Morphogenesis of the ureterovesical junction:a histologic and microanatomic study in the rat.

OBJECTIVES: To investigate the development of the ureterovesical junction in rats. METHODS: A total of 110 albino rats (50 prenatal and 60 newborn) with a gestation of 21 days were studied at the age of 17 days after conception until 5 days after birth. The lower urinary tract was microdissected. Microphotography (110 animals), histologic examination (44 animals), and scanning electron microscopy (66 animals) of the ureterovesical junction were performed. Urea and creatinine from the amniotic fluid of 20 fetuses and from the urine of 10 neonates were measured. RESULTS: At day 17 after conception, separate penetration of the mesonephric duct and ureter into the wall of the urogenital sinus was observed. Continuity between the lumen of the ureter and the urogenital sinus was established on day 19 after conception. The straight passage of the intramural ureter into the urogenital sinus at day 17 after conception changed to the definitive L-shape with a vertical entry into the bladder on day 5 after birth. In the distal ureter, the change of the mesenchymal tissue into immature smooth muscle was first observed at birth, and the muscle became mature on the fifth postnatal day. At birth, Waldeyer's sheath was recognized. The creatinine and urea levels were stable prenatally (average 22.4 micromol/L and 6.88 mmol/L, respectively) and rose significantly postnatally (average 133 micromol/L and 32.65 mmol/L, respectively). CONCLUSIONS: The attachment of the ureter to the urogenital sinus and later to the bladder, the modification of its passage, and its mobility within Waldeyer's sheath may be essential in preventing vesicoureteral reflux. The production of urine and its flow does not seem to be the trigger of ureteral smooth muscle formation.

Perinatal choline supplementation reveals a dissociation between two types of spatial strategies.

Choline supplementation improving memory functions in rodents is assumed to increase the synthesis and release of acetylcholine in the brain. We have found that a combined pre- and postnatal supplementation results in long-lasting facilitation of spatial memory in juvenile rats when training was conducted in presence of a local salient cue. The present work was aimed at analysing the effects of peri- and postnatal choline supplementation on spatial abilities of naive adult rats. Rats given a perinatal choline supplementation were trained in various cued procedures of the Morris navigation task when aged 5 months. The treatment had a specific effect of reducing the escape latency of the rats when the platform was at a fixed position in space and surrounded by a suspended cue. This effect was associated with an increased spatial bias when the cue and platform were removed. In this condition, the control rats showed impaired spatial discrimination following the removal of the target cue, most likely due to an overshadowing of the distant environmental cues. This impairment was not observed in the treated rats. Further training with the suspended cue at unpredictable places in the pool revealed longer escape latencies in the control than in the treated rats suggesting that this procedure induced a selective perturbation of the normal but not of the treated rats. A special probe trial with the cue at an irrelevant position and no escape platform revealed a significant bias of the control rats toward the cue and of the treated rats toward the uncued spatial escape position. This behavioural dissociation suggests that a salient cue associated with the target induces an alternative "non spatial" guidance strategy in normal rats, with the risk of overshadowing of the more distant spatial cues. In this condition, the choline supplementation facilities a spatial reliance on the cue, that is an overall facilitation of learning a set of spatial relations between several visual cues. As a consequence, the improved escape in presence of the cue is associated with a stronger memory of the spatial position following disappearance of the cue. This and previous observations suggest that a specific spatial attention process relies on the buffering of highly salient visual cues.to facilitate integration of their relative position in the environment.

Expression of SCG10 and stathmin proteins in the rat olfactory system during development and axonal regeneration.

The membrane-associated protein SCG10 is expressed specifically by neuronal cells. Recent experiments have suggested that it promotes neurite outgrowth by increasing microtubule dynamics in growth cones. SCG10 is related to the ubiquitous but neuron-enriched cytosolic protein stathmin. To better understand the role played by SCG10 and stathmin in vivo, we have analyzed the expression and localization of these proteins in both the olfactory epithelium and the olfactory bulb in developing and adult rats, as well as in adult bulbectomized rats. The olfactory epithelium is exceptional in that olfactory receptor neurons constantly regenerate and reinnervate the olfactory bulb throughout animal life-span. SCG10 and stathmin expression in the olfactory receptor neurons was found to be regulated during embryonic and postnatal development and to correlate with neuronal maturation. Whereas SCG10 expression was restricted to immature olfactory receptor neurons (GAP-43-positive, olfactory marker protein-negative), stathmin was also expressed by the basal cells. In the olfactory bulb of postnatal and adult rats, a moderate to strong SCG10 immunoreactivity was present in the olfactory nerve layer, whereas no labeling was detected in the glomerular layer. Olfactory glomeruli also showed no apparent immunoreactivity for several cytoskeletal proteins such as tubulin and microtubule-associated proteins. In unilaterally bulbectomized rats, SCG10 and stathmin were seen to be up-regulated in the regenerating olfactory epithelium at postsurgery stages corresponding to olfactory axon regeneration. Our data strongly suggest that, in vivo, both SCG10 and stathmin may play a role in axonal outgrowth during ontogenesis as well as during axonal regeneration.

