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

BACKGROUND: We 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. METHODS: To 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. RESULTS: Confocal 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. CONCLUSION: Mixed 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.     

Outcomes and surgical therapeutic index of Burch colposuspension in stress urinary incontinence

OBJECTIVE: To apply the new concept of a surgical therapeutic index to patients who suffer from stress urinary incontinence using the cure rate and complication rates of Burch colposuspension and to develop a preoperative counseling tool and objective comparison tool for the many surgical procedures that have been described. STUDY DESIGN: We reviewed the case histories of 22 patients between March 1999 and March 2000 who had stress urinary incontinence and underwent Burch colposuspension and in whom the diagnosis of stress urinary incontinence was made using urodynamic studies and the cotton-tipped-swab test. The surgical therapeutic index was then calculated using the median percentage cure rate and complication rate. RESULTS: The surgical cure rates were 81.8%, 81.8%, 90.9%, 90.9%, 95.4% and 95.4% at postoperative 1st, 3rd, 5th, 7th, 9th and 12th month, respectively, and the surgical complication rates were 69%, 36%, 31.5%, 27%, 22.5% and 27%. The surgical therapeutic indices for each postoperative period were 1.19, 2.27, 2.89, 3.37, 4.24 and 3.53, respectively. The surgical cure rate for Burch colposuspension in stress urinary incontinence was 95.4% 1 year after surgery, and the surgical therapeutic index 1 month and 1 year after surgery was 1.19 and 3.53, respectively. CONCLUSION: Burch colposuspension is a relatively effective and safe surgical procedure for managing stress urinary incontinence.     

Complete remission of esophageal undifferentiated carcinoma with nedaplatin and 5-FU chemotherapy and endoesophageal brachytherapy

The patient was a 74-year-old female. Type 1 undifferentiated carcinoma (non-small cell type) was detected in the middle of the thoracic esophagus in August 1999. Although the lesion was diagnosed as T2, N0, and Stage II, the patient was judged to be a poor risk, inoperable case because of a complex past history of renal and respiratory dysfunctions, and dysbasia. Intravenous administration of nedaplatin at 15.8 mg/m2 and 5-FU 590.6 mg/m2 were carried out for 5 consecutive days as chemotherapy. The second cycle of chemotherapy was performed with nedaplatin reduced to 11.8 mg/m2 on the basis of the adverse reactions observed after the first cycle, and PR was attained. As for radiotherapy, additional extracorporeal irradiation was judged to be too dangerous from her history, so endoesophageal brachytherapy alone was added, and CR was obtained. The patient has maintained a CR for more than 2 years after discharge. In this poor risk case with a highly malignant undifferentiated carcinoma, an "individualization strategy" was effective.     

Prenatal exposure to alcohol alters the light response in postnatal circadian rhythm

We studied the effect of prenatal exposure to alcohol on later circadian rhythm in the rat. In the normal light-dark cycle, an 8-h phase advance brought forward the deep body temperature rhythm in control rats, although it had a smaller effect in prenatally ethanol-exposed rats. In long constant darkness, the phase response of the deep body temperature rhythm to a light pulse at the early subjective night was less marked in ethanol-exposed rats in comparison to controls. These results indicate that prenatal exposure to alcohol has a long-lasting effect on the light responsiveness of the deep body temperature circadian rhythm.     

A case of Beh?et's disease with Weber's syndrome

A case of Beh?et's disease with right hemiplegia and left oculomotor nerve involvement is described. Computed tomography of the brain with or without contrast, and nuclear magnetic resonance demonstrated a low attenuation mass lesion in the right mid brain. Lumbar puncture revealed there was moderate leukocytosis in the cerebrospinal fluid. Corticosteroids seemed effective in reducing her clinical symptoms, and our patient started walking one week after taking 50 mg of prednisolone. This case of neuro-Beh?et's disease is the first with Weber's syndrome with documentation of the lesion by means of nuclear magnetic resonance.     

Chromosomal aberrations in tracheal epithelial cells of the fetal Syrian golden hamster after transplacental N-diethylnitrosamine administration

Transplacental effect of N-diethylnitrosamine (DEN) on chromosomal morphology, was investigated in fetal tracheal epithelium of Syrian hamsters. At the 15th day of pregnancy, Syrian golden hamster were injected subcutaneously with a tumorigenic dose fo DEN (50, 100 and 200 mg/kg body wt). Two hours later, the fetal tracheae were isolated, epithelial cells of the respiratory mucosa were separated from mesenchymal tissue and were transferred to cell culture. At 24, 48 and 72 h acter cultivation, chromosomal damages were examined. The results showed clearly that a high incidence of chromosomal aberrations, particularly chromatid-type exchanges, were seen in the epithelial cells from DEN-treated groups.     

Comparison of outcomes between Burch colposuspension with and without concomitant abdominal hysterectomy

A total abdominal hysterectomy may cause a postoperative vesicourethral dysfunction due to an injury to the pelvic nerves. However, many incontinent women with benign diseases of the uterus and its adnexae have undergone a Burch colposuspension with a concomitant abdominal hysterectomy. This study was undertaken to compare the outcomes of a Burch colposuspension performed alone with that of a Burch with a concomitant abdominal hysterectomy. This study included 132 women, who, were treated for primary urinary incontinence from February 1999 to February 2002 and were diagnosed with stress urinary incontinence by means of the urodynamic test at the Department of Obstetrics and Gynecology at Yonsei University Hospital. Forty-two women underwent a Burch colposuspension alone (Burch group) and 90 women underwent a Burch colposuspension with a concomitant abdominal hysterectomy (hysterectomy group). Between the Burch and hysterectomy groups, the mean age, parity, menopausal rate, Hormone Replacement Therapy (HRT) rate, 1 year follow-up outcomes and postoperative complications were compared using the subjective and objective stress tests according to the retrospective chart review. The mean age (54.6 +/- 0.5 vs 58.6 +/- 9.2 years, p=0.382), parity (3.3 +/- 1.2 vs 3.6 +/- 1.7), menopausal rate (71.4 vs 77.7%), or HRT rate (23.3 vs 11.2%) of the two groups were similar. Complications related to surgery were encountered in 5 patients (11.9%) in the Burch group and in 7 patients (7.8%) in the hysterectomy group (p=0.842). One year follow-up subjective symptoms were encountered in 2 patients in the Burch group and in 4 patients in the hysterectomy group (p=1.00). The stress test was positive in only one patient in the hysterectomy (p=1.00). No significant difference was observed in the 1 year follow-up outcomes, which were 91.4% (32/35 patients) in the Burch and 91.2% (73/80) in the hysterectomy groups. The results showed that there were no adverse effects on the 1 year follow-up outcomes or complications in patients who underwent a Burch colposuspension with an abdominal hysterectomy.