The craniosacral progression of muscle development influences the emergence of neuromuscular junction alterations in a severe murine model for spinal muscular atrophy.

AIMS As 4-day-old mice of the severe spinal muscular atrophy (SMA) model (dying at 5-8 days) display pronounced neuromuscular changes in the diaphragm but not the soleus muscle, we wanted to gain more insight into the relationship between muscle development and the emergence of pathological changes and additionally to analyse intercostal muscles which are affected in human SMA. METHODS Structures of muscle fibres and neuromuscular junctions (NMJs) of the diaphragm, intercostal and calf muscles of prenatal (E21) and postnatal (P0 and P4) healthy and SMA mice were analysed by light and transmission electron microscopy. NMJ innervation was studied by whole mount immunofluorescence in diaphragms of P4 mice. RESULTS During this period, the investigated muscles still show a significant neck-to-tail developmental gradient. The diaphragm and calf muscles are most and least advanced, respectively, with respect to muscle fibre fusion and differentiation. The number and depth of subsynaptic folds increases, and perisynaptic Schwann cells (PSCs) acquire a basal lamina on their outer surface. Subsynaptic folds are connected to an extensive network of tubules and beaded caveolae, reminiscent of the T system in adult muscle. Interestingly, intercostal muscles from P4 SMA mice show weaker pathological involvement (that is, vacuolization of PSCs and perineurial cells) than those previously described by us for the diaphragm, whereas calf muscles show no pathological changes. CONCLUSION SMA-related alterations appear to occur only when the muscles have reached a certain developmental maturity. Moreover, glial cells, in particular PSCs, play an important role in SMA pathogenesis.

Developmental self-construction and -configuration of functional neocortical neuronal networks.

The prenatal development of neural circuits must provide sufficient configuration to support at least a set of core postnatal behaviors. Although knowledge of various genetic and cellular aspects of development is accumulating rapidly, there is less systematic understanding of how these various processes play together in order to construct such functional networks. Here we make some steps toward such understanding by demonstrating through detailed simulations how a competitive co-operative ('winner-take-all', WTA) network architecture can arise by development from a single precursor cell. This precursor is granted a simplified gene regulatory network that directs cell mitosis, differentiation, migration, neurite outgrowth and synaptogenesis. Once initial axonal connection patterns are established, their synaptic weights undergo homeostatic unsupervised learning that is shaped by wave-like input patterns. We demonstrate how this autonomous genetically directed developmental sequence can give rise to self-calibrated WTA networks, and compare our simulation results with biological data.

Current role of enzyme analysis for urea cycle disorders

Urea cycle disorders (UCD) are due to defects of any of its six enzymes or two transporters. The definitive diagnosis of defects of the three mitochondrial enzymes, N-acetylglutamate synthase (NAGS), carbamylphosphate synthetase I (CPS1) and ornithine transcarbamylase (OTC) depends on either molecular mutation analysis or measurement of enzyme activity, whereas the diagnosis of deficiencies of the three cytosolic enzymes argininosuccinate synthetase (ASS), argininosuccinate lyase (ASL) and arginase I (ARG1) is usually straightforward, based on marker metabolites. Enzyme assays for all UCD have been used since their first description, for disease confirmation and in some instances even for prenatal diagnosis. The genetic bases of the UCD have only been unraveled from the 1980s; the last gene cloned being the NAGS gene in 2002. In this review we discuss the enzymatic assays for all urea cycle enzymes from a historical perspective, their potential and drawbacks, and the current role of enzymatic analysis in UCD in general.

