Biomedical subjects
Publications and source records attributed to T Gilbert.
Vitamin A closely modulates nephron endowment at birth. It is also required for the development of renal vasculature. Fetal vitamin A status may thus be responsible for most of the variations in nephron number found in the general population, and may play a major role in the intrauterine programming of chronic renal disease and hypertension.
BACKGROUND: It has been suggested that Helicobacter pylori may induce more or less severe gastroduodenal disease according to the strain virulence. DESIGN: We used Western blot to determine antigenic profiles associated with duodenal or gastric ulcer disease, MALT lymphoma and non-ulcer dyspepsia, and to identify geographical differences. METHODS: One hundred and eighty-two consecutive patients with H. pylori infection were studied. H. pylori infection was diagnosed by a rapid urease test or histological examination of gastric biopsy samples. Bacterial density and gastritis were assessed histologically by using the Sydney scoring system. Western blot was used to identify antibodies against eight antigens (CagA, VacA, urease A, heat shock protein B, and 19.5, 26.5, 30 and 35 kDa). Patients were questioned on their smoking habits and place of birth and childhood. RESULTS: There were 73 patients with duodenal ulcer, 30 with gastric ulcer, eight with erosive duodenitis, 17 with gastric MALT lymphoma and 54 with non-ulcer dyspepsia. Most (>85%) were seropositive for the heat shock protein B and 26.5-kDa antigens. The prevalence of the other antigens ranged from 45% (VacA) to 68% (urease B). The seroprevalence of CagA antigen was significantly higher (P < 0.01) in cases of gastroduodenal ulcer (84%) than non-ulcer dyspepsia (37%). Similarly, 35-kDa antigen reactivity was more frequent (P < 0.05) in duodenal ulcer patients (75%) than in those with non-ulcer dyspepsia (50%). The antigenic profiles associated with MALT gastric lymphoma and non-ulcer dyspepsia were similar. Multivariate analysis showed that only gastroduodenal ulcer was significantly associated with CagA. Gastroduodenal ulcer and a childhood spent in Africa were both associated with 35-kDa and combined CagA-35-kDa reactivity. CONCLUSIONS: This study confirms the strong seroprevalence of H. pylori CagA antigen and shows a high prevalence of the 35-kDa antigen in patients with gastroduodenal ulcer, especially those raised in Africa. There was no difference in the serological pattern between patients with non-ulcer dyspepsia and those with MALT lymphoma. Tests for antibodies to the CagA-35-kDa antigen combination might be used to select H. pylori-infected dyspeptic patients warranting treatment.
OBJECTIVE: To ascertain the surgical risk and long term outcome of patients over 80 years old undergoing aortic valve replacement (AVR). DESIGN: Consecutive cases with respective case note audit and a telephone questionnaire. SETTING: Single UK cardiothoracic surgical centre. PATIENTS: 103 (48 male) patients over 80 years old undergoing AVR. The median age was 82 years (80-95 years) and 95 of 103 patients were in New York Heart Association (NYHA) class III or IV. METHOD AND RESULTS: Preoperative characteristics, operative course, cost, and outcome measures were ascertained. Mean bypass time was 56 minutes and 25 patients had simultaneous coronary artery bypass grafting. Overall mortality was 19 of 103. Univariate analysis of pertinent variables found that impaired renal function and peripheral vascular disease were significantly associated with early postoperative death. 10 of 12 patients requiring ventilation for more than 24 hours died. The 50% actuarial survival was 62 months. Late complications were uncommon with 92% of patients in NYHA class I or II at follow up. CONCLUSIONS: AVR in patients over 80 years old has a significant risk. However, those patients who survive experience significant benefit with good long term prospects for general health and social independence.
