Rapamycin attenuates pathological hypertrophy caused by an absence of trabecular formation.

Cardiac trabeculae are mesh-like muscular structures within ventricular walls. Subtle perturbations in trabeculation are associated with many congenital heart diseases (CHDs), and complete failure to form trabeculae leads to embryonic lethality. Despite the severe consequence of an absence of trabecular formation, the exact function of trabeculae remains unclear. Since ErbB2 signaling plays a direct and essential role in trabecular initiation, in this study, we utilized the erbb2 zebrafish mutant as a model to address the function of trabeculae in the heart. Intriguingly, we found that the trabeculae-deficient erbb2 mutant develops a hypertrophic-like (HL) phenotype that can be suppressed by inhibition of Target of Rapamycin (TOR) signaling in a similar fashion to adult mammalian hearts subjected to mechanical overload. Further, cell transplantation experiments demonstrated that erbb2 mutant cells in an otherwise wildtype heart did not undergo hypertrophy, indicating that erbb2 mutant HL phenotypes are due to a loss of trabeculae. Together, we propose that trabeculae serve to enhance contractility and that defects in this process lead to wall-stress induced hypertrophic remodeling.

Calcium influx through L-type CaV1.2 Ca2+ channels regulates mandibular development.

The identification of a gain-of-function mutation in CACNA1C as the cause of Timothy Syndrome (TS), a rare disorder characterized by cardiac arrhythmias and syndactyly, highlighted unexpected roles for the L-type voltage-gated Ca2+ channel CaV1.2 in nonexcitable cells. How abnormal Ca2+ influx through CaV1.2 underlies phenotypes such as the accompanying syndactyly or craniofacial abnormalities in the majority of affected individuals is not readily explained by established CaV1.2 roles. Here, we show that CaV1.2 is expressed in the first and second pharyngeal arches within the subset of cells that give rise to jaw primordia. Gain-of-function and loss-of-function studies in mouse, in concert with knockdown/rescue and pharmacological approaches in zebrafish, demonstrated that Ca2+ influx through CaV1.2 regulates jaw development. Cranial neural crest migration was unaffected by CaV1.2 knockdown, suggesting a role for CaV1.2 later in development. Focusing on the mandible, we observed that cellular hypertrophy and hyperplasia depended upon Ca2+ signals through CaV1.2, including those that activated the calcineurin signaling pathway. Together, these results provide new insights into the role of voltage-gated Ca2+ channels in nonexcitable cells during development.

Counseling in isolated mild fetal ventriculomegaly.

In this Review we aim to provide up-to-date and evidence-based answers to the common questions regarding the diagnosis of isolated mild fetal ventriculomegaly (VM). A literature search was performed to identify all reports of antenatal VM in the English language literature. In addition, reference lists of articles identified using the search were scrutinized to further identify relevant articles. Fetal mild VM is commonly defined as a ventricular atrial width of 10.0-15.0 mm, and it is considered isolated if there are no associated ultrasound abnormalities. There is no good evidence to suggest that the width of the ventricular atria contributes to the risk of neurodevelopmental outcome in fetuses with mild VM. The most important prognostic factors are the association with other abnormalities that escape early detection and the progression of ventricular dilatation, which are reported to occur in about 13% and 16% of cases, respectively. Most infants with a prenatal diagnosis of isolated mild VM have normal neurological development at least in infancy. The rate of abnormal or delayed neurodevelopment in infancy is about 11%, and it is unclear whether this is higher than in the general population. Furthermore, the number of infants that develop a real handicap is unknown. There are limitations of existing studies of mild VM. Although they address many of the relevant questions regarding the prognosis and management of fetal isolated mild VM, there is a lack of good-quality postnatal follow-up studies. The resulting uncertainties make antenatal counseling for this abnormality difficult.

El hijo de madre diabética / Diabetic mother offspring

Dado que la diabetes mellitus puede estar presente a lo largo de todo el embarazo, la exposición prenatal a la misma puede resultar en diferentes patologías (transtornos del crecimiento, prematuridad, abortos, mortinatos, malformaciones y alteraciones de la homeostasis) que perduran en el periodo neonatal. El principal mecanismo patogenico de estas alteraciones es la hiperinsulinemia, producida por el incremento de glucosa y aminoácidos en la circulación fetal. Las manifestaciones clínicas más frecuentes son: macrosomía, hipoglucemia, hipocalcemia e hipomagnesemia e hipertrofia septal cardíaca. En nuestro país, la diabetes es la segunda causa de embriopatía con una tasa de 0,204 por cada 10000 recién nacidos, parece existir paralelismo entre el número de defectos congénitos y el grado de control metabólico. La relación entre la diabetes gestacional y las malformaciones congénitas no esta claramente establecida, incluso para algunos autores es incierta, en esta situación el mejor parámetro de predicción es la glucemia basal elevada.Las mejoras en el cuidado anteparto, la monitorización fetal, el control riguroso del metabolismo materno y la educación materna, disminuyen la morbi-mortalidad perinatal. Además un buen control del metabolismo materno durante el periodo periconcepcional resulta en un descenso de la incidencia de malformaciones congénitas.El mayor riesgo de diabetes mellitus en los hijos de madre diabética es independiente de los factores de riesgo para la morbilidad perinatal, sin embargo, presentan índice de masa corporal, tensión arterial y niveles de glucosa tras la curva de tolerancia a la glucosa elevados, cuando se evalúa a los 18 y 26 años. El índice de desarrollo mental no es significativamente diferente entre los hijos de madre diabética y los hijos de madres normales (AU)