BORN AT 27 WEEKS OF GESTATION WITH CLASSICAL PKU: CHALLENGES OF DIETETIC MANAGEMENT IN A VERY PRETERM INFANT

Only few cases of classical phenylketonuria (PKU) in premature infants have been reported. Treatment of these patients is challenging due to the lack of a phenylalanine-free amino acid solution for parenteral infusion. The boy was born at 27 weeks of gestation with a weight of 1000 g (P10). He received parenteral nutrition with a protein intake of 3 g/kg/day. On day 7 he was diagnosed with classical PKU (genotype IVS10-11G>A/IVS12+ 1G>A) due to highly elevated phenylalanine (Phe) level in newborn screening (2800 micromol/L). His maximum plasma Phe level reached 3696 micromol/L. Phe intake was stopped for 4 days. During this time the boy received intravenous glucose and lipids as well as little amounts of Phe-free formula by a nasogastric tube. Due to a deficit of essential amino acids and insufficient growth, a parenteral nutrition rich in branched-chain amino-acids and relatively poor in Phe was added, in order to promote protein synthesis without overloading in Phe. Under this regimen, Phe plasma levels normalized on day 19 when intake of natural protein was started. The boy has now a corrected age of 2 years. He shows normal growth parameters and psychomotor development. Despite a long period of highly elevated Phe levels in the postnatal period our patient shows good psychomotor development. The management of premature infants with PKU depends on the child's tolerance to enteral nutrition. It demands an intensive follow-up by an experienced team and dedicated dietician. Appropriate Phe-free parenteral nutrition would be necessary especially in case of gastro-intestinal complications of prematurity.

Prenatal Representations of Family in Parents and Coparental Interactions as Predictors of Triadic Interactions During Infancy

In this study, we explored the predictive role of family interactions and family representations in mothers and fathers during pregnancy for postnatal motherfatherinfant interactions during the first 2 years after birth. Families (N = 42) were seen at the fifth month of pregnancy and at 3 and 18 months after birth. During pregnancy, parents were asked to play with their baby at the first meeting by using a doll in accordance with the procedure of the prenatal Lausanne Trilogue Play (LTP; A. Corboz-Warnery & E. Fivaz-Depeursinge, 2001; E. Fivaz-Depeursinge, F. Frascarolo-Moutinot, & A. Corboz-Warnery, 2010). Family representations were assessed by administering the Family System Test (T. Gehring, 1998). Marital satisfaction and the history of the couple were assessed through self-reported questionnaires. At 3 and 18 months, family interactions were assessed in the postnatal LTP. Infant temperament was assessed through parent reports. Results show that (a) prenatal interactions and child temperament are the most important predictors of family interactions and (b) paternal representations are predictive of family interactions at 3 months. These results show that observational assessment of nascent family interactions is possible during pregnancy, which would allow early screening of family maladjustment. The findings also highlight the necessity of taking into account paternal representations as a significant variable in the development of family interactions.

Temporal and spatial appearance of the membrane cytoskeleton and perineuronal nets in the rat neocortex.

Parvalbumin-immunoreactive interneurons are surrounded by perineuronal nets, containing molecules of the extracellular matrix (e.g. tenascin-R). Furthermore, they seem to have a special cytoskeleton composed of, among others, ankyrinR and beta Rspectrin. In the present developmental study we showed that the intracellular markers parvalbumin, ankyrinR and beta Rspectrin as well as Vicia Villosa agglutinin, an extracellular marker for perineuronal nets, appeared in the second postnatal week. In the third postnatal week, ankyrinR and beta R spectrin were present in the parvalbumin-positive interneurons. Tenascin-R appeared in a similar topographic distribution as the intracellular markers. The adult pattern was established upon the end of the fourth postnatal week. Our results indicate that cytoskeletal maturity maybe a prerequisite for the organization of perineuronal nets of extracellular matrix.

Mirror extreme BMI phenotypes associated with gene dosage at the chromosome 16p11.2 locus.

