Comparative study of multiple thiol-based self-assembled monolayer coatings for the SERS detection of nitrite, nitrate, and perchlorate anions in water.

Raman-based sensors represent a promising solution to enable both detection and fingerprinting of anionic pollutants in the water distribution network. Due to the weak nature of Raman scattering, a signal intensity enhancement mechanism, such as surface enhanced Raman spectroscopy (SERS), is required. Given the combination of SERS being a first layer effect and the low affinity for metallic surfaces shown by anions, functionalization of the SERS substrates using positively charged self-assembled monolayers (SAMs) is required to guarantee a strong SERS signal. In this work, the performance of three thiol-based coatings, namely, 2-mercapto-4-methyl-pyrimidine, cysteamine, and 2-dimethyl-amino-ethanethiol, is systematically compared for the detection of nitrite, nitrate, and perchlorate ions in water. For each coating, the limit of detection of those analytes is studied in combination with commercial SERS substrates. Cysteamine-coated SERS substrates are shown to provide the lowest limit of detection for the three analytes of this study. Evaluation of this coating on real drinking water samples is reported.

New insights into factors influencing adult height in short SGA children: Results of a large multicentre growth hormone trial.

BACKGROUND: Growth hormone (GH) treatment is effective in improving adult height (AH) in short children born SGA. However, there is a wide variation in height gain, even after adjustment for predictive variables. It is therefore important to investigate new factors which can influence the response to GH. OBJECTIVE: To investigate the efficacy of GH treatment (1 mg/m(2/) day) in short SGA children on AH. To assess the relation between spontaneous catch-up growth after birth and growth during puberty on the total height gain SDS to AH. PATIENTS: Longitudinal GH trial in 170 children. RESULTS: Median age at start of GH was 7·1 years and height -3·0 SDS. AH was -1·8 SDS (TH-corrected AH -1·1 SDS) in boys and -1·9 SDS (TH-corrected AH -1·3 SDS) in girls. Spontaneous catch-up growth after birth was ≥0·5 SDS in 42% of children. In contrast to expectation, spontaneous catch-up growth was negatively correlated with total height gain SDS during GH (P = 0·009). During puberty, height SDS declined (-0·4 SDS in boys and -0·5 SDS in girls) resulting in a lower total height gain SDS than expected. Pubertal height gain was 25·5 cm in boys and 15·3 cm in girls, significantly lower compared to AGA children (P < 0·001). At onset of puberty, BA for boys and girls was moderately advanced (P = 0·02 and P < 0·001, respectively). Growth velocity was comparable to AGA children during the first two years of puberty, but thereafter significantly lower until reaching AH (P < 0·001). CONCLUSION: In contrast to our hypothesis, children with greater spontaneous catch-up growth after birth show a lower total height gain SDS during GH. Height SDS declines from mid-puberty, due to a marked early deceleration of growth velocity.

Noonan syndrome: comparing mutation-positive with mutation-negative dutch patients.

Noonan syndrome (NS) is an autosomal dominant disorder characterized by facial dysmorphisms, short stature and congenital heart defects. The disorder is genetically heterogeneous and shows clinical overlap with other RASopathies. These syndromes are caused by mutations in a variety of genes leading to dysregulation of the RAS-MAPK pathway: PTPN11, KRAS, SOS1, RAF1, CBL, SHOC2, NRAS, BRAF, MAP2K1, MAP2K2, HRAS, NF1 and SPRED1. In this study, we conduct a genotype-phenotype analysis of 33 patients with a clinical diagnosis of NS without a PTPN11 mutation. Mutation analysis of the genes involved in RASopathies was performed, except for NF1 and SPRED1. In 14 (42%) NS patients, a mutation was found, 7 (21%) had a mutation in SOS1, 3 (9%) in RAF1 and 1 (3%) in KRAS, MAP2K2, BRAF and SHOC2 each. The phenotype of these mutation-positive cases corresponded to that described in the literature. In the cases with a BRAF and MAP2K2 mutation, the diagnosis cardio-facio-cutaneous syndrome was made. The patient with the SHOC2 mutation had features compatible with 'Noonan-like syndrome with loose anagen hair'. Three major clinical features of NS - a typical face, short stature and a pulmonary valve stenosis - were less frequently present in the group without a mutation. Missense mutations in genes encoding proteins of the RAS-MAPK pathway cause NS. The 3 major clinical features of NS were less frequently present in the mutation-negative patients, which stresses the importance of the syndrome-specific symptoms of the face, heart and short stature in NS. However, all mutation-negative cases met the NS criteria, indicating that the involvement of novel genes is to be expected.

