In humans, tobacco withdrawal produces symptoms that contribute to the difficulty associated with smoking cessation. Nicotine withdrawal symptoms can also be observed in rodents. A major standing question is which nicotinic receptor subtypes and which areas of the brain are necessary for nicotine withdrawal to occur. Using knock-out mice, we previously showed that the ␤4, but not the ␤2 subunit of nicotinic acetylcholine receptors, is necessary for the somatic manifestations of nicotine withdrawal. Since the ␤4 subunit is highly expressed in the medial habenula, we focused our studies on the medial habenula and its primary target, the interpeduncular nucleus. In particular, we studied nicotine withdrawal in mice lacking the ␣2 or the ␣5 nicotinic receptor subunits, which are highly expressed in the interpeduncular nucleus. We precipitated withdrawal by systemically injecting the nicotinic antagonist mecamylamine in mice chronically treated with nicotine. Both the ␣2 and the ␣5 null mutations abolished the somatic manifestations of nicotine withdrawal. In addition, in wild-type mice chronically treated with nicotine, mecamylamine precipitated withdrawal when microinjected into the habenula or the interpeduncular nucleus, but not into the cortex, ventral tegmental area or hippocampus. Our results demonstrate a major role for the habenulo-interpeduncular system and the nicotinic receptor subunits expressed therein, in nicotine withdrawal symptoms. Our data suggest that the efforts to develop new smoking cessation therapies should concentrate on these areas and receptor types.

Summary Introduction Patient age and hospital volume have been shown to affect perioperative outcomes after pediatric pyeloplasty. However, to date, there are few multicenter studies that focus on outcomes at teaching hospitals, where many of the operations are performed. Objective The goal was to determine if surgical approach, age, case volume, or other factors influence perioperative outcomes in a large contemporary cohort. Study design Using the clinical database/resource manager (CDB/RM) of the University Health-System Consortium (UHC), children who underwent open, laparoscopic, or robotic pyeloplasty from 2011 to 2014 were identified at 102 academic institutions. Surgery type, age, race, gender, insurance type, geographic region, comorbidities, surgeon volume, and hospital volume were measured. Multivariable mixed-effects logistic regression analysis was used to analyze independent variables associated with complication rates, length of stay (LOS), readmission rates, and ICU admission. Results A total of 2,219 patients were identified. Complication rates were 2.1%, 2.2%, and 3% after open, laparoscopic, and robotic pyeloplasty, respectively. Approximately 12% of patients had underlying comorbidities. Comorbidities were associated with 3.1 times increased odds for complication (p = 0.001) and a 35% longer length of stay (p < 0.001). Age, gender, insurance type, and hospital volume had no effect on complication rates. A trend was seen towards a lower rate of complications with higher surgeon volume (p = 0.08). The mean LOS was 2.0 days in the open pyeloplasty group, 2.4 days in the laparoscopic group and 1.8 days in the robotic group. Patients who underwent robotic surgery had an estimated LOS 11% shorter than those after open surgery (p = 0.03) (table). Patients aged 5 years and under who had robotic surgery had an estimated LOS 14% shorter than those after open surgery (p = 0.06). ICU admission and hospital readmission were not associated with any variables. Discussion The study is limited by the accuracy of the data submitted by the hospitals and is subject to coding error. Complication rates remain low in all three approaches, validating their safety. Patients, including younger patients, had shorter lengths of stay after robotic surgery. The statistically significant differences between approaches were small so clinically there may not be a difference. Conclusions This large multicenter analysis demonstrates that patient comorbidity had the greatest impact upon complication rates and length of stay. Previous work showed that the benefits of laparoscopy were limited to older children. However, this large multicenter study suggests that these benefits now extend to young children with the application of robotics.

Substitution urethroplasty for the treatment of male stricture disease is often accompanied by subsequent tissue fibrosis and secondary stricture formation. Patients with pre-existing morbidities are often at increased risk of urethral stricture recurrence brought upon in-part by delayed vascularization accompanied by overactive inflammatory responses following surgery. Within the context of this study, we demonstrate the functional utility of a cell/scaffold composite graft comprised of human bone marrow-derived mesenchymal stem cells (MSC) combined with CD34+ hematopoietic stem/progenitor cells (HSPC) to modulate inflammation and wound healing in a rodent model of substitution urethroplasty. Composite grafts demonstrated potent anti-inflammatory effects with regards to tissue macrophage and neutrophil density following urethral tissue analyses. This was accompanied by a significant reduction in pro-inflammatory cytokines TNFα and IL-1β and further resulted in an earlier transition to tissue remodeling and maturation with a shift in collagen type III to I. Grafted animals demonstrated a progressive maturation and increase in vessel size compared to control animals. Overall, MSC/CD34+ HSPC composite grafts reduce inflammation, enhance an earlier transition to wound remodeling and maturation concurrently increasing neovascularization in the periurethral tissue. We demonstrate the feasibility and efficacy of a stem cell-seeded synthetic graft in a rodent substitution urethroplasty model.