Simone Funke

Postnatal Changes of Leptin Levels in Full-Term and Preterm Neonates: Their Relation to Intrauterine Growth, Gender and Testosterone

The present study was carried out to investigate leptin levels in arterial and venous cord serum and in amniotic fluid in full-term infants at birth and on the 5th postnatal day to define the relationship of leptin to intrauterine growth rate, gender and early postnatal life. The relation of weight gain to serum leptin levels in male preterm infants was determined measuring leptin concentration weekly in the first 5 postnatal weeks. Testosterone levels were determined simultaneously to explore a possible relationship between leptin and testosterone concentrations.Fifty-three term newborn infants with mean birth weight and gestational age of 3,419 g (range 2,150–4,480) and 38.9 weeks (range 36–41) and 19 preterm male infants (mean birth weight and gestational age were 1,416 g (770–1,800) and 30.2 weeks (26–35) were enrolled into the study. Leptin and testosterone levels were determined by radioimmunoassay. It was demonstrated that serum leptin levels were markedly elevated in the cord blood without discernible arteriovenous differences. Cord blood leptin was found to correlate with birth weight (r = 0.40, p < 0.002), weight to length ratio (r = 0.40, p < 0.002) and body mass index (r = 0.35, p < 0.005). It was significantly lower in boys as opposed to girls (p < 0.01) and there was an apparent fall by the 5th postnatal day (p < 0.001). Amniotic fluid contained leptin in much less concentration than cord blood and it proved to be independent of intrauterine growth or gender. Serum leptin concentration in preterm infants at 1 week of age was significantly lower compared with term infants (p < 0.002) and it increased progressively with age (p < 0.01). An inverse relationship was found between leptin and testosterone level (r = –0.358, p < 0.01) and a positive correlation between leptin level and weight/height ratio (r = 0.674, p < 0.01).It is concluded that leptin derived either from placenta or fetal adipose tissue may be involved in regulating fetal growth and development and it may be related to energy intake, storage and expenditure. In preterm male infants serum leptin concentration increases with postnatal weight and testosterone may suppress leptin synthesis.

Fatty acids in early human milk after preterm and full-term delivery.

Background: It has been much debated whether fatty acid composition of human milk differs after preterm as compared to full-term delivery. Subjects and Methods: Human milk samples were obtained from mothers of preterm (n = 8, gestational age: 28.0 [4.2] weeks, birthweight: 1,235 [420] g, median [interquartile range]) and full-term (n = 10, gestational age: 38.5 [2.7] weeks, birthweight: 3375 [282] g) infants every day during the first week and thereafter on the 14th, 21st, and 28th day of lactation. Fatty acid composition was measured by high-resolution capillary gas-liquid chromatography. Results: Maternal age and body mass index did not differ, and food frequency questionnaire did not reveal significant differences in diet between the two groups. Fat contents of human milk did not differ between the two groups. Values of linoleic acid (C18:2n-6) and alpha-linolenic acid (C18:3n-3) did not differ throughout the study. Values of the metabolites C18:3n-6 and C20:3n-6 as well as C18:4n-3 and C20:3n-3 were significantly higher after preterm as compared with full-term delivery. Values of arachidonic acid (C20:4n-6; e.g., day 4: 0.82 [0.4] vs. 0.44 [0.28]; day 7: 0.61 [0.25] vs. 0.34 [0.25]; day 21: 0.33 [0.18] vs. 0.44 [0.44]; in weight percent, preterm versus full-term, P < 0.05) and docosahexaenoic acid (C22:6n-3; e.g., day 4: 0.33 [0.23] vs. 0.15 [0.14]; day 7: 0.26 [0.16] vs. 0.13 [0.15]; day 21: 0.11 [0.08] vs. 0.21 [0.17]; P < 0.05) were significantly higher in human milk samples of mothers of preterm as compared with full-term infants. Conclusion: In this study, percentage contributions of arachidonic and docosahexaenoic acids as well as the those of the intermediary metabolites of essential fatty acid metabolism were all significantly higher in early human milk samples of mothers giving birth to very low birth weight preterm as compared with full-term infants.

Male reproductive tract abnormalities: more common after assisted reproduction?

