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Biomedical subjects

C Goodyer

Publications and source records attributed to C Goodyer.

12 recordsLinked to original sources
PubMed1997

Regulation of renal EGF receptor expression is normal in Denys-Drash syndrome.

In patients with Denys-Drash syndrome, mutations of the Wilms' tumor suppressor gene are associated with nephroblastomas and developmental abnormalities of the genital tract and renal glomerulus. Normally, the Wilms' tumor gene product (WT1) is expressed at high levels in visceral glomerular epithelial cells (VGEC) of the emerging fetal glomerulus. We demonstrate that WT1 could normally serve to suppress EGF receptor expression in VGEC, since immunoreactive EGF receptor is strikingly absent compared to epithelial cells of the emerging proximal and distal tubule, which lack WT1. When HEK293 cells were co-transfected with plasmids containing EGFR enhancer/promoter elements linked to a CAT reporter and plasmids containing WT1 cDNA, EGFR enhancer/promoter activity was suppressed by all wild-type WT1 isoforms, but not by deletion mutants of WT1 lacking normal zinc-finger or N-terminal domains. Surprisingly, plasmids expressing a Denys-Drash WT1 mutant (R394W) retained the ability to suppress EGFR promoter activity in this system. Furthermore, we found that immunoreactive EGFR was appropriately undetectable in glomeruli from a three-year-old girl with Denys-Drash syndrome and in sections of her Wilm's tumor. These data suggest that faulty suppression of EGFR cannot account for the abnormalities of glomerulogenesis seen in Denys-Drash patients.

Cell Line↗
PubMed1997

Curtailed respiration by repeated vs. isolated hypoxia in maturing piglets is unrelated to NTS ME or SP levels.

In early development, respiratory disorders can produce recurring hypoxic episodes during sleep. To examine possible effects of daily repeated vs. isolated hypoxic hypoxia, cardiorespiratory functions and central, respiratory-related neuromodulator levels in 21- to 32-day-old, chronically instrumented, unsedated piglets were compared between a fifth sequential daily hypoxia and an isolated hypoxia (10% O2-90% N2 for 30 min). Diaphragmatic electromyographic activity, heart rate and arterial pressure, and pH and gas tensions were measured. In vivo microdialysis, via chronically implanted guides, served to sample interstitial substance P (SP) and methionine-enkephalin (ME) at the level of the respiratory-related nucleus tractus solitarii (NTS). Compared with an isolated hypoxia, repeated hypoxia resulted in 1) lower respiratory frequency (f), ventilation equivalent, and arterial pH, higher arterial PO2 during hypoxia, and lower f in recovery from hypoxia; and 2) increased SP concentrations but no change in ME concentrations. We conclude that, in these maturing swine, repeated vs. isolated hypoxic exposure curtails respiratory responses to hypoxia by a mechanism(s) unrelated to SP or ME levels at the NTS.

Aging↗
PubMed1997

Insulin-like growth factor (IGF) and IGF binding protein gene expression in multicystic renal dysplasia.

Multicystic dysplastic kidney disease is the most common form of renal dysplasia that leads to ESRD in children. This study describes the histopathological changes of multicystic dysplasia that occur from early fetal life to the postnatal period. At 14 wk gestation, early cystic enlargement of various segments of the nephron have been identified, in addition to a displaced metanephric blastema adjacent to zones of normal nephrogenesis. At later stages, the predominant features include cyst enlargement with marked fibromuscular collars, architectural disorganization, and replacement of the interstitium with a disarray of mesenchymal tissue. This study investigated the expression of the mRNA encoding the insulin-like growth factors (IGF) and IGF binding proteins (IGFBP) and have demonstrated IGF-II, IGFBP-2, and IGFBP-3 to be altered. Apart from their expression in the displaced metanephric blastema, both IGF-II and IGFBP-2 were overexpressed in abnormal tissue elements in all kidneys from fetal to postnatal life. IGF-II gene expression was localized to mesenchymal tissue, specifically in the periductal fibromuscular collars. IGFBP-2 mRNA was found to be expressed exclusively in the cyst epithelia of all cysts at all ages studied, whereas IGFBP-3 mRNA was absent from these epithelia. This study details the failure of normal IGF expression in the development of multicystic renal dysplasia and suggests a role for the IGF system in the progressive histopathological changes of this disorder.

