Relationship between Foetal Growth Restriction and Maternal Nutrition Status Measured by Dual-Energy X-Ray Absorptiometry, Leptin, and Insulin-Like Growth Factor.

AIMS: The aim of this study was to determine if maternal nutritional status, as defined by body composition, leptin, and insulin-like growth factor (IGF)-I levels, relates to foetal growth. METHODS: In this prospective study, mothers of foetuses with foetal growth restriction (FGR; cases; n = 46) and mothers of appropriate-for-gestational-age (AGA) foetuses (controls; n = 81) were consecutively recruited over a 14- month period. A maternal blood sample was obtained during the third trimester (between 32 and 34 weeks of gestation) for the assessment of IGF-I and leptin. Body composition was assessed by dual-energy X-ray absorptiometry within the first 15 days after delivery. The study used the SPSS-PC statistical package, version 19.0, and p < 0.05 was considered statistically significant. RESULTS: Mean serum IGF-I levels were lower in the cases than in the controls (p < 0.05), whereas leptin concentrations were higher in the cases after adjusting for age, body mass index and cigarette consumption (p < 0.05). Cases had less lean and fat tissue than controls (p < 0.05) but a relatively higher fat percentage. CONCLUSIONS: The mothers of foetuses with FGR have a body composition pattern characterized by a slightly increased fraction of fat mass, lower IGF-I concentrations, and increased serum leptin levels. Optimization of maternal nutritional status should be considered, as the nutritional status may be involved in the pathogenesis of FGR.

Cost-effectiveness of a new internet-based monitoring tool for neonatal post-discharge home care.

BACKGROUND: The application of information and communication technologies in nursing care is becoming more widespread, but few applications have been reported in neonatal care. A close monitoring of newborns within the first weeks of life is crucial to evaluating correct feeding, growth, and health status. Conventional hospital-based postdischarge monitoring could be improved in terms of costs and clinical effectiveness by using a telemedicine approach. OBJECTIVE: To evaluate the cost-effectiveness of a new Internet-based system for monitoring low-risk newborns after discharge compared to the standard hospital-based follow-up, with specific attention to prevention of emergency department (ED) visits in the first month of life. METHODS: We performed a retrospective cohort study of two low-risk newborn patient groups. One group, born between January 1, 2011, and June 30, 2011, received the standard hospital-based follow-up visit within 48 hours after discharge. After implementing an Internet-based monitoring system, another group, born between July 19, 2011, and January 19, 2012, received their follow-up with this system. RESULTS: A total of 18 (15.8%) out of 114 newborns who received the standard hospital-based follow-up had an ED visit in the first month of life compared with 5 (5.6%; P=.026) out of 90 infants who were monitored by the Internet-based system. The cost of the hospital-based follow-up was 182.1€ per patient, compared with 86.1€ for the Internet-based follow-up. CONCLUSION: Our Internet-based monitoring approach proved to be both more effective and less costly than the conventional hospital-based follow-up, particularly through reducing subsequent ED visits.

Association of p.His38Leu, a rare CYP21A2 mutation, with the classical simple virilizing phenotype of 21-hydroxylase deficiency in a 6-year-old boy.

BACKGROUND/AIMS: Congenital adrenal hyperplasia due to 21-hydroxylase deficiency is one of the most common autosomal recessive disorders. Unequal crossing over or gene conversion between the active CYP21A2 gene and the inactive CYP21A1P pseudogene accounts for 95% of mutations, but many non-pseudogene-derived mutations have been described. It is important for these new mutations to be assigned to a specific phenotype. CASE REPORT AND RESULTS: We report a young boy diagnosed with the classical simple virilizing phenotype in whom the CYP21A2 genetic analysis disclosed that he was a compound heterozygous for p.His38Leu and the c.290-13A/C>G mutations. The p.His38Leu mutation has been recently described, but has not been associated with a specific phenotype thus far. Residue 38 is the only charged amino acid of a hydrophobic patch that interacts closely with the membrane. This mutation leads to a non-charged amino acid, suggesting a much more hydrophobic continuous domain. This patch is highly conserved through different mammals indicating the importance of this domain in the protein-membrane interaction. CONCLUSION: Our results support p.His38Leu as a severe mutation causing a classical simple virilizing phenotype.

Early development of visceral fat excess after spontaneous catch-up growth in children with low birth weight.