BACKGROUND In this era of increased use of assisted reproduction (AR) techniques, the prevalence rates of hypospadias, cryptorchidism, poor semen quality have been increasing in parallel with a rising incidence of testicular cancer. It is suggested that these problems result from the disruption of gonadal development during fetal life causing the testicular dysgenesis syndrome (TDS). AIM The aim of our study was to evaluate the influence of conventional in vitro fertilization (IVF) and intracytoplasmic sperm injection (ICSI), on the development of male genital tract abnormalities. STUDY DESIGN AND SUBJECTS We analyzed a cohort of 15,206 neonates born from January 1, 1999 through December 31, 2008 at the Department of Obstetrics and Gynecology, Medical School, University of Pécs, including 890 children (5.9%) born after IVF or ICSI. We examined the association between these AR methods and developmental abnormalities of the genital tract (hypospadias, cryptorchidism), after controlling for potential confounding factors, such as prematurity, low birthweight and twinning. RESULTS Preterm birth and low birthweight are risk factors for hypospadias and cryptorchidism (p<0.001), twinning increases the risk of hypospadias (p<0.001). ICSI was revealed as a risk factor for hypospadias in singletons (OR: 3.190, 95%CI: 1.266-8.042) and in normal birthweight (>2500 g) infants (OR: 3.966, 95%CI: 1.193-13.181, respectively). Similar but not nonsignificant trends were seen for cryptorchidism. CONCLUSION IVF and ICSI, by increasing the risks of prematurity, low birthweight, and multiple gestation, are indirect risk factors for developing male genital malformations. In infants with normal birhtweight or from singleton pregnancies, ICSI is a specific risk factor for hypospadias.

Changes of Fatty Acid Composition of Human Milk during the First Month of Lactation: A Day-to-Day Approach in the First Week

Background: Fatty acid composition of human milk (HM) is known to change considerably during lactation. However, we were unable to find data on changes of fatty acid composition of HM during the very early phase of lactation, i.e. in the first week of life. Subjects and Methods: HM samples were obtained from 18 healthy lactating women every day during the first week and thereafter on the 14th and 28th days of lactation. Fatty acid composition of colostrum and mature HM samples was determined by high-resolution capillary gas-liquid chromatography. Results: Values of the n-6 essential fatty acid, linoleic acid, in HM did not change significantly during the first month of lactation, whereas values of the n-3 essential fatty acid, α-linolenic acid, showed significant increases during the first 2 weeks of lactation (1st day: 0.49 [0.12], % weight/weight, median [ranges from the 1st to the 3rd quartile], 14th day: 0.69 [0.31], p < 0.05). In contrast, values of the n-6 long-chain metabolites, eicosadienoic-, dihomo-γ-linolenic- and arachidonic acid, as well as the values of the n-3 long-chain metabolites, eicosatrienoic-, and eicosapentaenoic acid exhibited significant decreases during the entire period investigated. The principal n-3 long-chain metabolite, docosahexaenoic acid, showed a significant increase between the 3rd and 14th days, but a significant decrease between the 14th and 28th days (3rd day: 0.15 [0.13], 14th day: 0.28 [0.11], p < 0.05, 28th day: 0.19 [0.12], p < 0.01). There were statistically significant positive correlations between arachidonic and docosahexaenoic acid values on the 1st (r = 0.67, p < 0.01), 5th (r = 0.56, p < 0.05) and the 6th (r = 0.53, p < 0.05) days of lactation. Conclusion: Fatty acid composition of HM changes significantly even during the first week of lactation. The lack of positive correlation between essential fatty acids and their long-chain metabolites suggests that it is not only the availability of essential fatty acids that influences the fatty acid composition of human colostrum.

Glycosylation defects underlying fetal alcohol spectrum disorder: a novel pathogenetic model. "When the wine goes in, strange things come out" - S.T. Coleridge, The Piccolomini.

Fetal alcohol spectrum disorder (FASD) is an umbrella term used to describe the craniofacial dysmorphic features, malformations, and disturbances in growth, neurodevelopment and behavior occurring in individuals prenatally exposed to alcohol. Fetal alcohol syndrome (FAS) represents the severe end of this spectrum. Many pathophysiological mechanisms have hitherto been proposed to account for the disrupted growth and morphogenesis seen in FAS. These include impaired cholesterol-modification of the Sonic hedgehog morphogen, retinoic acid deficiency, lipoperoxidative damage due to alcohol-induced reactive oxygen species combined with reduced antioxidant defences, and malfunctioning cell adhesion molecules. In this report, we propose a completely novel concept regarding the pathogenesis of FAS. Based on our observation that transferrin isoelectric focusing (TIEF) – the most widely used screening tool for congenital disorders of glycosylation (CDG) – was transiently abnormal in a newborn with FAS and a confirmed maternal history of gestational alcohol abuse, we came to believe that FAS exemplifies a congenital disorder of glycosylation secondary to alcohol-inflicted disruption of (N-linked) protein glycosylation. Various pieces of evidence were found in the literature to substantiate this hypothesis. This observation implies, among others, that one might need to consider the possibility of maternal alcohol consumption in newborns with transient glycosylation abnormalities. We also present an integrated pathophysiological model of FAS, which incorporates all existing theories mentioned above as well as our novel concept. This model highlights the pivotal role of disrupted isoprenoid metabolism in the origination of FAS.

