Excess lipid availability increases mitochondrial fatty acid oxidative capacity in muscle: evidence against a role for reduced fatty acid oxidation in lipid-induced insulin resistance in rodents

A reduced capacity for mitochondrial fatty acid oxidation in skeletal muscle has been proposed as a major factor leading to the accumulation of intramuscular lipids and their subsequent deleterious effects on insulin action. Here, we examine markers of mitochondrial fatty acid oxidative capacity in rodent models of insulin resistance associated with an oversupply of lipids. C57BL/6J mice were fed a high-fat diet for either 5 or 20 weeks. Several markers of muscle mitochondrial fatty acid oxidative capacity were measured, including (14)C-palmitate oxidation, palmitoyl-CoA oxidation in isolated mitochondria, oxidative enzyme activity (citrate synthase, beta-hydroxyacyl CoA dehydrogenase, medium-chain acyl-CoA dehydrogenase, and carnitine palmitoyl-transferase 1), and expression of proteins involved in mitochondrial metabolism. Enzyme activity and mitochondrial protein expression were also examined in muscle from other rodent models of insulin resistance. Compared with standard diet-fed controls, muscle from fat-fed mice displayed elevated palmitate oxidation rate (5 weeks +23%, P < 0.05, and 20 weeks +29%, P < 0.05) and increased palmitoyl-CoA oxidation in isolated mitochondria (20 weeks +49%, P < 0.01). Furthermore, oxidative enzyme activity and protein expression of peroxisome proliferator-activated receptor gamma coactivator (PGC)-1alpha, uncoupling protein (UCP) 3, and mitochondrial respiratory chain subunits were significantly elevated in fat-fed animals. A similar pattern was present in muscle of fat-fed rats, obese Zucker rats, and db/db mice, with increases observed for oxidative enzyme activity and expression of PGC-1alpha, UCP3, and subunits of the mitochondrial respiratory chain. These findings suggest that high lipid availability does not lead to intramuscular lipid accumulation and insulin resistance in rodents by decreasing muscle mitochondrial fatty acid oxidative capacity.     

Chondrocyte viability after intra-articular calcaneal fractures in humans

BACKGROUND: Chondral damage from the impact of injury may contribute to the high incidence of post-traumatic arthritis after calcaneal fractures, but this has yet to be proven. We sought to study the effect of intra-articular calcaneal fractures on chondrocyte viability and to correlate these effects with injury severity, time from injury to surgery, and patient age and co-morbidities. METHODS: Irreducible osteochondral fragments from 12 patients undergoing operative treatment for intra-articular calcaneal fractures were analyzed. Control cartilage was obtained from four tissue donors who died of unrelated causes. The cartilage was assessed for chondrocyte viability through the full thickness of tissue using a Live/Dead assay followed by laser scanning confocal microscopy. Patient demographics including injury classification and severity, time from injury to surgery, and patient age were recorded. RESULTS: Chondrocyte viability from fracture patients averaged 72.8% +/- 12.9% (range 53% to 95%), which was significantly lower than the 94.8% +/- 1.5% viability observed in the control specimens (p = 0.005). Chondrocyte viability declined with higher energy injuries (p = 0.13), time from injury to surgery (p = 0.07), and increasing patient age (p = 0.07). However, none of these factors reached a level of statistical significance. CONCLUSIONS: A significant decline in chondrocyte viability occurs after intra-articular fractures of the calcaneus. This may contribute to the development of post-traumatic arthritis.     

Infrequent delivery of a long-acting PTH-Fc fusion protein has potent anabolic effects on cortical and cancellous bone.

