Ablation of mixed lineage kinase 3 (Mlk3) does not inhibit ototoxicity induced by acoustic trauma or aminoglycoside exposure

Jun N-terminal kinase (JNK) is activated in cochlear hair cells following acoustic trauma or exposure to aminoglycoside antibiotics. Blockade of JNK activation using mixed lineage kinase (MLK) inhibitors prevents hearing loss and hair cell death following these stresses. Since current pharmacologic inhibitors of MLKs block multiple members of this kinase family, we examined the contribution of the major neuronal family member (MLK3) to stress-induced ototoxicity, usingMlk3(-/-) mice. Immunohistochemical staining revealed that MLK3 is expressed in cochlear hair cells of C57/BL6 mice (but not in Mlk3(-/-) animals). After exposure to acoustic trauma there was no significant difference in DPOAE and ABR values betweenMlk3(-/-) and wild-type mice at 48?h following exposure or 2 weeks later. Susceptibility of hair cells to aminoglycoside toxicity was tested by exposing explanted utricles to gentamicin. Gentamicin-induced hair cell death was equivalent in utricles from wild-type and Mlk3(-/-) mice. Blockade of JNK activation with the pharmacologic inhibitor SP600125 attenuated cell death in utricles from both wild-type and Mlk3(-/-) mice. These data show that MLK3 ablation does not protect against hair cell death following acoustic trauma or exposure to aminoglycoside antibiotics, suggesting that MLK3 is not the major upstream regulator of JNK-mediated hair cell death following these stresses. Rather, other MLK family members such as MLK1, which is also expressed in cochlea, may have a previously unappreciated role in noise- and aminoglycoside-induced ototoxicity.     

Endoluminal management of arterioportal fistulae in liver transplant recipients: a single-center experience

Transcatheter embolization of arterioportal fistulae in liver transplant recipients is restricted to symptomatic arterioportal fistulae. Angiograms of liver transplant recipients from a single university medical center were retrospectively reviewed. Hemodynamically significant arterioportal fistulae were defined as those exhibiting opacification of the main portal vein of the transplanted hepatic graft or its first order branch with or without portal venous changes by Doppler ultrasound imaging. Six arterioportal fistulae were found. Doppler ultrasound imaging detected 50% of all arterioportal fistulae and all 3 hemodynamically significant arterioportal fistulae. Three successful embolizations were performed. Follow-up (37 to 67 months) demonstrated patent hepatic arteries and no parenchymal ischemic changes with graft preservation. High-throughput arterioportal fistulae may require larger intrahepatic artery branch embolization. There is a window of opportunity for embolizing significant arterioportal fistulae before their progression to large symptomatic, high through-put arterioportal fistulae with their added risk of ischemic changes before and after embolization.     

Factors modifying contrast media induced fibrillation

Factors effecting contrast media induced ventricular fibrillation were studied in anesthetized dogs using contact time as the measured parameter. Injections of meglumine/sodium diatrizoate (370 mg I/ml) were made into the right coronary artery at 0.4 ml/s until fibrillation occurred. A contrast medium containing calcium chelators was found to produce fibrillation in a significantly shorter contact time than a similar medium without calcium chelators. Pre-treatment by the cardiac glycoside, ouabain, increased the contact time for fibrillation as did the production of a sub-acute infarction in the left coronary artery and a previous fibrillation and resuscitation. The data suggest that calcium binding additives increase the risk of fibrillation while pre-treatment with cardiac glycosides, the presence of stable infarcts in the non-injected areas, or a previous fibrillation and resuscitation do not increase risk.     

