Phenotypic diversity in siblings with partial androgen insensitivity syndrome

The androgen insensitivity syndrome is a heterogeneous disorder with a wide spectrum of phenotypic abnormalities, ranging from complete female to ambiguous forms that more closely resemble males. The primary abnormality is a defective androgen receptor protein due to a mutation of the androgen receptor gene. This prevents normal androgen action and thus leads to impaired virilisation. A point mutation of the androgen receptor gene affecting two siblings with partial androgen insensitivity syndrome is described. One had cliteromegaly and labial fusion and was raised as a girl, whereas the other sibling had micropenis and penoscrotal hypospadias and was raised as a boy. Both were shown to have the arginine 840 to cysteine mutation. The phenotypic variation in this family is thus dependent on factors other than abnormalities of the androgen receptor gene alone.     

Actuarial survival in the premature infant less than 30 weeks' gestation

OBJECTIVE: Because survival from admission to discharge does not provide parents and physicians information about future life expectancy in the premature neonate, we characterized the actuarial survival, defined as the future life expectancy from a given postnatal age, in a large inborn population of premature infants < 30 weeks' gestation. STUDY DESIGN: We determined daily actuarial survival of 1925 inborn infants (23 to 29 weeks' gestation) admitted to the Baylor Affiliated Nurseries from July 1986 through December 1994, stratified by 100-g birth weight and by 1-week gestational-age intervals. RESULTS: In the 501- to 600-g birth weight stratum, actuarial survival improved from 31% at birth, to 61% on day of life 7, and then to 75% on day of life 28; in the 901- to 1000-g birth weight stratum, actuarial survival improved from 88%, to 94%, and then to 98% throughout the same times, respectively. Similar trends were obtained when data were stratified by gestational age. CONCLUSIONS: Survival in the smallest infants improves dramatically during the first few days of life, but there is a significant risk for late death in the smallest of these infants.     

Antisense RNA-mediated reduction of p53 induces malignant phenotype in nontumorigenic rat urothelial cells

p53 mutation is commonly associated with high-grade, high-stage human urothelial carcinomas. Recent studies suggest that p53 mutation in low- grade, low-stage bladder carcinomas may be correlated with the progression of the disease. In the present study, we used antisense RNA methodology in vitro to evaluate the significance of the loss of p53 function at an early stage of urinary bladder carcinogenesis. An immortalized nontumorigenic rat urothelial cell line (MYP3) that strongly expresses wild-type (WT) p53 was transfected with a plasmid (pcDL-SR alpha-296) containing a rat WT p53 cDNA in antisense orientation. The transfection resulted in a significant reduction in p53 mRNA expression and protein synthesis, in stimulation of anchorage- dependent growth, and in acquisition of anchorage-independent growth potential. Three such clones, when tested in athymic nude mice, all formed muscle-invasive, high-grade transitional cell carcinomas at s.c. injection sites. When cells were inoculated into an orthotopic site (urinary bladder), one of two antisense transfectants tested formed bulky tumors in the bladder in all seven nude mice and metastases to lungs in three of the seven mice. Analysis of these cells revealed a decrease in the expression of p21 (WAF1, sdi1, or CIP1) and retinoblastoma (Rb) gene product. Phosphorylation of Rb protein was not inhibited when the cells were starved. No significant difference was observed in the expression of p16 protein. In cell cycle analysis, all antisense transfectants tested escaped from G1 arrest by starvation. Furthermore, secretion of interleukin (IL)-6 into culture medium was increased significantly. Treatment with anti-IL-6 antibody suppressed anchorage-dependent growth. This study directly demonstrates that the loss of p53 function at an early stage of urothelial carcinogenesis may result in acquisition of a malignant phenotype by regulating IL-6 production as well as cell cycle related genes.      