Skeletal anabolism with PTH is achieved through daily injections that result in brief exposure to the peptide. We hypothesized that similar anabolic effects could be achieved with less frequent but more sustained exposures to PTH. A PTH-Fc fusion protein with a longer half-life than PTH(1-34) increased cortical and cancellous BMD and bone strength with once- or twice-weekly injections. INTRODUCTION: The anabolic effects of PTH are currently achieved with, and thought to require, daily injections that result in brief exposure to the peptide. We hypothesized that less frequent but more sustained exposures to PTH could also be anabolic for bone, provided that serum levels of PTH were not constant. MATERIALS AND METHODS: PTH(1-34) was fused to the Fc fragment of human IgG1 to increase the half-life of PTH. Skeletal anabolism was examined in mice and rats treated once or twice per week with this PTH-Fc fusion protein. RESULTS: PTH-Fc and PTH(1-34) had similar effects on PTH/PTHrP receptor activation, internalization, and signaling in vitro. However, PTH-Fc had a 33-fold longer mean residence time in the circulation of rats compared with that of PTH(1-34). Subcutaneous injection of PTH-Fc once or twice per week resulted in significant increases in bone volume, density, and strength in osteopenic ovariectomized mice and rats. These anabolic effects occurred in association with hypercalcemia and were significantly greater than those achievable with high concentrations of daily PTH(1-34). PTH-Fc also significantly improved cortical bone volume and density under conditions where daily PTH(1-34) did not. Antiresorptive co-therapy with estrogen further enhanced the ability of PTH-Fc to increase bone mass and strength in ovariectomized rats. CONCLUSIONS: These results challenge the notion that brief daily exposure to PTH is essential for its anabolic effects on cortical and cancellous bone. PTH-derived molecules with a sustained circulating half-life may represent a powerful and previously undefined anabolic regimen for cortical and cancellous bone.     

Pain after percutaneous radiofrequency ablation of renal tumors

BACKGROUND AND PURPOSE: Most patients have minimal pain after percutaneous radiofrequency ablation (RFA) of a renal tumor. However, anecdotally, there is some variation in the amount of patient discomfort. Our goal was to identify relevant patient factors and characteristics of their renal tumors that may influence pain after percutaneous RF ablation. PATIENTS AND METHODS: We performed a retrospective chart review of 59 sequential patients who received percutaneous RFA between 2001 and 2005 at a single institution. Data on patient age, sex, body mass index (BMI), and narcotic administration in the periprocedural period were available for 46 patients. Preoperative imaging (CT or MRI) was reviewed to determine tumor size and location, as well as the shortest distance of the mass to the body-wall musculature. RESULTS: The distance from the renal mass to the body-wall musculature was significantly correlated with the total narcotics received in the periprocedural period. This measured distance did not correlate with the patient's BMI. No other relations between patient factors or tumor characteristics and peri-procedural narcotic usage were identified. CONCLUSION: Patients whose tumors lie close to their body-wall musculature have greater narcotic requirements in the periprocedural period. Knowledge of this correlation should result in better patient counseling and help anticipate periprocedural analgesia requirements.     

Fracture risk after parathyroidectomy among chronic hemodialysis patients

The impact of parathyroidectomy (PTX) on the long-term risks for hip and other fractures is unknown. Uncontrolled case series have reported an increase in bone mineral density after PTX. However, very low serum parathyroid hormone levels have been associated with decreased bone mineral density, adynamic bone disease, and fractures. This study compared long-term fracture rates among hemodialysis patients who underwent PTX with a matched control group. Data were obtained from the US Renal Data System. Patients who underwent a first PTX while receiving hemodialysis were matched with up to three control patients by age, race, gender, year of dialysis initiation, primary cause of renal failure, and the dosage of intravenous vitamin D used before PTX. Patients with a history of fracture or renal transplantation were excluded. Study outcomes were incident hip, vertebral, and distal radius-wrist fractures identified using hospitalization codes. Incident hip fracture rates in the PTX and matched control groups were 6.0 and 9.3 fractures per 1000 person-years, respectively. After adjustment, PTX was associated with a significant 32% lower risk for hip fracture (95% confidence interval 0.54 to 0.86; P = 0.001) and a 31% lower risk for any analyzed fracture (95% confidence interval 0.57 to 0.83; P < 0.001) compared with matched control subjects. Fracture risks were lower among hemodialysis patients who underwent PTX compared with matched control subjects. Surgical amelioration of secondary hyperparathyroidism may outweigh the risk of parathyroid hormone oversuppression in terms of bone health.     

