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Increased incidence of congenital heart disease (CHD) has been reported in the offspring of monochorionic twin gestations. Assisted reproductive technology (ART), which is related to increased rates of twinning, has also been associated with higher risk of birth defects. We studied the incidence of CHD in a cohort of twins to clarify the contribution of type of conception and chorionicity.Data concerning 874 live-born twins of which at least one was admitted in our Neonatal Unit during 1995-2012 were analysed. Forty-five % (N=197) of the gestations resulted from ART (in vitro fertilisation or intracytoplasmic sperm insertion).In the ART group 32/389 (8.2%) had CHD compared to 21/485 (4.3%) infants conceived naturally (OR 1.90, 95%CI 1.08-3.34, p=0.024). Spontaneous-conception gestations had higher incidence of monochorionic placentation (47/245 versus 4/197, p0.001), and included younger mothers (29.1±5.2 versus 33.9±5.5years, p0.001) who had higher parity (median 2 [range 1-7] versus 1 Pinborg (2005), Blondel and Kaminski (2002), Knopman et al. (2014), Kyvik and Derom (2006) ; p0.001). Multivariable logistic regression analysis showed that ART (OR 2.60, 95% CI 1.24-5.45) and monochorionicity (OR 3.49, 95% CI 1.57-7.77) were significant determinants of CHD, independently of maternal age, parity, and the gender of the offspring.We confirmed that monochorionic twins have increased risk of CHD and we documented a higher incidence of CHD in ART twins independently of chorionicity. We suggest improvement of echocardiographic skills of health care professionals involved in prenatal screening and foetal cardiology referral of ART dichorionic twins with suspicious findings at screening, in addition to all monochorionic gestations.

BackgroundNormal phosphate homeostasis is essential for normal linear growth. The phosphaturic fibroblast growth factor 23 (FGF23)/Klotho axis is a major regulator of phosphate homeostasis; therefore, an intact FGF23/Klotho axis is important for normal linear growth. On the other hand, GH/IGF1 axis has opposing effects on phosphate homeostasis, but the underline mechanisms remain unclear.AimThe main objective of this study was to investigate the possible interactions of FGF23 and its co-receptor Klotho, with growth hormone (GH)/IGF1 axis in the regulation of phosphate metabolism in GH-deficient children under GH treatment.MethodsWe studied 23 GH-deficient children, before and 3 months after the onset of GH treatment. Anthropometry and assessment of biochemical parameters were performed, as well as measurement of FGF23 (intact FGF23/iFGF23 and C-terminal FGF23/cFGF23) and soluble α-Klotho (sKlotho) levels.ResultsAfter 3 months on GH treatment, the elevation of serum phosphate and TmPO4/GFR (PPPPPPPPPPPPPPPConclusionThe increase in serum phosphate, which we found in GH-deficient children under GH treatment, is not associated with suppression but rather than with upregulation of the phosphaturic FGF23/Klotho axis.

The early postnatal cardiovascular consequences of intrauterine growth restriction (IUGR) have not been completely elucidated. This study aimed to evaluate the effect of IUGR on neonatal myocardial function and cardiovascular adaptation to extrauterine life. Conventional and tissue Doppler echocardiographic parameters were compared on the second and fifth postnatal day between 30 IUGR and 30 appropriate-for-gestational age (AGA) neonates. IUGR neonates presented relative interventricular septum (IVS) hypertrophy (IVS to left ventricular (LV) posterior wall diastolic ratio: median IUGR–AGA difference of 0.05 (interquartile range: 0.04–0.06); P = 0.020), relative LV dilatation (wall thickness to end-diastolic LV dimension difference of 0.12 (0.06–0.16); P = 0.012), and increased left myocardial performance index (MPI difference of 0.19 (0.05–0.28); P = 0.012). Repeated measurements ANOVA revealed a different pattern of change in LV stroke volume (LVSV; P < 0.001), LV cardiac output (LVCO; P < 0.001), MPI (P < 0.001), and heart rate (HR; P = 0.025) between AGA and IUGR infants. From the second to the fifth postnatal day, AGA neonates presented a decrease in MPI and HR with an increase in LVSV and LVCO. IUGR neonates failed to achieve similar changes in MPI, HR, and LVSV, whereas their LVCO decreased. IUGR neonates present changes in cardiac morphology and subclinical myocardial dysfunction, which may result in an altered pattern of cardiovascular adaptation to extrauterine life.

Background: Acute diarrhea remains a major public health issue worldwide, with gastroenteritis agents associated with a high morbidity, especially in infants and young children. A 1-year study (2009-2010) of rotavirus (RV)-caused pediatric diarrhea was performed on hospitalized children admitted with symptoms of acute diarrhea to the University Hospital of Patras, Greece. Methods: Twenty-nine fecal samples were investigated for RVs, adenoviruses (AdVs), and enteroviruses (EVs) in an attempt to characterize these enteric viruses, which have been implicated in hospitalized diarrhea. Results: A 44.8% (13/29) incidence of viral infection was reported for the viral targets. Monoinfections accounted for 31% (9/29), while bi-infections accounted for 13.4% (4/29). Sequencing of positive samples allowed identification of RVs G4P[8] (2/29), G9P[8] (1/29), and interestingly of the rare type G12P[8] (2/29). AdV types 1, 2, and 6 were also identified in 4/29, 1/29, and 1/29 of the samples, respectively. Regarding the EVs, EV71 (2/29), coxsackievirus A4 (1/29), echovirus 11 (1/29), and EV96 (1/29) were typed. Conclusion: The results of the present study, and specifically the detection of rare RV G12 and EV71 strains, address the need for continuous epidemiological surveys to provide epidemiological pictures of pediatric viral infections circulating in the community.