Decreased bone density and treatment in patients with autosomal recessive cutis laxa

Aim: Due to the occasional association pathological fractures and osteoporosis we evaluated four patients with cutis laxa syndrome for skeletal anomalies.

Influence of genetic polymorphisms on bone disease of preterm infants

Bone disease is an important complication among very low birth weight (VLBW, <1500 g) infants. In adults, osteoporosis is associated with polymorphisms of vitamin D receptor (VDR), estrogen receptor (ER), and collagen Iα1 (COLIA1) genes. However, limited information is available regarding the role of these polymorphisms in bone disease in premature infants. We have investigated the possible association between bone disease and the allelic polymorphisms of these three genes in 65 VLBW infants. Twenty infants (30.8%) were diagnosed with bone disease based on high activity of bone formation (serum alkaline phosphatase and osteocalcin), bone resorption (urinary excretion of calcium and pyridinium crosslink) markers, and positive radiologic signs. Statistically significant correlation between thymine-adenine repeat [(TA)n] allelic variant of ER gene and bone disease was observed. Infants without bone disorder more often carried a high number of repeats [(TA)n >18] [odds ratio (OR): 0.17, 95% confidence interval (CI): 0.05–0.55]. A low number of repeats [(TA)n <19] was found more frequently in infants suffering from bone disease (OR: 6.00, 95% CI: 1.77–20.31). Significant interaction (p = 0.009) between VDR and COLIA1 genotypes was observed. In a logistic regression model, bone disorder of preterms significantly correlated with male gender (p = 0.002), lower gestational age (p = 0.015), homozygous allelic variants of high number of (TA)n repeats (p = 0.006), and interaction between VDR and COLIA1 genotype (p = 0.009).

Congenital chylothorax in Opitz G/BBB syndrome†

Chylothorax is defined as a collection of lymph in the pleural space. It may be primary or secondary. Primary chylothorax is due to lymphatic duct abnormalities and may occur in isolation or in association with clinical conditions (polyhydramnios, hydrops, intrathoracic mass) or certain genetic syndromes (i.e., Noonan, Turner and Fryns syndromes [Van Straaten et al., 1993], Down syndrome [Ho et al., 1989], inversion of chromosome 2 and Kabuki syndrome [Maayan-Metzger et al., 2005]). Primary or congenital chylothorax is relatively uncommon: 1:10,000–15,000 live births. Secondary chylothorax occurs more often and is mostly associated with trauma or thoracic surgery. Opitz G/BBB syndrome is a heterogeneous disorder characterized by malformations of the ventral midline (OS; MIM 145410 and 300000). It was originally described as two distinct entities: the G syndrome characterized by hypospadias, hypertelorism, laryngo-tracheo-esophageal (LTE) abnormalities and central nervous system (CNS) midline defects [Opitz et al., 1969a] and the BBB syndrome with hypertelorism, hypospadias, cleft lip and/or palate, and anal anomalies [Opitz et al., 1969b]. The two syndromes were later merged and reclassified as G/BBB syndrome, comprising most prominently hypertelorism, hypospadias, and midline closure defects [Robin et al., 1996]. The autosomal dominant form maps to 22q11.2, the X-linked one maps to Xp22.3 [Robin et al., 1995]. No specific phenotypic findings have yet been shown to differentiate between the autosomal and X-linked genetic forms of OS. Mutations in the MID1 gene have been detected in 36–75% of the familial X-linked OS cases [Gaudenz et al., 1998, Cox et al., 2000] and in 6–36% of sporadic cases. A recent cohort reported a MID1 mutation detection rate of 22% for familial cases and 6% for sporadic cases [So et al., 2005]. Mutations in MID1 lead to a marked accumulation of protein phosphatase 2A (PP2A), a central cellular regulator. Elevated PP2A causes hypophosphorylation of microtubule-associated proteins, consistent with the OS phenotype [Trockenbacher et al., 2002]. Furthermore, it has been suggested that MID1 forms a large complex that is associated with microtubules and regulates microtubule dynamics [Schweiger and Schneider, 2003]. Interestingly, MID1 and its homolog MID2 share functional redundancy that may contribute to the wide variability of the MID1 associated OS phenotype [Granata et al., 2005]. Nonetheless, the low frequency of MID1 mutations and the high variability of the phenotype in general suggest the involvement of other genes in the pathogenesis of OS [De Falco et al., 2003]. Indeed, partial duplication of 5p [Leichtmann et al., 1991), and a terminal deletion of chromosome 13 (q32.3qter) in children with OS have also been described [Urioste et al., 1995]. These observations highlight the benefit of any report on unusual findings in OS patients that may improve our understanding of the genetically unresolved cases. Here we present a clinical case of Opitz G/BBB syndrome complicated by congenital chylothorax. Our patient, a 3.2 kg male, was delivered at 37 weeks of gestation by Cesarean following induction in a 27-year-old primigravid mother. The mother was noted tohavemarkedhypertelorism; theparents were healthy and the family history was otherwise

