Tar DNA Binding Protein-43 (TDP-43) is a principle component of inclusions in many cases of frontotemporal lobar degeneration (FTLD-U) and amyotrophic lateral sclerosis (ALS). TDP-43 resides predominantly in the nucleus, but in affected areas of ALS and FTLD-U central nervous system, TDP-43 is aberrantly processed and forms cytoplasmic inclusions. The mechanisms governing TDP-43 inclusion formation are poorly understood. Increasing evidence indicates that TDP-43 regulates mRNA metabolism by interacting with mRNA binding proteins that are known to associate with RNA granules. Here we show that TDP-43 can be induced to form inclusions in cell culture and that most TDP-43 inclusions co-localize with SGs. SGs are cytoplasmic RNA granules that consist of mixed protein - RNA complexes. Under stressful conditions SGs are generated by the reversible aggregation of prion-like proteins, such as TIA-1, to regulate mRNA metabolism and protein translation. We also show that disease-linked mutations in TDP-43 increased TDP-43 inclusion formation in response to stressful stimuli. Biochemical studies demonstrated that the increased TDP-43 inclusion formation is associated with accumulation of TDP-43 detergent insoluble complexes. TDP-43 associates with SG by interacting with SG proteins, such as TIA-1, via direct protein-protein interactions, as well as RNA-dependent interactions. The signaling pathway that regulates SGs formation also modulates TDP-43 inclusion formation. We observed that inclusion formation mediated by WT or mutant TDP-43 can be suppressed by treatment with translational inhibitors that suppress or reverse SG formation. Finally, using Sudan black to quench endogenous autofluorescence, we also demonstrate that TDP-43 positive-inclusions in pathological CNS tissue co-localize with multiple protein markers of stress granules, including TIA-1 and eIF3. These data provide support for accumulating evidence that TDP-43 participates in the SG pathway.

Peyronie’s Disease (PD) is a superficial fibrosing disorder of the penis resulting in plaque formation and penile deformity. Once considered rare, PD has more recently been found in up to 13% of men, and can negatively affect sexual and psychosocial function of both patients and their partners. While the etiology of PD is unclear, it is thought to result from an inciting traumatic event followed by aberrant fibrosis or dysregulated wound healing. The evaluation of men presenting with PD includes a detailed history and physical exam, focusing on the penis in both the flaccid and erect states. PD is often associated with erectile dysfunction (ED), as well as several other comorbidities. Laboratory testing is not needed to diagnose PD, although given the associations between PD and systemic diseases including hypogonadism, diabetes, and cardiovascular disease, screening and work-up for these conditions in men with PD may be warranted. Treatment modalities for PD are diverse and include oral, topical, intralesional, mechanical, and surgical therapies. Oral, topical, and mechanical therapies generally have little evidence supporting their efficacy. Several intralesional therapies, including interferon α2b and collagenase Clostridium hystiolyticum have demonstrated efficacy in the treatment of PD. Surgical treatment, indicated in men with significant, stable deformity, includes plication of the tunica albuginea, plaque incision/excision and grafting, and placement of inflatable penile prosthesis (IPP) with or without additional maneuvers to achieve desired results, and has high success rates.

Purpose Proximal hypospadias repair using a staged approach is a complex reconstructive operation with the potential for significant complications requiring repeat surgery. We report outcomes of staged hypospadias repair using transposed preputial skin flaps and factors predictive of postoperative complications. Materials and Methods We retrospectively analyzed patients who underwent staged proximal hypospadias repair using transposed preputial skin flaps between 2002 and 2013. Patient demographics, operative details, complications, reoperations and factors predictive of complications were reviewed. Results A total of 56 patients were identified with a mean age of 14.1 months (median 14.3) at first stage. Mean followup was 38.6 months (median 34.1). Complications requiring additional unplanned operation(s) were observed in 38 patients (68%), including fistulas in 32 (57%), diverticula in 8 (14%), meatal stenosis in 5 (9%), urethral stricture in 8 (14%) and glans dehiscence in 3 (5%). In addition, redo first stage repair was performed in 4 patients (7%). Since some patients had more than 1 complication, the total number of complications is greater than the number of patients undergoing a redo operation. On univariate analyses the use of small intestinal submucosa was significantly associated with an increased risk of fistula (91% vs 49%, p = 0.02) and urethral diverticulum (64% vs 24%, p = 0.04). Incision of the tunica albuginea of the corpora was associated with an increased likelihood of fistula (77% vs 44%, p = 0.03). Finally, patients with glans dehiscence were significantly younger at first stage (5.8 vs 14.8 months, p = 0.01). Conclusions The reoperation rate for complications in children undergoing staged hypospadias repair using transposed preputial skin flaps is higher than previously reported.