Genetic analysis of short children with apparent growth hormone insensitivity.

BACKGROUND/AIMS: In short children, a low IGF-I and normal GH secretion may be associated with various monogenic causes, but their prevalence is unknown. We aimed at testing GH1, GHR, STAT5B, IGF1, and IGFALS in children with GH insensitivity. SUBJECTS AND METHODS: Patients were divided into three groups: group 1 (height SDS <-2.5, IGF-I <-2 SDS, n = 9), group 2 (height SDS -2.5 to -1.9, IGF-I <-2 SDS, n = 6) and group 3 (height SDS <-1.9, IGF-I -2 to 0 SDS, n = 21). An IGF-I generation test was performed in 11 patients. Genomic DNA was used for direct sequencing, multiplex ligation-dependent probe amplification and whole-genome SNP array analysis. RESULTS: Three patients in group 1 had two novel heterozygous STAT5B mutations, in two combined with novel IGFALS variants. In groups 2 and 3 the association between genetic variants and short stature was uncertain. The IGF-I generation test was not predictive for the growth response to GH treatment. CONCLUSION: In severely short children with IGF-I deficiency, genetic assessment is advised. Heterozygous STAT5B mutations, with or without heterozygous IGFALS defects, may be associated with GH insensitivity. In children with less severe short stature or IGF-I deficiency, functional variants are rare.

Normal height and weight in a series of ambulant Duchenne muscular dystrophy patients using the 10 day on/10 day off prednisone regimen.

Prednisone treatment delays the progressive course of Duchenne muscular dystrophy. The aim of this study was to determine the influence of the 10 day on/10 day off treatment on height and weight. We retrospectively reviewed the growth and weight charts of Duchenne patients born between 1988 and 2006 (patients between 4 and 9 years old, being able to walk in the home situation). Forty-seven patients were eligible for further analysis and divided into two groups: 33 patients treated with prednisone and 14 non-prednisone treated patients. Results of a median follow-up of 57 months (range 27-146) are described. By using linear mixed models this study demonstrates that height and body mass index in prednisone-treated patients with 10/10 regimen are not significantly different compared to untreated patients. We cautiously conclude that the alternating prednisone regimen has no apparent side effects on weight and height in the ambulatory phase of Duchenne muscular dystrophy.

The severe short stature in two siblings with a heterozygous IGF1 mutation is not caused by a dominant negative effect of the putative truncated protein.

OBJECTIVE: While in previous studies heterozygosity for an Insulin-Like Growth Factor 1 (IGF1) defect only modestly decreased height and head circumference, we recently reported on two siblings with severe short stature with a maternally transmitted heterozygous duplication of 4 nucleotides, resulting in a frame shift and a premature termination codon in the IGF1 gene. In this paper we describe the structural and functional characteristics of the putative truncated IGF-I protein. DESIGN: Two children, their mother and maternal grandfather carried the mutation. In addition, two family members who were not affected were included in the study. Mutant (MT) IGF-I was synthesized in oxidized and reduced form using two methods. Neutral gel filtration studies were carried out with wild-type (WT) and synthetic MT IGF-I. Binding analysis of synthetic MT IGF-I to the IGF1R and insulin receptors were performed with EBNA-293 cells, stably transfected with the IGF-I receptor, and IM9 cells. L6 cells were used to examine the mitogenic potency and the potential antagonizing effect of synthetic MT IGF-I by [(3)H]-thymidine incorporation assays. RESULTS: In the sera of both the carriers and non-carriers the proportion of (125)I-IGF-I that was associated with the 150 kDa complex was somewhat less (varying between ~37 and ~52%) than in normal pooled serum (~53-~63%) and, instead, slightly increased amounts of radioactivity were eluted in the 40-50 kDa fraction (consisting of binary IGF-IGFBP complexes) or remained unbound. Synthetic MT IGF-I did not bind to the IGF-I receptor, nor antagonize the growth-promoting effect of IGF-I. It did bind to IGFBPs, but was barely incorporated into 150 kDa complexes. Because in all cases WT IGF-I immunoreactivity was recovered in one peak, corresponding to the MW of WT IGF-I, i.e. ~7.6 kDa, an interaction of circulating truncated mutant peptide with WT IGF-I is very unlikely. CONCLUSIONS: There is no evidence that the severe short stature associated with heterozygosity for this novel IGF1 mutation in children born from a mother with the same mutation is caused by a dominant negative effect of the truncated protein. We speculate that the growth failure is caused by a combination of partial IGF-I deficiency, placental IGF-I insufficiency, and other genetic factors.