Respiratory muscle function in patients with cystic fibrosis (CF) can be assessed by measurement of maximal inspiratory pressure (Pimax ), maximal expiratory pressure (Pemax ), and pressure-time index of the respiratory muscles (PTImus ). We investigated the differences in maximal respiratory pressures and PTImus between CF patients with no gross hyperinflation and healthy controls and described the effects of pulmonary function and nutrition impairment on respiratory muscle function in this group of CF patients. Forced expiratory volume in 1 sec (FEV1 ), forced vital capacity (FVC) and maximal expiratory flow between 25% and 75% of VC (MEF25-75 ), body mass index (BMI), upper arm muscle area (UAMA), Pimax , Pemax , and PTImus were assessed in 140 CF patients and in a control group of 140 healthy subjects matched for age and gender. Median Pimax and Pemax were significantly lower in CF patients compared to the controls [Pimax = 74 (57-94) in CF vs. 84 (66-102) in controls, P = 0.009], [Pemax = 71 (50-95) in CF vs. 84 (66-102) in controls, P

Background Tobacco use in pregnancy is considered a human developmental toxicant and potential teratogen. The aim of the study was to test for a possible association between periconceptional tobacco smoking and congenital heart disease (CHD) in the neonatal period. Methods Maternal and infant characteristics of 157 neonates diagnosed with CHD at the University of Patras Medical School were collected and were compared with 208 normal neonates (aged 1–28days) that were referred for echocardiography during a specified 3-year period. Results In neonates with CHD 64 of 157 mothers (40.8%) reported smoking in pregnancy, whereas in the control group 41 of 208 mothers (19.7%) were smokers ( p =0.000). Logistic regression analysis with pregestational diabetes, history of influenza-like illness in the first trimester, therapeutic drug exposure in pregnancy, maternal age, parity, family history of CHD, infant gender, prematurity and paternal smoking, as potential confounding factors showed that periconceptional tobacco smoking was associated with increased risk of CHD in the offspring (OR=2.750, 95% CI=1.659–4.476, p =0.00001). The incidence of neonatal heart disease in women who were non-smokers or smoked 1–10 and ≥11 cigarettes per day increased with the level of fetal tobacco exposure (35.8% versus 55.3% versus 64.3%, x 2 -test=20.303, p =0.000), suggesting a dose effect. Conclusions The results of the study are indicative of an association between periconceptional tobacco exposure and increased risk of CHD in the neonatal period. The potential role of gestational smoking as a risk factor for specific heart defect subgroups requires the conduction of large population based epidemiological studies.

The anomalies of the umbilical vessels are uncommon, with the exception of a single umbilical artery. We report a term female infant with fetal hydrops, hypertrophic cardiomyopathy, and a four-vessel umbilical cord consisting of two umbilical arteries and two umbilical veins. The presence of two veins in the umbilical cord has been attributed to persistence of both the normal left umbilical vein and the caudal part of the right umbilical vein. This fetal vascular pathology has been reported very rarely and may be associated with increased risk of congenital malformations and adverse perinatal outcome.

Background Only a few studies have examined the relationship of plasma BNP levels and congenital heart disease (CHD) in neonates and these mainly concern preterm neonates with patent ductus arteriosus. We aimed to investigate the diagnostic role of plasma BNP in neonates admitted in the neonatal intensive care unit, (NICU), with signs of congenital heart disease (CHD). Methods Prospective assessment of plasma BNP levels in 75 consecutive neonates with suspected CHD (heart murmur, respiratory distress, or cyanosis), admitted in the NICU of our university hospital. The final diagnosis was done with echocardiography. Results Haemodynamically significant Left to Right shunts, (hsLtR), were found in 29 neonates, insignificant LtR shunts in 22, no heart disease in 15 and cyanotic heart disease in 9. BNP levels were significantly higher in neonates with hsLtR shunts vs. all other groups (logBNP 2.9±0.5pg/ml vs. 1.5±0.4pg/ml vs. 1.5±0.3pg/ml vs. 1.6±0.2pg/ml, p 132.5pg/ml had 93.1% sensitivity and 100% specificity for diagnosing hsLtR shunts (accuracy 99.6%). Conclusions Plasma BNP is a reliable test for diagnosing hsLtR shunts in the NICU. This will alert the neonatologist for ordering an echocardiographic examination, or if the latter is not available, for transferring the neonate to an appropriate tertiary centre with neonatal-paediatric cardiology facilities. Normal BNP levels imply the absence of a significant LtR shunt, but may not exclude cyanotic heart disease.

Aim: To evaluate the potential benefits of introducing universal rotavirus (RV) vaccination in Greece. Methods: A decision analytic model was developed to compare the burden and cost of rotavirus gastroenteritis (RVGE) with and without a universal RV vaccination (88% vaccination coverage) for a cohort of children followed from birth until the age of five. Results: Universal RV vaccination would substantially decrease the RVGE burden on the National Health System by reducing RVGE-related hospitalizations/emergency visits and medical consultations by 83% and 75%, respectively. Total RVGE-related costs was estimated at about 7.6 M€ and would be reduced by 5.9 M€ (−78%) if RV vaccination was introduced. A rapid effect is expected with 76% of cases and 84% of costs avoided would be averted within 2 years postvaccine introduction. The societal benefit would also be significant: total annual number of RVGE cases and parent’s lost work days would be reduced by 67% and 78%, respectively. Including indirect costs, the total disease cost reduction would be 9 M€. Conclusion: Introduction of universal RV vaccination in Greece could offer considerable medical and economic benefits for the National Health System and society. Potential herd immunity would improve results in favour of vaccination.

