42 research outputs found
Novel Mutations In Cyp11b1 Gene Leading To 11β-hydroxylase Deficiency In Brazilian Patients
No full textBackground: Deficiency of 11β-hydroxylase results in the impairment of the last step of cortisol synthesis. In females, the phenotype of this disorder includes different degrees of genital ambiguity and arterial hypertension. Mutations in the CYP11B1 gene are responsible for this disease. Objective: The objective of the study was to screen the CYP11B1 gene for mutations in two unrelated Brazilian females with congenital adrenal hyperplasia due to 11β-hydroxylase deficiency. Design: The coding and intron-exon junction regions of CYP11B1 were totally sequenced. A putative splice mutation was further investigated by minigene transcription. Results: We report two novel CYP11B1 mutations in these Brazilian patients. An Arabian Lebanese descendent female was found to be homozygous for a cytosine insertion at the beginning of exon 8, changing the 404 arginine to proline. It alters the open reading frame, creating a putative truncated protein at 421 residue, which eliminates the domain necessary for the association of heme prosthetic group. A severely virilized female was homozygous for the g.2791G>A transition in the last position of exon 4. This nucleotide is also part of 5′ intron 4 donor splice site consensus sequence. Minigene experiments demonstrated that g.2791G>A activated an alternative splice site within exon 4, leading to a 45-bp deletion in the transcript. The putative translation of such modified mRNA indicates a truncated protein at residue 280. Conclusions: We describe two novel mutations, g.4671-4672insC and g.2791G>A, that drastically affects normal protein structure. These mutations abolish normal enzyme activity, leading to a severe phenotype of congenital adrenal hyperplasia due to 11β-hydroxylase deficiency. Copyright © 2009 by The Endocrine Society.94934813485White, P.C., Curnow, K.M., Pascoe, L., Disorders of steroid 11β- hydroxylase isoenzymes (1994) Endocr Rev, 15, pp. 421-438White, P.C., Speiser, P.W., Congenital adrenal hyperplasia due to 21-hydroxylase deficiency (2000) Endocrine Reviews, 21 (3), pp. 245-291. , DOI 10.1210/er.21.3.245Mornet, E., Dupont, J., Vitek, A., White, P.C., Characterization of two genes encoding human steroid 11β-hydroxylase (P-450(11β)) (1989) Journal of Biological Chemistry, 264 (35), pp. 20961-20967Spoudeas, H.A., Slater, J.D., Rumsby, G., Honour, J.W., Brook, C.G., Deoxycorticosterone, 11β-hydroxylase and the adrenal cortex (1993) Clin Endocrinol, 39, pp. 245-251. , OxfHague, W., Honour, J., Malignant hypertension in congenital adrenal hyperplasia due to 11β-hydroxylase deficiency (1983) Clin Endocrinol, 18, pp. 505-510. , OxfKrawczak, M., Cooper, D.N., The human gene mutation database (1997) Trends Genet, 13, pp. 121-122Chabre, O., Portrat-Doyen, S., Vivier, J., Morel, Y., Defaye, G., Two novel mutations in splice donor sites of CYP11B1 in congenital adrenal hyperplasia due to 11β-hydroxylase deficiency (2000) Endocrine Res, 26, pp. 797-801Curnow, K.M., Slutsker, L., Vitek, J., Cole, T., Speiser, P.W., New, M.I., White, P.C., Pascoe, L., Mutations in the CYP11B1 gene causing congenital adrenal hyperplasia and hypertension cluster in exons 6, 7, and 8 (1993) Proc Natl Acad Sci USA, 90, pp. 4552-4556Skinner, C.A., Rumsby, G., Honour, J.W., Single strand conformation polymorphism (SSCP) analysis for the detection of mutations in the CYP11B1 gene (1996) Journal of Clinical Endocrinology and Metabolism, 81 (6), pp. 2389-2393. , DOI 10.1210/jc.81.6.2389De Carvalho, C.E., Castro, M., Moreira, A.C., De Mello, M.P., CYP11B1 mutation and polymorphisms in congenital adrenal hyperplasia due to 11β-hydroxylase deficiency (1999) J Endocr Genet, 1, pp. 79-86Moreira, A.C., Elias, L.L.K., Pituitary-adrenal responses to corticotropin- releasing hormone in different degrees of adrenal 21-hydroxylase deficiency (1992) J Clin Endocrinol Metab, 74, pp. 198-203Mermejo, L.M., Elias, L.L.K., Marui, S., Moreira, A.C., Mendonca, B.B., De Castro, M., Refining hormonal diagnosis of type II 3β-hydroxysteroid dehydrogenase deficiency in patients with premature pubarche and hirsutism based on HSD3B2 genotyping (2005) Journal of Clinical Endocrinology and Metabolism, 90 (3), pp. 1287-1293. , DOI 10.1210/jc.2004-1552De-Araujo, M., Sanches, M.R., Suzuki, L.A., Guerra Jr., G., Farah, S.B., De-Mello, M.P., Molecular analysis of CYP21 and C4 genes in Brazilian families with the classical form of steroid 21-hydroxylase deficiency (1996) Brazilian Journal of