Primary localized amyloidosis of the bladder: experience with dimethyl sulfoxide therapy

PURPOSE: We present our long-term experience with intravesical dimethyl sulfoxide (DMSO) for primary localized amyloidosis of the bladder. MATERIALS AND METHODS: The study included 4 males and 2 females 28 to 68 years old (mean age 54) at diagnosis of biopsy proven primary localized amyloidosis involving the bladder diffusely or extensively in 1 locale. All patients had normal upper urinary tracts. They continued to be symptomatic (hematuria in 3, irritative voiding symptoms in 1, and hematuria and irritative voiding symptoms in 2) despite conventional transurethral destructive therapy. Every 2 weeks they received 30-minute instillations of 50 ml. 50% DMSO intravesically for 3 months (patient 1), 6 months (1) and 1 year (4). RESULTS: Therapy failed at 3 and 6 months in 2 patients of whom 1 with a contracted bladder underwent cystectomy and another was stabilized for 1 year with laser therapy. In the remaining 4 patients who were followed for 6 years disease stabilized for 2 to 6 years (mean 3.5) but 3 later required additional therapy including repeat DMSO in 1 and laser therapy in 2. CONCLUSIONS: Diffuse or locally extensive bladder involvement by primary localized amyloidosis usually fails to respond to conventional transurethral destructive surgical procedures. Collectively, our experience and the literature suggest that intravesical DMSO can be a bladder saving measure and help resolve ureterovesical obstruction in some patients. High recurrence rate mandates lifelong cystoscopic surveillance.     

Outcomes after concurrent inguinal hernia repair and robotic-assisted radical prostatectomy

Inguinal hernias occur more frequently following radical prostatectomy. Simultaneous inguinal hernia repair during open and laparoscopic radical prostatectomy for prostate cancer has been described previously. The emergence of robotic-assisted radical prostatectomy (RALP) has necessitated the evaluation of concomitant herniorrhaphy in this new setting. We report the outcomes of this operation in our series of patients. Retrospective review was performed on 700 patients with localised prostate cancer who underwent RALP performed by a single surgeon from 2004 to 2009. Details of cases where concurrent inguinal hernia repair was performed were recorded and compared with the remainder of the cohort. Hernia repair was performed using a monofilament knitted polypropylene cone mesh plug and fascial defect closure with Hem-o-Lok clips. A total of 38 inguinal herniorraphies were performed in 37 patients as a simultaneous procedure during transperitoneal RALP. The hernia repair on average added 5–10 min to the total procedure time. One patient underwent a bilateral repair. Across this group, mean age was 62.9 years, average body mass index was 27.1, and median follow-up was 29 months. There were no complications at the time of mesh placement. There were no cases complicated by wound infection, fluid collection, or chronic pain. Recurrence of an inguinal hernia occurred in one patient due to migration of the mesh. We conclude that concomitant inguinal hernia repair during RALP is safe, feasible, and effective. The herniorrhaphy can be performed quickly, adds little to the overall procedure time and avoids a further operative procedure for the patient.     

The role of radiologic imaging and biopsy in renal tumor ablation

Purpose  

The rate of unintentionally discovered renal masses has been increasing along with a parallel increased incidence of renal cell carcinoma both in men and women. Ablation therapy has emerged as an alternative for the treatment of these small renal tumors. Several techniques have been developed for renal tumor ablation with cryoablation (CA) and radiofrequency ablation (RFA) being among the most widely used and studied. The purpose of this article is to review the role of imaging and renal mass biopsy in renal tumor ablation with focus on CA and RFA.