The aim of this study was to evaluate indices of respiratory failure in terms of their ability to predict respiratory impairment and need for ventilatory support in late-preterm neonates with respiratory distress. Arterial blood gas data during the first 12 postnatal hours or until intubation were recorded in 155 neonates with gestational age 34(0/7)-36(6/7) weeks admitted in the NICU with respiratory distress between January 2006 and June 2008. Alveolar-arterial oxygen tension difference (A-aDO(2)), arterial to alveolar oxygen tension ratio (a/A ratio), and partial arterial oxygen tension to inspired oxygen fraction ratio (PaO(2)/FiO(2)) were calculated. Considering the worst single value of each parameter, receiver operating characteristic curve analyses and area under the curve (AUC) comparisons were used to evaluate their predictive performance. Fifty-five neonates (35.5%) required mechanical ventilation. The predictive performances of the maximum A-aDO(2) (AUC 0.97), minimum a/A ratio (AUC 0.95), and minimum PaO(2)/FiO(2) (AUC 0.95) were similar. The A-aDO(2) at a threshold of200 mmHg proved to be more effective than the other parameters, having excellent positive and negative likelihood ratios of 24.5 and 0.02, respectively. This threshold was achieved by 98.25% of the neonates who developed respiratory failure at a median of 3 h before the ventilatory support to be definitely decided. Composite indices, such as A-aDO(2), a/A ratio, and PaO(2)/FiO(2), can reasonably predict respiratory failure in late-preterm neonates with respiratory distress, allowing for closer monitoring, early medical intervention, or transfer to a level III neonatal unit.

OBJECTIVE: The objective of this study was to provide data on transcutaneous bilirubin (TcB) levels for the first 120 postnatal hours and to develop an hour-specific TcB nomogram for healthy term and near-term neonates. METHODS: From September 2005 to August 2008, we obtained 14864 TcB measurements from 2818 healthy neonates (gestational age ≥ 35 weeks and birth weight ≥ 2000 g). All measurements were performed with the BiliCheck bilirubinometer, at designated times from 12 to 120 postnatal hours. TcB percentiles for each designated time were calculated and used for the development of an hour-specific nomogram. TcB percentiles for neonates who required phototherapy are also presented. RESULTS: The developed TcB nomogram reflects the natural history of TcB levels in healthy neonates up to the fifth postnatal day. A different pattern of TcB increasing rate was noted in neonates who did and did not require phototherapy but with substantial overlap of TcB values between the 2 groups. CONCLUSIONS: We provide data on TcB levels for the first 120 postnatal hours from a large population of white, healthy, term and near-term neonates. We also present a percentile-based TcB nomogram designated for noninvasive and hour-specific evaluation of neonatal hyperbilirubinemia.

OBJECTIVE: The goal was to develop a predictive nomogram, based on transcutaneous bilirubin (TcB) measurements, for assessment of the risk of significant hyperbilirubinemia in healthy term and near-term neonates. METHODS: A total of 10382 TcB measurements were performed with 2039 healthy neonates (gestational age of ≥35 weeks and birth weight of ≥2000 g), with a BiliCheck bilirubinometer (SpectRx, Norcross, GA), at designated time points between 12 and 120 hours of life. According to their severity, these TcB measurements were selectively cross-checked with a direct spectrophotometric device, and significant hyperbilirubinemia was defined on the basis of the hour-specific threshold values for phototherapy proposed by the American Academy of Pediatrics. With the use of likelihood ratios (LRs), the high- and low-risk demarcators for each designated time were calculated and presented on an hour-specific nomogram. RESULTS: Significant hyperbilirubinemia was documented for 122 neonates (6%). At 24 hours of life, the high-risk zone of the nomogram had 73.9% sensitivity and a positive LR of 12.1 in predicting significant hyperbilirubinemia, whereas the low-risk zone had 97.7% sensitivity and a negative LR of 0.04. At 48 hours, the high-risk zone had 90% sensitivity and a positive LR of 12.1, whereas the low-risk zone had 98.8% sensitivity and a negative LR of 0.02. In our study population, the probability of significant hyperbilirubinemia would be >35% for values in the high-risk zone and CONCLUSIONS: We provide a predictive TcB tool that could allow for a noninvasive, risk-based approach to neonatal hyperbilirubinemia.

We report on a neonate with a disorder of sex development, Prader 3-4 external genitalia and a palpable structure in the right inguinal canal suggestive of gonadal tissue. Chromosome studies on blood lymphocytes showed monosomy of chromosome X. Laparoscopy identified a streak-like gonad on the left side, unicorn uterus and a dysgenetic testis on the right, attached to a Fallopian tube. Because of the unilateral palpable gonad and the presence of ambiguous genitalia we investigated further for the presence of Y material. Quantitative fluorescent PCR analysis of material from the dysgenetic gonad and skin fibroblasts revealed the presence of chromosome Y-derived sequences, suggesting sex chromosome mosaicism. In 45,X/46,XY mosaicism, chromosome studies carried out on peripheral lymphocytes do not always reflect the proportion of cell lines in the gonads. The detection of Y chromosome material in a dysgenetic gonad is extremely significant, due to the high risk of malignant transformation.