Medical and Biological Research, 29 (1), pp. 1-13Soardi, F.C., Lemos-Marini, S.H.V., Coeli, F.B., Maturana, V.G., Silva, M.D., Bernardi, R.D., Justo, G.Z., De Mello, M.P., Heterozygosis for CYP21A2 mutation considered as 21-hydroxylase deficiency in neonatal screening (2008) Arq Bras Endocrinol Metab, 52, pp. 1388-1392White, P.C., Slutsker, L., Haplotype analysis of CYP11B2 (1995) Endocr Res, 21, pp. 437-442Ravichandran, K.G., Boddupalli, S.S., Hasemann, C.A., Peterson, J.A., Deisenhofer, J., Crystal structure of hemoprotein domain of P450BM-3, a prototype for microsomal P450's (1993) Science, 261 (5122), pp. 731-736Roumen, L., Sanders, M.P.A., Pieterse, K., Hilbers, P.A.J., Plate, R., Custers, E., De Gooyer, M., Hermans, J.J.R., Construction of 3D models of the CYP11B family as a tool to predict ligand binding characteristics (2007) Journal of Computer-Aided Molecular Design, 21 (8), pp. 455-471. , DOI 10.1007/s10822-007-9128-9Mount, S.M., A catalogue of splice junction sequences (1982) Nucleic Acids Res, 10, pp. 459-472Buratti, E., Chivers, M., Královicová, J., Romano, M., Baralle, M., Krainer, A.R., Vorechovsky, I., Aberrant 5′ splice sites in human disease genes: Mutation pattern, nucleotide structure and comparison of computational tools that predict their utilization (2007) Nucleic Acids Res, 35, pp. 4250-426
A Systematic Review of Pathogenic COL4A5 Variants and Proteinuria in Women and Girls With X-linked Alport Syndrome
No full textINTRODUCTION: Women and girls with X-linked Alport syndrome have a risk of disease progression that is difficult to predict. This systematic review examined whether proteinuria correlated with genotype and disease severity in this population. METHODS: PubMed and Scopus were searched for manuscripts from the past 20 years with "COL4A5," "female," "proteinuria" and related terms. Genotypes and clinical data for women and girls with pathogenic heterozygous COL4A5 variants were extracted. Features were then compared between females with proteinuria or without proteinuria; and genotype-phenotype correlations for age at proteinuria and kidney failure determined. RESULTS: Three-hundred sixty-six women and girls with COL4A5 variants and a median age of 29 years (interquartile range 15-46) were identified. Eighty-eight (24%) had large rearrangements or truncating variants, 63 (17%) had splicing variants, and 215 (59%) had missense changes. In all, 236 (64%) had proteinuria, 56 (16%) had kidney failure, 40 (16%) had a hearing loss, and 15 (7%) had ocular abnormalities. Women and girls with proteinuria were more likely to have large rearrangements or truncating variants (P = 0.005), and less likely to have missense changes (P = 0.0002). Those with proteinuria were also more likely to develop kidney failure (P < 0.0001). Women and girls with truncating, large or splicing variants developed proteinuria earlier than those with missense changes (P = 0.001, P < 0.0001 respectively). Those whose proteinuria was detected before the age of 15 progressed to kidney failure sooner (P < 0.0001). CONCLUSION: Proteinuria correlates with a more severe genotype in women and girls with X-linked Alport syndrome and is an indicator of disease severity and likely progression
Multimodal CEA-Targeted Image-Guided Colorectal Cancer Surgery using In-111-Labeled SGM-101
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228440.pdf (Publisher’s version ) (Open Access
Parathyroid hormone(1-34) and parathyroid hormone-related protein(1-34) stimulate calcium release from human syncytiotrophoblast basal membranes via a common receptor
No full textBlood lead levels in the adult Victorian population: results from the Victorian Health Monitor
No full textWide variation in tissue, systemic, and drain fluid exposure after oxaliplatin-based HIPEC: results of the GUTOX study
No full textPURPOSE: In this exploratory study, the effect of postprocedural flushing with crystalloids after oxaliplatin-based hyperthermic intraperitoneal chemotherapy (HIPEC) on platinum concentrations in peritoneal tissue, blood, and drain fluid was studied. Interpatient variability in oxaliplatin pharmacokinetics and the relation between platinum concentration in peritoneal fluid and platinum exposure in tissue and blood was explored. METHODS: Ten patients with peritoneal carcinomatosis of colorectal origin were treated with HIPEC including postprocedural flushing, followed by ten patients without flushing afterwards. Tissue, peritoneal fluid, blood, and drain fluid samples were collected for measurement of total and ultrafiltered