Modified Blalock-Taussig shunt with compensatory properties.

Determination of the proper length of the tubular prosthesis is a major issue when performing a systemic-pulmonary artery shunt. The procedure is simplified by using a prosthesis with accordionlike properties. This was demonstrated in 7 consecutive infants with complex congenital heart defects, in whom systemic-pulmonary artery shunts were placed without early or late complications.

Beneficial effect of insulin-like growth factor-1 on hypoxemic renal dysfunction in the newborn rabbit.

Acute normocapnic hypoxemia can cause functional renal insufficiency by increasing renal vascular resistance (RVR), leading to renal hypoperfusion and decreased glomerular filtration rate (GFR). Insulin-like growth factor 1 (IGF-1) activity is low in fetuses and newborns and further decreases during hypoxia. IGF-1 administration to humans and adult animals induces pre- and postglomerular vasodilation, thereby increasing GFR and renal blood flow (RBF). A potential protective effect of IGF-1 on renal function was evaluated in newborn rabbits with hypoxemia-induced renal insufficiency. Renal function and hemodynamic parameters were assessed in 17 anesthetized and mechanically ventilated newborn rabbits. After hypoxemia stabilization, saline solution (time control) or IGF-1 (1 mg/kg) was given as an intravenous (i.v.) bolus, and renal function was determined for six 30-min periods. Normocapnic hypoxemia significantly increased RVR (+16%), leading to decreased GFR (-14%), RBF (-19%) and diuresis (-12%), with an increased filtration fraction (FF). Saline solution resulted in a worsening of parameters affected by hypoxemia. Contrarily, although mean blood pressure decreased slightly but significantly, IGF-1 prevented a further increase in RVR, with subsequent improvement of GFR, RBF and diuresis. FF indicated relative postglomerular vasodilation. Although hypoxemia-induced acute renal failure was not completely prevented, IGF-1 elicited efferent vasodilation, thereby precluding a further decline in renal function.

Prise en charge des fentes labio-maxillo-palatines au CHUV = [Children born with a cleft: treatment at the CHUV in Lausanne]

A cleft can be labial, labial-maxillary, unilateral or bilateral labial-maxillary-palatal, or isolated palatal. A multidisciplinary team includes several specialists who will handle the diverse problems of children born with a cleft. This team will follow the child through each developmental stage and assemble an optimal treatment plan, thus reducing the onus on the family. Depending on the type of cleft and the age of the child, feeding, speech, ORL, dental, orthodontic, esthetic and possibly also psychological problems will be taken care of. This is why cleft treatment starts at the time it is diagnosed, before or after birth, and ends when the child is fully grown. It requires a complete interdisciplinary team and the collaboration with obstetricians and geneticians.

BCOR analysis in patients with OFCD and Lenz microphthalmia syndromes, mental retardation with ocular anomalies, and cardiac laterality defects.

Oculofaciocardiodental (OFCD) and Lenz microphthalmia syndromes form part of a spectrum of X-linked microphthalmia disorders characterized by ocular, dental, cardiac and skeletal anomalies and mental retardation. The two syndromes are allelic, caused by mutations in the BCL-6 corepressor gene (BCOR). To extend the series of phenotypes associated with pathogenic mutations in BCOR, we sequenced the BCOR gene in patients with (1) OFCD syndrome, (2) putative X-linked ('Lenz') microphthalmia syndrome, (3) isolated ocular defects and (4) laterality phenotypes. We present a new cohort of females with OFCD syndrome and null mutations in BCOR, supporting the hypothesis that BCOR is the sole molecular cause of this syndrome. We identify for the first time mosaic BCOR mutations in two females with OFCD syndrome and one apparently asymptomatic female. We present a female diagnosed with isolated ocular defects and identify minor features of OFCD syndrome, suggesting that OFCD syndrome may be mild and underdiagnosed. We have sequenced a cohort of males diagnosed with putative X-linked microphthalmia and found a mutation, p.P85L, in a single case, suggesting that BCOR mutations are not a major cause of X-linked microphthalmia in males. The absence of BCOR mutations in a panel of patients with non-specific laterality defects suggests that mutations in BCOR are not a major cause of isolated heart and laterality defects. Phenotypic analysis of OFCD and Lenz microphthalmia syndromes shows that in addition to the standard diagnostic criteria of congenital cataract, microphthalmia and radiculomegaly, patients should be examined for skeletal defects, particularly radioulnar synostosis, and cardiac/laterality defects.