Both obesity and being underweight have been associated with increased mortality. Underweight, defined as a body mass index (BMI) ≤ 18.5 kg per m(2) in adults and ≤ -2 standard deviations from the mean in children, is the main sign of a series of heterogeneous clinical conditions including failure to thrive, feeding and eating disorder and/or anorexia nervosa. In contrast to obesity, few genetic variants underlying these clinical conditions have been reported. We previously showed that hemizygosity of a ∼600-kilobase (kb) region on the short arm of chromosome 16 causes a highly penetrant form of obesity that is often associated with hyperphagia and intellectual disabilities. Here we show that the corresponding reciprocal duplication is associated with being underweight. We identified 138 duplication carriers (including 132 novel cases and 108 unrelated carriers) from individuals clinically referred for developmental or intellectual disabilities (DD/ID) or psychiatric disorders, or recruited from population-based cohorts. These carriers show significantly reduced postnatal weight and BMI. Half of the boys younger than five years are underweight with a probable diagnosis of failure to thrive, whereas adult duplication carriers have an 8.3-fold increased risk of being clinically underweight. We observe a trend towards increased severity in males, as well as a depletion of male carriers among non-medically ascertained cases. These features are associated with an unusually high frequency of selective and restrictive eating behaviours and a significant reduction in head circumference. Each of the observed phenotypes is the converse of one reported in carriers of deletions at this locus. The phenotypes correlate with changes in transcript levels for genes mapping within the duplication but not in flanking regions. The reciprocal impact of these 16p11.2 copy-number variants indicates that severe obesity and being underweight could have mirror aetiologies, possibly through contrasting effects on energy balance.

Exome sequencing identifies INPPL1 mutations as a cause of opsismodysplasia.

Opsismodysplasia (OPS) is a severe autosomal-recessive chondrodysplasia characterized by pre- and postnatal micromelia with extremely short hands and feet. The main radiological features are severe platyspondyly, squared metacarpals, delayed skeletal ossification, and metaphyseal cupping. In order to identify mutations causing OPS, a total of 16 cases (7 terminated pregnancies and 9 postnatal cases) from 10 unrelated families were included in this study. We performed exome sequencing in three cases from three unrelated families and only one gene was found to harbor mutations in all three cases: inositol polyphosphate phosphatase-like 1 (INPPL1). Screening INPPL1 in the remaining cases identified a total of 12 distinct INPPL1 mutations in the 10 families, present at the homozygote state in 7 consanguinous families and at the compound heterozygote state in the 3 remaining families. Most mutations (6/12) resulted in premature stop codons, 2/12 were splice site, and 4/12 were missense mutations located in the catalytic domain, 5-phosphatase. INPPL1 belongs to the inositol-1,4,5-trisphosphate 5-phosphatase family, a family of signal-modulating enzymes that govern a plethora of cellular functions by regulating the levels of specific phosphoinositides. Our finding of INPPL1 mutations in OPS, a severe spondylodysplastic dysplasia with major growth plate disorganization, supports a key and specific role of this enzyme in endochondral ossification.

Prenatal diagnosis of urinary malformations: results in a series of 93 consecutive cases.

OBJECTIVE: To evaluate the pertinence of prenatal diagnosis in cases of congenital uropathy. STUDY DESIGN: Retrospective evaluation over a period of 6.5 years. METHOD: 93 cases were involved in the comparison of prenatal ultrasonographic diagnosis with neonatal findings, autopsy results, and follow-up data. RESULTS: 33 fetuses had renal parenchymal lesions, 44 had excretory system lesions, and 6 had bladder and/or urethral lesions. Seventy-three pregnancies lead to live births. Eighteen terminations of pregnancy were performed on the parents' request for extremely severe malformations. Two intrauterine deaths were observed, and two infants died in the postnatal period. Prenatal diagnosis was obtained at an average of 27 weeks gestation. Diagnostic concordance was excellent in 82% and partial in 12% of cases with renal parenchymal lesions; the false-positive rate was 6%. For excretory system lesions, concordance was excellent in 87% and partial in 7.4% of cases, with a false-positive rate of 5.6%. Finally, concordance was excellent in 100% of cases of bladder and/or urethral lesions. The overall rate of total concordance was 86%. Partial concordance cases consisted of malformations different from those previously diagnosed, but prenatal diagnosis nevertheless lead to further investigations in the neonatal period and to proper management. The false-positive diagnoses (5.4%) never lead to termination of pregnancy. CONCLUSION: Prenatal diagnosis of congenital uropathy is effective. A third-trimester ultrasonographic examination is necessary to ensure proper neonatal management, considering that the majority of cases are diagnosed at this gestational age.