CONTEXT: The sequence of prenatal growth restraint and infantile catch-up of weight is by the age of 4 yr associated with hyperinsulinemic adiposity. We studied whether the adiposity of post-catch-up children born small for gestational age (SGA) is further amplified between age 4 and 6 yr and whether visceral fat excess has already emerged by the age of 6 yr. SETTING: The study took place at a university hospital. STUDY POPULATION AND DESIGN: A longitudinal cohort (age 2-6 yr) of 22 children born appropriate for gestational age (AGA) and 29 born SGA were studied. Auxological, endocrine, metabolic, and body composition (by absorptiometry) assessments were made at 2, 4, and 6 yr, and visceral fat was assessed (by magnetic resonance imaging) at 6 yr. MAIN OUTCOMES: Outcome measures included fasting glucose, insulin, IGF-I, neutrophil to lymphocyte ratio, lean mass, and total, abdominal, and visceral fat mass. RESULTS: Between ages 4-6 yr, the relative adiposity of SGA children was further amplified. Between ages 2-6 yr, SGA children gained more total and abdominal fat and raised their insulin, IGF-I, and neutrophil to lymphocyte ratio more than did AGA children (all P<0.0001). At age 6 yr, the average amount of visceral fat was in SGA children more than 50% higher than in AGA children (P<0.005). The 0- to 2-yr increment in weight Z-score together with the 2- to 6-yr increment in fasting insulin accounted for 62% of visceral fat variability at age 6 yr. CONCLUSION: The amount of visceral fat is in post-catch-up SGA children excessive by the age of 6 yr. In populations at risk for type 2 diabetes or metabolic syndrome after fetal growth restraint, the time window for early intervention may have to be advanced into prepubertal childhood.

Cord serum visfatin at term birth: maternal smoking unmasks the relation to foetal growth.

OBJECTIVE: Visfatin is an adipocytokine involved in insulin action and oxidative stress. The regulation of circulating concentrations in the human foetus is unknown. We studied whether, at term birth, the serum concentrations of visfatin are related to foetal size, both in the absence and in the presence of maternal smoking during pregnancy. DESIGN: A cross-sectional, hospital-based study. PATIENTS: Seventy-eight singleton, healthy neonates [39 girls and 39 boys; gestational age (GA) 39.5 +/- 0.2 weeks; birth weight (BW) 3.3 +/- 0.04 kg]. METHODS: Cord serum visfatin, insulin and IGF-I measured by specific immunoassays. RESULTS: In infants from nonsmoking mothers (N = 48), cord serum visfatin levels were unrelated to either BW or birth length (BL). In infants from smoking mothers (N = 30), however, serum visfatin was inversely associated with both BW (r = -0.57; P < 0.001) and BL (r = -0.60; P < 0.0001) and it was directly associated with the number of cigarettes smoked (P < 0.05) in heavy smokers. In a multiple regression analysis, cord serum visfatin accounted for 36% of BW and 32% of BL variance in infants from smoking mothers. Cord serum visfatin was unrelated to insulin or IGF-I in either subgroup. CONCLUSION: At term birth, there is no readily detectable relation between circulating visfatin and indices of foetal size; however, maternal smoking unmasked a strikingly inverse relationship between cord serum visfatin and the foetal growth status, indicating that smoking can elicit a rise or a fall of cord serum visfatin, depending on whether the foetus is, respectively, of smaller or larger size.

Pioglitazone (7.5 mg/day) added to flutamide-metformin in women with androgen excess: additional increments of visfatin and high molecular weight adiponectin.

BACKGROUND AND AIM: Low-dose pioglitazone (Pio), flutamide (Flu), metformin (Met) plus an oestro-progestagen is a novel polytherapy lowering total and visceral adiposity, and reducing carotid intima media thickness (IMT) in hyperinsulinaemic women with androgen excess, without changing their body mass index (BMI). In a search for mediators of PioFluMet's actions, we measured serum levels of visfatin and high molecular weight (HMW) adiponectin. DESIGN AND PATIENTS: In a double-blind study, we enrolled 38 young women with hyperinsulinaemic androgen excess [mean BMI: 23.7 kg/m(2)], all of whom started on Flu (62.5 mg/day), Met (850 mg/day) and a transdermal oestro-progestagen, each for 21/28 days over 1 year. Patients were randomly assigned to receive, in addition, placebo (n = 19) or Pio (7.5 mg/day; n = 19) on the same 21/28 days. MEASUREMENTS: Serum concentrations of visfatin and HMW adiponectin, visceral fat by magnetic resonance imaging, carotid IMT by ultrasound, all carried out during study start and after 1 year. RESULTS: PioFluMet raised visfatin by a mean 84% and HMW adiponectin by 157% (P < 0.001), and reduced visceral fat and IMT by a mean 22% and 31% (both P < 0.001). Low-dose Pio accounted for about half of the PioFluMet effects on IMT, visfatin and HMW adiponectin. CONCLUSION: In hyperinsulinaemic women with androgen excess, low-dose polytherapy with PioFluMet evoked striking rises in both circulating visfatin and HMW adiponectin, while lowering IMT and reducing visceral adiposity within 1 year.

