Paul Hofman

Olive (Olea europaea L.) Leaf Polyphenols Improve Insulin Sensitivity in Middle-Aged Overweight Men: A Randomized, Placebo-Controlled, Crossover Trial

Background Olive plant leaves (Olea europaea L.) have been used for centuries in folk medicine to treat diabetes, but there are very limited data examining the effects of olive polyphenols on glucose homeostasis in humans. Objective To assess the effects of supplementation with olive leaf polyphenols (51.1 mg oleuropein, 9.7 mg hydroxytyrosol per day) on insulin action and cardiovascular risk factors in middle-aged overweight men. Design Randomized, double-blinded, placebo-controlled, crossover trial in New Zealand. 46 participants (aged 46.4±5.5 years and BMI 28.0±2.0 kg/m2) were randomized to receive capsules with olive leaf extract (OLE) or placebo for 12 weeks, crossing over to other treatment after a 6-week washout. Primary outcome was insulin sensitivity (Matsuda method). Secondary outcomes included glucose and insulin profiles, cytokines, lipid profile, body composition, 24-hour ambulatory blood pressure, and carotid intima-media thickness. Results Treatment evaluations were based on the intention-to-treat principle. All participants took >96% of prescribed capsules. OLE supplementation was associated with a 15% improvement in insulin sensitivity (pu200a=u200a0.024) compared to placebo. There was also a 28% improvement in pancreatic β-cell responsiveness (pu200a=u200a0.013). OLE supplementation also led to increased fasting interleukin-6 (pu200a=u200a0.014), IGFBP-1 (pu200a=u200a0.024), and IGFBP-2 (pu200a=u200a0.015) concentrations. There were however, no effects on interleukin-8, TNF-α, ultra-sensitive CRP, lipid profile, ambulatory blood pressure, body composition, carotid intima-media thickness, or liver function. Conclusions Supplementation with olive leaf polyphenols for 12 weeks significantly improved insulin sensitivity and pancreatic β-cell secretory capacity in overweight middle-aged men at risk of developing the metabolic syndrome. Trial Registration Australian New Zealand Clinical Trials Registry #336317.

Overexpression of carbonic anhydrase XII in tissues from resectable non-small cell lung cancers is a biomarker of good prognosis

The pattern of protein expression in tumors is under the influence of nutrient stress, hypoxia and low pH, which determines the survival of neoplastic cells and the development of tumors. Carbonic anhydrase XII (CAXII) is a transmembrane enzyme that catalyzes the reversible hydration of cell‐generated carbon dioxide into protons and bicarbonate. Hypoxic conditions activate its transcription and translation and enhanced expression is often present in several types of tumors. The aim of our study was to assess the prognostic significance of CAXII tumor tissues expression in patients with NSCLC. Five hundred fifty‐five tumors were immunostained for CAXII on tissue microarrays (TMA) and the results were correlated with clinicopathological parameters and outcome of patients. CAXII overexpression was present in 105/555 (19%) cases and was associated with tumors of lower grade (p = 0.015) and histological type (p < 0.001), being significantly higher in squamous cell carcinoma. High CAXII expression correlated with better overall and disease‐specific survival of patients with resectable NSCLC in univariate (p < 0.001) and multivariate survival analyses (p < 0.001). In conclusion, this is the first study demonstrating that a high CAXII tumor tissue expression evaluated on TMAs is related to a better outcome in a large series of patients with resectable NSCLC.