Patterns and factors associated with low adherence to psychotropic medications during pregnancy-a cross-sectional, multinational web-based study.

BACKGROUND: No previous studies have explored how closely women follow their psychotropic drug regimens during pregnancy. This study aimed to explore patterns of and factors associated with low adherence to psychotropic medication during pregnancy. METHODS: Multinational web-based study was performed in 18 countries in Europe, North America, and Australia. Uniform data collection was ensured via an electronic questionnaire. Pregnant women were eligible to participate. Adherence was measured via the 8-item Morisky Medication Adherence Scale (MMAS-8). The Beliefs about Prescribed Medicines Questionnaire (BMQ-specific), the Edinburgh Postnatal Depression Scale (EPDS), and a numeric rating scale were utilized to measure women's beliefs, depressive symptoms, and antidepressant risk perception, respectively. Participants reporting use of psychotropic medication during pregnancy (n = 160) were included in the analysis. RESULTS: On the basis of the MMAS-8, 78 of 160 women (48.8%, 95% CI: 41.1-56.4%) demonstrated low adherence during pregnancy. The rates of low adherence were 51.3% for medication for anxiety, 47.2% for depression, and 42.9% for other psychiatric disorders. Smoking during pregnancy, elevated antidepressant risk perception (risk≥6), and depressive symptoms were associated with a significant 3.9-, 2.3-, and 2.5-fold increased likelihood of low medication adherence, respectively. Women on psychotropic polytherapy were less likely to demonstrate low adherence. The belief that the benefit of pharmacotherapy outweighed the risks positively correlated (r = .282) with higher medication adherence. CONCLUSIONS: Approximately one of two pregnant women using psychotropic medication demonstrated low adherence in pregnancy. Life-style factors, risk perception, depressive symptoms, and individual beliefs are important factors related to adherence to psychotropic medication in pregnancy.

Population pharmacokinetic study to evaluate dosing strategies of imipenem in neonates and infants

Objective: Imipenem is a broad spectrum antibiotic used to treat severe infections in critically ill patients. Imipenem pharmacokinetics (PK) was evaluated in a cohort of neonates treated in the Neonatal Intensive Care Unit of the Lausanne University Hospital. The objective of our study was to identify key demographic and clinical factors influencing imipenem exposure in this population. Method: PK data from neonates and infants with at least one imipenem concentration measured between 2002 and 2013 were analyzed applying population PK modeling methods. Measurement of plasma concentrations were performed upon the decision of the physician within the frame of a therapeutic drug monitoring (TDM) programme. Effects of demographic (sex, body weight, gestational age, postnatal age) and clinical factors (serum creatinine as a measure of kidney function; co-administration of furosemide, spironolactone, hydrochlorothiazide, vancomycin, metronidazole and erythromycin) on imipenem PK were explored. Model-based simulations were performed (with a median creatinine value of 46 μmol/l) to compare various dosing regimens with respect to their ability to maintain drug levels above predefined minimum inhibitory concentrations (MIC) for at least 40 % of the dosing interval. Results: A total of 144 plasma samples was collected in 68 neonates and infants, predominantly preterm newborns, with median gestational age of 27 weeks (24 - 41 weeks) and postnatal age of 21 days (2 - 153 days). A two-compartment model best characterized imipenem disposition. Actual body weight exhibited the greatest impact on PK parameters, followed by age (gestational age and postnatal age) and serum creatinine on clearance. They explain 19%, 9%, 14% and 9% of the interindividual variability in clearance respectively. Model-based simulations suggested that 15 mg/kg every 12 hours maintain drug concentrations over a MIC of 2 mg/l for at least 40% of the dosing interval during the first days of life, whereas neonates older than 14 days of life required a dose of 20 mg/kg every 12 hours. Conclusion: Dosing strategies based on body weight and post-natal age are recommended for imipenem in all critically ill neonates and infants. Most current guidelines seem adequate for newborns and TDM should be restricted to some particular clinical situations.

Dysregulated ADAM10-Mediated Processing of APP during a Critical Time Window Leads to Synaptic Deficits in Fragile X Syndrome.

The Fragile X mental retardation protein (FMRP) regulates neuronal RNA metabolism, and its absence or mutations leads to the Fragile X syndrome (FXS). The β-amyloid precursor protein (APP) is involved in Alzheimer's disease, plays a role in synapse formation, and is upregulated in intellectual disabilities. Here, we show that during mouse synaptogenesis and in human FXS fibroblasts, a dual dysregulation of APP and the α-secretase ADAM10 leads to the production of an excess of soluble APPα (sAPPα). In FXS, sAPPα signals through the metabotropic receptor that, activating the MAP kinase pathway, leads to synaptic and behavioral deficits. Modulation of ADAM10 activity in FXS reduces sAPPα levels, restoring translational control, synaptic morphology, and behavioral plasticity. Thus, proper control of ADAM10-mediated APP processing during a specific developmental postnatal stage is crucial for healthy spine formation and function(s). Downregulation of ADAM10 activity at synapses may be an effective strategy for ameliorating FXS phenotypes.