Short stature associated with a novel heterozygous mutation in the insulin-like growth factor 1 gene.

CONTEXT: Homozygous IGF1 deletions or mutations lead to severe short stature, deafness, microcephaly, and mental retardation. Heterozygosity for an IGF-I defect may modestly decrease height and head circumference. OBJECTIVE: The objective of the study was to investigate the clinical features of heterozygous carriers of a novel mutation in the IGF1 gene in comparison with noncarriers in a short family and to establish the effect of human GH treatment. SUBJECTS: Two children, their mother, and their maternal grandfather carried the mutation and were compared with two relatives who were noncarriers. RESULTS: The two index cases had severe short stature (height sd score -4.1 and -4.6), microcephaly, and low IGF-I levels. Sequencing of IGF1 revealed a heterozygous duplication of four nucleotides, resulting in a frame shift and a premature termination codon. The mother and maternal grandfather had the same IGF1 mutation. Adult height (corrected for shrinking and secular trend) and head circumference sd score of carriers of the paternally transmitted mutation was -2.5 and -1.8, in comparison with -1.6 and 0.3 in noncarriers, respectively. After 2 yr of GH treatment, both index cases exhibited increased growth. CONCLUSIONS: Heterozygosity for this novel IGF1 mutation in children born from a mother with the same mutation, presumably in combination with other genetic factors for short stature, leads to severe short stature, which can be successfully treated with GH.

Successful treatment of severe subcutaneous insulin resistance with inhaled insulin therapy.

The potential of inhaled insulin therapy for severe resistance to subcutaneous insulin was tested in a 7-yr old boy with type 1 diabetes mellitus. The efficiency of 1 mg inhaled insulin (Exubera) was examined by a 4-h euglycemic clamp study. During the clamp, the glucose infusion rate started to increase 25 min after inhalation and peaked 120 min after inhalation. Subsequently, a trial of inhaled insulin monotherapy was initiated consisting of pre-meal inhalations and one inhalation during the night. Since glycemic control remained fair (HbA1c approximately 8.5%), this therapy was continued. Over the ensuing 18 months, mild keto-acidosis occurred twice during gastro-enteritis. Inhaled insulin was well tolerated and pulmonary function did not deteriorate. We conclude that severe resistance to subcutaneous insulin does not preclude sufficient absorption of insulin delivered by pulmonary.

Growth in Noonan syndrome.

Growth failure in Noonan syndrome is mainly postnatal of character and is dominated by slow maturation and late puberty. The postnatal early decline seems to be an intrinsic part of the syndrome. Reported adult heights are about -2 SD and are indicative of a secular trend.

Growth hormone and the heart in Noonan syndrome.