Maintenance of regional histodifferentiation patterns and a spatially restricted expression of type X collagen in rat Meckel's cartilage explants in vitro.

The major, central portion of Meckel's cartilage undergoes fibrous transformation and contributes to the sphenomandibular ligament, whereas its distal end undergoes endochondral ossification ultimately giving rise to inner-ear ossicles. This regional histodifferentiation of Meckel's cartilage is known to be associated with the spatially restricted expression of type X collagen. The objective of this study was to determine if this unique histodifferentiation is regulated by local environmental factors or by a preprogrammed genetic mechanism. Meckel's cartilage, and condylar cartilage used for comparison, were isolated from 17-day-old rat embryos and from newborn rats, respectively. The cartilage explants were maintained in vitro for 50 days with or without supplementation with 10% fetal bovine serum. When the explants were cultured under serum-free conditions, well-regulated cartilage development was observed. Expression of type X collagen, a differentiation marker for hypertrophic cartilage, was restricted to the distal end of Meckel's cartilage, whereas type II and IX collagens were found uniformly along the entire explant. Matrix calcification was examined histochemically using alizarin red S staining and found to be restricted to the distal end of Meckel's cartilage. Both Meckel's and condylar cartilage cultured with 10% fetal bovine serum developed unregulated dysmorphogenesis. These data suggest that, although Meckel's cartilage has an intrinsic potential to differentiate to its terminal stage, external regulatory factors can significantly influence its normal development at the molecular level.

Asymmetric septal hypertrophy in infants of diabetic mothers. Fetal echocardiography and the impact of maternal diabetic control.

Maternal hyperglycemia may result in fetal hyperinsulinemia and asymmetric septal hypertrophy, macrosomia, and hypoglycemia in infants of diabetic mothers. We monitored glycosylated hemoglobin levels in 61 pregnant diabetic women each trimester as an index of maternal glycemic control and did serial fetal echocardiograms starting at 18 weeks of gestation. At delivery, cord blood C-peptide levels were obtained as an index of fetal hyperinsulinemia. Infants were assessed for hypoglycemia, macrosomia and septal thickening by echocardiography. Nineteen of the 61 infants (31%) had septal hypertrophy, were heavier, and had higher cord blood C-peptide levels and lower serum glucose levels than unaffected infants. Maternal glycosylated hemoglobin levels were higher during the third trimester in mothers of affected infants. Our data support a possible relationship between third-trimester maternal hyperglycemia and neonatal asymmetric septal hypertrophy, macrosomia, and hypoglycemia.

Compensatory adrenal hypertrophy following unilateral adrenalectomy of fetuses of rats given alcohol throughout gestation.

The effect of maternal alcohol consumption on fetal compensatory adrenal hypertrophy following unilateral adrenalectomy was studied in rats. Females were given 20% alcohol in tap water for 4 weeks prior to mating and 30% alcohol in tap water throughout gestation (alcohol), or were pair-fed to the alcohol group (pair-fed) or were fed ad libitum (control). On day 20, fetuses were unilaterally left-adrenalectomized or sham operated. Mothers were sacrificed on day 22 of gestation and right adrenals of adrenalectomized, sham-operated, and unoperated fetuses were removed and weighed. Some adrenals were fixed, sectioned, and stained for histological examination. Adrenalectomized fetuses of all three dietary treatment groups demonstrated compensatory hypertrophy. Adrenals of alcohol-exposed fetuses weighed less than those of pair-fed or control fetuses, and the ratio of adrenal weight/body weight was greater, regardless of surgical procedure. Histological sections of right adrenals of left-adrenalectomized fetuses showed larger cells and widened sinusoids, compared to unoperated fetuses in the corresponding dietary treatment groups. These results are consistent with a retardation in adrenal growth and development as a result of alcohol exposure, but show that alcohol consumption throughout gestation does not affect the ability of the adrenals to undergo compensatory hypertrophy following unilateral adrenalectomy.