Considerations for prenatal counselling of patients with cardiac rhabdomyomas based on their cardiac and neurologic outcomes.

Cardiac rhabdomyomas are benign cardiac tumours with few cardiac complications, but with a known association to tuberous sclerosis that affects the neurologic outcome of the patients. We have analysed the long-term cardiac and neurological outcomes of patients with cardiac rhabdomyomas in order to allow comprehensive prenatal counselling, basing our findings on the records of all patients seen prenatally and postnatally with an echocardiographic diagnosis of cardiac rhabdomyoma encountered from August, 1982, to September, 2007. We analysed factors such as the number and the location of the tumours to establish their association with a diagnosis of tuberous sclerosis, predicting the cardiac and neurologic outcomes for the patients.Cardiac complications include arrhythmias, obstruction of the ventricular outflow tracts, and secondary cardiogenic shock. Arrhythmias were encountered most often during the neonatal period, with supraventricular tachycardia being the commonest rhythm disturbance identified. No specific dimension or location of the cardiac rhabdomyomas predicted the disturbances of rhythm.The importance of the diagnosis of tuberous sclerosis is exemplified by the neurodevelopmental complications, with four-fifths of the patients showing epilepsy, and two-thirds having delayed development. The presence of multiple cardiac tumours suggested a higher risk of being affected by tuberous sclerosis. The tumours generally regress after birth, and cardiac-related problems are rare after the perinatal period. Tuberous sclerosis and the associated neurodevelopmental complications dominate the clinical picture, and should form an important aspect of the prenatal counselling of parents.

An effector-reduced anti-β-amyloid (Aβ) antibody with unique aβ binding properties promotes neuroprotection and glial engulfment of Aβ.

Passive immunization against β-amyloid (Aβ) has become an increasingly desirable strategy as a therapeutic treatment for Alzheimer's disease (AD). However, traditional passive immunization approaches carry the risk of Fcγ receptor-mediated overactivation of microglial cells, which may contribute to an inappropriate proinflammatory response leading to vasogenic edema and cerebral microhemorrhage. Here, we describe the generation of a humanized anti-Aβ monoclonal antibody of an IgG4 isotype, known as MABT5102A (MABT). An IgG4 subclass was selected to reduce the risk of Fcγ receptor-mediated overactivation of microglia. MABT bound with high affinity to multiple forms of Aβ, protected against Aβ1-42 oligomer-induced cytotoxicity, and increased uptake of neurotoxic Aβ oligomers by microglia. Furthermore, MABT-mediated amyloid plaque removal was demonstrated using in vivo live imaging in hAPP((V717I))/PS1 transgenic mice. When compared with a human IgG1 wild-type subclass, containing the same antigen-binding variable domains and with equal binding to Aβ, MABT showed reduced activation of stress-activated p38MAPK (p38 mitogen-activated protein kinase) in microglia and induced less release of the proinflammatory cytokine TNFα. We propose that a humanized IgG4 anti-Aβ antibody that takes advantage of a unique Aβ binding profile, while also possessing reduced effector function, may provide a safer therapeutic alternative for passive immunotherapy for AD. Data from a phase I clinical trial testing MABT is consistent with this hypothesis, showing no signs of vasogenic edema, even in ApoE4 carriers.

Considerations for prenatal counselling of patients with cardiac rhabdomyomas based on their cardiac and neurologic outcomes.

Cardiac rhabdomyomas are benign cardiac tumours with few cardiac complications, but with a known association to tuberous sclerosis that affects the neurologic outcome of the patients. We have analysed the long-term cardiac and neurological outcomes of patients with cardiac rhabdomyomas in order to allow comprehensive prenatal counselling, basing our findings on the records of all patients seen prenatally and postnatally with an echocardiographic diagnosis of cardiac rhabdomyoma encountered from August, 1982, to September, 2007. We analysed factors such as the number and the location of the tumours to establish their association with a diagnosis of tuberous sclerosis, predicting the cardiac and neurologic outcomes for the patients.Cardiac complications include arrhythmias, obstruction of the ventricular outflow tracts, and secondary cardiogenic shock. Arrhythmias were encountered most often during the neonatal period, with supraventricular tachycardia being the commonest rhythm disturbance identified. No specific dimension or location of the cardiac rhabdomyomas predicted the disturbances of rhythm.The importance of the diagnosis of tuberous sclerosis is exemplified by the neurodevelopmental complications, with four-fifths of the patients showing epilepsy, and two-thirds having delayed development. The presence of multiple cardiac tumours suggested a higher risk of being affected by tuberous sclerosis. The tumours generally regress after birth, and cardiac-related problems are rare after the perinatal period. Tuberous sclerosis and the associated neurodevelopmental complications dominate the clinical picture, and should form an important aspect of the prenatal counselling of parents.