Natural course of pontocerebellar hypoplasia type 2A

INTRODUCTION Pontocerebellar hypoplasia Type 2 (PCH2) is a rare autosomal recessive condition, defined on MRI by a small cerebellum and ventral pons. Clinical features are severe developmental delay, microcephaly and dyskinesia.Ninety percent carry a p.A307S mutation in the TSEN54-gene. Our aim was to describe the natural course including neurological and developmental features and other aspects of care in a homogeneous group of PCH2 patients all carrying the p.A307S mutation. PATIENTS AND METHODS Patients were recruited via the German patients' organizations. Inclusion criteria were imaging findings of PCH2 and a p.A307S mutation. Data were collected using medical reports and patient questionnaires discussed in a standardized telephone interview. RESULTS Thirty-three patients were included. When considering survival until age 11 years, 53% of children had died Weight, length and head circumference, mostly in the normal range at birth, became abnormal, especially head circumference (-5.58 SD at age 5 yrs). Neurologic symptoms: Choreathetosis was present in 88% (62% with pyramidal signs), 12% had pure spasticity. Epileptic seizures were manifest in 82%, status epilepticus in 39%. Non-epileptic dystonic attacks occurred in 33%. General symptoms: feeding difficulties were recorded in 100%, sleep disorder in 96%, apneas in 67% and recurrent infections in 52%; gastroesophageal reflux disease was diagnosed in 73%, 67% got percutaneous endoscopic gastrostomy and 36% a Nissen-fundoplication. Neurodevelopmental data: All children made progress, but on a low level: such as fixing and following with the eyes was seen in 76%, attempting to grasp objects (76%), moderate head control (73%), social smile (70%), rolling from prone to supine (58%), and sitting without support (9%). Ten percent lost achieved abilities on follow-up. The presence of prenatal symptoms did not correlate with outcome. CONCLUSION Phenotype of this genetically homogeneous group of PCH2 children was severe with reduced survival, but compatible with some developmental progress. Our data support the hypothesis of an early onset degeneration which thereafter stabilizes.

Fetal megacystis: experience of a single tertiary center in Switzerland over 20 years

OBJECTIVES Megacystis (MC) is rare and often associated with other structural and chromosomal anomalies. In euploid cases with early oligohydramnios, prognosis is poor mainly due to pulmonary hypoplasia and renal damage. We report our experience of the past 20 years. METHODS A retrospective review of cases with prenatally diagnosed MC was performed. Complete prenatal as well as postnatal medical records from 1989 to 2009 were reviewed focusing on diagnostic precision, fetal interventions [vesicocentesis (VC), vesicoamniotic shunt (VAS)], short- and long-term outcome, and potential prognostic factors. RESULTS 68 cases were included. Follow-up was available in 54 cases (9 girls and 45 boys including 3 cases with aneuploidy). We found 39 isolated MC at sonography (5 girls and 34 boys). 24 fetuses with isolated MC underwent VC and VAS at 19.6 ± 6.3 and 20 ± 4.9 weeks of gestation, respectively. Survival rate was higher in male than in female fetuses (51 vs. 33%). Renal problems occurred in 4/14 prenatally treated fetuses and in 1/10 when cases with prune belly syndrome (PBS) were excluded from the analysis. CONCLUSIONS Our study shows that a careful selection of cases with MC excluding fetuses with PBS and early treatment has still the potential to improve outcome.

MRI of the Fetal Brain.

The purpose of this article is to provide an overview of the possibilities for fetal magnetic resonance imaging (MRI) in the evaluation of the fetal brain. For brain pathologies, fetal MRI is usually performed when an abnormality is detected by previous prenatal ultrasound, and is, therefore, an important adjunct to ultrasound. The most commonly suspected brain pathologies referred to fetal MRI for further evaluation are ventriculomegaly, missing corpus callosum, and abnormalities of the posterior fossa. We will briefly discuss the most common indications for fetal brain MRI, as well as recent advances.

In vivo definition of genetic and cellular aspects of mammalian sexual differentiation

The differentiation of the reproductive organs is an essential developmental process required for the proper transmission of the genetic material. Müllerian inhibiting substance (MIS) is produced by testes and is necessary for the regression of the Müllerian ducts: the anlagen of the uterus, fallopian tubes and cervix. In vitro and standard transgenic mouse studies indicate that the nuclear hormone receptor Steroidogenic factor 1 (SF-1) and the transcription factor SOX9 play an essential role in the regulation of Mis. To test this hypothesis, mutations in the endogenous SF-1 and SOX9 binding sites in the mouse Mis promoter were introduced by gene targeting in embryonic stem (ES) cells. In disagreement with cell culture and transgenic mouse studies, male mice homozygous for the mutant SF-1 binding site correctly initiated Mis transcription in the fetal testes, although at significantly reduced levels. Surprisingly, sufficient Mis was produced for complete elimination of the Müllerian duct system. However, when the SF-1 binding site mutation was combined with an Mis -null allele, the further decrease in Mis levels led to a partial retention of uterine tissue, but only at a distance from the testes. In contrast, males homozygous for the mutant SOX9 binding site did not initiate Mis transcription, resulting in pseudohermaphrodites with a uterus and oviducts. These studies suggest an essential role for SOX9 in the initiation of Mis transcription, whereas SF-1 appears to act as a quantitative regulator of Mis transcript levels perhaps for influencing non-Müllerian duct tissues. ^ The Mis type II receptor, a member of the TGF- b superfamily, is also required for the proper regression of the Müllerian ducts. Mis type II receptor-deficient human males and their murine counterparts develop as pseudohermaphrodites. A lacZ reporter cassette was introduced into the mouse Mis type II receptor gene, by homologous recombination in ES cells. Expression studies, based on b -galactosidase activity, show marked expression of the MIS type II receptor in the postnatal Sertoli cells of the testis as well as in the prenatal and postnatal granulosa cells of the ovary. Expression is also seen in the mesenchymal cells surrounding the Müllerian duct and in the longitudinal muscle layer of the uterus. ^