Life expectancy of extremely preterm infants

Extremely preterm infants [gestational age (GA) between 24-28 weeks] should be delivered optimally in an institute where neonatal intensive care unit (NICU) is available and their short- and long-term care is ensured. At the Department of Obstetrics and Gynecology, Medical School, University of Pécs, 7499 infants were born between 1st of January, 2000 and 31st of December, 2004. During this period the rate of preterm deliveries was 20% (1499/7499). Among preterm infants the incidence of extremely preterm babies (GA 28 weeks or less) was 18% (272/1499), the rate of profoundly preterm infants (GA less than 25 weeks) was 3.2% (48/1499). Advancing with gestational age the survival rate is increasing. At the department, the rate of handicapped infants among extremely premature babies was 15.3%. The majority of the handicapped infants were profoundly preterm, meanwhile, more than 50% of infants born at the 26 gestational weeks were free of symptoms influencing social activities. It is important to stress the prognostic value of the screening for hearing loss (otoacoustic emission), visual problems, and intracranial bleeding for the early detection and cure of the possible complications of prematurity.

Koraszülöttek csontanyagcsere-betegsége és genetikai polimorfizmusok@@@Metabolic bone disease in premature infants and genetic polymorphisms

UNLABELLED Metabolic bone disease is an important complication among infants very-low-birth-weight (< 1500 g). In adults, osteoporosis has been shown to be associated with polymorphisms of vitamin D receptor, estrogen receptor, and collagen Ialpha1 receptor genes. AIM The primary goal of the study was to investigate the possible association between metabolic bone disease and the allelic polymorphisms of these three genes. METHOD 104 infants very-low-birth-weight were enrolled to the study. Bone formation (serum alkaline phosphatase, osteocalcin) and bone resorption (urinary excretion of calcium and pyridinium crosslink) markers were determined and x-rays of the chest and wrist (together with the distal portions of associated long bones) were obtained. RESULTS Thirty infants (28,8%) were diagnosed with metabolic bone disease based on high activity of bone formation, bone resorption markers, and positive radiologic signs. Statistically significant correlation between thymine-adenine repeat [(TA) n ] allelic variant of estrogen receptor gene and bone disease was observed. Infants with metabolic bone disease more often carried low number of repeats [(TA) n < 19] [odds ratio (OR): 5.82, 95% confidence interval (CI): 2.26-14.98]. Significantly higher number of repeats [(TA)n > 18] was found more frequently in the control group (OR: 0.20, 95% CI: 0.05-0.82). Furthermore significant interaction between vitamin D receptor and collagen Ialpha1 receptor genotypes ( p = 0.023) was observed. In a forward stepwise logistic regression model, bone disorder of preterms correlated with male gender ( p = 0.001), duration of hospitalization ( p = 0.007), homozygous allelic variants of high number of (TA) n repeats ( p = 0.025) and interaction between vitamin D receptor (Tt) and estrogen receptor (homozygous allelic variants of low number of repeats) genotype ( p = 0.037). CONCLUSION The results suggest that the development of metabolic bone disease in infants very-low-birth-weight may be associated with genetic polymorphisms.