Increased Adiposity in Adults Born Preterm and Their Children

Background Preterm birth is associated with abnormalities in growth, body composition, and metabolism during childhood, but adult data are scarce and none exist for their offspring. We therefore aimed to examine body composition and cardiovascular risk factors in adults born preterm and their children. Methods A cohort of 52 adults (aged 35.7 years, 54% female, 31 born preterm) and their term-born children (n=61, aged 8.0 years, 54% female, 60% from a preterm parent) were studied. Auxology and body composition (whole-body dual-energy X-ray absorptiometry) were measured, and fasting blood samples taken for metabolic and hormonal assessments. Results Adults born preterm had greater abdominal adiposity, displaying more truncal fat (p=0.006) and higher android to gynoid fat ratio (p=0.004). Although women born preterm and at term were of similar weight and BMI, men born preterm (n=8) were on average 20 kg heavier (p=0.010) and of greater BMI (34.2 vs 28.4 kg/m2; p=0.021) than men born at term (n=16). Adults born preterm also displayed a less favourable lipid profile, including lower HDL-C concentrations (p=0.007) and greater total cholesterol to HDL-C ratio (p=0.047). Children of parents born preterm tended to have more body fat than the children of parents born at term (21.3 vs 17.6%; p=0.055). Even after adjustment for mean parental BMI, children of parents born preterm had altered fat distribution, with more truncal fat (p=0.048) and greater android to gynoid fat ratio (p=0.009). Conclusions Adults born preterm, particularly men, have markedly increased fat mass and altered fat distribution. A similar increase in abdominal adiposity was observed in the term born offspring of parents born preterm, indicating that adverse outcomes associated with preterm birth may extend to the next generation.

Quantifying the use of bioresources for promoting their sharing in scientific research

An increasing portion of biomedical research relies on the use of biobanks and databases. Sharing of such resources is essential for optimizing knowledge production. A major obstacle for sharing bioresources is the lack of recognition for the efforts involved in establishing, maintaining and sharing them, due to, in particular, the absence of adequate tools. Increasing demands on biobanks and databases to improve access should be complemented with efforts of end-users to recognize and acknowledge these resources. An appropriate set of tools must be developed and implemented to measure this impact.To address this issue we propose to measure the use in research of such bioresources as a value of their impact, leading to create an indicator: Bioresource Research Impact Factor (BRIF). Key elements to be assessed are: defining obstacles to sharing samples and data, choosing adequate identifier for bioresources, identifying and weighing parameters to be considered in the metrics, analyzing the role of journal guidelines and policies for resource citing and referencing, assessing policies for resource access and sharing and their influence on bioresource use. This work allows us to propose a framework and foundations for the operational development of BRIF that still requires input from stakeholders within the biomedical community.

Insulin Sensitivity and β-Cell Function in Adults Born Preterm and Their Children

We aimed to evaluate insulin secretion and insulin sensitivity in adults born preterm and their children. Subjects were adults born both preterm and at term, with their children aged 5–10 years born at term. Insulin sensitivity and secretion were assessed using hyperglycemic clamps in adults and frequently sampled intravenous glucose tolerance tests using Bergman minimal model in children. In total, 52 adults aged 34–38 years participated (31 born preterm, mean gestational age 33.3 weeks). Adults born preterm were less insulin sensitive than those born at term (19.0 ± 2.5 vs. 36.3 ± 5.2 mg ⋅ kg−1 ⋅ min−1mU ⋅ L; P < 0.05) with compensatory increased first-phase insulin secretion (56.1 ± 8.5 vs. 25.3 ± 3.7 mU/L; P < 0.001) but similar disposition index indicating appropriate insulin secretion. These differences were independent of sex and remained when subjects born <32 weeks gestation were excluded from analyses. In total, 61 children were studied (37 of preterm parents, mean age 7.9 ± 0.3 years). Children of parents born preterm had similar insulin sensitivity to children of parents born at term, but a correlation between parental and offspring insulin sensitivity was noted only among children of parents born preterm. In conclusion, adults born preterm have insulin resistance in midadulthood, but this was not associated with insulin resistance in their children.

A new role for the oncogenic high-mobility group A2 transcription factor in myogenesis of embryonic stem cells.