A framework to analyse gender bias in epidemiological research.

The design and analysis of research may cause systematic gender dependent errors to be produced in results because of gender insensitivity or androcentrism. Gender bias in research could be defined as a systematically erroneous gender dependent approach related to social construct, which incorrectly regards women and men as similar/different. Most gender bias can be found in the context of discovery (development of hypotheses), but it has also been found in the context of justification (methodological process), which must be improved. In fact, one of the main effects of gender bias in research is partial or incorrect knowledge in the results, which are systematically different from the real values. This paper discusses some forms of conceptual and methodological bias that may affect women's health. It proposes a framework to analyse gender bias in the design and analysis of research carried out on women's and men's health problems, and on specific women's health issues. Using examples, the framework aims to show the different theoretical perspectives in a social or clinical research context where forms of selection, measurement and confounding bias are produced as a result of gender insensitivity. Finally, this paper underlines the importance of re-examining results so that they may be reinterpreted to produce new gender based knowledge.

Persisting benefits 12-18 months after discontinuation of pubertal metformin therapy in low birthweight girls.

BACKGROUND: Discontinuation of metformin therapy, if started beyond menarche in adolescents or young women with hyperinsulinaemia following low birthweight, is rapidly followed by rebound deteriorations in body fat, insulin resistance and blood lipid profile. OBJECTIVE: We hypothesized that early commencement of metformin and its continuation throughout puberty might have more persisting benefits. PATIENTS AND MEASUREMENTS: We followed up on a previously reported randomized study cohort at 12 months and 18 months after treatment discontinuation, including body composition by absorptiometry, fasting insulin, glucose and blood lipids. In that open-labelled, prospective study, 22 low birthweight girls with early normal puberty (Stage 2 breast development at age 8-9 years) were randomized to remain untreated (N = 12] or to receive metformin (850 mg/day; N = 10) for 36 months (between time -36 months to 0 month). RESULTS: The significant improvements previously reported at the end of the 36-month active treatment period in per cent body fat, abdominal fat mass, fasting insulin sensitivity, high density lipoprotein (HDL) cholesterol and triglyceride levels all persisted at follow-up 12 months after treatment discontinuation. Further anthropometry at 18 months off therapy confirmed the persistence of benefits in height, body mass index (BMI) and waist circumference in the previously metformin-exposed girls. CONCLUSION: In low birth weight girls with early normal onset of puberty, metformin treatment for 3 years across puberty resulted in auxological, endocrine and metabolic benefits that persisted for at least 1 year after metformin withdrawal. Further follow-up and longer-term studies are needed to explore the possibility that insulin sensitization therapy during puberty might reprogramme predisposition to metabolic disease.

Combined low-dose pioglitazone, flutamide, and metformin for women with androgen excess.

