Recent epidemiological evidence indicates that insulin resistance, a proximal cause of Type II diabetes [a non-insulin dependent form of diabetes mellitus (NIDDM)], is associated with an increased relative risk for Alzheimer's disease (AD). In this study we examined the role of dietary conditions leading to NIDDM-like insulin resistance on amyloidosis in Tg2576 mice, which model AD-like neuropathology. We found that diet-induced insulin resistance promoted amyloidogenic beta-amyloid (Abeta) Abeta1-40 and Abeta1-42 peptide generation in the brain that corresponded with increased gamma-secretase activities and decreased insulin degrading enzyme (IDE) activities. Moreover, increased Abeta production also coincided with increased AD-type amyloid plaque burden in the brain and impaired performance in a spatial water maze task. Further exploration of the apparent interrelationship of insulin resistance to brain amyloidosis revealed a functional decrease in insulin receptor (IR)-mediated signal transduction in the brain, as suggested by decreased IR beta-subunit (IRbeta) Y1162/1163 autophosphorylation and reduced phosphatidylinositol 3 (PI3)-kinase/pS473-AKT/Protein kinase (PK)-B in these same brain regions. This latter finding is of particular interest given the known inhibitory role of AKT/PKB on glycogen synthase kinase (GSK)-3alpha activity, which has previously been shown to promote Abeta peptide generation. Most interestingly, we found that decreased pS21-GSK-3alpha and pS9-GSK-3beta phosphorylation, which is an index of GSK activation, positively correlated with the generation of brain C-terminal fragment (CTF)-gamma cleavage product of amyloid precursor protein, an index of gamma-secretase activity, in the brain of insulin-resistant relative to normoglycemic Tg2576 mice. Our study is consistent with the hypothesis that insulin resistance may be an underlying mechanism responsible for the observed increased relative risk for AD neuropathology, and presents the first evidence to suggest that IR signaling can influence Abeta production in the brain.
Objective
To report the risk factors and natural history of urinary fistula (UF) after partial nephrectomy (PN), as their incidence has been reported to be 3–6% in large series of PN but there are few reports of the risk factors associated with the development of UF after PN, and the natural history of UF in a large group of patients.
Patients and Methods
This was a retrospective review of 1118PN at one tertiary-care institution. Most patients had a drain placed in the perinephric space after surgery. Fifty-two patients were identified as having a UF if they had persistent flank drainage for >14 days after surgery, or presented with evidence of a UF after the drain had been removed. Risk factors for development and the course of the UF are reported.
Results
Fifty-two patients developed a UF after PN (4.4%, 95% confidence interval, CI, 3.5–6.1%) The rate of a persistent urine leak (defined as drain fluid consistent with urine for >2 weeks after surgery) was 4.0 (95% CI 2.9–5.3)%. The overall rate of delayed UF presentation was only 0.4 (0.09–0.9)%. Patients who developed a UF had larger tumours (3.5 vs 2.6cm, P = 0.03), a higher estimated blood loss (400 vs 300mL, P < 0.001), and longer ischaemia time (50 vs 39min, P < 0.001) than patients who did not develop a UF. Differences in tumour histology, laterality, multifocality, type of surgery (laparoscopic vs open), and intraoperative collecting system entry were not statistically different in patients who did or did not develop a UF. Patients with tumours of >2.5cm were twice as likely to develop a UF than patients with tumours of <2.5cm (P = 0.02). Most patients were managed conservatively with a percutaneous drain until the UF resolved, if they were asymptomatic. Overall, in 36 patients (69%) the fistula resolved with no intervention, while 16 (31%) required intervention. Stenting was the commonest intervention (15%). No patient required re-operative open surgery.
Conclusion
The rate of development of UF after PN is low. Tumour size, blood loss and ischaemia time were all associated with the development of a UF. In most patients with a urine leak immediately after surgery the UF will resolve with no intervention, and can be managed conservatively with patience, in the absence of clinical symptoms.
Hypospadias repair with onlay preputial graft is an option for single-stage repair, especially in cases of proximal hypospadias or where the urethral plate width and/or the glanular groove is insufficient for other types of repair. Compared with flaps, the use of grafts may decrease the risk of penile torsion and prevent less bulk around the urethra, improving skin and glans closure.
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