Child, Preschool↗
PubMed1997

Repeated microdialysis from the nucleus tractus solitarii of chronically instrumented, unsedated piglets.

Normal development of respiratory rhythm and control, and perturbations thereof, likely relate to neuromodulators in brainstem regions. To assess the feasibility of repeated neurochemical sampling by in vivo microdialysis from the respiratory-related nucleus tractus solitarii (NTS) during development. 19-24 day-old piglets (n = 7) were implanted under anesthesia with chronic microdialysis guides near NTS around obex. Unsedated piglets then underwent in vivo microdialysis twice, 3 days apart, through probes inserted acutely via the guides to abut against the NTS. The probe tips, surrounded by normal neurons and only diffuse gliosis, either intersected, or were within < or = 300 microns from the NTS. Thirty-min microdialysates were collected for 120 min in normoxia, HPLC-fractionated, and assayed for substance-P (SP), a respiratory excitatory neuropeptide. SP levels stabilized within 90 min from probe placement, and did not differ between the 2 experimental days. Thus, repeated in vivo microdialysis from NTS of conscious piglets is feasible, and can illuminate respiratory-related normal and pathological neurochemical processes during development.

Animals↗
PubMed1996

Amyloid beta peptide of Alzheimer's disease downregulates Bcl-2 and upregulates bax expression in human neurons.

Neuronal apoptosis is a suspected cause of neurodegeneration in Alzheimer's disease (AD). Increased levels of amyloid beta peptide (Abeta) induce neuronal apoptosis in vitro and in vivo. The underlying molecular mechanism of Abeta neurotoxicity is not clear. The normal concentration of Abeta in cerebrospinal fluid is 4 nM. We treated human neuron primary cultures with 100 nM amyloid beta peptides Abeta(1-40) and Abeta(1-42) and the control reverse peptide Abeta(40-1). We find that although little neuronal apoptosis is induced by either peptide after 3 d of treatment, Abeta(1-42) provokes a rapid and sustained downregulation of a key anti-apoptotic protein, bcl-2, whereas it increases levels of bax, a protein known to promote cell death. In contrast, the Abeta(1-40) downregulation of bcl-2 is gradual, although the levels are equivalent to those of Abeta(1-42)-treated neurons by 72 hr of treatment. Abeta(1-40) does not upregulate bax levels. The control, reverse peptide Abeta(40-1), does not affect either bcl-2 or bax protein levels. In addition, we found that the Abeta(1-40)- and Abeta(1-42)- but not Abeta(40-1)-treated neurons had increased vulnerability to low levels of oxidative stress. Therefore, we propose that although high physiological amounts of Abeta are not sufficient to induce apoptosis, Abeta depletes the neurons of one of its anti-apoptotic mechanisms. We hypothesize that increased Abeta in individuals renders the neurons vulnerable to age-dependent stress and neurodegeneration.

Alzheimer Disease↗
PubMed1996

The pathogenesis of multicystic dysplastic kidney disease: insights from the study of fetal kidneys.

The pathogenesis of multicystic dysplastic kidney disease (MCDKD) is unknown. Most morphologic studies of MCDKD kidneys have been performed when the kidneys are resected postnatally, when their architecture has been distorted by massive cyst enlargement. We obtained two MCDKD kidneys at an early stage of development (14 and 19 weeks' gestation) and examined the pattern of nephrogenesis in detail. In both affected kidneys, we identified islands of spatially dislocated metanephric blastema adjacent to zones containing all the normal structural elements of nephrogenesis, including aggregates of induced mesenchyme, S-shaped bodies and maturing glomerull, and proximal and distal tubules. Metanephric blastemal cells displayed characteristic vimentin and smooth muscle actin immunoreactivity and insulin-like growth factor II gene expression, whereas induced elements exhibited appropriate cytokeratin immunoreactivity and Wilms' tumor gene expression. In most other zones, renal cysts were lined with epithelia varying from a flattened squamous to a cuboidal morphology and expression of markers suggested their origin to be from all portions of the nephron including Bowman's space, proximal tubule, and collecting duct. In some cysts, small clusters of epithelial cells were identified within the cyst lumen. These studies suggest that in the early stages of MCDKD, normal nephrogenesis occurs in what seems to be a normal metanephric blastema; however, an intrinsic abnormality in the branching morphogenesis of the ureteric duct might be responsible for the development of the histopathologic changes described.