The essential role of vitamin A and its metabolites, retinoids, in kidney development has been demonstrated in vitamin A deficiency and gene targeting studies. Retinoids signal via nuclear transcription factors belonging to the retinoic acid receptor (RAR) and retinoid X receptor (RXR) families. Inactivation of RARaplpha and RARbeta2 receptors together, but not singly, resulted in renal malformations, suggesting that within a given renal cell type, their concerted function is required for renal morphogenesis. At birth, RARalpha beta2(-) mutants displayed small kidneys, containing few ureteric bud branches, reduced numbers of nephrons and lacking the nephrogenic zone where new nephrons are continuously added. These observations have prompted us to investigate the role of RARalpha and RARbeta2 in renal development in detail. We have found that within the embryonic kidney, RARalpha and RARbeta2 are colocalized in stromal cells, but not in other renal cell types, suggesting that stromal cells mediate retinoid-dependent functions essential for renal development. Analysis of RARalpha beta2(-) mutant kidneys at embryonic stages revealed that nephrons were formed and revealed no changes in the intensity or distribution of molecular markers specific for different metanephric mesenchymal cell types. In contrast the development of the collecting duct system was greatly impaired in RARalpha beta2(-) mutant kidneys. Fewer ureteric bud branches were present, and ureteric bud ends were positioned abnormally, at a distance from the renal capsule. Analysis of genes important for ureteric bud morphogenesis revealed that the proto-oncogene c-ret was downregulated. Our results suggest that RARalpha and RARbeta2 are required for generating stromal cell signals that maintain c-ret expression in the embryonic kidney. Since c-ret signaling is required for ureteric bud morphogenesis, loss of c-ret expression is a likely cause of impaired ureteric bud branching in RARalpha beta2(-) mutants.
OBJECTIVE: Using the Agency for Health Care Policy and Research Depression Guideline Panel's recommendations as its focus, this article describes a step-by-step approach for disseminating a paper-based depression guideline to primary care physicians via a commercially available electronic medical record (EMR) system. METHOD: Description of the author's approach to disseminate an evidence-based depression treatment guideline to a group of primary care physicians using a commercially available EMR system and to evaluate the results. RESULTS: We review clinical considerations and practical barriers faced in this process with the expectation that our experiences can guide others attempting to disseminate psychiatric treatment guideline via EMR systems. CONCLUSIONS: The EMR offers critical efficiencies in disseminating state-of-the-art clinical practice guidelines and in directing the primary care physicians' use of them. Still, well-designed, randomized controlled trials are necessary to demonstrate their effectiveness at enhancing patient outcomes for major depression in primary care settings.
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Protease-activated receptors 1-3 (PAR1, PAR2, and PAR3) are members of a unique G protein-coupled receptor family. They are characterized by a tethered peptide ligand at the extracellular amino terminus that is generated by minor proteolysis. A partial cDNA sequence of a fourth member of this family (PAR4) was identified in an expressed sequence tag database, and the full-length cDNA clone has been isolated from a lymphoma Daudi cell cDNA library. The ORF codes for a seven transmembrane domain protein of 385 amino acids with 33% amino acid sequence identity with PAR1, PAR2, and PAR3. A putative protease cleavage site (Arg-47/Gly-48) was identified within the extracellular amino terminus. COS cells transiently transfected with PAR4 resulted in the formation of intracellular inositol triphosphate when treated with either thrombin or trypsin. A PAR4 mutant in which the Arg-47 was replaced with Ala did not respond to thrombin or trypsin. A hexapeptide (GYPGQV) representing the newly exposed tethered ligand from the amino terminus of PAR4 after proteolysis by thrombin activated COS cells transfected with either wild-type or the mutant PAR4. Northern blot showed that PAR4 mRNA was expressed in a number of human tissues, with high levels being present in lung, pancreas, thyroid, testis, and small intestine. By fluorescence in situ hybridization, the human PAR4 gene was mapped to chromosome 19p12.
The plight of people with learning disabilities who have mental health problems has become an issue of contemporary importance in the provision of health services to this section of the population. This paper will argue that learning disability nursing has a central role to play in the promotion of mental health for this client group (Department of Health 1995a). However, learning disability nursing presently operates without a clear model of mental health. Therefore, before this potential can be realized there is a need to establish the common ground between the discourses of learning disability nursing and those of psychiatric nursing which might be related to this client group. This paper begins by identifying the background issues relating to the problems of meeting the mental health needs of people with learning disabilities. It then proposes that an applied behavioural approach has the potential to provide a coherent theory that can link the discourses of normalization, developmental psychiatry and mental health nursing, whilst also establishing the applied behavioural approach as a powerful technology upon which meaningful interventions can be designed.