Imaging findings in fetal diaphragmatic abnormalities.

Imaging plays a key role in the detection of a diaphragmatic pathology in utero. US is the screening method, but MRI is increasingly performed. Congenital diaphragmatic hernia is by far the most often diagnosed diaphragmatic pathology, but unilateral or bilateral eventration or paralysis can also be identified. Extralobar pulmonary sequestration can be located in the diaphragm and, exceptionally, diaphragmatic tumors or secondary infiltration of the diaphragm from tumors originating from an adjacent organ have been observed in utero. Congenital abnormalities of the diaphragm impair normal lung development. Prenatal imaging provides a detailed anatomical evaluation of the fetus and allows volumetric lung measurements. The comparison of these data with those from normal fetuses at the same gestational age provides information about the severity of pulmonary hypoplasia and improves predictions about the fetus's outcome. This information can help doctors and families to make decisions about management during pregnancy and after birth. We describe a wide spectrum of congenital pathologies of the diaphragm and analyze their embryological basis. Moreover, we describe their prenatal imaging findings with emphasis on MR studies, discuss their differential diagnosis and evaluate the limits of imaging methods in predicting postnatal outcome.

Pre-existing astrocytes form functional perisynaptic processes on neurons generated in the adult hippocampus.

The adult dentate gyrus produces new neurons that morphologically and functionally integrate into the hippocampal network. In the adult brain, most excitatory synapses are ensheathed by astrocytic perisynaptic processes that regulate synaptic structure and function. However, these processes are formed during embryonic or early postnatal development and it is unknown whether astrocytes can also ensheathe synapses of neurons born during adulthood and, if so, whether they play a role in their synaptic transmission. Here, we used a combination of serial-section immuno-electron microscopy, confocal microscopy, and electrophysiology to examine the formation of perisynaptic processes on adult-born neurons. We found that the afferent and efferent synapses of newborn neurons are ensheathed by astrocytic processes, irrespective of the age of the neurons or the size of their synapses. The quantification of gliogenesis and the distribution of astrocytic processes on synapses formed by adult-born neurons suggest that the majority of these processes are recruited from pre-existing astrocytes. Furthermore, the inhibition of astrocytic glutamate re-uptake significantly reduced postsynaptic currents and increased paired-pulse facilitation in adult-born neurons, suggesting that perisynaptic processes modulate synaptic transmission on these cells. Finally, some processes were found intercalated between newly formed dendritic spines and potential presynaptic partners, suggesting that they may also play a structural role in the connectivity of new spines. Together, these results indicate that pre-existing astrocytes remodel their processes to ensheathe synapses of adult-born neurons and participate to the functional and structural integration of these cells into the hippocampal network.

Educational issues perceived by expectant lesbian couples /

Despite the increasing public profile of lesbian childbearing, public health resources for expectant women often bear heterosexist assumptions and create barriers to accessing information relevant to lesbian mothering experiences. This descriptive, exploratory study examined one lesbian couple's perceived educational needs for effective support, barriers to access, strategies for locating care, and the impact of childbearing on their lives, as well as their reflections on inviting ways to offer supportive practices in a public health context. A case study approach used feminist ethnographic methodology and purposeful convenience sampling. A prenatal and a postnatal open-ended interview were completed with 1 white, middle-class, able, lesbian childbearing couple, each ofwhom has birthed as coparent and biological mother in this couple relationship. Despite this couple's immense situated privilege, they struggled to locate the support they sought for childbearing in a way that offered optimal emotional and physical care from the preconceptual to postpartum stages and which maintained confidentiality or anonymity as desired. They created meaningful care through personal networks. The findings were framed using invitational and feminist theories: how people, places, programs, processes, policies, and politics contributed to educational support. A three part conceptual framework emerged which identified components of access to support: perceived safety of resources, disclosure status, situated privilege, and public or private availability of information. The consequences of lack of public access to comprehensive childbearing care for lesbian women and their communities are described. Educational possibilities addressed systemic heterosexism through the development of sensitive educators, meaningful curriculum, program planning, explicit policies, community partnerships, and political leadership with respect to both institutional and research venues.