Heat shock protein 27 (Hsp27), apart from its protective function in response to stress, is implicated in the regulation of cell growth, differentiation and apoptosis. Data on the expression of Hsp27 in the developing human epidermis are sparse and partially conflicting. Thus, the purpose of the present study was to investigate Hsp27 expression during the morphogenesis of human epidermis. Skin biopsies and dispase-separated epidermal sheets obtained from 7 human embryos (7 and 8 weeks estimated gestational age, EGA), from 79 human fetuses (9-23 weeks EGA) and from 10 healthy adult volunteers were investigated by immunohistochemistry and Western blotting, respectively. The earliest detection of Hsp27 expression was found by immunohistochemistry at the 12th week EGA (basal and intermediate layer) and by Western blotting at the 9th week EGA. From the 16th to the 23rd week EGA immunoreactivity was not detectable in the basal layer, whereas in the overlying layers it revealed a differentiation-related pattern. The simultaneous onset of epidermal stratification and Hsp27 expression (9th week EGA) and the alterations of the latter in the subsequent stages of development, suggest that this stress protein may be involved in the molecular events underlying human epidermal morphogenesis.

Intrauterine growth restriction (IUGR) is associated with structural and functional cardiac alterations but the electrophysiological consequences of these disturbances remain unknown.To explore the distribution of ventricular repolarization and its relation to myocardial mechanics in newborns with IUGR. STUDY DESIGN, SUBJECTS AND OUTCOME MEASUREMENTS: Conventional and tissue Doppler echocardiographic data, and electrocardiographic parameters used to describe the distribution of ventricular repolarization (dispersion of QT [QTd] and JT [JTd]), were obtained on the second (D2) and fifth (D5) postnatal day and compared between 25 IUGR newborns and 25 matched-for-gestational age controls.IUGR was associated with relative interventricular septum hypertrophy, increased left ventricular (LV) E/E' ratio and higher LV myocardial performance index (MPI). On both study days, the IUGR infants presented higher QTd and JTd compared to controls (QTd-D2: 66±20 ms vs. 36±12 ms, P0.001; JTd-D2: 54±13 ms vs. 34±9 ms, P0.001; QTd-D5: 61±14 ms vs. 27±12 ms, P0.001; JTd-D5: 54±13 ms vs. 27±9 ms, P0.001). The association between QTd and LV E/E' (D2: regression coefficient beta 0.747, R(2) 0.585; D5: beta 0.843, R(2) 0.646) and QTd and MPI (D2: beta 0.680, R(2) 0.576; D5: beta 0.698, R(2) 0.650) was also significant (P0.001 for all analyses).Our findings suggest that IUGR is associated with electrophysiological remodeling of the neonatal heart, a process which is closely related to the underlying alterations in ventricular mechanics and might predispose to adverse electrophysiological events.

