulated glucose disposal was similar in AA and AW (7.5 ± 1.0 vs. 7.3 ± 0.9 mg/kg FFM/min), IS tended to be lower (2.5 ± 0.4 vs. 3.8 ± 0.6 mg/kg FFM/min per µU/mL, p = 0.081). First‐phase insulin (175.7 ± 52.9 vs. 66.6 ± 10.8 µU/mL, p = 0.01) and second‐phase insulin (236.2 ± 40.7 vs. 105.1 ± 17.9 µU/mL, p = 0.008), and first‐phase C‐peptide (8.2 ± 1.2 vs. 5.0 ± 0.3 ng/mL, p = 0.02) and second‐phase C‐peptide (10.8 ± 0.9 vs. 7.6 ± 0.6 ng/mL, p = 0.012) were higher in AA. β‐Cell function relative to IS was higher in AA vs. AW (259.5 ± 35.3 vs. 168.8 ± 25.1 mg/kg FFM/min, p = 0.043). Conclusions: Racial differences in insulin secretion can be demonstrated with the clamp technique in obese adolescents with T2DM. Similar to non‐diabetic youth, AA adolescents with T2DM compared with their AW counterparts have an upregulated β‐cell function relative to IS, the reasons for which remain to be investigated.     

Can severity‐of‐illness indices for neonatal intensive care predict outcome at 4 years of age?

Aim: To test four neonatal severity-of-illness indices (CRIB, NTISS, SNAP, SNAP-PE) for their ability to predict short- and long-term outcome in very low-birthweight infants receiving neonatal intensive care.

Methods: Data on 240 newborns with birthweights below 1500 g from two Swedish neonatal units were collected. The predictive values of the indices for an adverse outcome in the neonatal period and at 4 y of age were compared with those of gestational age and birthweight.

Results: An early adverse outcome (in-hospital death, severe haemorrhagic-ischaemic brain lesion, retinopathy, chronic lung disease) was better predicted with CRIB (area under ROC curve (Az) = 0.87) and SNAP-PE (Az = 0.86), while SNAP-PE was best for predicting late problems (deviations in growth and psychomotor development, neurosensory impairment, difficulties in concentration, and impairment in vision, and hearing,) (Az = 0.63). All indices predicted the early outcome better than the outcome at the 4-y follow-up. Severity-of-illness indices can be used as instruments to follow and improve the level of neonatal intensive care, but unfortunately seem to be of little value in long-term follow-up.

Conclusion: CRIB and SNAP-PE indices are better in predicting hospital mortality than birthweight. None of the systems can predict adverse outcome at 4 y of age.     

Guidelines for treatment of neonatal jaundice. Is there a place for evidence‐based medicine?

Treatment of neonatal jaundice continues to be a controversial issue. Arguments that traditional practice results in over-treatment have led to the adoption of more liberal guidelines in some countries. The importation of liberal guidelines from one country to the next, however, is fraught with danger, because differences in epidemiology, sociology and healthcare delivery systems between countries may not be adequately reflected. The unreflected extension of liberalization to non-target groups of patients can expose the latter to significant risk. It is not clear that the evidence on which guidelines for treatment of neonatal jaundice are based satisfy the requirements for evidence-based medicine. Evidence of adequate quality may be hard to obtain.Conclusions: Introduction of more liberal guidelines for the treatment of neonatal jaundice, if at all contemplated, must be adapted to local circumstances, and any available evidence pertaining to local epidemiology, sociology and healthcare organization has to be carefully weighed and incorporated. The time is ripe for a joint international effort to secure adequate funding for basic and applied research within the mechanisms of bilirubin encephalopathy in the newborn.     

Is phototherapy exposure associated with better or worse outcomes in 501‐ to 1000‐g‐birth‐weight infants?

Aim: To compare risk‐adjusted outcomes at 18‐ to 22‐month‐corrected age for extremely low birth weight (ELBW) infants who never received phototherapy (NoPTx) to those who received any phototherapy (PTx) in the NICHD Neonatal Research Network randomized trial of Aggressive vs. Conservative Phototherapy. Methods: Outcomes at 18 to 22‐month‐corrected age included death, neurodevelopmental impairment (NDI) and Bayley Scales Mental Developmental Index (MDI). Regression models evaluated the independent association of PTx with adverse outcomes controlling for centre and other potentially confounding variables. Results: Of 1972 infants, 216 were NoPTx and 1756 were PTx. For the entire 501‐ to 1000‐g‐BW cohort, PTx was not independently associated with death or NDI (OR 0.85, 95% CI: 0.60–1.20), death or adverse neurodevelopmental endpoints. However, among infants 501–750 g BW, the rate of significant developmental impairment with MDI < 50 was significantly higher for NoPTx (29%) than PTx (12%) (p = 0.004). Conclusions: Phototherapy did not appear to be independently associated with death or NDI for the overall ELBW group. Whether PTx increases mortality could not be excluded because of bias from deaths before reaching conservative treatment threshold. The higher rate of MDI < 50 in the 501‐ to 750‐g‐BW NoPTx group is concerning and consistent with NRN Trial results.     