Case control study identifying the maternal risk factors for congenital syphilis in Texas: 1998--2001

Background. Congenital syphilis (CS) is the oldest recognized congenital infection in the world. CS infection can affect multiple organs and can even cause neonatal death. CS is largely preventable when maternal syphilis is treated in an adequate and timely manner. During the decade of the nineties, rates of CS in Texas have often exceeded the overall US rate. Few studies, with adequate sample sizes, have been conducted to determine the risk factors associated with CS while controlling for factors associated with adult (maternal) syphilis infection. Objective. To determine the current maternal risk factors for CS infection in Texas from 1998–2001. Methods. A total of 1083 women with positive serological tests for syphilis during pregnancy or at delivery were reported to, and assessed by, health department surveillance staff. Mothers delivering infants in Texas between January 1, 1998 and June 30, 2001 comprised the study population. Mothers of infants diagnosed with confirmed or presumptive CS (N = 291) were compared to mothers of infants diagnosed as non-cases (N = 792) to determine the risk factors for vertical transmission (while controlling for risk factors of horizontal transmission). Logistic regression analyses were conducted to determine the associated odds between selected maternal variables and the outcome of CS. Results. Among 291 case infants, 5 (1.7%), 12 (4.1%), 274 (94.2%) were classified as confirmed cases, syphilitic stillbirths, and presumptive cases, respectively. Lack of maternal syphilis treatment was the strongest predictor of CS: odds ratio (OR) = 199.57 (95% CI 83.45–477.25) compared to those receiving treatment before pregnancy, while women treated during their pregnancies were also at increased risk (OR = 6.67, 95% CI 4.01–11.08). Women receiving no prenatal care were more likely (OR = 2.77, 95% CI 1.60–4.79) to have CS infants than those receiving prenatal care. Single women had higher odds (OR = 1.90, 95% CI 1.10–3.26) than ever-married women. African-Americans (OR 0.91, 95% CI 0.37–2.23) and Hispanics (OR = 1.66, 95% CI 0.68–4.05) may be more likely to have a CS infant than non-Hispanic Whites. Conclusions. The burden of CS in Texas can be alleviated through the provision of quality health care services, particularly prenatal care and treatment for sexually transmitted diseases. ^

Effects of health disparities on Helicobacter pylori infection among children on the US-Mexico border

The objective of this study is to determine whether health disparities influence the odds of developing H. pylori infections among the children enrolled in the Pasitos Cohort Study on the US-Mexico border. The study variables were the number of prenatal care visits, ways of transportation, car in household, location of health services and insurance coverage. The study recruited eligible pregnant women to complete baseline questionnaires. Every six months after the birth of the child, infection status is measure by the 13-C urea breath test. Results indicate that having medical insurance consistently decreases the odds of being infected. Children with mothers who went to a private physician had decreased odds of infection compared to those utilizing public clinics, and having a car in the household increased the odds of infection. Limitations include bias due to loss to follow-up and the transient nature of the infection.^

A constellation of factors associated with premature births among African American women

A cohort, cross-sectional, historical study design was used to study factors related to spontaneous premature birth outcomes among African American women. The cohort consisted of 4,294 mothers drawn from the 1988 National Maternal and Infant Health Survey conducted by the National Center for Health Statistics. The objectives of the study were: (1) to examine the distribution of gestational ages of African American infants for selected variables reported for their families and (2) to describe risk factors associated with birth at 20–31 weeks of gestational age and at 32–36 weeks of gestational age. Risk factors examined include maternal age, maternal marital status, maternal living arrangements, maternal education, maternal work status, household income, gestational bleeding, month prenatal began, adequacy of prenatal care, parity, previous viable preterm birth, and behavioral factors of attitude toward pregnancy, smoking, drug, and alcohol use during pregnancy. Frequency distributions, cross tabulations, stratified analysis, and logistic regression analysis were used. ^ Risk factors associated with a 50 percent or more increase in preterm birth were cocaine use, low maternal education, teenaged mother, prenatal care deficits or overuse, and bleeding during the second half of pregnancy. The other risk factors of not living with the baby's father, smoking cigarettes and having a mistimed pregnancy carried statistically significance but lower strength of association. ^ Health care services, educational systems, and community organizations can develop and evaluate comprehensive health education and information campaigns that address preventable risk factors during pregnancy. Although preterm birth cannot always be prevented, preconception care can help identify and modify maternal risk and promote optimum health before conception. Quality care should include continued risk assessment, health promotion, and interventions. ^