The high mobility group type A-2 (HMGA2) transcription factor is involved in proliferation and differentiation, mainly during embryogenesis. Its activated form (HMGA2/T) presents oncogenic activities both in vivo and in vitro. However, its precise role during embryogenesis is unknown. We investigated its role during the commitment of mouse embryonic stem (ES) cells by constructing cell lines expressing either wild type (wt) or HMGA2/T forms of the gene. Following differentiation, control and wt HMGA2 ES cells did not display myotubes; whereas HMGA2/T ES cell lines massively formed contractile myotubes. Furthermore, as opposed to control cells, HMGA2/T ES cells highly expressed the muscle myosin heavy chain (MHC) marker. Interestingly, in experimental conditions inhibitory for myogenesis, we observed a strong expression of MyoD and myogenin in HMGA2/T cells. By contrast, commitment into adipocyte, neuron, and cardiomyocyte lineages was not affected. Teratocarcinomas induced by HMGA2/T ES cell lines presented numerous skeletal muscle-differentiated tissues that were not observed in wt HMGA2 or control tumours. Finally, rapamycin, an inhibitor of the mTOR kinase, downregulated endogenous HMGA-2 expression and inhibited myogenesis. This effect was prevented by overexpression of exogenous HMGA-2. Our results reveal a novel function of HMGA-2 in skeletal muscle differentiation.

First-born Children Have Reduced Insulin Sensitivity and Higher Daytime Blood Pressure Compared to Later-Born Children

BACKGROUNDnEvidence suggests that first-born children and adults are phenotypically different to later-born children. Therefore, we aimed to assess whether birth order would be associated with changes in metabolism in childhood.nnnMETHODSnWe studied 85 healthy prepubertal children aged 4 to 11 years, born 38 to 40 weeks gestation, and birth weight appropriate for gestational age: 32 first-born and 53 later-born children. Clinical assessments included measurement of childrens height, weight, fasting lipid and hormonal profiles, and dual-energy x-ray absorptiometry-derived body composition. Children also underwent 24-hour ambulatory blood pressure monitoring, and frequently sampled intravenous glucose tests with Bergmans minimal model.nnnRESULTSnFirst-born children were approximately 3 cm taller (height SD scores 0.88 vs 0.39; P = .009) and were slimmer (body mass index SD scores -0.05 vs 0.39; P = .048) than later-born children. Consistent with their taller stature, first-born children also had a 27% increase in IGF-I concentrations (227 vs 173 ng/mL; P = .002). Insulin sensitivity was reduced by 21% among first-borns compared to later-borns (8.4 vs 10.6 × 10(-4)/min/[mU/L]; P = .019). Further, 24-hour ambulatory blood pressure monitoring showed that first-borns had higher daytime systolic (+5 mm Hg; P = .032) and diastolic (+4 mm Hg; P = .029) blood pressure. Blood lipids were unaffected by birth order.nnnCONCLUSIONSnAlthough first-borns were taller and slimmer, these children had reduced insulin sensitivity and increased daytime blood pressure compared to later-borns. Thus, first-borns may be at a greater risk of metabolic and cardiovascular diseases in adult life. This finding may have important public health implications, in light of a worldwide trend toward smaller families.

Neurodevelopmental and body composition outcomes in children with congenital hypothyroidism treated with high-dose initial replacement and close monitoring

BACKGROUNDnDespite newborn screening and early levothyroxine replacement, there are continued reports of mild neurocognitive impairment in children with congenital hypothyroidism (CHT). In Auckland, New Zealand, cases are identified by a neonatal screening program with rapid institution of high-dose levothyroxine replacement (10-15 μg/kg·d), producing prompt normalization of thyroid function. Subsequently, frequent monitoring and dose alterations are performed for 2 years. We aimed to assess whether the Auckland treatment strategy prevents impairment of intellectual and motor development.nnnMETHODSnThis study encompassed all children with CHT born in 1993-2006 in Auckland and their siblings. Neurocognitive assessments included the following: 1) intelligence quotient via Weschler Preschool and Primary Scale of Intelligence III or Weschler Intelligence Scale for Children IV; 2) Movement Assessment Battery for Children; and 3) Beery Developmental Test of Visual-Motor Integration. Body composition was assessed by dual-energy x-ray absorptiometry.nnnRESULTSnForty-four CHT cases and 53 sibling controls aged 9.6 ± 3.9 years were studied. Overall intelligence quotient was similar among CHT cases and controls (95.2 vs 98.6; P = .20), and there were also no differences in motor function. Severity of CHT did not influence outcome, but greater time to normalize free T4 was associated with worse motor balance. There were no differences in anthropometry or body composition between groups.nnnCONCLUSIONSnThese findings suggest that a strategy of rapidly identifying and treating infants with CHT using high-dose levothyroxine replacement is associated with normal intellectual and motor development. The subtle negative impact on motor function associated with time to normalize free T4 levels is consistent with benefit from rapid initial correction.