Actins↗
PubMed1995

Differential susceptibility of human CNS-derived cell populations to TNF-dependent and independent immune-mediated injury.

We examined whether oligodendrocytes, neurons, and astroglia derived from the human central nervous system differ in susceptibility to injury mediated by tumor necrosis factor (TNF)-alpha and by activated CD4+ T cells acting via a TNF-independent mechanism. Injury was assessed either as cell membrane-directed (lysis), measured by 51chromium (Cr) or lactate dehydrogenase (LDH) release, or nucleus-directed (apoptosis), measured by morphologic features based on propidium iodide (PI) staining and by DNA fragmentation measured by a terminal transferase (TdT)-mediated dUTP biotin nick end labeling technique (TUNEL). TNF did not induce 51Cr or LDH release in any cell targets, but did induce nuclear (66 +/- 2% of cells) and DNA (68 +/- 2% of cells) fragmentation selectively in the oligodendrocytes over 96 hr. At this time, there was no significant loss of oligodendrocyte cell number. Nuclear injury could be induced in neurons by serum deprivation and in malignant astrocytes by the combination of TNF and low serum. CD4+ T cells activated with phytohemagglutin (pha) or anti-CD3 plus interleukin-2 induced significant 51Cr and LDH release in all target cells tested; only pha-activated CD4+ T-cell cocultures showed reduced target cell numbers. Significant nuclear fragmentation was observed only for glioma cells (22 +/- 1% of cells). Differences in susceptibility to different immune effector mechanisms and in the nature of the injury response to the same effector mediator among human CNS-derived neural cells will need to be considered in design of therapeutic strategies aimed at protecting or limiting target cell injury consequent to disease or trauma.

Apoptosis↗
PubMed1994

Fetal isoform of human retinoic acid receptor beta expressed in small cell lung cancer lines.

The retinoic acid receptor type beta (RAR beta) complementary DNA from a small cell tumor line was amplified, sequenced, and found to be homologous to the murine RAR beta 1. Seventeen lung tumor lines were analyzed. Five of seven small cell lung carcinoma lines expressed RAR beta 1, but only one other line (epidermoid) expressed the isoform, and this was at trace levels. Two other epidermoid lines, as well as three adenocarcinoma, two adenosquamous, and two large cell-derived lines did not express RAR beta 1. Nine adult human tissues, including lung, were analyzed, and in contrast to what has been reported for the mouse, undetectable or barely detectable levels were observed. On the other hand, a total of 13 different fetal tissues, at three different developmental stages, all expressed RAR beta 1. RAR beta 1 may be a master developmental gene in humans, and the remarkably specific association with small cell lung carcinoma suggests a molecular link between this type of cancer and development.

Amino Acid Sequence↗
PubMed1993

Expression of the epidermal growth factor receptor in fetal kidney.

Formation of the human kidney begins at the 6th week of fetal life when the first generations of nephrons are generated from foci of metanephric mesenchyme through contact with the branches of the ureteric bud. This process requires a proliferative burst which must be tightly regulated by local signals. In this report, we review the evidence that the epidermal growth factor receptor molecule is an important arbiter of these events.

Animals↗
PubMed1977

Short term culture of human midterm and term placenta: parameters of hormonogenesis.

Monolayer cultures of human midterm and term placentae have been established following trypsin dispersion of placental minces. Maintenance of endocrine function was monitored by the concentrations of specific hormones in the culture media. At either gestational age the cultures 1) secret estradiol-17beta(1) and estrone (in a ratio of about 1:20) and aromatize 3H- or 14C-dehydroepiandrosterone sulfate and 14C-androstenedione, estrogen production being markedly enhanced by addition of dehydroepiandrosterone (10(-6)7) to the culture medium; 2) metabolize 3H-pregnenolone to progesterone and 14C-cortisol to cortisone; and 3) produce increasing amounts of chorionic gonadotropin and decreasing amounts of placental lactogen during the first week in culture. It is proposed that the model is highly suited to the study of factors affecting hormonogenesis by the human placenta whether they be of maternal or of fetal origin.

Chorionic Gonadotropin↗