Loss of chloride channel ClC-5 impairs endocytosis by defective trafficking of megalin and cubilin in kidney proximal tubules

Loss of the renal endosome-associated chloride channel, ClC-5, in Dent's disease and knockout (KO) mice strongly inhibits endocytosis of filtered proteins by kidney proximal tubular cells (PTC). The underlying mechanism remains unknown. We therefore tested whether this endocytic failure could primarily reflect a loss of reabsorption by the multiligand receptors, megalin, and cubilin, caused by a trafficking defect. Impaired protein endocytosis in PTC of ClC-5 KO mice was demonstrated by (i) a major decreased uptake of injected 125I-beta 2-microglobulin, but not of the fluid-phase tracer, FITC-dextran, (ii) reduced labeling of endosomes by injected peroxidase and for the endogenous megalin/cubilin ligands, vitamin D- and retinol-binding proteins, and (iii) urinary appearance of low-molecular-weight proteins and the selective cubilin ligand, transferrin. Contrasting with preserved mRNA levels, megalin and cubilin abundance was significantly decreased in kidney extracts of KO mice. Percoll gradients resolving early and late endosomes (Rab5a, Rab7), brush border (villin, aminopeptidase M), and a dense peak comprising lysosomes (acid hydrolases) showed a disappearance of the brush border component for megalin and cubilin in KO mice. Quantitative ultrastructural immunogold labeling confirmed the overall decrease of megalin and cubilin in PTC and their selective loss at the brush border. In contrast, total contents of the rate-limiting endocytic catalysts, Rab5a and Rab7, were unaffected. Thus, impaired protein endocytosis caused by invalidation of ClC-5 primarily reflects a trafficking defect of megalin and cubilin in PTC.     

The inside-out transobturator male sling for the surgical treatment of stress urinary incontinence after radical prostatectomy: midterm results of a single-center prospective study

Background

Transobturator slings are currently promoted for the treatment of stress urinary incontinence (SUI) after radical prostatectomy (RP), but data on outcome remain limited.

Objective

To assess, at midterm, the efficacy and safety of the inside-out transobturator male sling for treating post-RP SUI and to determine factors associated with failure.

Design, setting, and participants

Prospective one-center trial involving 173 consecutive patients without detrusor overactivity, treated between 2006 and 2011 for SUI following RP.

Intervention

Placement of an inside-out transobturator sling.

Measurements

Baseline and follow-up evaluations included uroflowmetry and continence and quality-of-life (QoL) questionnaires. Cure was defined as no pad use and improvement as a number of pads per day reduced by ≥50% and two or fewer pads. Complications were recorded, and factors associated with treatment failure were evaluated.

Results and limitations

Preoperatively, 21%, 35%, and 44% of the patients were using two, three to five, and more than five pads per day, respectively. After a median follow-up of 24 mo (range: 12-60 mo), 49% were cured, 35% improved, and 16% not improved. QoL was enhanced (p < 0.001), and 72% of patients were moderately to completely satisfied with the procedure. Maximum flow rates were slightly reduced (p = 0.004); postvoid residual volumes were similar (p = 0.097). Complications were urinary retention after catheter removal (15%), perineal/scrotal hematoma (9%), pain lasting >6 mo (3%), and sling infection (2%); all were managed conservatively. Severe SUI before sling surgery was not associated with a worse outcome, whereas obesity and a history of pelvic irradiation or bladder neck stenosis were independent risk factors of failure, with risk ratios of 7.9 (95% confidence interval [CI], 3.3-18.9), 3.3 (95% CI, 1.4-7.8), and 2.6 (95% CI, 1.1-6.5), respectively.

Conclusions

The inside-out transobturator male sling is an efficient and safe treatment for post-RP SUI at midterm. Patients with prior pelvic irradiation may not be suitable candidates.     

Debt relief and public health spending in heavily indebted poor countries

The Heavily Indebted Poor Countries (HIPC) Initiative, which was launched in 1996, is the first comprehensive effort by the international community to reduce the external debt of the world's poorest countries. The Initiative will generate substantial savings relative to current and past public spending on health and education in these countries. Although there is ample scope for raising public health spending in heavily indebted poor countries, it may not be advisable to spend all the savings resulting from HIPC resources for this purpose. Any comprehensive strategy for tackling poverty should also focus on improving the efficiency of public health outlays and on reallocating funds to programmes that are most beneficial to the poor. In order to ensure that debt relief increases poverty-reducing spending and benefits the poor, all such spending, not just that financed by HIPC resources, should be tracked. This requires that countries improve all aspects of their public expenditure management. In the short run, heavily indebted poor countries can take some pragmatic tracking measures based on existing public expenditure management systems, but in the longer run they should adopt a more comprehensive approach so as to strengthen their budget formulation, execution, and reporting systems.     