CONTEXT AND OBJECTIVE: One of the treatments for hyperinsulinemic hyperandrogenism in nonobese women is combined androgen receptor blockade (with flutamide; Flu), insulin sensitization (with metformin; Met) plus an estroprogestagen contraceptive. We tested whether adding low-dose pioglitazone (Pio; 7.5 mg/d) confers more benefit. SETTING: The study was conducted at a university hospital. STUDY POPULATION AND DESIGN: This double-blind study enrolled 38 young women with hyperinsulinemic hyperandrogenism [mean body mass index (BMI) 24 kg/m(2)], all of whom started on Flu (62.5 mg/d) and Met (850 mg/d) plus a transdermal estroprogestagen, each for 21 of 28 d over 6 months. Patients were randomly assigned to receive, in addition, placebo (n=19) or Pio (n=19; 7.5 mg/d) for the same 21 of 28 d over 6 months. MAIN OUTCOMES: BMI, waist to hip ratio, hirsutism score, fasting endocrine-metabolic markers, body composition, abdominal fat (visceral vs. sc), and carotid intima-media thickness were measured at study start and after 6 months. RESULTS: PioFluMet reduced intima-media thickness more than FluMet and lowered glucose, IGF-I, and C-reactive protein more as well as the ratio of low-density lipoprotein to high-density lipoprotein cholesterol and the ratio of neutrophils to lymphocytes. PioFluMet treatment was followed by a leaner body composition and a loss of visceral fat (both P < 0.001). In the total group, the changes included not only decreases in waist to hip ratio, hirsutism score, and testosterone (all P < 0.001) but also minor drops in alanine aminotransferase, aspartate aminotransferase, gamma-glutamyl transpeptidase, and lactate dehydrogenase (all P < 0.005), indicating absence of hepatotoxicity; BMI remained unchanged. Clinical side effects were not detected. CONCLUSION: In this proof-of-concept study, addition of Pio to FluMet plus an estroprogestagen led to improvements in the endocrine-metabolic condition, in low-grade inflammation, in total and visceral adiposity, and in markers of cardiovascular health.

Metformin treatment to prevent early puberty in girls with precocious pubarche.

CONTEXT AND OBJECTIVE: Girls with precocious pubarche (PP, pubic hair at < 8 yr of age) are at high risk for early onset and rapid progression of puberty, in particular if their prenatal growth was restrained, i.e. low birth weight (LBW), and followed by rapid postnatal catch-up of weight gain. We postulated that insulin resistance contributes to early onset and rapid progression of puberty in LBW-PP girls and thus explored the puberty-delaying effects of insulin sensitization with metformin initiated shortly after PP diagnosis. SETTING, DESIGN, AND PATIENTS: The study population consisted of 38 prepubertal LBW girls with PP attributed to exaggerated adrenarche [mean body weight, 2.4 kg; age, 7.9 yr; body mass index (BMI), 18.4 kg/m(2)]. These girls were randomly assigned to remain untreated (n = 19) or to receive metformin (n = 19; 425 mg/d) for 2 yr. MAIN OUTCOME MEASURES: Pubertal staging, age at menarche, body composition by absorptiometry, fasting insulin, glucose, lipids, leptin, IGF-I, IGF-binding protein-1, testosterone, dehydroepiandrosterone sulfate, and SHBG were the main outcome measures. RESULTS: Metformin treatment was associated with a less adipose body composition (and lower serum leptin levels) and with a 0.4-yr delay in the clinical onset of puberty (Tanner B2; 9.5 vs. 9.1 yr; P < 0.01). These findings were corroborated by a delay of at least 1 yr in the puberty-associated rise of circulating IGF-I (P < 0.01). Available results also point to a metformin-associated delay of menarche (P < 0.02). Gain in height and lean mass was not divergent between study subgroups. CONCLUSION: The efficacy of early metformin treatment in PP girls is here extended to include not only a less adipose body composition after 2 yr but also a less advanced onset of puberty, whereas height gain is maintained. These findings open the perspective that, ultimately, metformin treatment may also prove to heighten the short adult stature of LBW-PP girls.

Metformin therapy during puberty delays menarche, prolongs pubertal growth, and augments adult height: a randomized study in low-birth-weight girls with early-normal onset of puberty.

CONTEXT AND OBJECTIVE: Low-birth-weight (LBW) girls who enter puberty earlier (around 8-9 yr) tend to have earlier menarche, earlier growth arrest, and a shorter adult stature. At present, there is no therapy for most of these girls. In LBW girls with early puberty, hyperinsulinemic insulin resistance could underpin their rapid transit through puberty and their loss of adult stature. We explored the effects of insulin sensitization with metformin during puberty. SETTING, DESIGN, AND PATIENTS: In an open-labeled, prospective study, 22 LBW girls (birth weight < -1.5 sd score for gestational age) with early-normal puberty (stage 2 breast development at age 8-9 yr) were randomized to remain untreated (n = 12) or to receive metformin (850 mg/d; n = 10) for 36 months (mean age at start, 9.0 yr). All girls remained untreated between 36 and 42 months. MAIN OUTCOME MEASURES: Pubertal growth, body composition by absorptiometry, uterine-ovarian size by ultrasound, fasting insulin, glucose, lipids, leptin, IGF-I, and IGF-binding protein-1 were assessed. RESULTS: Metformin treatment resulted in a longer duration from stage 2 breast development to menarche (P < 0.01; median difference, +1.0 yr), taller near-adult height (P < 0.01), and leaner body composition (P < 0.001). Metformin was also associated with lower insulin resistance and leptin and IGF-I levels and higher SHBG and IGF-binding protein-1 levels and with a more favorable lipid profile. Bone mineral density and uterine-ovarian growth were unaffected. CONCLUSION: Metformin treatment for 36 months in LBW girls with early-normal puberty normalized their pubertal progression to menarche and increased height gains up to adult stature. These data support the concept that insulin is a major codeterminant of the pubertal tempo and pubertal height gain in girls.