BACKGROUND: The clinical hallmarks of Noonan syndrome (NS) are facial dysmorphism, short stature and cardiac defects. As one of the common cardiac defects in NS is hypertrophic cardiomyopathy, there have been concerns regarding cardiac safety since the start of human growth hormone (hGH) therapy for NS. METHODS: Review of currently available data on the prevalence of cardiac defects, the theoretical effects of hGH on the heart and the results of studies on the effects of hGH on the heart. RESULTS: The prevalence of cardiac defects in NS is high, and the spectrum is very broad. Progression of ventricular wall thickness during hGH therapy has never been reported. There are barely any data available on children with NS and hypertrophic cardiomyopathy collected during hGH therapy. In post-marketing surveillance studies, there are no reports of adverse cardiac events related to hGH therapy. CONCLUSION: The reported absence of negative effects of hGH therapy on the heart in NS and especially on ventricular wall thickness is reassuring. Still, keeping in mind the current limited experience, any effects on the heart resulting from hGH therapy should be monitored carefully in NS.

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. PATIENT/METHODS: We prospectively evaluated four patients, a male and a female child and a brother-sister sib pair, with dysmorphic features, growth delay, joint anomalies, psychomotor retardation and congenital cutis laxa. The clinical features and the family history were suggestive for autosomal recessive cutis laxa syndrome type II, partially overlapping with geroderma osteodysplastica. Skeletal survey, sequential bone density measurements, endocrine and metabolic investigations were performed including N- and O-linked glycosylation analysis. ATP6V0A2 and FBLN5 mutations were ruled out in all patients. RESULTS: All children were diagnosed with significantly decreased bone density, especially in the lumbar spine, including spontaneous vertebral and rib fractures in three children. Following 24 months of bisphosphonate treatment a total restitution of bone density was observed in three cases and no relapse was detected in the 2-year follow-up period. A spontaneous improvement was found in one female during puberty. CONCLUSION: Bone disease might occur early in the course in autosomal recessive cutis laxa syndrome. We report on a significant clinical improvement and stabilization in our patients following bisphosphonate therapy. We suggest early, systemic evaluation and follow up of bone density in all children presenting with inherited cutis laxa.

Response to growth hormone treatment and final height in Noonan syndrome in a large cohort of patients in the KIGS database.

BACKGROUND: Noonan syndrome (NS) is an autosomal dominant inherited disease, characterized by a distinctive facial appearance, congenital heart defects, and short stature. Treatment with growth hormone (GH) is an option to enhance height, but long-term effects are still unclear. PATIENTS AND METHODS: A cohort of 402 patients (269 males, 133 females), mean age 9.7 years at start with GH, was studied within the KIGS International growth database with respect to long-term response to GH therapy and final height after GH therapy. RESULTS: At the start of GH therapy median height was -2.61 SDS (Tanner 1966 standards). Seventy-three patients who were followed longitudinally for 3 years had an increment in height SDS (Ht SDS) over the first 3 successive years of 0.54, 0.13 and 0.13, respectively. Twenty-four patients had reached their final height after 4-12 years of GH treatment. Their Ht SDS increased from a median of -3.28 to a median of -2.41 at final height. CONCLUSION: This group of patients with NS showed an early response to GH treatment, with an attenuation of this effect thereafter. At final height the median increment of final height was 0.61 SDS according to Tanner standards and 0.97 SDS according to Noonan standards. No serious side effects were reported.

Long-term GH treatment improves adult height in children with Noonan syndrome with and without mutations in protein tyrosine phosphatase, non-receptor-type 11.

CONTEXT: Noonan syndrome (NS) is characterized by short stature, typical facial dysmorphology and congenital heart defects. Short-term effect of GH therapy in NS is beneficial, reports on the effect on adult height are scarce. OBJECTIVE: To determine the effect of long-term GH therapy in children with NS. DESIGN: Twenty-nine children with NS were treated with GH until final height was reached. SETTING: Hospital endocrinology departments. PATIENTS: Children with the clinical diagnosis of NS, with mean age at the start of therapy of 11.0 years, 22 out of 27 tested children had a mutation in the protein tyrosine phosphatase, non-receptor-type 11 gene (PTPN11 gene). Interventions GH was administered subcutaneously at 0.05 mg/kg per day until growth velocity was 1 cm/6 months. MAIN OUTCOME MEASURE: Linear growth (height) was measured at 3-month intervals in the first year and at 6-month intervals thereafter until final height. RESULTS: At the start of treatment, median height SDS (H-SDS) was -2.8 (-4.1 to -1.8) and 0.0 (-1.4 to +1.2), based on national and Noonan standards respectively. GH therapy lasted for 3.0-10.3 years (median, 6.4), producing mean gains in H-SDS of +1.3 (+0.2 to +2.7) and +1.3 (-0.6 to +2.4), based on national and Noonan standards respectively. In 22 children with a mutation in PTPN11 mean gain in H-SDS for National standards was +1.3, not different from the mean gain in the five children without a mutation in PTPN11+1.3 (P=0.98). CONCLUSION: Long-term GH treatment in NS leads to attainment of adult height within the normal range in most patients.