Incidence and risk factors of postoperative stress urinary incontinence following laparoscopic sacrocolpopexy in patients with negative preoperative prolapse reduction stress testing

Introduction and hypothesis

The objectives of this study were to evaluate the incidence of postoperative stress urinary incontinence (SUI) after laparoscopic sacrocolpopexy (LSCP) in women with negative preoperative prolapse reduction stress testing (PPRST) and to identify associated risk factors.

Methods

This was a retrospective cohort study comprising women who consecutively underwent double-mesh LSCP without concomitant SUI surgery after a negative PPRST at a tertiary referral center. Negative PPRST was defined by the absence of SUI during cough testing and urodynamic studies with prolapse reduction.

Results

Fifty-five patients were assessed in the final analysis. No significant complication was encountered during and after LSCP. Mean follow-up was 25?±?11 (range 12–48) months. No patient developed recurrent pelvic organ prolapse (POP) or mesh erosion at last follow-up. Thirty (54.5 %) patients reported the symptom of SUI (subjective SUI) postoperatively, 13 (23.6 %) had a positive cough test (objective SUI) at last visit, and nine (16.4 %) underwent a sling procedure. In univariate analyses, advanced cystocele (stage 3–4) and a history of patient-reported SUI before surgery were associated with a higher risk of postoperative subjective and objective SUI after LSCP. Multivariate analyses identified preoperative SUI as the sole independent predictor of subjective SUI [risk ratio (RR?=?4.03; 95% confidence interval (CI)?=?1.16–14.09), objective SUI, (RR?=?4.67; 95% CI?=?1.14–19.23), and subsequent anti-SUI surgery after LSCP (RR?=?6.17; 95% CI?=?1.30–29.41).

Conclusions

SUI is far from uncommon in women after LSCP despite negative PPRST, especially in those with advanced cystocele and a history of SUI preoperatively; after at least 1 year of follow-up, approximately one in six women eventually underwent a sling surgery. These data are useful for counseling patients.     

Sinonasal involvement as a rare extraintestinal manifestation of Crohn’s disease

Crohn’s disease is a chronic idiopathic slowly developing transmural inflammation of the digestive system. It usually involves the small intestine and/or the area around the anus but can also affect the entire gastrointestinal tract anywhere from the mouth to the anus. Extra intestinal manifestations occur frequently and multiple organ systems may be affected: the skin, joints, spine, eyes, liver and bile ducts. In contrast, nasal manifestations are extremely rare and only a few cases have been reported up to date in the worldwide literature. The authors report two cases with nasal manifestations concomitant to intestinal Crohn’s disease and go over the relevant literature on such an association.     

Spinal Cord Stimulation vs. Conventional Medical Management: A Prospective,Randomized, Controlled,Multicenter Study of Patients with Failed Back Surgery Syndrome (PROCESS Study)

Introduction. Since its first application in 1967, numerous case series indicate that spinal cord stimulation (SCS) is an effective treatment for the management of failed back surgery syndrome (FBSS). However, only one randomized controlled trial has demonstrated that SCS provides more effective pain relief than re‐operation and conventional medical management. The PROCESS randomized, controlled, multicenter trial aims to assess the clinical effectiveness and cost‐effectiveness of SCS when added to conventional medical management compared to conventional medical management alone in patients with FBSS. Methods/Design. A total of 100 FBSS patients with predominantly neuropathic leg pain will be recruited from 12 centers and randomized to receive either conventional medical management alone or in combination with SCS for a period of 24 months. Patients will be evaluated at 1, 3, 6, 9, 12, 18, and 24 months. At the 6‐month visit, patients will be classified as successful (≥  50% pain relief in the legs) or unsuccessful (< 50% pain relief in the legs). If the results of the randomized treatment are unsuccessful, patients can cross over to the alternative treatment arm. Discussion. This paper highlights the rationale, design, methods, and challenges of an ongoing prospective, randomized, controlled, multicenter clinical trial that has been undertaken to obtain conclusive evidence of the clinical efficacy and cost‐effectiveness of an SCS system in patients with FBSS.