Dear Sir, I am Neoklis A. Georgopoulos, from Department of Obstetrics and Gynaecology, Division of Reproductive Endocrinology, University of Patras Medical School, Greece. We present an early prepubertal diagnosis of Kallmann syndrome (KS) in a child with anosmia, renal agenesis and mirror movements. KS is a congenital defect characterized by the presence of hypogona-dotropic hypogonadism and anosmia or hyposmia 1. Besides hypogonadism and anosmia, the clinical phenotype is characterized by the presence of other associated features, including, among others, mirror movements (synkinesis), cleft palate and renal agenesis/dysgenesis. KS is a genetically heterogeneous disease showing X-linked, dominant or recessive autosomal, or oligogenic inheritance. The gene responsible for an X-linked mode of inheritance was identified in the short arm of the X chromosome (Xp22.3) and named KAL1 2. Mutations within the FGFR1 and the Prok2/ProkR2 genes have been implicated in the autosomal dominant and recessive inheritance forms, respectively. Certain non-reproductive features of KS might be linked to either KAL1 or FGFR1 gene defects. The mirror movements are present in approximately 80% of males with KAL1 mutations, but only in 10% of patients with FGFR1 gene defects. The frequency of KAL1 gene defects is estimated to be around 10% of all sporadic cases, whereas in the presence of associated renal agenesis/dysgenesis the frequency is as high as 89% 3, 4. To date, no case of KS and its associated renal agenesis caused by an FGFR1 mutation has been reported. The diagnosis of hypogonadotropic hypogonadism can be made in a male infant during the first 6 months of life on the basis of activation of the hypothalamic–pituitary–gonadotropic axis 5. Later, in childhood, the axis is suppressed and the definitive diagnosis of KS is therefore delayed until late adolescence, when the lack of pubertal development and the absence of secondary sex characteristics become obvious. The lack of pubertal development can cause considerable psychological damage to the young patient. We report on a child who was admitted to the Paediatric Clinic of Patras Medical School (Rio, Greece) at the age of 12 years for the evaluation of right renal agenesis. His height was 146.6 cm (25th percentile) and his weight was 38.8 kg (50th percentile). On clinical examination by a paediatric endocrinologist, his penis size was found to be normal for a prepubertal boy (length 5 cm, diameter 3.5 cm); his right testis was palpable in the scrotum, which was 2 cm in diameter, but his left testis was not palpable. The associated clinical features included an arched palate, mirror movements and anosmia. He was the only child in the family. As a detailed family history showed no evidence of hypogonadism, anosmia/hyposmia and/or delayed puberty in any relatives, the case was considered sporadic. Serum testosterone level was 8.46 ng dL-1, and there was no response of luteinizing hormone (LH) or follicle-stimulating hormone (FSH) to a gonadotropin-releasing hormone (GnRH) (100 μg) challenge (LH: < 0.01 mIU mL-1, FSH: 0.2 mIU mL-1). A detailed magnetic resonance imaging of the brain showed the absence of the olfactory bulbs and tracts and atrophy of the olfactory gyri. On the basis of the knowledge that KAL1 gene defects are highly probable in the presence of renal agenesis, we decided to sequence the KAL1 gene for a possible early clinical and genetic diagnosis of KS in our patient. We believed that the result of the genetic test would be worth considering, along with the fact that the patient had no clinical signs of hypogonadism. Sequence analysis of the KAL1 gene identified two genetic defects in the patient. The first mutation was a 259G to A transition in exon 1, turning codon 37 encoding glutamic acid into lysine (E37K), and the second an 835A to T transversion in exon 5, turning codon 235 encoding threonine into serine (T235S) (Figure 1). Neither mutation has been described earlier, and they are not identified in the sequence analysis of KAL1 gene in 53 normal men or in the two major public Single Nudeotide Polymorphism (SNP) databases, GenBank and Ensembl. Sequence analysis was carried out for the mother, because the KAL1 gene is located on the X chromosome that is passed on from the mother to the male proband. The mother was a heterozygote for exon 1 with a normal and mutant allele, but she was a wild-type homozygote for exon 5. Therefore, the mother transmitted the mutation in exon 1 to her son. The fact that the second mutation in her genome was absent suggested that the son had a de novo mutation in exon 5 (Figure 1). Figure 1 Electrochromatograms showing the two point mutations. (A) at 259 bp of exon 1 and (B) at 835 bp of exon 5 of KAL1 gene identified in the patient with Kallmann syndrome and renal aplasia and the heterozygotous status of his mother for (C) exon 1 and homozygotous ... The protein encoded by the KAL1 gene, named anosmin-1, is a glycoprotein of the extracellular matrix of unknown function. It has an amino terminus with a cysteine-rich domain, including a whey acidic protein-like four-disulphide core motif (WAP), four fibronectin type III domains (FnIII R1–R4) and a carboxyl-terminal histidine-rich domain. The E37K mutation is localized to the amino-terminal cysteine-rich domain of anosmin-1 and involves the non-conservative replacement of an acidic amino acid by a basic amino acid. The T235S mutation lies within the first R1 FNIII of the protein near a major cell adhesion site, which contains one of the predicted heparin sulphate binding sites of anosmin. A sequence-based prediction of the effects of these amino acid substitutions using the SIFT (Sorting Intolerant From Tolerant) software (http://blocks.fhcrc.org/sift/SIFT.html) revealed that the 259G to A transition (E37K) could affect protein function (with a score of 0.04), whereas the 835A to T transversion (T235S) was predicted to be tolerable. Indeed, with the latter mutation, at the protein level, the amino acid threonine was replaced by serine at position 235. Both amino acids are polar and they differ by only one methyl group (–CH3); therefore, the change was predicted to be tolerable. In contrast, the change from glutamic acid to lysine at position 37 replaces an acidic amino acid with a basic one, which might seriously affect protein function. To our knowledge, a genetic diagnosis of KS has never been reported during childhood. As our case was sporadic, any attempt to identify the genotype would have been extremely costly and time consuming. The KAL1 gene consists of 14 exons, and all reported causative mutations are scattered within the gene without any specific clustering. The finding of a right renal agenesis in a child with coexistent anosmia made sequencing the entire coding region of the KAL1 gene worthwhile, because the possibility of the identification of a causative mutation increased from 9% to 89%. It is therefore worthwhile to apply a genetic test only in the presence of associated non-reproductive clinical phenotypes in KS. Although a normal sequence in the KAL1 gene would not exclude KS, the finding of a causative mutation would further strengthen the diagnosis. Previously, an X-linked mode of inheritance dissociation of anosmia, delayed puberty and hypogonadotropic hypogonadism was reported in members of the same family 4, 6. In this study, the association of the right renal agenesis with anosmia strengthened the clinical diagnosis of KS, and it was further supported by the identification of the causative molecular defect. A normal clinical phenotype has not been reported in a case with KAL1 gene mutation. Through this letter, we wish to emphasise the im- portance of the presence of renal dysgenesis/agenesis and mirror movements as strong indicators for the presence of KAL1 gene mutations in patients with anosmia, even in childhood. Upon a prepubertal genetic diagnosis of the syndrome, the clinician can undertake therapeutic intervention for puberty induction at the age of 14 years, offering the patient a pubertal maturation that is similar to that of his teenage peers. As the correlations between genotypes and phenotypes cannot be predicted with certainty, treatment can be discontinued and the gonadotropic axis can be re-evaluated after puberty is reached. The documentation of the X-linked mode of inheritance could reassure these patients that the disease can only be transmitted as a recessive trait in their female offspring, and prenatal diagnosis could identify the presence of the causative mutation in the KAL1 gene in the male offspring of the next generation.

We present the case of a 4-year-old boy who was admitted to hospital with intracranial hypertension, headache, diplopia, papilledema, and a normal brain MRI.Brucella melitensisin the cerebrospinal fluid was confirmed with PCR assay. We believe that neurobrucellosis should be included in the differential diagnosis when headaches persist following brucellosis. In addition, we suggest that when cerebrospinal fluid culture is negative, PCR may prove to be an optimal alternative tool for an immediate and accurate diagnosis.