Neurodevelopmental outcome of neonates treated with nitric oxide for persistent pulmonary hypertension

Persistent pulmonary hypertension of the newborn (PPHN) is a life threatening condition associated with an increased risk of neurodevelopmental impairment. The recommended treatment for this condition is inhaled nitric oxide (iNO) and has been used in our Neonatal Intensive Care Unit since 1998. We prospectively offered neurodevelopmental follow-up to children treated with iNO for PPHN, including extensive neurological evaluation, developmental/cognitive evaluation at 18 months and 3.5-5 years old, and evaluated the rate of severe and moderate handicap and normal neurodevelopmental outcome, compared to a control group and the literature. Population consisted of 29 patients treated only with iNO, born between 01.01.1999 and 31.12.2005 (study group), and 32 healthy term infants born in 1998 in our maternity (control group). During those seven years, 65 infants were admitted in our Unit with PPHN, of whom 40 were treated with iNO alone. 34 children survived (85%) and were offered neurodevelopmental follow-up, 7 children were lost to follow-up due to various reasons. 22 children were examined at the age of 18 months (76%) with a rate of moderate handicap of 22% (2 with expressive language delay, 2 with difficult behavior, and 1 child with moderate hearing loss), and a rate of major handicap of 4.5% (1 child with cerebral palsy due to perinatal stroke, and moderate hearing loss). At preschool age, 17 (50%) were examined, the rate of moderate handicap was 22% (4 borderline intelligence, 1 hearing loss), and the rate of major handicap was 4.5% (one child with cerebral palsy and hearing loss), compared to 26.9% and 0% in the control group. Mean developmental quotient at 18 months was 100.3 ± 8.7 (control group 118.3), and at preschool age mean cognitive indices were within normal limits for the 2 tests performed at 3.5 or 5 years (108 ± 21, 94.4 ± 17). Most of the children with a less favorable neurodevelopmental outcome suffered from birth asphyxia (ruptured uterus, placental abruption, maternal hypotension, diabetic cardiomyopathy), and notably, the 2 children with sensorineural hearing loss both suffered from severe hypoxic-ischemic enkelopathy. Treatment with iNO was not the direct cause of the neurodevelopmental impairments observed in children treated for PPHN.

SDF 1-alpha (CXCL12) triggers glutamate exocytosis from astrocytes on a millisecond time scale: Imaging analysis at the single-vesicle level with TIRF microscopy

Chemokines are small chemotactic molecules widely expressed throughout the central nervous system. A number of papers, during the past few years, have suggested that they have physiological functions in addition to their roles in neuroinflammatory diseases. In this context, the best evidence concerns the CXC-chemokine stromal cell-derived factor (SDF-1alpha or CXCL12) and its receptor CXCR4, whose signalling cascade is also implicated in the glutamate release process from astrocytes. Recently, astrocytic synaptic like microvesicles (SLMVs) that express vesicular glutamate transporters (VGLUTs) and are able to release glutamate by Ca(2+)-dependent regulated exocytosis, have been described both in tissue and in cultured astrocytes. Here, in order to elucidate whether SDF-1alpha/CXCR4 system can participate to the brain fast communication systems, we investigated whether the activation of CXCR4 receptor triggers glutamate exocytosis in astrocytes. By using total internal reflection (TIRF) microscopy and the membrane-fluorescent styryl dye FM4-64, we adapted an imaging methodology recently developed to measure exocytosis and recycling in synaptic terminals, and monitored the CXCR4-mediated exocytosis of SLMVs in astrocytes. We analyzed the co-localization of VGLUT with the FM dye at single-vesicle level, and observed the kinetics of the FM dye release during single fusion events. We found that the activation of CXCR4 receptors triggered a burst of exocytosis on a millisecond time scale that involved the release of Ca(2+) from internal stores. These results support the idea that astrocytes can respond to external stimuli and communicate with the neighboring cells via fast release of glutamate.