This paper draws upon sociological theory to demonstrate that the manufacture and deployment of trust is an integral part of the function of complex systems such as health care. The discussion begins by identifying the error within the nursing literature which arises from a rather technical conceptualization of trust. This tends to limit the dimensions to trust which is established, and fails to recognize that trust may be subject to competition and conflict. The paper continues by drawing upon the work of two theorists, Niklas Luhmann and Susan P. Shapiro, to demonstrate how trust functions within systems such as health care and the mechanisms through which it is controlled. The title of this paper, 'Towards a politics of trust', identifies that this is merely the first stage in the analysis. Further stages are necessary which analyse the ways in which power is exercised in the conflict for control within discrete elements of the system.
BACKGROUND: Vitamin A plays a critical role in fetal organogenesis, and its severe deficiency during pregnancy is known to result in malformations of several organs, including the kidney. However, the consequences of mild vitamin A deficiency (VAD) has received little attention. In the present study, we examined the effect of in utero exposure to mild VAD on renal organogenesis. METHODS: A rat model of mild VAD compatible with normal gestation was developed. Plasma retinol was determined by reverse phase HPLC in mothers and fetuses. Nephron counting was performed in kidneys of fetuses and pups issued from control and VAD mothers. Metanephroi explanted from 14-day-old fetuses from both groups were cultured in the presence or absence of retinoic acid (RA), and growth and differentiation were assessed. c-ret expression was analyzed from fetuses exposed in utero to VAD or to normal vitamin A status and also in metanephroi grown in culture with or without RA using RT-PCR. RESULTS: The 50% reduction in circulating vitamin A levels induced by vitamin A deprivation in pregnant rats did not affect the overall fetal development. However, the number of nephrons was reduced by 20% in 21-day-old VAD fetuses. The number of nephrons was closely correlated with circulating vitamin A level in both VAD and control fetuses. Metanephroi taken from VAD fetuses developed to a lesser extent in vitro, but their capacity to respond to exogenous retinoic acid was not altered. Finally, we found that the expression of the proto-oncogene c-ret was modulated according to the retinoid environment. CONCLUSION: We conclude that vitamin A supply to the fetus is critical in determining the number of nephrons. Data available thus far on the frequency of mild VAD during pregnancy and on the long-term consequences of inborn nephron deficit highlight the clinical relevance of the present study.
Vitamin A and its derivatives have been shown to promote kidney development in vitro in a dose-dependent fashion. To address the molecular mechanisms by which all-trans-retinoic acid (RA) may regulate the nephron mass, rat kidneys were removed on embryonic day 14 (E14) and grown in organ culture under standard or RA-stimulated conditions. By using RT-PCR, we studied the expression of the glial cell line-derived neurotrophic factor (GDNF), its cell surface receptor-alpha (GDNFR-alpha), and the receptor tyrosine kinase c-ret, known to play a major role in renal organogenesis. Expression of GDNF and GDNFR-alpha transcripts was high at the time of explantation and remained unaffected in culture with or without RA. In contrast, c-ret mRNA level, which was low in E14 metanephros and dropped rapidly in vitro, was increased by RA in a dose-dependent manner. The same is true at the protein level. Exogenous GDNF barely promotes additional nephron formation in vitro. Thus the present data establish c-ret as a key target of retinoids during kidney organogenesis.
We report the case of an Escherichia coli O157:H7 infection in a patient with hemorrhagic colitis. Initial diagnosis was ischemic colitis because of the age of the patient and clinical presentation. After one week, a hemolytic-uremic syndrome occurred and serologic antibodies to the lipopolysaccharide O157 of Escherichia coli O157:H7 were positive, leading to the diagnosis of hemorrhagic colitis caused by this bacteria. Escherichia coli O157:H7 colonic infection is not well known, specially in France where only two cases has been reported in adults. This bacteria and the toxin produced (Shiga-like toxin) should be searched in cultures of stools and colonic biopsies in case of bloody diarrhea, in particular when a hemolytic-uremic syndrome is associated. As clinical, pathological and endoscopic findings in Escherichia coli O157:H7-associated colitis may be similar to the ischemic colitis pattern, differential diagnosis may be difficult.