Respiratory muscle function in patients with cystic fibrosis (CF) can be assessed by measurement of maximal inspiratory pressure (Pimax ), maximal expiratory pressure (Pemax ), and pressure-time index of the respiratory muscles (PTImus ). We investigated the differences in maximal respiratory pressures and PTImus between CF patients with no gross hyperinflation and healthy controls and described the effects of pulmonary function and nutrition impairment on respiratory muscle function in this group of CF patients. Forced expiratory volume in 1 sec (FEV1 ), forced vital capacity (FVC) and maximal expiratory flow between 25% and 75% of VC (MEF25-75 ), body mass index (BMI), upper arm muscle area (UAMA), Pimax , Pemax , and PTImus were assessed in 140 CF patients and in a control group of 140 healthy subjects matched for age and gender. Median Pimax and Pemax were significantly lower in CF patients compared to the controls [Pimax = 74 (57-94) in CF vs. 84 (66-102) in controls, P = 0.009], [Pemax = 71 (50-95) in CF vs. 84 (66-102) in controls, P 0.001]. Median PTImus in CF patients compared to controls was significantly increased [PTImus = 0.110 (0.076-0.160) in CF vs. 0.094 (0.070-0.137) in controls, P = 0.049] and it was significantly higher in CF patients with impaired pulmonary function. In CF patients, PTImus was significantly negatively related to upper arm muscle area (r = 0.184, P = 0.031). These findings suggest that CF patients with no severe lung disease compared to healthy subjects exhibit impaired respiratory muscle function, while CF patients with impaired pulmonary function and nutrition indices exhibit higher PTImus values.

Respiratory distress syndrome (RDS) is a common problem and the leading cause of death in premature infants (PI). The introduction of surfactant treatment for RDS management has lowered mortality and morbidity; nevertheless, some neonates do not improve and are at increased risk of pulmonary hemorrhage. Inflammation, not only local but also systemic, seems to play an important role in the pathogenesis of RDS. To determine whether cytokine patterns characterize RDS and its outcome, we measured type-1 (IL-2, TNF-α, IFN-γ, IL-6) and type-2 (IL-4, IL-5, IL-10, TGF-β1) serum cytokines of 47 PI with established RDS and a control group of 30 healthy, appropriate for gestational age, full-term neonates. Cord blood samples were obtained at the time of delivery from PI and controls. Venous blood samples were collected from PI who received surfactant treatment and/or developed pulmonary hemorrhage. Significantly elevated cord blood cytokine levels were observed in PI at time of delivery, compared to controls, except for IL-5 and TNF-α levels that were within control range. The type-1/type-2 cytokine ratio was significantly increased in PI vs controls. Neonates who developed pulmonary hemorrhage between 2 and 3 days of life and/or died, presented the strongest Th1 and type-1 cytokine polarization that was mainly due to increased IFN-γ and TNF-α, and decreased TGF-β1. The majority of these PI were female with very low gestational age. Overall, PI with RDS present a Th1/type-1 cytokine polarization, which persists irrespective of the treatment provided, and is amplified when complications appear. Th1 polarization is associated with poor prognosis.

To evaluate the potential benefits of introducing universal rotavirus (RV) vaccination in Greece.A decision analytic model was developed to compare the burden and cost of rotavirus gastroenteritis (RVGE) with and without a universal RV vaccination (88% vaccination coverage) for a cohort of children followed from birth until the age of five.Universal RV vaccination would substantially decrease the RVGE burden on the National Health System by reducing RVGE-related hospitalizations/emergency visits and medical consultations by 83% and 75%, respectively. Total RVGE-related costs was estimated at about 7.6 M€ and would be reduced by 5.9 M€ (-78%) if RV vaccination was introduced. A rapid effect is expected with 76% of cases and 84% of costs avoided would be averted within 2 years postvaccine introduction. The societal benefit would also be significant: total annual number of RVGE cases and parent's lost work days would be reduced by 67% and 78%, respectively. Including indirect costs, the total disease cost reduction would be 9 M€.Introduction of universal RV vaccination in Greece could offer considerable medical and economic benefits for the National Health System and society. Potential herd immunity would improve results in favour of vaccination.

Objective To determine whether composite extubation indices can predict extubation outcome in preterm infants. Design Prospective observational study. Setting Level III neonatal intensive care unit. Patients Fifty-six preterm infants cared for in the neonatal intensive care unit of a tertiary teaching hospital during 2007 and 2008. Interventions None. Measurements and main results The study consisted of two parts. In the first part, different extubation indices were evaluated in a group of 28 neonates (derivation group). These indices included the diaphragmatic pressure-time index, the respiratory muscle pressure-time index, the maximal transdiaphragmatic pressure, the maximal inspiratory pressure, the airway pressure generated 100 milliseconds after an occlusion/maximal transdiaphragmatic pressure ratio, the airway pressure generated 100 milliseconds after an occlusion/maximal inspiratory pressure ratio, the tidal volume, and the respiratory rate to tidal volume ratio. After exploratory analysis, the best performing indices and the optimal threshold values to predict extubation outcome were selected. In the second part of the study, these indices were validated at the predetermined threshold values in an additional group of 28 preterm neonates (validation group). Four infants (14.3%) in the derivation group and four in the validation group (14.3%) failed extubation. Receiver operator characteristic curve analysis revealed that a diaphragmatic pressure-time index of ≤0.12, a respiratory muscle pressure-time index ≤0.10, a airway pressure generated 100 milliseconds after an occlusion/maximal transdiaphragmatic pressure of ≤0.14, and a airway pressure generated 100 milliseconds after an occlusion/maximal inspiratory pressure of ≤0.09 were the most accurate predictors of extubation outcome in the derivation group. In the validation group, a diaphragmatic pressure-time index of ≤0.12 and a respiratory muscle pressure-time index of ≤0.10 both had zero false-positive results, predicting with accuracy successful extubation. Conclusion Composite extubation indices such as the diaphragmatic pressure-time index and the noninvasive respiratory muscle pressure-time index can accurately predict extubation outcome in preterm neonates.