The tumour necrosis factor (TNF)-alpha-308GA promoter polymorphism is related to prenatal growth and postnatal insulin resistance.

OBJECTIVE: Variation in the tumour necrosis factor gene, (TNF) has been associated with insulin resistance traits. We questioned whether the TNF-308G/A polymorphism is associated with birthweight and insulin resistance in children born small for gestational age (SGA), a patient population known to be at risk for insulin resistance. DESIGN: A cross-sectional, hospital-based study assessing insulin sensitivity in SGA children. PATIENTS: One hundred and ninety-eight school-age children born either SGA (n=90, age 7.4+/- 4.5 years) or appropriate for gestational age (AGA, n=108, age 8.7+/- 4.0 years). MEASUREMENTS: All children were genotyped for the TNF-308G/A polymorphism; a biochemical profile was also performed in prepubertal SGA (n=58) and AGA (n=57) subjects. RESULTS: Genotype frequencies for the TNF-308G/A single nucleotide polymorphisms (SNPs) (GG and GA/AA) differed between SGA and AGA children (86%vs. 72% and 14%vs. 28%, respectively; P=0.025). The GG genotype was associated with lower birthweight and birth length (2747.0+/- 23.3 g vs. 2851.0+/- 45.7 g, P=0.045, and 47.0+/- 0.2 cm vs. 48.2+/- 0.4 cm, P=0.011, respectively) and, in AGA but not in SGA children, with higher systolic blood pressure [103.3 (95% confidence interval (CI) 96.4-110.2) mmHg vs. 92.8 (84.9-100.7) mmHg; P=0.028], higher blood glucose [4.8 (4.7-5.0) mmol/l vs. 4.5 (4.3-4.8) mmol/l; P=0.042] and higher homeostasis model assessment for insulin resistance (HOMA-IR) index [1.4 (1.1-1.7) vs. 0.9 (0.4-1.3); P=0.005]. In multivariate analysis, the TNF-308GG genotype was an independent predictor of HOMA-IR during childhood, explaining 8% of its variance. CONCLUSION: SGA children show increased frequency of the TNF-308G allele, an allele that is associated with prenatal growth and with postnatal insulin resistance. The TNF-308G/A polymorphism may have implications in the growth and metabolic abnormalities that characterise SGA children.

Discontinuous low-dose flutamide-metformin plus an oral or a transdermal contraceptive in patients with hyperinsulinaemic hyperandrogenism: normalizing effects on CRP, TNF-alpha and the neutrophil/lymphocyte ratio.

BACKGROUND: Low-dose flutamide-metformin (Flu-Met) with an oral contraceptive is a therapeutic option for women with hyperinsulinaemic hyperandrogenism. We questioned (i) whether Flu-Met maintains efficacy if given discontinuously; (ii) how the efficacy of discontinuous Flu-Met plus a transdermal contraceptive compares with Flu-Met plus oral contraceptive; and (iii) whether these treatments also lower circulating C-reactive protein (CRP) and tumour necrosis factor alpha (TNF-alpha) and the high neutrophil/lymphocyte ratio. METHODS: Non-obese, young patients (n = 31) with hyperinsulinaemic hyperandrogenism were started on Flu-Met (21/28 days) and randomized to receive in addition either a drospirenone oral contraceptive or a transdermal contraceptive for 6 months. RESULTS: The effects of Flu-Met were similar whether combined with oral or transdermal contraceptive. In both groups, CRP and TNF-alpha levels fell and the high neutrophil/lymphocyte ratio normalized (P < 0.001). Lean body mass increased (P < 0.001) in both groups but, in contrast to earlier experience with continuous Flu-Met, fat mass failed to decrease in either group. CONCLUSIONS: Flu-Met seems less lipolytic, if given for only 21 days in every 28-day period. The efficacy of Flu-Met is comparable when combined with an oral contraceptive or a transdermal contraceptive. The range of Flu-Met effects may henceforth include lower levels of CRP and TNF-alpha, and a normalization of the neutrophil/lymphocyte ratio.

