Engagement of transferrin receptor by polymeric IgA1: evidence for a positive feedback loop involving increased receptor expression and mesangial cell proliferation in IgA nephropathy

IgA nephropathy (IgAN), the most common primary glomerulonephritis in the world, is characterized by IgA immune complex-mediated mesangial cell proliferation. The transferrin receptor (TfR) was identified previously as an IgA1 receptor, and it was found that, in biopsies of patients with IgAN, TfR is overexpressed and co-localizes with IgA1 mesangial deposits. Here, it is shown that purified polymeric IgA1 (pIgA1) is a major inducer of TfR expression (three- to four-fold increase) in quiescent human mesangial cells (HMC). IgA-induced but not cytokine-induced HMC proliferation is dependent on TfR engagement as it is inhibited by both TfR1 and TfR2 ectodomains as well as by the anti-TfR mAb A24. It is dependent on the continued presence of IgA1 rather than on soluble factors released during IgA1-mediated activation. In addition, pIgA1-induced IL-6 and TGF-beta production from HMC was specifically inhibited by mAb A24, confirming that pIgA1 triggers a TfR-dependent HMC activation. Finally, upregulation of TfR expression induced by sera from patients with IgAN but not from healthy individuals was dependent on IgA. It is proposed that deposited pIgA1 or IgA1 immune complexes could initiate a process of auto-amplification involving hyperexpression of TfR, allowing increased IgA1 mesangial deposition. Altogether, these data unveil a functional cooperation between pIgA1 and TfR for IgA1 deposition and HMC proliferation and activation, features that are commonly implicated in the chronicity of mesangial injuries observed in IgAN and that could explain the recurrence of IgA1 deposits in the mesangium after renal transplantation.     

Possibilities and limitations of fibrin glue usage in nephron-sparing surgery: experimental study

INTRODUCTION: The possibilities and limitations of fibrin glue (FG) usage in nephron-sparing surgery were studied. MATERIALS AND METHODS: A prospective experimental study was carried out in 50 pigs: 30 with polar resection, and 20 with mediorenal wedge resection of the kidney. Hemostatic sutures, FG, and FG with a muscle 'cup' in animals with polar resection of the kidney were compared. FG and sutures in animals with the wedge resection of the kidney were studied as well. Bleeding, hot ischemia time, complication rate, and additional scarring were also analyzed. RESULTS: Suture hemostasis is safe but with significant adverse effects in both polar and wedge resection of kidney. FG was not efficient as a sole hemostatic agent for polar resection. It was as efficient as hemostatic suture for wedge resection of the kidney. FG with a muscle 'cup' on a pole of the kidney achieved good results in animals with polar resection of the kidney. Histological analysis confirmed better results with FG because of both the less intense and smaller area of additional scarring. CONCLUSION: FG is a reliable and efficient hemostatic agent for nephron-sparing surgery whenever both sided gluing is possible.     

Carnosine as a protective factor in diabetic nephropathy: association with a leucine repeat of the carnosinase gene CNDP1

The risk of diabetic nephropathy is partially genetically determined. Diabetic nephropathy is linked to a gene locus on chromosome 18q22.3-q23. We aimed to identify the causative gene on chromosome 18 and to study the mechanism by which the product of this gene could be involved in the development of diabetic nephropathy. DNA polymorphisms were determined in 135 case (diabetic nephropathy) and 107 control (diabetes without nephropathy) subjects. The effect of carnosine on the production of extracellular matrix components and transforming growth factor-beta (TGF-beta) after exposure to 5 and 25 mmol/l d-glucose was studied in cultured human podocytes and mesangial cells, respectively. A trinucleotide repeat in exon 2 of the CNDP1 gene, coding for a leucine repeat in the leader peptide of the carnosinase-1 precursor, was associated with nephropathy. The shortest allelic form (CNDP1 Mannheim) was more common in the absence of nephropathy (P = 0.0028, odds ratio 2.56 [95% CI 1.36-4.84]) and was associated with lower serum carnosinase levels. Carnosine inhibited the increased production of fibronectin and collagen type VI in podocytes and the increased production of TGF-beta in mesangial cells induced by 25 mmol/l glucose. Diabetic patients with the CNDP1 Mannheim variant are less susceptible for nephropathy. Carnosine protects against the adverse effects of high glucose levels on renal cells.     

