Biomedical subjects
Publications and source records attributed to A A Gibson.
We report a comparison of the results obtained at 500 MHz for heteronuclear shift correlation (HSQC) experiments with very small natural product samples using conventional and cryogenically cooled 3 mm NMR probes. The cryo probe affords a 12- to 16-fold reduction in data acquisition time for a comparable signal-to-noise ratio.
The expression of genes that regulate Fas-induced apoptosis has been examined in 10 human cultured colon carcinoma cell lines with defined and varied sensitivity to the cytolytic anti-Fas MoAb CH-11. Four lines demonstrated sensitivity to CH-11 (HT29, GC3/c1, TS-, Thy4), and six were resistant to the induction of apoptosis vis Fas. In nine lines expressing Fas, PCR-sequencing indicated that the death domain contained wt sequences. Downstream of Fas, expression of FADD/MORT1 and FLICE, essential components of the DISC, and negative regulators of Fas signalling including sFas, FAP-1 and Bcl-2, showed no correlation between levels of expression and sensitivity to Fas-mediated cytotoxicity. However, levels of the Fas antigen varied by >1000-fold, and correlated with CH-11 sensitivity. Following fourfold elevation in Fas expression in HT29 cells treated with interferon-gamma, a synergistic effect on Fas-mediated apoptosis was obtained when CH-11 and interferon-gamma were combined.
Drug-induced cytotoxicity or apoptosis may be influenced by the expression of the p53 tumor suppressor gene and by the specific oncogene expressed, which may dictate the threshold at which a cytotoxic response may by induced. The objective of the study was to elucidate how DNA-damaging agents with different mechanisms of action were sensitized in the context of expression of the Pax3/FKHR fusion protein, a transformation event unique to alveolar rhabdomyosarcomas (ARMSs), and wild-type p53 (wtp53). A wtp53 cDNA was subcloned into the pGRE5-2/EBV vector with dexamethasone-inducible overexpression and transfected into Rh30 ARMS cells that express Pax3/FKHR and a mutant p53 phenotype. Following dexamethasone induction of wtp53 overexpression in a derived clone (Cl.#27), growth was slowed, and cells accumulated in G1. Functional wtp53 activity was demonstrated by selective transactivation of p50-2, a wtp53 chloramphenicol acetyltransferase reporter construct, and by up-regulated expression of endogenous p21Waf1. Data demonstrated p53-dependent sensitization (> or = 4-fold) to bleomycin, actinomycin D, and 5-fluorouracil and considerably less p53-dependence (< or = 2-fold) for doxorubicin, topotecan, etoposide, and cisplatin in Cl.#27 compared to an equivalent clone containing the pGRE5-EBV vector alone (VC#3). Data demonstrate that ARMS cells show a selective sensitization to DNA-damaging agents when wtp53 is overexpressed. The cytotoxic activity of agents that are not potentiated substantially must, therefore, depend upon p53-independent factors that relate to the mechanism of drug action.
Fas is expressed in colonic epithelial cells and is also expressed in colon carcinomas, although its functional significance in the regulation of apoptosis in cells outside of the immune system remains unknown. In this study, we determined the role of Fas signaling on cellular growth of cultured colon carcinoma cells and demonstrated apoptosis induced by a cytotoxic anti-Fas monoclonal antibody (CH-11) in cells of the GC3/c1 lineage (GC3/c1, TS-, Thy4) but not in HCT116 or CaCo2 cells. Growth inhibition was detected at concentrations of CH-11 as low as 1 ng/ml, and clonogenic survival studies yielded IC50 values of 3-26 ng/ml. Cytotoxicity was inhibited by ZB4, a monoclonal antibody inhibitory to Fas signaling. In addition, the survival factor Bcl-2, which has demonstrated inconsistent protective effects against Fas signaling in other systems, was inhibitory to Fas-induced apoptosis in colon carcinoma cells after adenoviral transduction. Fas was expressed at the highest levels in TS- and Thy4 cells, which were the most sensitive cell lines to Fas-induced apoptosis. FAP-1, a protein tyrosine phosphatase that interacts with the cytosolic negative regulatory domain of Fas, was expressed in each cell line but did not correlate with sensitivity to Fas-mediated apoptosis. These data have therefore identified a functional Fas pathway in colon carcinoma cells when Fas is expressed at high levels. Hence, the role of Fas signaling in the regulation of apoptosis in colon carcinoma cells and its role in influencing the response to treatment with chemotherapeutic agents should be further explored.
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An attempt was made to identify all the cases of abdominal wall defects occurring in the West of Scotland over a 7-year period to determine the current incidence, prenatal diagnosis, management, and prognosis for fetuses and neonates with abdominal wall defects. Cases were identified because they presented either for prenatal diagnosis, or to the Department of Pathology following termination or spontaneous pregnancy loss, or as neonates to the Neonatal Surgical Department. The incidence of abdominal wall defects was found to be 1 in 2500 births. Exomphalos was diagnosed before birth in 66 per cent of cases, and in 30 per cent of cases it was associated with another major abnormality. There was a 20 per cent intact survival in the cases diagnosed prenatally who had no fetal anomaly and who opted to continue with the pregnancy. Gastroschisis was diagnosed before delivery in 70 per cent of cases, and in the group who continued with the pregnancy there was an intact survival of 77 per cent. Body stalk anomalies were all diagnosed prenatally and terminated. Maternal serum alpha-fetoprotein was elevated in 89 per cent of the cases with exomphalos and in 100 per cent of the cases with gastroschisis and body stalk anomalies in which it was tested.