Risk factors for microalbuminuria in children and adolescents with type 1 diabetes

OBJECTIVES: The aim of this study was to investigate the influence of sex, age, diabetes duration, puberty, blood pressure, glycemic control and parental blood pressure on microalbuminuria in children with type 1 diabetes. STUDY DESIGN: The study was a multicenter cross-sectional survey including 702 children and adolescents (age = 14.3+/-2.9 yr) with type 1 diabetes duration of 7.6+/-3.1 yr. One third of the population had not undergone pubertal development. Blood pressure was measured in children and their parents using a Dinamap instrument. Microalbuminuria was defined as a urinary albumin excretion rate > or = 15 microg/min measured on at least two out of three urine collections. HbA1c centrally measured by HPLC, was 8.7+/-1.5%. RESULTS: The proportion of permanent microalbuminuria was 5.1+/-1.6%. The prevalence was significantly enhanced after 10 yr of diabetes duration (11.6+/-5.2%) and complete puberty (8.2+/-3.1%). Independent risk factors for microalbuminuria tested in a logistic regression model were diabetes duration (OR/1 yr = 1.04-1.32), complete puberty (OR = 5.02-8.0), and maternal hypertension (OR = 1.94-4.28). HbA1c had a borderline independent and significant effect (OR/1% = 0.96-1.62; p = 0.07). CONCLUSIONS: Our results indicate that pubertal adolescents with a long duration of the disease and maternal history of hypertension are candidates for targeted interventions with the objective of reducing the rate of developing nephropathy in these individuals.     

Comparison of vasa vasorum after intravascular stent placement with sirolimis drug‐eluting and bare metal stents

The cytostatic drug, sirolimis has shown prevention in neointimal hyperplasia after stent placement. Recent studies have shown persistent inflammation seen with drug‐eluting stents (DES) may result in late stent thrombosis. The aim of this study is to compare effects of bare metal stents (BMS) and sirolimis DES on the neointima and vasa vasorum in stented rabbit aortas. Stents were implanted in eight New Zealand rabbits for 9 weeks. Group I rabbits received BMS. Group II rabbits received sirolimis DES. A balloon‐mounted BMS or DES was placed in the infrarenal aorta. Following euthanasia, aortas were perfused with barium sulfate and sectioned for histology. After 9 weeks the qualitative intrastent luminal diameter was fairly uniform in both the DES and the BMS. The thickness of neointima was similar in both groups. The number of vasa vasorum in the sirolimis DES increased compared with the BMS (P < 0.05). An increased number of vasa vasorum produced by the DES when compared with the BMS shows a difference in response to local vessel injury in rabbits. This result suggests that vasa vasorum may play a role in the persistent inflammation generated by sirolimis‐coated stents.     

Incidental Non-Inguinals Hernias in Totally Extra-Peritoneal Hernia Repair

Introduction

Totally extra-peritoneal (TEP) inguinal hernia repair allows identification and repair of incidental non-inguinal groin hernias. We assessed the prevalence of incidental hernias during TEP inguinal hernia repair and identified the risk factors for incidental hernias.

Materials and Methods

Consecutive patients undergoing TEP repair from May 2005 to November 2012 were the study cohort. Inspection for ipsilateral femoral, obturator and rarer varieties of hernia was undertaken during TEP repair. Patient characteristics and operative findings were recorded on a prospectively collected database.

Results

A total of 1,532 TEP repairs were undertaken in 1,196 patients. Ninety-three patients were excluded due to incomplete data, leaving 1,103 patients and 1,404 hernias for analyses (1,380 male; 802 unilateral and 301 bilateral repairs; median age, 59 years). Among the 37 incidental hernias identified (2.6% of cases), the most common type of incidental hernia was femoral (n=32, 2.3%) followed by obturator (n=2, 0.1%). Increasing age was associated with an increased risk of incidental hernia, with a significant linear trend (p<0.01). The risk for patients >60 years of age was 4.0% vs 1.4% for those aged <60 years (p<0.01). Incidental hernias were found in 29.2% of females vs 2.2% of males, (p<0.0001). Risk of incidental hernia in those with a recurrent inguinal hernia was 3.0% vs 2.6% for primary repair (p=0.79).

Conclusions

Incidental hernias during TEP inguinal hernia repair were found in 2.6% of cases and, though infrequent, could cause complications if left untreated. The risk of incidental hernia increased with age and was significantly higher in patients aged >60 years and in females.