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The development of the permanent mammalian kidney, or metanephros, depends on mesenchymal-epithelial interactions, leading to branching morphogenesis of the ureteric bud that forms the collecting ducts and to conversion of the metanephric mesenchyme into epithelium that forms the nephrons. Rat metanephric organ culture in which these interactions are maintained is a valuable in vitro model system for investigating normal and abnormal renal organogenesis. Methods were designed to evaluate either the capacity of the ureteric bud to branch or that of the mesenchyme to form nephrons. Both are based on specific staining of the ureteric bud and the glomeruli with lectins. Using this approach, we have shown that retinoids are potent stimulating factors of nephrogenesis, acting through an increase in the branching capacity of the ureteric bud. On the other hand, several drugs such as gentamicin and cyclosporin A were found to reduce the number of nephrons formed in vitro. While gentamicin affects the early branching pattern of the ureteric bud, cyclosporin may affect the capacity of the mesenchyme to convert into epithelium. This methodology therefore appears a potentially useful tool for toxicological studies of new drugs.
Vitamin A and its metabolic derivatives are known to be key signalling molecules in regulating morphogenetic events in vertebrate development. Here we investigated their possible involvement during mammalian kidney development using paired rat metanephros organ culture. Metanephroi were explanted from 14-day-old embryos and cultured for six days in a chemically defined medium containing a retinoid at a dose of 10(-11) to 10(-4) M. Retinol, all-trans and 9-cis retinoic acid were able to promote metanephros growth and differentiation in vitro. A significant increase in the number of nephrons was observed from 10(-8) M of retinol and 10(-10) M of all-trans retinoic acid, before any change in growth parameters. A threefold increase in the number of nephrons was obtained at a dose of 10(-6) M. At low retinoid concentrations, there was a modulating effect of triiodothyronine on retinoid-stimulated nephrogenesis since the absence of triiodothyronine in the medium enhanced the nephrogenic stimulation. Exposure of metanephroi from 13-day-old embryos to all-trans retinoic acid (10(-7) M) led to a sixfold increase of nephron formation. Finally, we analyzed the branching pattern of the ureteric bud and showed that within 48 hours of culture, it was significantly more developed upon retinoid exposure. In conclusion, this study demonstrates that retinoic acid is a key regulator of renal organogenesis in controlling nephrogenic induction processes and ureteric bud patterning, and that the younger the metanephros, the greater the effect.
Development of the metanephric kidney during embryogenesis can be altered both in vivo and in vitro by exposure to gentamicin, which may lead to oligonephronia. To study the role of the ureteric bud in nephron deficit genesis, we used metanephros organ cultures exposed to gentamicin as a model of impaired nephrogenesis. Ultrastructural localization of the antibiotic showed that by eight hours it was already present within the epithelial cells of the ureteric bud and in its growing ends, and also trapped in the adjacent blastema. Using confocal microscopy and image analysis, we devised a quantitative approach to analyze the branching pattern of the ureteric bud, and showed that by 24 hours of culture, despite no change of explants growth, gentamicin had significantly decreased the number of branching points. This effect involved the early branching events and was limited to end buds that had no nephron anlagen nearby. Our findings indicate that impaired branching morphogenesis of the ureteric bud is the likely event of gentamicin-induced nephron deficit.
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This study examines the recognition and treatment of emotional distress in physically healthy primary care patients who perceive themselves to be in fair or poor physical health. Patients (N = 892) from three private primary care practices completed a mental health screening form prior to their medical visit which included an overall assessment of their physical health (1 = excellent, 2 = good, 3 = fair, 4 = poor). Following the visit, their physicians completed a questionnaire that included the same physical health assessment item. The study group, physically healthy patients who perceive poor physical health (HPPPH), included those patients who rated their physical health as 2 or 3 points more impaired than it was rated by their physician. HPPPH (N = 39) were significantly more likely than other patients (N = 853) to report a prior psychiatric hospitalization (p < 0.05), marital difficulties (p < 0.01), recent missed work due to a mental health problem (p < 0.001), and a range of anxiety, depressive, and psychosomatic symptoms. However, HPPPH were also significantly more likely than other patients to receive excellent emotional health ratings (p < 0.001) from their physicians and were less likely to receive mental health treatment (p < 0.05). Detection of emotional distress may be particularly difficult in physically healthy patients who have low physical health perceptions. Identification of pessimistic physical health perceptions may serve as an indicator for underlying emotional distress.