Is deoxypyridinoline a good resorption marker to detect osteopenia in phenylketonuria?

OBJECTIVES: To evaluate deoxypyridinoline as a resorption marker in phenylketonuria (PKU) and to search for a relationship between deoxypyridinoline, calcium/creatinine index (Ca/Cr I), osteocalcin and bone alkaline phosphatase (BAP). METHODS: This was a transversal analytical study of 46 PKU patients [17.5 (4-38) years]. Deoxypyridinoline and osteocalcin were measured with a chemiluminescent assay and BAP was measured with an immunoradiometric assay. RESULTS: Deoxypyridinoline was significantly increased in patients aged 7-14 and >18 years old, being associated with age (r=-0.724, P<0.001). Adult patients showed significantly higher Ca/Cr I, which correlates with Phe values for the year prior to the study (P=0.014). Serum BAP was significantly increased in pediatric patients (9-13 years), while it was decreased in adult patients (P=0.003). Decreased osteocalcin levels were found in patients>15 years (P=0.028). Altered deoxypyridinoline and BAP values were related (P=0.042). CONCLUSION: PKU patients excreted increased D-Pyr, suggesting high bone resorption. Bone formation seems active in childhood but deteriorates in adult PKU patients. Periodic measurement of D-Pyr and BAP may be useful in the prevention of osteopenia in PKU patients.

The use of biochemical markers in prenatal diagnosis of intrauterine growth retardation: insulin-like growth factor I, Leptin, and alpha-fetoprotein.

OBJECTIVE: To determine the relation between weight deficit at birth and IGF-I, IGFBP-I, Leptin, and AFP levels in amniotic fluid after 14-18 weeks; to assess the diagnostic usefulness of these biochemical markers. STUDY DESIGN: Longitudinal, prospective study. Amniocentesis was performed in pregnant women after 14-18 weeks of gestation. STUDY POPULATION: 86 controls, 18 IUGR <10 percentile, and 17 IUGR <5 percentile. RESULTS: No significant correlation was found between severity of IUGR and IGF-I, IGFBP-I, or Leptin. AFP was inversely correlated with severity of IUGR; results for the IUGR <10 percentile were: S: 65.7%, SP: 56.9%, PPV: 38.3%, NPV: 80.3%, and an overall diagnostic capacity of 65.6%. Results for the IUGR <5 percentile were: S: 76.4%, SP: 54.8%, PPV: 21.6%, NPV: 93.4% were obtained, and an overall capacity of 70.6%. CONCLUSIONS: Elevated values of AFP in amniotic fluid may help early detection of populations at risk of developing IUGR.

Neutrophil count in small-for-gestational age children: contrasting effects of metformin and growth hormone therapy.

A minority of children born small for gestational age (SGA) maintain a slow weight gain and a short stature (SS). At the other end of the spectrum are SGA children who show rapid postnatal weight gain and catch-up growth; these subjects may develop hyperinsulinemia, exaggerated adrenarche with precocious pubarche (PP), and an associated proinflammatory state with raised IL-6 and reduced adiponectin levels. Metformin therapy in SGA-PP girls attenuates the hyperinsulinemia, the adrenal androgen excess, and the proinflammatory state. In contrast, GH therapy in SGA-SS children promotes height gain but may induce hyperinsulinemia. Both groups are associated with increased risk markers for future cardiovascular disease. Therefore, we studied markers of inflammation in both SGA subpopulations at baseline and after their respectively corrective therapies. SGA-PP girls (n = 33; mean age, 8 yr; body mass index, 18.5 kg/m(2)) were randomized to remain untreated or to receive metformin (425 mg/d) for 6 months. SGA-SS children (n = 29; mean age, 7 yr; body mass index, 14.7 kg/m(2)) were randomly assigned to remain untreated or to receive GH (60 mug/kg/d). In SGA-PP girls, the mean neutrophil count (4.0 x 1000/mm(3)) was more than 2 sd above the mean reference level (2.8 x 1000/mm(3), P < 0.001); this remained stable over 6 months in untreated girls but dropped in metformin-treated girls by -1.1 x 1000/mm(3) (P = 0.002). In SGA-SS children, neutrophil counts were also higher at baseline (3.3 x 1000/mm(3), P < 0.01). This remained stable in untreated children but rose in GH-treated children by +1.1 x 1000/mm(3) (P = 0.004). GH-treated children also showed a rise in circulating IL-6 and dehydroepiandrosterone-sulfate levels and a fall in adiponectin levels. In conclusion, neutrophil counts were elevated in SGA children. In SGA girls with PP, the present results corroborate the antiinflammatory benefits of metformin therapy. In contrast, high-dose GH therapy in short SGA children may increase neutrophil counts and lead to a less favorable adipocytokine profile. Future studies with combined GH plus metformin treatment in short SGA children may clarify whether insulin resistance is a mechanism linking GH therapy to markers of inflammation.