The strain of Chlamydia psittaci causing enzootic abortion in ewes (the EAE strain) may cause serious infection in pregnant women, often resulting in hepatic and renal dysfunction, disseminated intravascular coagulation and fetal loss. The first case of such an infection in an abattoir worker is described and the possibility of human-to-human transmission considered. Direct handling of sheep or their products of conception can usually be established but this is not always so. There is much still to be learned about this uncommon but severe zoonosis.
OBJECTIVE: To characterize the pattern of renin containing cells (RCC) within the human kidney between 20 weeks of gestation and 6 months of postnatal life. DESIGN: Descriptive study using paraffin-embedded blocks of kidney stored following postmortem examination. METHODS: Sections of kidney were stained immunocytochemically using an antibody to human renin; the proportion of RCC within each of three zones (superficial, middle and deep) of the cortex, and their anatomical relation to individual glomeruli were determined. The cases were divided into five groups for analysis to gestational or postnatal age. RESULTS: Fetal RCC were usually at the vascular pole of the most mature glomeruli within the deeper areas of the cortex and were occasionally located within glomeruli. This distribution persisted until birth, even when the kidney was histologically mature. By contrast there were fewer RCC in neonatal and infant kidneys and, as in adult kidneys, these were located predominantly in the superficial cortex. CONCLUSION: The change in RCC distribution around the time of normal birth may relate to the transition to independent renal function. The location and density of RCC during fetal life may influence renal perfusion and amniotic fluid production.
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A patent ductus venosus has been reported on only two previous occasions. Both involved adults who presented with recurrent bouts of encephalopathy. We present the case of an infant with complex congenital heart disease and multiple other abnormalities, in whom a patent ductus venosus was an incidental finding at necropsy. The etiology of this condition and the options for management are discussed.
Most cases of nephroblastoma have high plasma levels of prorenin which is biologically inactive. Plasma prorenin levels fall to normal following nephrectomy. In order to ascertain whether renin synthesis occurs in nephroblastomas we decided to search for renin-specific mRNA using a cDNA probe and Northern blot analyses on total RNA purified from snap-frozen human tumour tissue obtained at nephrectomy. We demonstrated renin-specific mRNA in 5/11 (45 per cent) nephroblastomas. It was 1.6 Kb in length, similar to the mRNA detected in normal kidney tissue and in kidneys with renal artery stenosis. In one of the cases of nephroblastoma, in which we could detect no normal renin mRNA at 1.6 Kb, the cDNA probe hybridized with a higher molecular weight mRNA 3 Kb in length. We conclude that some nephroblastomas synthesize renin.
The prenatal diagnosis of a presacral (type IV) sacrococcygeal teratoma (SCT) is described. The initial ultrasound appearance was suggestive of a lower urinary tract obstruction, but further ultrasonic examination and radiological imaging using contrast medium led to the diagnosis of SCT. This is the first prenatal diagnosis of a totally intra-abdominal SCT.
The infantile cholangiopathies are a group of conditions associated with neonatal jaundice, which include extrahepatic biliary atresia, paucity of intra-hepatic bile ducts and disorders associated with persistence of fetal biliary structures, the so-called ductal plate malformations. Although previously regarded as distinct entities, it has recently been suggested that they may represent parts of a disease spectrum in which the principal process is one of bile duct destruction, the morphological manifestations in individual cases being influenced by the stage of intra-uterine development at which such injury occurs and by the site within the biliary system at which there is maximum damage. To further examine this concept, we have studied liver biopsy specimens from 37 neonates with extrahepatic biliary atresia, with particular reference to abnormalities of the intrahepatic bile ducts. Paucity of intrahepatic ducts, defined as a bile duct: portal tract ratio of less than 0.9, was identified in six cases (16.2%). In eight cases (21.6%) we found concentric tubular ductal structures similar to those observed in ductal plate malformations. In one case, both abnormalities could be demonstrated. Our findings support the concept that there is overlap between the various types of infantile cholangiopathy.
Over an eight year period 21 different viral strains excluding polioviruses were isolated in 44 (19%) of 237 cot deaths. The percentage of viral positive cases was significantly greater in over 16 week age groups and in cultures obtained less than 24 hours after death.
In 2 cases of hydrops fetalis and intrauterine death associated with human parvovirus B19 infection that produced very few symptoms during the second trimester of pregnancy, maternal serum alpha-fetoprotein levels were raised, before the ultrasonic detection of hydropic features. Fetal blood sampling in 1 case revealed the features of aplastic crisis. A retrospective study of 3 other affected and 11 unaffected cases of B19 infection during pregnancy showed a correlation between raised maternal serum alpha-fetoprotein level and poor prognosis for the affected pregnancies, with the subsequent development of hydrops fetalis.
The Jarcho-Levin syndrome (spondylothoracic dysostosis) is a rare autosomal recessive disorder characterized by a short neck, short trunk and a constricted thorax due to multiple rib and vertebral defects; other visceral malformations are occasionally present. Most cases die in infancy due to respiratory failure. In this report we describe two cases in one family from the United Kingdom. Prenatal diagnosis by ultrasound examination during the second trimester was successfully accomplished in the second case.
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We used a panel of two polyclonal antisera and two monoclonal antibodies to human renin to assess the tissue distribution of immunoreactive renin in a range of tumours and normal human tissues. The only tissue showing positive staining for renin was kidney and all four antisera stained the myoepithelioid cells in the renal cortex. In the survey of tumours we found immunoreactive renin only in renal tumours, namely, renal cell carcinoma, and nephroblastoma (Wilms' tumour). The renin-positive cells were sparse and distributed mainly along the course of the tumour blood vessels. They stained positively with all four antibodies and, in pairs of serial sections, we showed that the same cell reacted with two different antisera. This suggests that renal cell carcinoma and nephroblastoma have within them cells which contain renin.