The aim of this study was to assess whether cardiac auscultation performed by pediatric trainees and neonatologists can reliably distinguish innocent from pathologic heart murmurs in asymptomatic neonates. From January 2008 to April 2009 the pediatric trainees of our institution were requested to refer all asymptomatic neonates with a murmur and classify the murmurs as “innocent,” “pathologic,” or “possibly pathologic.” Prior to echocardiography, each neonate was evaluated by two experienced neonatologists. The echocardiographic studies of 169 neonates were analyzed. Abnormal cardiac anatomy was found in 55 neonates (32.6%). The overall ability of pediatric trainees in identifying congenital heart disease (CHD) was moderate [area under the curve (AUC) = 0.855] and significantly lower compared to neonatologists (AUC = 0.919, p = 0.007). However, at “lower” levels of clinical confidence (i.e., clinical diagnosis of possibly pathologic murmurs), pediatric trainees had good ability in excluding CHD (sensitivity 94.6%; negative likelihood ratio = 0.09). The ability of cardiac auscultation for diagnosing CHD in asymptomatic neonates is limited and dependent on the physician’s experience and level of clinical confidence. Echocardiography should remain an option for all neonates with a possibly pathologic murmur.

Objective Angiotensin-converting enzyme (ACE) gene contains a polymorphism consisting of either the presence (I) or absence (D) of a 287-bp fragment. Recent studies have suggested that the I-allele may be associated with superior exercise endurance; respiratory muscle function may be similarly influenced. The pressure–time index of inspiratory muscles (PTImus) is a measure of the load–capacity ratio of the inspiratory muscles. The objective of this study was to determine whether infants homozygous for the I-allele have lower PTImus compared to infants homozygous for the D-allele or heterozygous I/D. Patients and Methods One hundred thirty-two infants were studied. ACE genotyping was performed by polymerase chain reaction amplification, using DNA from peripheral blood. PTImus was calculated as (Pimean/Pimax) × (Ti/Ttot), where Pimean was the mean inspiratory pressure estimated from airway pressure, generated 100 ms after an occlusion (P0.1), Pimax was the maximum inspiratory pressure and Ti/Ttot was the ratio of the inspiratory time to the total respiratory cycle time. Pimax was the largest pressure generated during brief airway occlusions performed at the end of a spontaneous crying effort. Results Infants with I/I genotype had significantly lower PTImus than infants with either D/D or I/D genotypes (P = 0.000007). ACE genotype was significantly related (P = 0.005) to PTImus measurements, independent of other factors that may affect respiratory muscle function. Conclusion These results suggest that an association of ACE genotypes with PTImus measurements may exist in infants. Pediatr Pulmonol. 2010;45:1233–1239. © 2010 Wiley-Liss, Inc.

Objective To assess the effect of selected maternal medical conditions and complications of pregnancy on the risk for morbidity among late preterm neonates. Design Prospective cohort study. Material and methods A total of 548 late preterm neonates (34 0/7 to 36 6/7 weeks' gestation) delivered from August 2006 to July 2009, were included. Information regarding demographics, gestational age, mode of delivery, maternal age and parity, pre-existing medical conditions and complications of pregnancy were obtained and associated with neonatal morbidity, both independently and as joint exposures. Newborn morbidity was defined by combining specific diagnoses, length of hospital stay, and transfer to the Neonatal Intensive Care Unit. Results Overall, 165 (30.1%) of the late preterm infants suffered from morbidity. The morbidity rates were 16.8% at 36weeks' gestation, and then approximately doubled from 38.2% at 35weeks to 59.7% at 34weeks. The joint effect of gestational age (OR 8.43 for 34weeks and 3.60 for 35weeks' gestation), small for gestational age (SGA) (OR 4.18), multiple gestation (OR 3.68) and lack of antenatal steroid administration (OR 4.03), was greater than the independent effect of each of these factors, and greater than additive. Emergency caesarean section (OR 1.43) and antepartum haemorrhage (OR 3.07) were also associated with a significant impact on neonatal morbidity. Conclusions The risk for morbidity among late preterm infants, changes with each passing week of gestation. This risk seems to be intensified, when other exposures such as SGA, multiple gestation, emergency caesarean section, lack of antenatal steroid administration and antepartum haemorrhage, are also present.

The hyper-IgE syndrome (HIES) is a rare primary immunodeficiency characterized by a highly elevated serum IgE, recurrent staphylococcal skin abscesses and cyst-forming pneumonia. Non-immunological abnormalities, including a distinctive facial appearance, hyperextensive joints, scoliosis, fracture following minor trauma, and the retention of primary teeth are also observed in many patients. Recently, it was shown that heterozygous mutations in signal transducer and activator of transcription 3 (STAT3), can cause autosomal-dominant HIES. Here we identify and characterize a novel mutation in the DNA-binding domain of STAT3 in a patient with hyper-IgE syndrome. Sequence analysis revealed a de novo heterozygous transition of a G-to-A, causing a substitution of a glycine residue for an aspartic acid in the translated sequence (G342D). The patient has normal levels of STAT3, which is able to translocate to the nucleus upon IL-6 stimulation. However, enzyme-linked DNA-protein interaction analysis showed that the G342D mutation affects the binding ability of STAT3 to target DNA sequences. In addition, as shown by qRT-PCR, the mutation abrogates the STAT3-dependent transcription of the retinoid-related orphan receptor gammat (ROR gammat) gene, an indispensable transcription factor for the commitment of naive CD4+ T cells to the Th17 lineage. These data suggest that the novel G342D mutation affects the binding of STAT3 on DNA and the STAT3-dependent expression of ROR gammat mRNA, leading to the HIES phenotype.