The value of interleukin-8, interleukin-6 and interleukin-1beta in vaginal wash as predictors of preterm delivery.

AIMS: To study the value of interleukin (IL)-8, IL-6 and IL-1beta in vaginal wash as predictors of preterm delivery. METHODS: A prospective analysis of a study group of 200 pregnant women between 24 and 34 weeks of gestation with intact membranes and preterm labor and a control group of 50 pregnant women during the same period of gestation. The controls had uncomplicated pregnancies and subsequently delivered at term. Samples of vaginal secretions were collected from both groups and analyzed for IL-1beta, IL-6 and IL-8 concentrations. RESULTS: Of the women in the study group, 70 had preterm deliveries, while all women in the control group had full-term deliveries. Compared with the control group, the study group had significantly higher concentrations (p < 0.021) of IL-1beta, IL-6 and IL-8. The women in the study group delivering preterm also had IL-1beta, IL-6 and IL-8 concentrations significantly greater (p < 0.001) than those of the same group delivering full term. ROC curves were used to establish cut-off points for the three interleukins to predict preterm delivery. We did not find a cut-off point with an appropriate sensitivity and specificity. CONCLUSION: The concentrations of interleukins in vaginal wash were significantly higher both in the women with preterm labor and in those delivering preterm. While values differed between controls and those with the preterm labor, no cut-off can be obtained to use the results of IL-1beta, IL-6 and IL-8 as a predictor clinically.

Validez de la escala de Norton para valorar el riesgo de presentar úlceras por presión en un hospital terciario. Comparación con la escala EMINA© / Validity of the Norton scale in evaluating the risk of pressure ulcers in a tertiary hospital. Comparison with the EMINA© scale

Objetivo. El objetivo del estudio es comparar la eficiencia de la escala de Norton con la de la escala EMINA©. Pacientes y método. Estudio observacional, transversal y retrospectivo. Los sujetos incluidos son los pacientes hospitalizados en un hospital de tercer nivel. Las variables analizadas son: evaluación del riesgo con la escala de Norton y aparición o no de úlceras por presión durante el período de hospitalización. Resultados. Se ha estudiado a un total de 865 pacientes distribuidos en 3 grupos cronológicos: G1, con 288 pacientes, G2, con 300, y G3, con 277 pacientes. La prueba de la X2 no ha revelado diferencias en el número de pacientes ni en el número de úlceras por presión. Tampoco se han observado diferencias significativas con el test de ANOVA al comparar la puntuación de la escala de Norton en los 3 grupos. La regresión logística de la escala de Norton en relación con la presencia de úlceras por presión a los 7 días muestra una clara significación estadística (p < 0,0005).El valor de la odds ratio fue de 0,707 (intervalo de confianza del 95 por ciento, 0,647-0,772), valor que indica que el incremento de la puntuación en la escala de Norton es un factor protector. El mejor punto de corte del valor de la escala Norton para predecir el riesgo de aparición de úlcera es de 14 (con una sensibilidad del 84 por ciento y una especificidad del 83 por ciento), cifra que coincide con el valor descrito en la bibliografía. La comparación de la escala de Norton con la escala EMINA© indica que las áreas de la curva ROC son distintas. Sin embargo, la comparación de los intervalos de confianza no permite inferir que las escalas sean estadísticamente distintas. Conclusiones. Se pone de manifiesto que la escala de Norton es una herramienta eficaz en un hospital de tercer nivel. Si comparamos los resultados del estudio con los de validación de la escala EMINA©, los resultados obtenidos son similares en términos de eficiencia. No parece que esté indicado plantearse el cambio de escala en nuestro medio (AU)

Insulin sensitization for girls with precocious pubarche and with risk for polycystic ovary syndrome: effects of prepubertal initiation and postpubertal discontinuation of metformin treatment.