One‐hour plasma glucose concentration during the OGTT: what does it tell about β‐cell function relative to insulin sensitivity in overweight/obese children?

Tfayli H, Jung Lee S, Bacha F, Arslanian S. One‐hour plasma glucose concentration during the OGTT: what does it tell about β‐cell function relative to insulin sensitivity in overweight/obese children? Background: In adults 1‐h plasma glucose concentration cut‐point of 155 mg/dL (8.6 mmol/L) during the oral glucose tolerance test (OGTT) is a strong predictor of future diabetes risk. Objective: We tested the hypothesis that a 1‐h glucose concentration ≥155 mg/dL is associated with lower β‐cell function in overweight/obese youth. Research design and methods: One hundred and thirteen diabetes free overweight/obese youth aged 10–20 yr, underwent evaluation of β‐cell function during a 2 h hyperglycemic clamp ～225 mg/dL (12.5 mmol/L), and insulin sensitivity during a 3 h hyperinsulinemic–euglycemic clamp, and a standard 2 h OGTT. Body composition and abdominal adiposity were determined by DEXA and CT scan. The disposition index (DI) was calculated as the product of first‐phase insulin secretion and insulin sensitivity. Subjects were divided into two categories of 1‐h plasma glucose concentration: <155 mg/dL (n = 69) and ≥155 mg/dL (n = 44). Results: Youth with 1‐h glucose ≥155 mg/dL had lower DI than those with 1‐h glucose <155 mg/dL (295.1 ± 27.4 vs. 498.6 ± 37.7 mg/kg/min, p < 0.001), independent of the glucose tolerance status. In multiple regression models, DI was the strongest contributor to 1‐h glucose concentration explaining ～21% of its variance. Conclusions: Overweight/obese youth with 1‐h glucose ≥155 mg/dL during the oral glucose tolerance test have a significantly lower β‐cell function relative to insulin sensitivity even within the normal glucose tolerance range. Such youth may be at higher risk of future diabetes.     

Differences in β‐cell function and insulin secretion in Black vs. White obese adolescents: do incretin hormones play a role?

Black youth are at higher risk for type 2 diabetes (T2D) than their White peers. Previously we demonstrated that for the same degree of insulin sensitivity, Black youth have an upregulated β‐cell function and insulin hypersecretion, in response to intravenous (iv) glucose, compared with Whites. To investigate if the same holds true during an oral glucose challenge and because of the important role of glucagon‐like peptide 1 (GLP‐1) and glucose‐dependent insulinotropic polypeptide (GIP) in augmenting insulin secretion, we examined β‐cell function and incretin hormones in 85 Black and 78 White obese adolescents, with normal glucose tolerance (NGT), during a 2‐h oral glucose tolerance test (OGTT) with mathematical modeling of plasma glucose and C‐peptide concentrations to assess β‐cell glucose sensitivity (βCGS), rate sensitivity, potentiation factor, and insulin sensitivity. Incretin, pancreatic polypeptide, and glucagon concentrations were measured during the OGTT. Black obese youth had a heightened early insulin secretion together with significantly greater βCGS, rate sensitivity, and potentiation factor compared with Whites, with no differences in incretin and glucagon concentrations. Basal and stimulated insulin clearance was lower (p = 0.001) in Black vs. White youth. In conclusion, during an OGTT Black obese youth with NGT demonstrate a pronounced early insulin secretion jointly with heightened β‐cell glucose sensitivity, rate sensitivity, and potentiation factor. These racial disparities in β‐cell function and the pathophysiological components of T2D are unlikely to be attributed to incretin hormones and remain to be investigated further to explain the metabolic basis for the enhanced risk of T2D in back youth.     

How do parents of 4‐ to 5‐year‐old children perceive the weight of their children?

Introduction: A heavier weight in adults is becoming the norm rather than an abnormal weight. Whether the same trend is happening in children is unknown. Objective: To assess the perception of the weight of 4‐ to 5‐year‐old children and the recognition of overweight by both parents. Design: Population‐based survey. Participants: A questionnaire was sent to parents of 1155 4‐ to 5‐year‐old children. Results: In total, 439 questionnaires (35%) were returned. Of all, 90% of the children had a normal weight, 9.3% were overweight and 4.1% were obese. For all weight classes, the parents depicted the child as lighter on both the verbal and visual scale. Of all, 75% of mothers of overweight children stated that the child had a normal weight. In obese children, 50% of the mothers believed that the child had a normal weight. Conclusion: Children with a weight in the normal range were considered by their parents as a little too light or too light. Overweight was considered as normal weight, and obesity as normal or a little too heavy. The perception of a normal weight in children at 4–5 years is distorted.