Homozygous and heterozygous expression of a novel mutation of the acid-labile subunit.

CONTEXT: Acid-labile subunit (ALS) deficiency due to homozygous inactivation of the ALS gene (IGFALS) is associated with moderate short stature, and in few cases pubertal delay. The clinical expression of heterozygosity is unknown. OBJECTIVE: To investigate the clinical, laboratory, and radiological features of homozygous and heterozygous carriers of a novel mutation in the ALS gene in comparison with non-carriers. SUBJECTS: Three short Kurdish brothers and their relatives. RESULTS: The index cases presented with short stature, microcephaly, and low circulating IGF-I and IGF-binding protein-3 (IGFBP-3), and undetectable ALS levels. Two were known with a low bone mineral density and one of them had suffered from two fractures. We found a novel homozygous ALS gene mutation resulting in a premature stop codon (c.1490dupT, p.Leu497PhefsX40). The IGF-I, IGFBP-3, and ALS 150 kDa ternary complex was absent, and ALS proteins in serum were not detected with western blot. IGFPB-1 and IGFPB-2 were low and there was a mild insulin resistance. Five heterozygous carriers tended to have a lower height and head circumference than five non-carriers, and had low plasma ALS and IGFBP-3 levels. Bone mineral (apparent) density was low in two out of three homozygous carriers, and also in four out of nine relatives. CONCLUSIONS: The clinical presentation of homozygous ALS mutations may, besides short stature, include microcephaly. Heterozygous carriers may have less statural and head growth, suggestive for a gene dosage effect.

Are ECG abnormalities in Noonan syndrome characteristic for the syndrome?

Of all patients with Noonan syndrome, 50-90% have one or more congenital heart defects. The most frequent occurring are pulmonary stenosis (PS) and hypertrophic cardiomyopathy. The electrocardiogram (ECG) of a patient with Noonan syndrome often shows a characteristic pattern, with a left axis deviation, abnormal R/S ratio over the left precordium, and an abnormal Q wave. The objective of this study was to determine if these ECG characteristics are an independent feature of the Noonan syndrome or if they are related to the congenital heart defect. A cohort study was performed with 118 patients from two university hospitals in the United States and in The Netherlands. All patients were diagnosed with definite Noonan syndrome and had had an ECG and echocardiography. Sixty-nine patients (58%) had characteristic abnormalities of the ECG. In the patient group without a cardiac defect (n = 21), ten patients had a characteristic ECG abnormality. There was no statistical relationship between the presence of a characteristic ECG abnormality and the presence of a cardiac defect (p = 0.33). Patients with hypertrophic cardiomyopathy had more ECG abnormalities in total (p = 0.05), without correlation with a specific ECG abnormality. We conclude that the ECG features in patients with Noonan syndrome are characteristic for the syndrome and are not related to a specific cardiac defect. An ECG is very useful in the diagnosis of Noonan syndrome; every child with a Noonan phenotype should have an ECG and echocardiogram for evaluation.

Impaired Sertoli cell function in males diagnosed with Noonan syndrome.