Photodynamic inactivation of pathogenic species <Emphasis Type="Italic">Pseudomonas aeruginosa</Emphasis> and <Emphasis Type="Italic">Candida albicans</Emphasis> with lutetium (III) acetate phthalocyanines and specific light irradiation

Photodynamic inactivation (PDI) is a light-associated therapeutic approach suitable for treatment of local acute infections. The method is based on specific light-activated compound which by specific irradiation and in the presence of molecular oxygen produced molecular singlet oxygen and other reactive oxygen species, all toxic for pathogenic microbial cells. The study presents photodynamic impact of two recently synthesized water-soluble cationic lutetium (III) acetate phthalocyanines (LuPc-5 and LuPc-6) towards two pathogenic strains, namely, the Gram-negative bacterium Pseudomonas aeruginosa and a fungus Candida albicans. The photodynamic effect was evaluated for the cells in suspensions and organized in 48-h developed biofilms. The relatively high levels of uptakes of LuPc-5 and LuPc-6 were determined for fungal cells compared to bacterial cells. The penetration depths and distribution of both LuPcs into microbial biofilms were investigated by means of confocal fluorescence microscopy. The photoinactivation efficiency was studied for a wide concentration range (0.85–30 μM) of LuPc-5 and LuPc-6 at a light dose of 50 J cm^?2 from red light-emitting diode (LED; 665 nm). The PDI study on microbial biofilms showed incomplete photoinactivation (<3 logs) for the used gentle drug-light protocol.     

Predictors and outcomes of unplanned early rehospitalization in the first year following lung transplantation

Unplanned early rehospitalization (UER), defined as an unscheduled admission within 30 days of a hospital discharge, is associated with graft loss and recipient mortality in some solid organ transplants but has not been investigated in lung transplant. In this retrospective study, we collected socio‐demographic and clinical factors to determine predictors and outcomes of UER in the first year following lung transplantation. There were 193 patients who underwent lung transplantation and survived to discharge during the 7.9‐year study period. There were 116 (60.1%) patients with at least one UER. Infections (32.8%) and post‐surgical complications (11.8%) were the most common reasons for UER. On multivariate analysis, the strongest predictor of having an UER was discharge to a long‐term acute care facility (odds ratio: 3.01, 95% confidence interval [CI] 1.46–6.20; P=.003). Patients with any UER in the first year following transplantation had worse adjusted survival (hazard ratio: 1.89, 95% CI 1.02–3.50; P=.04). It is unclear, however, to what extent UERs reflect preventable outcomes. Further large‐scale, prospective research is needed to identify the extent to which certain types of UER are modifiable and to define patients at high‐risk for preventable UER.     

Head‐locking durability of fixed and variable angle locking screws under repetitive loading