platinum concentrations. RESULTS: Peritoneal tissue concentration and systemic ultrafiltered platinum exposure showed large inter individual variability, ranging from 65 to 1640 µg/g dry weight and 10.5 to 28.0 µg*h/ml, respectively. No effect of flushing was found on geometric mean platinum concentration in peritoneal tissue (348 vs. 356 µg/g dry weight), blood (14.8 vs. 18.1 µg*h/ml), or drain fluid (day 1: 7.6 vs. 7.7 µg/ml; day 2: 1.7 vs. 1.9 µg/ml). The platinum concentration in peritoneal fluid at the start of HIPEC differed twofold between patients and was positively correlated with systemic exposure (p = .04) and peak plasma concentration (p = .04). CONCLUSION: In this exploratory study, no effect was found for postprocedural flushing on platinum concentrations in peritoneal tissue, blood, or drain fluid. BSA-based HIPEC procedure leads to large interpatient variability in platinum exposure in all compartments. The study was registered at ClinicalTrials.gov on 7 December 2017 under registration number NCT03364907
Blood lead levels in the adult Victorian population: results from the Victorian Health Monitor
No full textAbstract Objective : To estimate blood lead levels (BLLs) in the adult Victorian population and compare the distribution of BLLs with the current national reference level to better inform public health prevention and management of lead toxicity. Methods : Population‐based cross‐sectional health measurement survey of 50 randomly selected Census Collection Districts (CDs) throughout Victoria. The Victorian Health Monitor (VHM) was conducted over 12 months from May 2009 to April 2010. One eligible person (aged 18–75 years) from each household selected within each CD was randomly selected to participate. Persons with an intellectual disability and pregnant women were excluded from the sampling frame. BLLs were obtained from 3,622 of the 3,653 (99%) VHM participants. Results : The geometric mean and median BLLs from the adult sample were 0.070 μmol/L (95%CI, 0.068–0.073) and 0.05 μmol/L (range: 0.05 to 1.22 μmol/L), respectively. Elevated BLLs (≥0.483 μmol/L or ≥10 μg/dL) were identified in 19 participants (0.7%; 95%CI, 0.3–1.6). Additionally, 86 participants (1.8%; 95%CI, 1.3–2.4) were identified with BLLs between 0.242 and <0.483 μmol/L (5 to <10 μg/dL). The geometric mean BLL was significantly higher for males, compared with females (0.077 μmol/L vs 0.064 μmol/L; p<0.001). BLLs increased significantly with age for both sexes. Conclusions : The first population estimates of BLLs in Victorian adults indicate the average adult BLL to be well below the current national reference level. However, some groups of the population have BLLs at which adverse effects may occur. Implications : The results provide baseline estimates for future population health surveillance and comparison with studies of at‐risk groups
The effect of IFN-? alum and complete Freund adjuvant on TNP-KLH induced IgG1, IgE and IgG2a responses in mice
No full textRandomised phase III study of biweekly 24-h infusion of high-dose 5FU with folinic acid and oxaliplatin versus monthly plus 5-FU/folinic acid in first-line treatment of advanced colorectal cancer
No full textBackground: A phase III study was started to compare oxaliplatin/5FU/LV in the first-line with bolus FU/LV in metastatic colorectal cancer. Patients and methods: 302 patients were randomised and received bolus 5-FU 425 mg/m(2) day 1-5, FA 20 mg/m(2) day 1-5, q 4 wk or oxaliplatin 85 mg/m(2), 2 h-infusion, FA 200 mg/m(2), 1-h infusion. 5-FU 2600 mg/m(2), 24-h infusion day 1, q 2 wk. The primary endpoint was response rate (RR). Results: The median follow-up is 31.8 months, 90.4% of the patients have died. Confirmed RR, progression free survival (PFS; months) and median overall survival (OS; months) in 5FU/LV versus 5FU/LV/oxaliplatin were respectively 18.5% versus (vs) 33.8% (P = 0.004), 5.6 vs 6.7 (P = 0.016) and 13.3 vs 13.8 (P = 0.619). In the 5FU/LV/oxaliplatin arm less grade 3/4 toxicity was measured for diarrhoea, stomatitis, an increase in idiosyncratic side effects and neurosensory events compared with 5FU/LV. The quality of life (QOL) was equal in both arms. Second line treatment was given in 62% of the patients, crossover of 5FU/LV to 5FU/LV/oxaliplatin occurred in 14%. Conclusions: Oxaliplatin in the first-line resulted in an increased RR and PFS with less grade 3/4 mucositis/diarrhoea compared with 5FU/LV alone. Idiosyncratic side effects deserve attention with oxaliplatin. Despite a low treatment cross over rate, OS in both groups was comparable
