Biomedical subjects
Publications and source records attributed to Brian Little.
On occasion, difficulty will be encountered removing an indwelling urethral catheter. This may be as a consequence of failure of the catheter balloon to deflate. This article reviews the published data on managing the non-deflating Foley catheter balloon, and suggests an evidence-based sequence of interventions to deflate the catheter balloon.
CONTEXT: The central clinical feature of GH insensitivity (GHI) is severe growth failure associated with elevated serum concentrations of GH and abnormally low serum levels of IGF-I. GHI can be the result of an abnormality in the GH receptor or aberrancies downstream of the GH receptor. OBJECTIVE: We investigated the GH-IGF-I axis in a young female GHI subject who presented with a height of 114 cm (-7.8 sd score) at age 16.4 yr. PATIENT: The subject, from a consanguineous pedigree, had circulating levels of GH and GH-binding protein that were normal to elevated, whereas IGF-I (7.2 ng/ml; normal, 242-600), IGF-binding protein-3 (543 ng/ml; normal, 2500-4800), and acid-labile subunit (1.22 microg/ml; normal, 5.6-16) levels were abnormally low and failed to increase during an IGF-I generation test. DESIGN: Dermal fibroblast cultures were established with the consent of the patient and family. Immunoblot analysis of cell lysates and DNA sequencing of her signal transducer and activator of transcription 5b (STAT5b), a critical intermediate of the GH-IGF-I axis, were performed. RESULTS: Sequencing of the STAT5b gene revealed a novel homozygous insertion of a single nucleotide in exon 10. The insertion resulted in a frame shift, leading to early protein termination and consequent lack of immunodetectable STAT5b protein. CONCLUSION: The identification of a second case of severe growth failure associated with STAT5b mutation implicates a unique and critical role for STAT5b in GH stimulation of IGF-I gene expression and statural growth.
Growth hormone insensitivity (GHI) has been attributable, classically, to mutations in the gene for the GH receptor. After binding to the GH receptor, GH initiates signal transduction through a number of pathways, including the JAK-STAT pathway. We describe the first patient reported with a mutation in the gene for STAT5b, a protein critical for the transcriptional regulation of insulin-like growth factor-I.
Biochemical analysis indicates that the STAT-5b mutation affects signaling by both growth hormone (GH) and gamma-interferon. A patient with such a mutation thus manifests two new clinical disorders: (1) growth hormone insensitivity (GHI), which results from a post-receptor defect in GH signaling and (2) a new form of primary immunodeficiency. Given that the GH receptor is a member of the hematopoietin-receptor family, it seems reasonable to predict that additional cases of defects in GH signaling will be identified. The predicted phenotype would be GHI combined with defects in the immune system.
Insulin-like growth factor (IGF)-I, a growth factor important for cell proliferation, cellular differentiation, and multiple metabolic functions, is regulated in vivo by growth factors and cytokines, but the mechanism(s) of regulation at the cellular level is not well understood. We now demonstrate, employing primary human dermal fibroblasts (CF), that the multipotent cytokine, interferon-gamma (IFN-gamma), can up-regulate IGF-I mRNA expression and that this regulation occurs via activation of the signal transducer and activator of transcription-5b (STAT-5b) pathway. IFN-gamma (100 units/ml) treatment of CF cells resulted in a preferential, time-dependent activation of STAT-5b, although both STAT-5a and STAT-5b isoforms are present. The activated STAT-5b translocated to the nucleus within 30 min of treatment and induced an increase in IGF-I mRNA of 6 +/- 1.0-fold, 3 h post-treatment, with a further increase to 8 +/- 1.7-fold at 5 h. In contrast, IFN-gamma treatment of primary human dermal fibroblasts with a nonfunctional STAT-5b (PF cells) resulted in activation of only STAT-5a and an increase of the IGF-I mRNA level of 1.7 +/- 0.6-fold, 5 h post-treatment. The IFN-gamma-induced regulation of the interferon regulatory factor-1 gene, whose expression is dependent on activated STAT-1, was the same between CF and PF cells. In summary, our results provide evidence of the following in human primary dermal fibroblasts: (a). IFN-gamma preferentially activates STAT-5b, but, in the absence of a functional STAT-5b, STAT-5a is activated; (b). IFN-gamma time-dependently up-regulates IGF-I mRNA expression; (c). the regulation of IGF-I requires an active STAT-5b, and activated STAT-5a cannot substitute for an inactive STAT-5b; and (d). STAT-5b has an essential role in the transcriptional up-regulation of IGF-I.
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At present, the gold standard for the detection of bladder carcinoma is cystoscopy, often as part of the investigation of haematuria. There has been substantial research into the development of a non-invasive test for voided urine that would obviate the requirement for flexible cystoscopy. If such a test was 100% sensitive and 100% specific, and was cost-effective, it could represent a way of separating patients who required tumour resection from those with no bladder carcinoma development. This article reviews the development of non-invasive tests for the detection of bladder carcinoma, with emphasis on the most recent developments in fields such as microsatellite analysis, telomerase, and matrix metalloproteinase detection, in addition to the more widely researched tests such as NMP22 and BTA.
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A cohort of 113 patients underwent prospective evaluation with a panel of seven microsatellites, on chromosomes 9, 13 and 17. Thirty-seven patients had histologically confirmed bladder tumors, 53 patients had a history of previous transitional cell carcinoma of the bladder (TCC) but normal cystoscopies (control Group 1), and 23 patients had no previous history of TCC and normal cystoscopies (control Group 2). Urinary DNA was considered to show a deletion if an allele was reduced by more than 50%, and this was considered diagnostic of bladder carcinoma. The sensitivity of the method was 50%, positive predictive value was 80%, and specificity was 93%. Reducing the threshold for defining allelic loss increases sensitivity, but reduces specificity. The concentration of urinary DNA in the sample did not influence detection rate. The grade and stage of the bladder tumor did not influence the likelihood of detection. This method detects bladder carcinoma with high specificity, and increasing the number of microsatellites used should increase sensitivity.