Esrrg functions in early branch generation of the ureteric bud and is essential for normal development of the renal papilla

Congenital anomalies of the kidney and urinary tract (CAKUTs) are common disorders of human development affecting the renal parechyma, renal pelvis, ureter, bladder and urethra; they show evidence of shared genetic aetiology, although the molecular basis of this remains unknown in the majority of cases. Breakpoint mapping of a de novo, apparently balanced, reciprocal translocation associated with bilateral renal agenesis has implicated the gene encoding the nuclear steroid hormone receptor ESRRG as a candidate gene for CAKUT. Here we show that the Esrrg protein is detected throughout early ureteric ducts as cytoplasmic/sub-membranous staining; with nuclear localization seen in developing nephrons. In 14.5–16.5 dpc (days post-conception) mouse embryos, Esrrg localizes to the subset of ductal tissue within the kidney, liver and lung. The renal ductal expression becomes localized to renal papilla by 18.5 dpc. Perturbation of function was performed in embryonic mouse kidney culture using pooled siRNA to induce knock-down and a specific small-molecule agonist to induce aberrant activation of Esrrg. Both resulted in severe abnormality of early branching events of the ureteric duct. Mouse embryos with a targeted inactivation of Esrrg on both alleles (Esrrg−/−) showed agenesis of the renal papilla but normal development of the cortex and remaining medulla. Taken together, these results suggest that Esrrg is required for early branching events of the ureteric duct that occur prior to the onset of nephrogenesis. These findings confirm ESRRG as a strong candidate gene for CAKUT

Persistent demographic differences in colorectal cancer screening utilization despite Medicare reimbursement

BACKGROUND: Colorectal cancer screening is widely recommended, but often under-utilized. In addition, significant demographic differences in screening utilization exist. Insurance coverage may be one factor influencing utilization of colorectal cancer screening tests. METHODS: We conducted a retrospective analysis of claims for outpatient services for Washington state Medicare beneficiaries in calendar year 2000. We determined the proportion of beneficiaries utilizing screening fecal occult blood tests, flexible sigmoidoscopy, colonoscopy, or double contrast barium enema in the overall population and various demographic subgroups. Multiple logistic regression analysis was used to determine the relative odds of screening in different demographic groups. RESULTS: Approximately 9.2% of beneficiaries had fecal occult blood tests, 7.2% had any colonoscopy, flexible sigmoidoscopy, or barium enema (invasive) colon tests, and 3.5% had invasive tests for screening indications. Colonoscopy accounted for 41% of all invasive tests for screening indications. Women were more likely to receive fecal occult blood test screening (OR 1.18; 95%CI 1.15, 1.21) and less likely to receive invasive tests for screening indications than men (OR 0.80, 95%CI 0.77, 0.83). Whites were more likely than other racial groups to receive any type of screening. Rural residents were more likely than urban residents to have fecal occult blood tests (OR 1.20, 95%CI 1.17, 1.23) but less likely to receive invasive tests for screening indications (OR 0.89; 95%CI 0.85, 0.93). CONCLUSION: Reported use of fecal occult blood testing remains modest. Overall use of the more invasive tests for screening indications remains essentially unchanged, but there has been a shift toward increased use of screening colonoscopy. Significant demographic differences in screening utilization persist despite consistent insurance coverage

Serum CD26 is related to histopathological polyp traits and behaves as a marker for colorectal cancer and advanced adenomas

<p>Abstract</p> <p>Background</p> <p>Serum CD26 (sCD26) levels were previously found diminished in colorectal cancer (CRC) patients compared to healthy donors, suggesting its potential utility for early diagnosis. Therefore we aimed to estimate the utility of the sCD26 as a biomarker for CRC and advanced adenomas in a high-risk group of patients. The relationship of this molecule with polyp characteristics was also addressed.</p> <p>Methods</p> <p>sCD26 levels were measured by ELISA in 299 symptomatic and asymptomatic patients who had undergone a colonoscopy. Patients were diagnosed as having no colorectal pathology, non-inflammatory or inflammatory bowel disease, polyps (hyperplastic, non-advanced and advanced adenomas) or CRC.</p> <p>Results</p> <p>At a 460 ng/mL cut-off, the sCD26 has a sensitivity and specificity of 81.8% (95% CI, 64.5-93.0%) and 72.3% (95% CI, 65.0-77.2%) for CRC regarding no or benign colorectal pathology. Clinicopathological analysis of polyps showed a relationship between the sCD26 and the grade of dysplasia and the presence of advanced adenomas. Hence, a 58.0% (95% CI, 46.5-68.9%) sensitivity detecting CRC and advanced adenomas was obtained, with a specificity of 75.5% (95% CI, 68.5-81.0%).</p> <p>Conclusions</p> <p>Our preliminary results show that measurement of the sCD26 is a non-invasive and reasonably sensitive assay, which could be combined with others such as the faecal occult blood test for the early diagnosis and screening of CRC and advanced adenomas. Additional comparative studies in average-risk populations are necessary.</p

Diagnosis of pancreaticobiliary malignancy by detection of minichromosome maintenance protein 5 in bile aspirates

Biliary brush cytology is the standard method of sampling a biliary stricture but has a low sensitivity for the detection of malignancy. We have previously shown that minichromosome maintenance (MCM) replication proteins (Mcm2–7) are markers of dysplasia and have utilised these novel biomarkers of growth for the diagnosis of cervical and bladder cancer. We aimed to determine if MCM proteins are dysregulated in malignant pancreaticobiliary disease and if levels in bile are a sensitive marker of malignancy. In 30 tissue specimens from patients with malignant/benign biliary strictures, we studied Mcm2 and -5 expression by immunohistochemistry. Bile samples were also collected prospectively at endoscopic retrograde cholangiopancreatography from 102 consecutive patients with biliary strictures of established (n=42) or indeterminate aetiology (n=60). Patients with indeterminate strictures also underwent brush cytology as part of standard practice. Bile sediment Mcm5 levels were analysed using an automated immunofluorometric assay. In benign biliary strictures, Mcm2 and -5 protein expression was confined to the basal epithelial proliferative compartment – in contrast to malignant strictures where expression was seen in all tissue layers. The percentage of nuclei positive for Mcm2 was higher in malignant tissue (median 76.5%, range 42–92%) than in benign tissue (median 5%, range 0–33%) (P<0.0005), with similar results for Mcm5. Minichromosome maintenance protein 5 levels in bile were significantly more sensitive than brush cytology (66 vs 20%; P=0.004) for the detection of malignancy in patients with an indeterminate stricture, with a comparable positive predictive value (97 vs 100%; P=ns). In this study, we demonstrate that Mcm5 in bile detected by a simple automated test is a more sensitive indicator of pancreaticobiliary malignancy than routine brush cytology

Phenotypic Consequences of Copy Number Variation: Insights from Smith-Magenis and Potocki-Lupski Syndrome Mouse Models

The characterization of mice with different number of copies of the same genomic segment shows that structural changes influence the phenotypic outcome independently of gene dosage