Basic fibroblast growth factor (bFGF) enhances functional recovery following severe spinal cord injury to the rat

We have recently demonstrated that following a moderate contusion spinal cord injury (SCI) to rats, subsequent administration of basic fibroblast growth factor (bFGF) significantly enhances functional recovery and tissue sparing. To further characterize the effects of bFGF, we evaluated its efficacy after a more severe contusion injury at T(10) using the NYU impactor. Immediately after SCI, osmotic minipumps were implanted into the lateral ventricle and lumbar thecal sac to deliver bFGF at 3 or 6 microg per day versus control vehicle for 1 week. Animals were behaviorally tested for 6 weeks before histological assessment of tissue sparing through the injured segment and glial reactivity distal to the lesion. Compared to moderate SCI, all rats had more prolonged and sustained functional deficits 6 weeks after severe contusion. Subjects treated with bFGF had pronounced recovery of hindlimb movements from 2 to 6 weeks compared to controls, manifested in significantly higher behavioral scores. Only marginal tissue sparing was seen rostral to the injury in bFGF-treated spinal cords versus controls. Optical density measurements of astrocyte and microglial cell immunoreactivity in bFGF-treated spinal cords showed that after 6 weeks they approximated controls, although astrocyte immunoreactivity remained higher in controls rostrally. In summary, intrathecal infusion of bFGF following severe SCI significantly restores gross hindlimb motor function that is not correlated with significant tissue sparing. In light of previous evidence that pharmacological intervention with bFGF after moderate SCI enhances tissue preservation, the current findings indicate that yet undefined mechanisms contribute to the enhanced functional recovery following bFGF treatment.     

Protein kinase C iota protects neural cells against apoptosis induced by amyloid beta-peptide

Protein kinase C (PKC) isoforms are increasingly recognized as playing important roles in the regulation of neuronal plasticity and survival. Recent findings from studies of non-neuronal cells suggest that atypical isoforms of PKC can modulate apoptosis in various paradigms. Because increasing data support a role for neuronal apoptosis in the pathogenesis of Alzheimer's disease (AD), we tested the hypothesis that PKCiota (PKCiota) can modify vulnerability of neural cells to apoptosis induced by amyloid beta-peptide (ABP), a cytotoxic peptide linked to neuronal degeneration in AD. Overexpression of PKCiota increased the resistance of PC12 cells to apoptosis induced by ABP. Associated with the increased resistance to apoptosis were improved mitochondrial function and reduced activity of caspases. In addition, ABP-induced increases in levels of oxidative stress and intracellular calcium levels were attenuated in cells overexpressing PKCiota. These findings suggest that PKCiota prevents apoptosis induced by ABP by interrupting the cell death process at a very early step, thereby allowing the cells to maintain ion homeostasis and mitochondrial function.     

Cingulate gyrus morphology in children and adolescents with fetal alcohol spectrum disorders

Alcohol consumption during pregnancy can lead to a variety of cognitive and other birth defects, collectively termed fetal alcohol spectrum disorders (FASD), and including the Fetal Alcohol Syndrome (FAS). This study examined the impact of gestational alcohol exposure on the morphology of the cingulate gyrus, given this region's role in cognitive control, attention, and emotional regulation, all of which are affected in children with FASD. Thirty-one youth (ages 8–16) with histories of heavy prenatal alcohol exposure (n = 21) and demographically matched comparison subjects (n = 10) underwent structural magnetic resonance imaging. The cingulate gyrus was manually delineated, and parcellated volumes of grey and white matter were compared across groups. Alcohol-exposed individuals had significantly smaller raw cingulate grey matter, white matter, and tissue volumes compared with controls. After adjustment for respective cranial tissue constituents, only white matter volumes remained significantly reduced, and this held regardless of whether or not the child qualified for a diagnosis of FAS. A correlation between posterior cingulate grey matter volume and the WISC-III Freedom from Distractibility Index was also observed in alcohol-exposed children. These data suggest that cingulate white matter is compromised beyond global white matter hypoplasia in alcohol-exposed individuals, regardless of FAS diagnosis. The observed volumetric reductions in the cingulate gyrus may contribute to the disruptive and emotionally dysregulated behavioral profile commonly observed in this population.