Among girls with precocious pubarche (PP), those with low birth weight (LBW) are, even if nonobese, at risk for progression to polycystic ovary syndrome (PCOS) including hyperinsulinemic hyperandrogenism, dyslipidemia, dysadipocytokinemia, and central fat excess. Recently, we disclosed the efficacy of insulin sensitization with metformin to disrupt progression from PP to PCOS in formerly LBW girls who were postmenarche. In LBW-PP girls, we have now extended the exploration of early insulin sensitization therapy in two directions: 1) metformin therapy was started before puberty; and 2) we assessed the effects of metformin discontinuation in girls who had started metformin treatment after menarche. Prepubertal LBW-PP girls (n = 33; mean age, 8.0 yr; body mass index, 18.5 kg/m(2)) were randomly assigned to remain untreated or to receive metformin (425 mg/d) for 6 months. Postpubertal LBW-PP girls (n = 24; age, 12.4 yr; body mass index, 21.0 kg/m(2)) had been randomized (at -12 months) to remain untreated or to receive metformin (850 mg/d) for 12 months, at which time (0 month) a treatment cross-over was performed for 6 months. Fasting blood glucose and serum insulin, SHBG, dehydroepiandrosterone sulfate, androstenedione, testosterone, lipid profile, IL-6, and adiponectin were assessed at 0 and 6 months, as was body composition (by dual x-ray absorptiometry). In the prepubertal study (group A), comparisons of untreated vs. treated girls disclosed normalizing effects of metformin on SHBG, androstenedione, dehydroepiandrosterone sulfate, low and high density lipoprotein cholesterol, triglycerides, IL-6, adiponectin, total and abdominal fat mass, and lean body mass. In the postpubertal study (group B), treatment cross-over at 0 month was in each subgroup followed by a striking reversal in the course of the endocrine-metabolic state, adipocytokinemia, and body composition; all changes pointed to normalizing effects of metformin treatment. In conclusion, these two studies provide the first evidence that 1) prepubertal metformin therapy has normalizing effects on PCOS features in high risk girls with a combined history of LBW and PP; and 2) in adolescence, metformin's normalizing effects are reversed as soon as metformin therapy is discontinued.

Flutamide-metformin plus ethinylestradiol-drospirenone for lipolysis and antiatherogenesis in young women with ovarian hyperandrogenism: the key role of early, low-dose flutamide.

A low-dose combination of flutamide-metformin and ethinylestradiol-drospirenone was recently found to reduce the excess of total and abdominal fat, to diminish the deficit in lean mass, and to attenuate the dysadipocytokinemia of young women with ovarian hyperandrogenism, a variant of polycystic ovary syndrome. We questioned the need to give flutamide, an androgen receptor blocker, together with an oral contraceptive that contains drospirenone, a progestin claimed to have antiandrogen properties. The additive effects of low-dose flutamide (62.5 mg/d) were assessed over 3 months in young patients with hyperinsulinemic ovarian hyperandrogenism (n = 40; age, approximately 17 yr; body mass index, approximately 22 kg/m(2)); all participants started on metformin (850 mg/d) and a fourth-generation contraceptive (ethinylestradiol 30 microg plus drospirenone 3 mg, 21 d/month), and they were randomized to receive flutamide in addition (n = 20) or not (n = 20). Fasting blood glucose, serum insulin, lipid profile, testosterone, adiponectin, and IL-6 were determined at baseline and after 3 months, together with body composition (by dual x-ray absorptiometry) and with Doppler assessment of ovarian arterial resistance. At start, the pulsatility and resistance indices of ovarian arteries were elevated. By comparison of 3-month changes between randomized subgroups, the addition of low-dose flutamide was found to have consistently (more) normalizing effects on low-density lipoprotein cholesterol, IL-6, and adiponectin, lean body mass, total and abdominal fat mass, and arterial flow in the ovaries. In conclusion, low-dose flutamide is herewith identified as a pivotal component within a first contraceptive combination therapy that has been shown to attenuate the hypoadiponectinemia, ovarian vascular hyperresistance, lean mass deficit, and central adiposity of young women with polycystic ovary syndrome. Finally, these data challenge any claim that drospirenone, as currently used in a contraceptive, is a clinically significant antiandrogen.