In order to study male gonadal function in Noonan syndrome, clinical and laboratory data, including inhibin B, were gathered in nine pubertal males diagnosed with Noonan syndrome. Bilateral testicular maldescent was observed in four, and unilateral cryptorchidism occurred in two. Puberty was delayed in three patients. Luteinising hormone (LH) levels were normal in all patients in our series, while follicle stimulating hormone (FSH) levels were raised in seven. Inhibin B was low in six males and just above the lower limit of normal in two. Importantly, all three men with normal testicular descent displayed signs of Sertoli cell dysfunction, indicating, in contrast to earlier reports, that bilateral cryptorchidism does not seem to be the main contributing factor to impairment of testicular function in Noonan syndrome. These findings suggest different mechanisms of disturbance in male gonadal function, which is frequently associated with Sertoli dysfunction.

[Persistent neonatal hypoglycaemia caused by arterial positioning of the umbilical venous catheter]. / Persisterende onverklaarde neonatale hypoglykemie door arteriële positie van een navelvenelijn.

Two neonates, a girl born at 40 2/7 weeks weighing 4165 g and a boy born at 37 6/7 weeks weighing 4040 g, received umbilical venous catheters to help manage hypoglycaemia. The catheter was ineffective or only effective when high doses of glucose were used, due to what later appeared to be arterial positioning of the catheter. Both patients recovered without consequences. Persistent hypoglycaemia is a common problem in newborns and can cause severe neurological sequelae. A relatively uncommon cause is malpositioning of the umbilical catheter. Positioning in an artery leads to direct infusion of glucose into the pancreas, which causes hyperinsulinaemia and can lead to potentially dangerous nonketotic hypoglycaemia. Arterial positioning of the umbilical catheter should be ruled out at an early stage. Correct catheter positioning can be determined using careful inspection of the umbilical veins, radiological examination of the catheter position, blood gas analysis or vascular pulsation.

Klinefelter's syndrome and Prader-Willi syndrome: a rare combination.

In this paper a review is presented of the rare combination of Klinefelter's syndrome and Prader-Willi syndrome (PWS) and a second case of this combination with a uniparental disomy (UPD) etiology of PWS is described. Patients outlined in all other 8 reports and the present case have a PWS phenotype. Virtually no information is available on the behavioral and psychopathological phenotype in this combination. The latter may be explained by the observation that psychiatric syndromes are especially prevalent in PWS patients with a UPD. It is concluded that instability in mood and behavior in this and other syndromes should be preferentially treated with mood stabilizing agents.

Hepatocyte nuclear factor-1 beta mutations cause neonatal diabetes and intrauterine growth retardation: support for a critical role of HNF-1beta in human pancreatic development.

AIM: The transcription factor hepatocyte nuclear factor-1beta (HNF-1beta) is expressed in rodent pancreatic progenitor cells, where it is an important member of the genetic hierarchy that regulates the generation of pancreatic endocrine and exocrine cells. The recent description of an HNF-1beta mutation in a patient with neonatal diabetes suggests that HNF-1beta may also play a key role in human pancreatic B-cell development. We aimed to investigate the role of HNF-1beta mutations in neonatal diabetes and also the impact of HNF-1beta mutations on fetal growth. METHODS: We sequenced the HNF-1beta gene in 27 patients with neonatal diabetes in whom other known genetic aetiologies had been excluded. Birth weight was investigated in 21 patients with HNF-1beta mutations. RESULTS: A heterozygous HNF-1beta mutation, S148L, was identified in one patient with neonatal diabetes diagnosed at 17 days, which rapidly resolved only to relapse at 8 years. This patient had pancreatic atrophy, mild exocrine insufficiency and low birth weight (1.83 kg at 40 weeks' gestation). Intrauterine growth was markedly reduced in patients born to unaffected mothers with a median birth weight of 2.4 kg (range 1.8-3.3) (P = 0.006), median centile weight 3 (0.008-38), and 69% were small for gestational age. CONCLUSION: HNF-1beta mutations are a rare cause of neonatal diabetes as well as pancreatic exocrine and endocrine dysfunction. Low birth weight is a common feature of patients with HNF-1beta mutations and is consistent with reduced insulin secretion in utero. These findings support a key role for HNF-1beta in early pancreatic progenitor cells in man.