Increasing Maternal Age Is Associated with Taller Stature and Reduced Abdominal Fat in Their Children

Background Maternal age at childbirth continues to increase worldwide. We aimed to assess whether increasing maternal age is associated with changes in childhood height, body composition, and metabolism. Methods 277 healthy pre-pubertal children, born 37–41 weeks gestation were studied. Assessments included: height and weight corrected for parental measurements, DEXA-derived body composition, fasting lipids, glucose, insulin, and hormonal profiles. Subjects were separated according to maternal age at childbirth: <30, 30–35, and >35 years. Results Our cohort consisted of 126 girls and 151 boys, aged 7.4±2.2 years (range 3–10); maternal age at childbirth was 33.3±4.7 years (range 19–44). Children of mothers aged >35 and 30–35 years at childbirth were taller than children of mothers aged <30 years by 0.26 (pu200a=u200a0.002) and 0.23 (pu200a=u200a0.042) SDS, respectively. There was a reduction in childhood BMISDS with increasing maternal age at childbirth, and children of mothers aged >35 years at childbirth were 0.61 SDS slimmer than those of mothers <30 years (pu200a=u200a0.049). Children of mothers aged 30–35 (pu200a=u200a0.022) and >35 (pu200a=u200a0.036) years at childbirth had abdominal adiposity reduced by 10% and 13%, respectively, compared to those in the <30 group. Children of mothers aged 30–35 years at childbirth displayed a 19% increase in IGF-I concentrations compared to offspring in <30 group (pu200a=u200a0.042). Conversely, IGF-II concentrations were lower among the children born to mothers aged 30–35 (6.5%; pu200a=u200a0.004) and >35 (8.1%; pu200a=u200a0.005) compared to those of mothers aged <30 years. Girls of mothers aged 30–35 years at childbirth also displayed improved HOMA-IR insulin sensitivity (pu200a=u200a0.010) compared to girls born to mothers aged <30 years. Conclusions Increasing maternal age at childbirth is associated with a more favourable phenotype (taller stature and reduced abdominal fat) in their children, as well as improved insulin sensitivity in girls.

Severe Hyperemesis Gravidarum Is Associated With Reduced Insulin Sensitivity in the Offspring in Childhood

BACKGROUNDnHyperemesis gravidarum alters maternal (and possibly fetal) nutrition throughout pregnancy, but there are no data on long-term effects on offspring metabolism. Thus, we aimed to assess whether severe hyperemesis gravidarum (SHG) affects glucose homeostasis and body composition in the offspring in childhood.nnnMETHODSnHealthy prepubertal children (aged 4-11 years) born at term were studied: offspring of mothers who were admitted to hospital with SHG (n = 36) and offspring of mothers from control pregnancies (n = 42). Primary outcome was insulin sensitivity measured using iv glucose tolerance tests and Bergmans minimal model. Other assessments included lipid and hormonal profiles and body composition using whole-body dual-energy x-ray absorptiometry.nnnRESULTSnInsulin sensitivity in SHG children was 20% lower than in controls (8.49 vs 10.60 × 10(-4)·min(-1)·(mU/L); P = .014). SHG children also had higher fasting insulin (6.88 vs 5.04 mIU/L; P = .024) and lower IGF binding protein 1 (11.8 vs 19.0 ng/mL; P = .004) concentrations than controls. Baseline cortisol concentrations were 22% higher in SHG offspring (256 vs 210 nmol/L; P = .021). Children in both groups were anthropometrically similar.nnnCONCLUSIONnChildren born to mothers who experienced SHG have lower insulin sensitivity, which may increase their long-term risk of developing diabetes mellitus. Follow-up of SHG offspring is essential to determine later risk of metabolic disease.