Hepatitis B vaccination of high risk pregnant women: A clinical trial at Parkland Memorial Hospital

Hepatitis B infection is a major public health problem of global proportions. It is estimated that 2 billion people worldwide are infected by the Hepatitis B virus (HBV) at some point, and 350 million are chronic carriers. The Centers for Disease Control and Prevention (CDC) report an incidence in the United States of 140,000–320,000 infections each year (asymptomatic and symptomatic), and estimate 1–1.25 million people are chronically infected. Hepatitis B and its chronic complications (cirrhosis of the liver, liver failure, hepatocellular carcinoma) responsible for 4,000–5,000 deaths in America each year. ^ One quarter of those who become chronic carriers develop progressive liver disease, and chronic HBV infection is thought to be responsible for 60 million cases of cirrhosis worldwide, surpassing alcohol as a cause of liver disease. Since there are few treatment options for the person chronically infected with Hepatitis B, and what is available is expensive, prevention is clearly best strategy for combating this disease. ^ Since the approval of the Hepatitis B vaccine in 1981, national and international vaccination campaigns have been undertaken for the prevention of Hepatitis B. Despite encouraging results, however, studies indicate that prevalence rates of Hepatitis B infection have not been significantly reduced in certain high risk populations because vaccination campaigns targeting those groups do not exist and opportunities for vaccination by individual physicians in clinical settings are often missed. Many of the high-risk individuals who go unvaccinated are women of childbearing age, and a significant proportion of these women become infected with the Hepatitis B virus (HBV) during pregnancy. Though these women are often seen annually or for prenatal care (because of the close spacing of their children and their high rate of fertility), the Hepatitis B vaccine series is seldom recommended by their health care provider. In 1993, ACOG issued a statement recommending Hepatitis B vaccination of pregnant women who were defined as high-risk by diagnosis of a sexually transmitted disease. ^ Hepatitis B vaccine has been extensively studied in the non-pregnant population. The overall efficacy of the vaccine in infants, children and adults is greater than 90%. In the small clinical trials to date, the vaccine seemed to be effective in those pregnant women receiving 3 doses; however, by using the usual 0, 1 and 6 month regimen, most pregnant women were unable to complete a full series during pregnancy. There is data now available supporting the use of an "accelerated" dosing schedule at 0, 1 and 4 months. This has not been evaluated in pregnant women. A clinical trial proving the efficacy of the 0, 1, 4 schedule and its feasibility in this population would add significantly to the body of research in this area, and would have implications for public health policy. Such a trial was undertaken in the Parkland Memorial Hospital Obstetrical Infectious Diseases clinic. In this study, the vaccine was very well tolerated with no major adverse events reported, 90% of fully vaccinated patients achieved immunity, and only Body Mass Index (BMI) was found to be a significant factor affecting efficacy. This thesis will report the results of the trial and compare it to previous trials, and will discuss barriers to implementation, lessons learned and implications for future trials. ^

Progestational agents and preterm birth: An updated review of the literature

The preterm birth rate has been increasing over time in the United States, causing a large social and individual financial burden. Though the cause of preterm birth is now known, risk factors such as a previous preterm birth and a short cervical length have been identified as possible predictors. There are many contributing social and behavioral factors that play a role was well as medical problems that occur before and during pregnancy. Though there have been prevention methods identified, such as prenatal care, tocolytic therapy and cervical cerclage, none of these methods have shown to definitively prevent preterm birth over a long period of time. 17 alpha hydroxyprogesterone has been recognized as a possible prevention method for women at high risk for preterm birth. Three out of the five studies assessed in this review showed a significant reduction in preterm birth with administration of progesterone, both for women with a previous preterm birth and with a short cervical length. Currently there is no standard of care for those at high risk for preterm birth. More large clinical trials need to be conducted to determine if this progesterone for the prevention of preterm birth is effective. ^