Characterization of MAP1B heavy chain interaction with actin.

Microtubule-associated protein 1B is an essential protein during brain development and neurite outgrowth and was studied by several assays to further characterize actin as a major interacting partner. Tubulin and actin co-immunoprecipitated with MAP1B at similar ratios throughout development. Their identity was identified by mass spectrometry and was confirmed by Western blots. In contrast to previous reports, the MAP1B-actin interaction was not dependent on the MAP1B phosphorylation state, since actin was precipitated from brain tissue throughout development at similar ratios and equal amounts were precipitated before and after dephosphorylation with alkaline phosphatase. MAP1B heavy chain was able to bind actin directly and therefore the N-terminal part of MAP1B heavy chain must also contain an actin-binding site. The binding force of this interaction was measured by atomic force microscopy and values were in the same range as those of MAP1B binding to tubulin or that measured in MAP1B self-aggregation. Aggregation was confirmed by negative staining and electron microscopy. Experiments including COS-7 cells, PC12 cells, cytochalasin D and immunocytochemistry with subsequent confocal laser microscopy, suggested that MAP1B may bind to actin but has no obvious microfilament stabilizing effect. We conclude, that the MAP1B heavy chain has a microtubule-stabilization effect, and contains an actin-binding site that may play a role in the crosslinking of actin and microtubules, a function that may be important in neurite elongation.

Parents living with HIV in a high-income country: do patients need specific support?

The number of HIV-infected persons with children and caregiving duties is likely to increase. From this statement, the present study was designed to establish how HIV infected caregivers organise their parenting routines and to determine their support needs. A further aim was to ascertain caregivers' perception of conspicuous behaviours displayed by their children. Finally, it sought to determine the extent to which the caregivers' assessment of their parenting activity is influenced by the required support and their children's perceived conspicuous behaviours. The study design was observational and cross-sectional. Sampling was based on the 7 HIV Outpatient Clinics associated with the national population-based Swiss HIV Cohort Study. It focused on persons living with HIV who are responsible for raising children below the age of 18. A total of 520 caregivers were approached and 261 participated. An anonymous, standardised, self-administered questionnaire was used for data collection. The data were analysed using descriptive statistical procedures and backward elimination multiple regression analysis. The 261 respondents cared for 406 children and adolescents under 18 years of age; the median age was 10 years. The caregivers' material resources were low. 70% had a net family income in a range below the median of Swiss net family income and 30% were dependent on welfare assistance. 73% were undergoing treatment with 86% reporting no physical impairments. The proportion of single caregivers was 34%. 92% of the children were living with their HIV infected caregivers. 80% of the children attended an institution such as a school or kindergarten during the day. 89% of the caregivers had access to social networks providing support. Nevertheless, caregivers required additional support in performing their parenting duties and indicated a need for assistance on the material level, in connection with legal problems and with participation in the labour market. 46% of the caregivers had observed one or more conspicuous behaviours displayed by their children, which indicates a challenging situation. However, most of these caregivers assessed their parenting activity very favourably. Backward elimination multiple regression analysis indicated that a smaller number of support needs, younger age of the eldest child and fewer physical impairments on the part of the caregiver enhance the caregivers' assessment of their parenting activity. Physicians should speak to caregivers living with HIV about their parenting responsibilities and provide the necessary scope for this subject in their consultation sessions. Physicians are in a position to draw their patients' attention to the services available to them.

Effects of paralysis with pancuronium bromide on joint mobility in premature infants.

To study the effects of muscle paralysis on joint mobility, we compared eight premature infants treated with pancuronium bromide with a control group. A significant reduction was observed in hip and knee flexion, and in ankle dorsal extension, which tended to resolve in time. We conclude that muscle paralysis reduces the mobility of selected joints; spontaneous activity appears to prevent long-term contractures.

Evaluation of the compliance with recommended procedures in newborns exposed to HBsAg-positive mothers: a multicenter collaborative study.