This manuscript reports on two very low birth weight premature infants with respiratory distress, receiving parenteral nutrition and broad-spectrum antibiotics for about 3 weeks, who developed Candida albicans sepsis associated with fungal mycoses and endocarditis, despite treatment with Amphotericin B and Caspofungin. On days 40 and 47, respectively, antifungal therapy was modified to liposomal Amphotericin B combined with Fluconazole 6 mg/kg/day for 4 weeks, resulting in complete resolution of the mycetomas. Our observations suggest that the combination of liposomal Amphotericin B with Fluconazole is able to result in complete resolution of cardiac mycetomas in preterm infants.

Insertion of a grass awn in the parotid duct and migration through the duct into the gland caused suppurative parotitis. This is an extremely rare condition, with few such cases reported in literature. As it happened here, under a quite common infection, such as suppurative parotitis is, an unexpected cause triggering inflammation was underlying. In an era of modern, expensive and sophisticated diagnostic methods, it is meticulous clinical examination and inspection of details that can give answers to such problems.

Objectives This study describes the epidemiology of rotavirus (RV) gastroenteritis (GE) disease following the introduction of RV vaccination in Greece in 2006. Design A prospective hospital-based surveillance. Setting A multicentre study was conducted at six hospitals in Greece between July 2008 and March 2010. The hospitals selected served 70% of the paediatric population in Greece. Participants Children aged

Gianotti-Crosti syndrome (GCS) is a relatively common skin disorder characterized by a distinctive, self-limiting, non-recurrent erythematous or skin-coloured papulo-vesicular eruption symmetrically distributed mainly on the extremities, buttocks and face of infants and young children and, infrequently, of adults. A wide spectrum of infectious agents, mostly viruses [hepatitis A, B and C, cytomegalovirus (CMV), Epstein-Barr, HIV, human her-pes virus 6, Coxsackie, rota-, echo- and parvovirus, para-influenza, mumps

Background/Aims: Premature or seriously ill neonates, often undergo a considerable number of radiographic examinations during their stay in the Neonatal Intensive Care Unit. The increased radiosensitivity of neonates due to the highly mitotic state of their cells in conjunction with longer life expectancy, increase the risk of radiation induced cancer. This highlights the importance of minimising radiation dose, while maintaining satisfactory image quality. An optimisation study concerning radiation dose and image quality in neonatal radiography is presented. Methods: Neonates were categorised into 4 groups, according to birth weight ( 2500g). For a total of 190 chest and chest-abdomen radiographs, exposure parameters (tube voltage-kVp, product of tube current and exposure time-mAs, field size) were recorded. Entrance surface dose (ESD) was estimated and Dose-Area product (DAP) was measured directly. Assessment of image quality was performed blindly by two independent observers (a radiologist and a paediatrician) based on the visibility of certain anatomical features and catheters, using a 5-grade scale. Results: ESD values increased with neonatal weight and demonstrated a wide variation, ranging from 15.2 to 60.3microGy (mean 31.6microGy). A wide variation was also observed in DAP values (0.23–0.92microGym2, mean 0.41microGym2). Evaluation of image quality revealed the feasibility to achieve satisfactory image quality (total image quality score >70%) using both high and low kVp techniques. Higher tube voltage techniques resulted in lower ESD values due to the increased beam penetration and the decreased mAs applied. Conclusions: The majority (98.5%) of ESD values are in accordance with the reference level of 50microGy recommended by the National Radiological Protection Board. However, results advocate that the use of high kVp techniques could result to further reduction in radiation dose, without degradation of image quality. Wide dose variations highlight the need of establishing standard examination protocols for neonatal radiography, with respect to weight.

Background Angiotensin converting enzyme (ACE) gene contains a polymorphism, consisting of either the presence (I) or absence (D) of a 287 base pair fragment. Deletion (D) is associated with increased circulating ACE (cACE) activity. It has been suggested that the D-allele of ACE genotype is associated with power-oriented performance and that cACE activity is correlated with muscle strength. Respiratory muscle function may be similarly influenced. Respiratory muscle strength in infants can be assessed specifically by measurement of the maximum inspiratory pressure during crying (Pimax). Pressure-time index of the respiratory muscles (PTImus) is a non-invasive method, which assesses the load to capacity ratio of the respiratory muscles. The objective of this study was to determine whether increased cACE activity in infants could be related to greater respiratory muscle strength and to investigate the potential association of cACE with PTImus measurements as well as the association of ACE genotypes with cACE activity and respiratory muscle strength in this population. Methods Serum ACE activity was assayed by using a UV-kinetic method. ACE genotyping was performed by polymerase chain reaction amplification, using DNA from peripheral blood. PTImus was calculated as (Pimean/Pimax) × (Ti/Ttot), where Pimean was the mean inspiratory pressure estimated from airway pressure, generated 100 milliseconds after an occlusion (P0.1), Pimax was the maximum inspiratory pressure and Ti/Ttot was the ratio of the inspiratory time to the total respiratory cycle time. Pimax was the largest pressure generated during brief airway occlusions performed at the end of a spontaneous crying effort. Results A hundred and ten infants were studied. Infants with D/D genotype had significantly higher serum ACE activity than infants with I/I or I/D genotypes. cACE activity was significantly related to Pimax and inversely related to PTImus. No association between ACE genotypes and Pdimax measurements was found. Conclusions These results suggest that a relation in cACE activity and respiratory muscle function may exist in infants. In addition, an association between ACE genotypes and cACE activity, but not respiratory muscle strength, was demonstrated.