Attention-Deficit/Hyperactivity Disorder and antidepressants and prescription medications: A pilot study

Background. Attention Deficit-Hyperactivity Disorder (AD/HD) diagnosis in children and adolescents has been on the rise over the last couple of decades and a multitude of studies have been conducted in an aim to better understand the disease. Literature has explored the role of several factors suspected of contributing to development of the disease, including: prenatal smoking exposures, environmental exposures, and low-birth weight. However, there is very limited reporting of fetal/infant exposure to antidepressants and prescription medications and the long-term behavioral outcomes, namely development of AD/HD. The purpose of this study was to evaluate the relationship between mother's exposure to prescription medications and/or antidepressants around the time of conception, during pregnancy, or while breastfeeding and the development of Attention-Deficit/Hyperactivity Disorder in offspring. Methods. Secondary analysis of data from a case-control study was performed. Exposure histories were collected for the mother and offspring. Data were collected using a secure, confidential, self-report, online survey to evaluate the relationship between antidepressant and/or prescription medication exposure and the development of AD/HD. The period of exposure to these drugs was defined as: around the time of conception, during pregnancy, or while breastfeeding. Cases were defined as a child who had been diagnosed with AD/HD. Controls were defined as a child who had not been diagnosed with AD/HD. Results. Prescription medication and antidepressant medication exposures around the time of conception, during pregnancy, or while breastfeeding were not associated with development of AD/HD. However, traumatic brain injury (OR=2.77 (1.61–4.77)) and preterm birth (OR=1.48 (1.04–2.12)) were identified as potential risk factors. These results support existing literature on AD/HD, but future work must be undertaken to better evaluate fetal/infant medication exposures and long-term behavioral outcomes.^

Epidemiology of isolated obstructive genitourinary defect in Texas: 1999--2003

Background. Obstructive genitourinary defects include all anomalies causing obstruction anywhere along the urinary tract. Previous studies have noted a large excess of males among infants affected by these types of defects. This is the first epidemiologic study focused solely on obstructive genitourinary defects (OGD). ^ Methods. Data on 1,683 mild and 302 severe cases of isolated OGD born between 1999 and 2003 and ascertained by the Texas Birth Defects Registry were compared to all births in Texas during the same time period. Adjusted prevalence odds ratios (POR) were calculated for infant sex, birth weight, gestational age, mother’s race/ethnicity, mother’s age, mother’s education, parity, birth year, start of prenatal care, multiple birth, and public health region of birth. Severe cases were defined as those cases that died prior to birth, died after birth, or underwent surgery for OGD in the first year of life. Cases of OGD that had other major birth defects besides OGD were excluded from this study. ^ Results. Severe cases of OGD were more likely than mild cases to have multiple obstructive genitourinary anomalies (37.8% vs. 18.9%) and bilateral defects (40.9% vs. 31.3%). Males had a significantly greater risk of OGD than females for both severe and mild cases: adjusted POR = 3.26 (95% CI = 2.45-4.33) and adjusted POR = 2.60 (95% CI = 2.33-2.90), respectively. Infants with both severe and mild OGD were more likely to be very preterm birth at birth compared with infants without OGD: crude POR of 16.19 (95% CI = 10.60-24.74) and 4.75 (95% CI = 3.54-6.37), respectively. Among the severe group, minority races had a decreased risk of OGD with an adjusted POR of 0.74 (95% CI = 0.55-0.98) compared with whites. Among the mild cases, increased rates of OGD were found in older mothers (adjusted POR = 1.10, 95% CI = 1.05-1.15), college/higher educated mothers (adjusted POR = 1.07, 95% CI = 1.01-1.13) and multiple births (adjusted POR = 1.28, 95% CI = 1.01-1.62). There was also a decreased risk of mild cases among black mothers compared to whites (adjusted POR = 0.63, 95% CI = 0.52-0.76). Compared to 1999, the prevalence of mild cases of OGD increased significantly over the 5 year study period with an adjusted POR of 1.10 (95% CI = 1.06-1.15) by 2003. ^ Conclusion. Risk factors of OGD for both severe and mild forms were male sex and preterm birth. Severe cases were more likely to have multiple OGD defects and be affected bilaterally. An increase in prevalence of mild cases of OGD over time and differences in rates of black, older, and higher educated mothers in mild cases may be attributed to ultrasound use. ^