Pathogenesis of nephrogenic diabetes insipidus by aquaporin-2 C-terminus mutations

Pathogenesis of nephrogenic diabetes insipidus by aquaporin-2 C-terminus mutations.BackgroundWe previously reported three aquaporin-2 (AQP2) gene mutations known to cause autosomal-dominant nephrogenic diabetes insipidus (NDI) (Am J Hum Genet 69:738, 2001). The mutations were found in the C-terminus of AQP2 (721delG, 763 to 772del, and 812 to 818del). The wild-type AQP2 is a 271 amino acid protein, whereas these mutant genes were predicted to encode 330 to 333 amino acid proteins due to the frameshift mutations leading to the creation of a new stop codon 180 nucleotides downstream. The Xenopus oocyte expression study suggested that the trafficking of the mutant AQP2s was impaired.MethodsTo determine the cellular pathogenesis of these NDI-causing mutations in mammalian epithelial cells, Madin-Darby canine kidney (MDCK) cells were stably transfected with the wild-type AQP2, or the 763 to 772del mutant AQP2, or both. Cells were grown on the membrane support to examine the localization of AQP2 proteins by immunofluorescence microscopy.ResultsConfocal immunofluorescence microscopy showed that the wild-type AQP2 was expressed in the apical region, whereas the mutant AQP2 was apparently located at the basolateral region. Furthermore, the wild-type and mutant AQP2s were colocalized at the basolateral region when they were cotransfected, suggesting the formation of mixed oligomers and thereby mistargeting.ConclusionMixed oligomers of the wild-type and the 763 to 772del mutant AQP2s are mistargeted to the basolateral membrane due to the dominant-negative effect of the mutant. This defect is very likely to explain the pathogenesis of autosomal-dominant NDI. The mistargeting of the apical membrane protein to the basolateral membrane is a novel molecular pathogenesis of congenital NDI

Over 10 years follow-up of Coats’ disease in adulthood

Coats’ disease diagnosed in adulthood is rare; therefore, the treatment options and longer clinical course are not well established. We report on two cases of adult onset Coats’ disease, which have been observed for more than 10 years after conventional treatment. In the first case, a 76-year-old man with 9 years of diabetic retinopathy noticed a visual field defect in his left eye. Yellowish subretinal exudation with serous retinal detachment in his superior peripheral retina, and telangiectatic vessels with fluorescein leakage, numerous microaneurysms, and areas of capillary nonperfusion observed in a fluorescein angiography indicated adult Coats’ disease, and retinal photocoagulation was applied. Within 1 year, subretinal exudation was regressed and visual acuity was improved from 20/50 to 20/20, and was maintained for the next 11 years. In the second case, a 71-year-old man presented with decreased vision in his right eye. The fundus of his right eye showed multiple telangiectasic vessels and subretinal exudates extended to the fovea, which is diagnosed as adult Coats’ disease. Despite retinal photocoagulation, an increase of exudation and an enlargement of retinal detachment was observed within 1 month, and subsequently, additional treatment of cryotherapy was performed. Two months after these therapies, the exudation was regressed without retinal detachment, and visual acuity was improved to 20/200 which was maintained for the next 10 years. Even with adult Coats’ disease, conventional therapies of retinal photocoagulation and cryotherapy are effective and are the initial choice for improving or maintaining visual function

Finishing the euchromatic sequence of the human genome

The sequence of the human genome encodes the genetic instructions for human physiology, as well as rich information about human evolution. In 2001, the International Human Genome Sequencing Consortium reported a draft sequence of the euchromatic portion of the human genome. Since then, the international collaboration has worked to convert this draft into a genome sequence with high accuracy and nearly complete coverage. Here, we report the result of this finishing process. The current genome sequence (Build 35) contains 2.85 billion nucleotides interrupted by only 341 gaps. It covers ∼99% of the euchromatic genome and is accurate to an error rate of ∼1 event per 100,000 bases. Many of the remaining euchromatic gaps are associated with segmental duplications and will require focused work with new methods. The near-complete sequence, the first for a vertebrate, greatly improves the precision of biological analyses of the human genome including studies of gene number, birth and death. Notably, the human enome seems to encode only 20,000-25,000 protein-coding genes. The genome sequence reported here should serve as a firm foundation for biomedical research in the decades ahead

Effectiveness of combined thoracoscopic-laparoscopic esophagectomy: comparison of postoperative complications and midterm oncological outcomes in patients with esophageal cancer.