Polyaxial locking screws are increasingly applied in fracture fixation. To investigate the durability of the head‐locking mechanism, the removal torque of variable angle (VA) and fixed angle (FA) stainless steel and titanium locking screws was investigated without and after a cyclic loading test. Stainless steel (St) and titanium (Ti) 2.4 mm orthogonally inserted FA screws and 2.4 mm VA screws inserted in different inclinations (0°–15°) (n = 6 per group) were locked at 0.8 Nm. Removal torque was determined without (W) and after (A) cyclic loading (sinusoidal load, 5 Hz, constant amplitude of 25 N, up to 10′000 cycles, or failure). Significant differences in‐between the groups were detected by Student's t‐test (p < 0.05). Except VA Ti in 0deg and FA, all groups exhibited a drop in removal torque below the insertion torque without and after cyclic testing. The removal torque was (St: FA W:0.81 Nm ± 0.04 A:0.72Nm ± 0.04; VA0deg W:0.73 Nm ± 0.04 A:0.65 Nm ± 0.05; VA15deg W:0.51 Nm ± 0.05 A:0.50 Nm ± 0.08; Ti: FA W:0.82 Nm ± 0.03 A:0.70 Nm ± 0.04; VA0deg W:0.80 Nm ± 0.02 A:0.72 Nm ± 0.05; VA15deg W:0.55 Nm ± 0.03 A:0.54 Nm ± 0.06). In all groups, the removal torque after cyclic testing did not drop below 16% of the removal torque without cyclic testing. No head loosening was observed after cyclic testing. Stainless steel and titanium 2.4 mm fixed and variable angle locking screws provide a stable and lasting head‐locking mechanism. © 2015 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 34:949–952, 2016.     

Sexual satisfaction of women partners of circumcised men in a randomized trial of male circumcision in Rakai,Uganda

OBJECTIVE

To investigate the effect of adult medical male circumcision on female sexual satisfaction.

SUBJECTS AND METHODS

We investigated self‐reported sexual satisfaction among 455 women partners of men circumcised in a randomized trial of male circumcision for the prevention of human immunodeficiency virus in Rakai, Uganda. Women aged 15–49 years were interviewed about their sexual satisfaction before and after their partners were circumcised. We analysed female‐reported changes in sexual satisfaction using chi‐square or Fisher’s exact tests.

RESULTS

Only 2.9% (13/455) of women reported less sexual satisfaction after their partners were circumcised; 57.3% (255/455) reported no change in sexual satisfaction and 39.8% (177/455) reported an improvement in sexual satisfaction after their partner’s circumcision. There were no statistically significant differences in sexual satisfaction before and after partner’s circumcision by age, religion and education status.

CONCLUSION

The overwhelming majority of women (97.1%) report either no change or improved sexual satisfaction after their male partner was circumcised. These findings suggest that male circumcision has no deleterious effect on female sexual satisfaction.     

Designing a workplace return-to-work program for occupational low back pain: an intervention mapping approach

Background  

Despite over 2 decades of research, the ability to prevent work-related low back pain (LBP) and disability remains elusive. Recent research suggests that interventions that are focused at the workplace and incorporate the principals of participatory ergonomics and return-to-work (RTW) coordination can improve RTW and reduce disability following a work-related back injury. Workplace interventions or programs to improve RTW are difficult to design and implement given the various individuals and environments involved, each with their own unique circumstances. Intervention mapping provides a framework for designing and implementing complex interventions or programs. The objective of this study is to design a best evidence RTW program for occupational LBP tailored to the Ontario setting using an intervention mapping approach.     

Kidney transplant complications and obesity

Objective

To determine the rate of graft failure and complications secondary to morbid obesity in kidney transplant patients at our institution.

Methods

A retrospective study involving recipients renal transplants from 2002 to 2007. Patients were divided into 3 groups: group 1, body mass index (BMI) >35 underwent a diet plan and gained weight posttransplant; group 2, BMI >35 underwent successful diet modifications posttransplant; and group 3, BMI <35 did not undergo a diet regimen.

Results

Sixty-six patients were studied. Group 1 patients, (n = 21, BMI >35) had higher postoperative complications, longer operative time, and longer hospital stay when compared with their obese counterparts group 3 (n = 23, BMI <35). We saw no significant change in postoperative complications between group 2 and group 3 (n = 22, BMI > 35).

Conclusions

Worse graft function and complications were seen with patients who gained weight post operatively. Conversely, a good outcome was seen with those patients that lost weight pre and post operatively. The results of this study may open the field for pretransplant weight loss procedures to improve quality of life, nutrition, and overall health of transplant candidates.