BACKGROUND: Maternal-infant transmission of hepatitis B virus (HBV) during birth carries a high risk for chronic HBV infection in infants with frequent subsequent development of chronic disease. This can be efficiently prevented by early immunization of exposed newborns. The purpose of this study was to determine the compliance with official recommendations for prevention of perinatal HBV transmission in hepatitis B surface antigen (HBsAg) exposed infants. METHODS: Records of pregnant women at 4 sites in Switzerland, admitted for delivery in 2005 and 2006, were screened for maternal HBsAg testing. In HBsAg-exposed infants, recommended procedures (postnatal active and passive immunization, completion of immunization series, and serological success control) were checked. RESULTS: Of 27,131 women tested for HBsAg, 194 (0.73%) were positive with 196 exposed neonates. Of these neonates, 143 (73%) were enrolled and 141 (99%) received simultaneous active and passive HBV immunization within 24 hours of birth. After discharge, the HBV immunization series was completed in 83%. Only 38% of children were tested for anti-HBs afterwards and protective antibody values (>100 U/L) were documented in 27% of the study cohort. No chronically infected child was identified. Analysis of hospital discharge letters revealed significant quality problems. CONCLUSIONS: Intensified efforts are needed to improve the currently suboptimal medical care in HBsAg-exposed infants. We propose standardized discharge letters, as well as reminders to primary care physicians with precise instructions on the need to complete the immunization series in HBsAg-exposed infants and to evaluate success by determination of anti-HBs antibodies after the last dose.

Differential protein labeling with thiol-reactive infrared DY-680 and DY-780 maleimides and analysis by two-dimensional gel electrophoresis.

Differential protein labeling with 2-DE separation is an effective method for distinguishing differences in the protein composition of two or more protein samples. Here, we report on a sensitive infrared-based labeling procedure, adding a novel tool to the many labeling possibilities. Defined amounts of newborn and adult mouse brain proteins and tubulin were exposed to maleimide-conjugated infrared dyes DY-680 and DY-780 followed by 1- and 2-DE. The procedure allows amounts of less than 5 microg of cysteine-labeled protein mixtures to be detected (together with unlabeled proteins) in a single 2-DE step with an LOD of individual proteins in the femtogram range; however, co-migration of unlabeled proteins and subsequent general protein stains are necessary for a precise comparison. Nevertheless, the most abundant thiol-labeled proteins, such as tubulin, were identified by MS, with cysteine-containing peptides influencing the accuracy of the identification score. Unfortunately, some infrared-labeled proteins were no longer detectable by Western blots. In conclusion, differential thiol labeling with infrared dyes provides an additional tool for detection of low-abundant cysteine-containing proteins and for rapid identification of differences in the protein composition of two sets of protein samples.

Low immunoglobulin levels in patients with cystic fibrosis: reduced inflammation or sign of common variable immunodeficiency syndrome?

Introduction: In children with cystic fibrosis (CF), low immunoglobulin (IgG) levels have been reported to be associated with significantly less severe lung disease. However, decreased IgG can be a sign for common variable immunodeficiency (CVID) and affect clinical outcome. The aim of this study was to analyze clinical and serological data of patients having low IgG levels in routine blood tests at annual assessment, particularly their antibody response to polysaccharide antigens. Method: Retrospective chart review of demographic data of CF patients followed at the pediatric CF clinic throughout 2009. Clinical parameters (genotype, pancreas sufficiency, FEV1), presence of Pseudomonas aeruginosa (PA) and number of exacerbations per year were correlated with immunoglobulin and vaccination antibodies levels (antibodies to pneumococcal serotypes 14, 19, 23, 1, 5 and 7F measured by enzyme-linked immune-sorbent assay). Results: 4 out of 60 patients (6.7%) had lower IgG-levels for age. Ages ranged from 1 year 8 months to 11 years, 2 boys, 2 girls. Three patients were delF508 homozygotes, one heterozygote composite delF508/G542X. All were pancreatic insufficient. FEV1 ranged from 74 to 108%. One patient never had colonization by PA, 2 had intermittent PA colonization and one was chronically infected. After conjugated vaccination all patients had protective antibodies against serotypes 14, 19, 23F. For serotypes not included in the vaccine, only one patient had protective titers for 1 out of 3 serotypes. None of the patients had received unconjugated pneumococcal vaccine. There was no significant clinical difference in FEV1, PA colonization or number of exacerbations according to IgG and vaccination antibody levels. Conclusion: Cystic Fibrosis patients with low immunoglobulin levels have normal antibody response to protein antigens. However, despite recurrent infections, there seems to be delayed or deficient antibody response to polysaccharide antigens. Prospective studies are needed to evaluate the development of polysaccharide antibody responses in CF-patients to monitor for CVID. With early detection of CF by newborn screening program, long term follow up could be started early in childhood.