[Background ] : During esophagectomy, laparoscopy can be used together with thoracoscopy, but it is not known whether a combined thoracoscopic–laparoscopic procedure is associated with fewer postoperative complications than open esophagectomy, and without compromising oncological outcome. [Methods ] : This was a longitudinal cohort study that included 185 esophageal cancer patients, including 72 who underwent combined thoracoscopic–laparoscopic esophagectomy (TLE), 34 who underwent thoracoscopic esophagectomy (TE), and 79 who underwent open esophagectomy (OE) between January 2002 and May 2010. The main outcome measures were postoperative respiratory and overall complications. The secondary outcome was 2-year relapse-free survival (RFS). [Results ] : Respiratory complications occurred in 9 patients who underwent TLE, 13 who underwent TE, and 31 who underwent OE. TLE was associated with fewer respiratory complications (TLE vs. OE: odds ratio [OR], 0.22; 95% confidence interval [CI], 0.09–0.53 and TE vs. OE: OR, 0.71; 95% CI 0.29–1.76). Overall complications occurred in 34 patients who underwent TLE, 20 who underwent TE, and 54 who underwent OE. TLE was associated with fewer overall complications (TLE vs. OE: OR, 0.47; 95% CI 0.23–0.94 and TE vs. OE: OR, 0.51; 95% CI 0.21–1.25). The 2-year RFS rates were similar among the three groups: 71.6% for TLE, 57.7% for TE, and 58.3% for OE (TLE vs. OE: hazard ratio, 0.65; 95% CI 0.35–1.20 and TE vs. OE: hazard ratio, 0.91; 95% CI 0.45–1.82). [Conclusion ] : Unlike TE, TLE was associated with fewer postoperative complications than was OE, with no compromise of 2-year RFS. A randomized controlled trial with longer follow-up is needed

Incorporation of apical lymph node status into the seventh edition of the TNM classification improves prediction of prognosis in stage III colonic cancer.

[Background]The node classification outlined in the seventh edition of the TNM classification is based solely on the number of metastasized lymph nodes. This study examined the prognostic value of apical lymph node (ALN) metastasis and the additional value of incorporating ALN status into a risk model based on the seventh edition. [Methods]This was a cohort study of patients with stage III colonic cancer who underwent tumour resection with dissection of regional (including apical) lymph nodes at 71 hospitals across Japan between 2000 and 2002. The main exposure was pathologically confirmed ALN metastasis, and the primary endpoint was cancer-specific death. [Results]ALN metastasis was present in 113 (8·3 per cent) of 1355 patients. During 5356 patient-years of follow-up (median 5·0 years), 221 instances (16·3 per cent) of cancer-specific death were observed. After adjustment for tumour and node classification (as described in the seventh edition of the TNM classification) and other prognostic factors, ALN metastasis was found to be independently associated with cancer-specific death (hazard ratio 2·29, 95 per cent confidence interval (c.i.) 1·49 to 3·52). Incorporation of ALN metastasis into the prognostic model based on the seventh edition of the TNM classification significantly improved discriminative performance for cancer-specific death (difference in concordance index 0·0146, 95 per cent c.i. 0·0030 to 0·0262) and risk reclassification for cancer-specific death at 5 years (category-free net reclassification improvement 19·4 (95 per cent c.i. 5·0 to 33·4) per cent). [Conclusion]Assessment of ALN metastasis provided independent prognostic information beyond that achievable with the seventh edition of the TNM classification in patients with stage III colonic cancer

Evaluation of high temporal resolution magnetic resonance imaging of the liver with gadoxetate disodium in combination with compressed sensing and parallel imaging under single breath-holding using a 1.5-T magnetic resonance system

Abstract Background This study aimed to determine the optimal scan time for high temporal resolution magnetic resonance (MR) imaging of the liver with gadoxetate disodium injection in combination with compressed sensing (CS) and parallel imaging (PI) techniques under single breath-holding using a 1.5-T MR system. Methods Sixty-two participants underwent multiple arterial phases of dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) of the liver with gadoxetate disodium using fat-suppressed GRE T1-weighted imaging—liver acquisition with volume acceleration (LAVA)—in combination with CS and PI using a 1.5-T MR system. Forty-six and 22 participants underwent 6-s and 10-s scans, respectively. Pre-contrast, multiple arterial, portal venous, and hepatobiliary phase images were acquired. Two radiologists evaluated the visual scores for the outline of the liver, inferior right hepatic vein (IRHV), right portal vein, right hepatic artery, appropriateness of the arterial phase, and overall image quality using a 4- or 5-point scale. Results The overall image quality and the image quality of the outline of the liver in the pre-contrast and arterial phases and IRHV in the pre-contrast phase were significantly better (P < 0.05) in the 10-s scan group than those in the 6-s scan group. No significant difference was observed between the two groups in terms of the appropriateness of the arterial phase (obtaining the optimal arterial phase) (P = 0.731). Conclusions A 10-s scan protocol is recommended for high temporal resolution DCE-MRI of the liver with gadoxetate disodium injection in combination with CS and PI under single breath-holding using a 1.5-T MR system