Protective effect of 20-hydroxyeicosatetraenoic acid (20-HETE) on glomerular protein permeability barrier

BACKGROUND: Proteinuria is a significant problem in medicine today, although glomerular events underlying it are unknown. Products of cytochrome P450 (CYP450) pathway of arachidonic acid metabolism are increasingly recognized as playing major roles in renal function. We used in vitro albumin permeability (P(alb)) as a measure of injury and puromycin aminonucleoside (PAN) as an injurious agent to test the hypothesis that 20-hydroxyeicosatetraenoic acid (20-HETE) protects the glomerular filtration barrier from increased P(alb). METHODS: We determined P(alb) in the following experimental groups: (1) isolated rat glomeruli incubated with PAN (5 microg/mL) for 5, 15, 30 or 60 minutes; (2) isolated glomeruli preincubated with 20-HETE (1.0 nmol/L to 100 nmol/L) for 15 minutes followed by additional incubation with PAN (5 microg/mL) for 15 minutes; (3) isolated glomeruli from rats treated with the CYP450 4A inducer clofibrate, and incubated with PAN (5 microg/mL) for 15 minutes; and (4) appropriate controls for each group. CYP450 4A levels were measured in glomeruli isolated from rats treated with clofibrate or vehicle. RESULTS: PAN increased P(alb) of isolated glomeruli as early as 5 minutes (P(alb) 0.33 +/- 0.21, P < 0.05 vs. control). Maximal effect occurred at 30 minutes (P(alb) 0.75 +/- 0.16, P < 0.001 vs. control). Inclusion of 20-HETE (100 nmol/L) blocked the increased P(alb) caused by PAN (P(alb) 0.05 +/- 0.13). Likewise, glomeruli isolated from rats treated with clofibrate were protected from PAN-induced increase in P(alb) (P(alb) 0.19 +/- 0.03). Treatment with clofibrate significantly increased glomerular CYP450 4A expression. CONCLUSION: PAN directly and immediately affects the glomerular permeability barrier. Furthermore, exogenous 20-HETE or clofibrate treatment protects glomeruli from increased P(alb) caused by PAN. Relative lack of 20-HETE may be a general characteristic of proteinuric states. Conversely, measures used to treat and/or prevent proteinuria may act to restore or increase glomerular 20-HETE levels.     

Histopathologic excision margin affects local recurrence rate: analysis of 2681 patients with melanomas < or =2 mm thick

OBJECTIVE: Prospective trials have shown that 1-cm and 2-cm margins are safe for melanomas <1 mm thick and > or =1 mm thick, respectively. It is unknown whether narrower margins increase the risk of LR or mortality. SUMMARY BACKGROUND DATA: To determine the relationship between histopathologic excision margin, local recurrence (LR) and survival for patients with melanomas < or =2 mm thick. METHODS: Data were extracted from the Sydney Melanoma Unit database for all patients with cutaneous melanoma < or =2 mm thick, diagnosed up to 1996. Patients with positive excision margins or follow-up <12 months were excluded, leaving 2681 for analysis. Outcome measures were LR (recurrence <5 cm from the excision scar), in-transit recurrence, and disease-specific survival. Factors predicting LR and overall survival were tested with Cox proportional hazards analysis. RESULTS: Median follow-up was 83.8 months. LR was identified in 55 patients (median time to recurrence, 37 months). At 120 months, the actuarial LR rate was 2.9%. Five-year survival after LR was 52.8%. In multivariate analysis, only margin of excision and tumor thickness were predictive of LR (both P = 0.003). When all patients with a margin <0.8 cm in fixed tissue (corresponding to a margin of <1 cm in vivo) were excluded from analysis, margin was no longer significant in predicting LR. Thickness, ulceration, and site were predictive of survival, but margin was not (P = 0.49). CONCLUSIONS: Histopathologic margin affects the risk of LR. However, if the in vivo margin is > or =1 cm, it no longer predicts risk of LR. Patient survival is not affected by margin.     

Merkel Cell Carcinoma Arising from the Subcutaneous Fat of the Arm with Intact Skin

BACKGROUND: Merkel cell carcinoma is a rare malignant neuroendocrine neoplasm characteristically arising from the dermis of sunlight-exposed skin. It rarely arises outside the skin. OBJECTIVE: We present a patient with primary Merkel cell carcinoma arising from subcutaneous fat, with no involvement of the overlying skin. We describe the clinical manifestations and magnetic resonance imaging (MRI) findings. METHODS: We report a 63-year-old woman with a primary lesion of Merkel cell carcinoma that arose from the subcutaneous fat layer of the left arm. The lesion presented as a subcutaneous nodule with intact overlying skin. MRI showed that the nodular lesion was located entirely in the subcutaneous fat layer, with no involvement of the dermis. Peritumoral infiltration around the lesion and enlarged lymph nodes deep to the lesion were noted. The patient received wide excision of the lesion with dissection of the regional lymph nodes and adjuvant radiotherapy and chemotherapy. RESULTS: Histopathologic examination confirmed the diagnosis of Merkel cell carcinoma with local lymphatic metastasis, and the lesion was completely located in the subcutaneous fat, with no involvement of the dermis. These findings were well correlated with MRI findings. CONCLUSION: Primary Merkel cell carcinoma may arise from the subcutaneous fat and present as an entirely subcutaneous lesion with intact skin. MRI is helpful to evaluate the local extension of the lesion and regional lymphatic metastasis.     

Can cost utility evaluations inform decision making about interventions for low back pain?

Background contextLow back pain (LBP) is associated with high health-care utilization and lost productivity. Numerous interventions are routinely used, although few are supported by strong evidence. Cost utility analyses (CUAs) may be helpful to inform decision makers.PurposeTo conduct a systematic review of CUAs of interventions for LBP.Study designSystematic review.MethodsA search strategy combining medical subject headings and free text related to LBP and health economic evaluations was executed in MEDLINE. Cost utility analyses combined with randomized controlled trials for LBP were included. Studies that were published before 1998, non-English, decision analyses, and duplicate reports were excluded. Search results were evaluated by two reviewers, who extracted data independently related to clinical study design, economic study design, direct cost components, utility results, cost results, and CUA results.ResultsThe search produced 319 citations, and of these 15 met eligibility criteria. Most were from the United Kingdom (n=8), published in the past 3 years (n=12), studied chronic LBP or radiculopathy (n=13), and had a follow-up >12 months (n=13). Combined, there were 33 study groups who received a mean 2.1 interventions, most commonly education (n=17), exercise therapy (n=13), spinal manipulation therapy (n=7), surgery (n=7), and usual care from a general practitioner (n=7). Mean baseline utility was 0.57, improving to 0.67 at follow-up; the mean difference in utility improvement between study groups was 0.04. Based on available data and converted to US dollars, the cost per quality-adjusted life year ranged from $304 to $579,527, with a median of $13,015.ConclusionsFew CUAs were identified for LBP, and there was heterogeneity in the interventions compared, direct cost components measured, indirect costs, other methods, and results. Reporting quality was mixed. Currently published CUAs do not provide sufficient information to assist decision makers. Future CUAs should attempt to measure all known direct cost components relevant to LBP, estimate indirect costs such as lost productivity, have a follow-up period sufficient to capture meaningful changes, and clearly report methods and results to facilitate interpretation and comparison.     

Histological and molecular analysis of the biceps tendon long head post‐tenotomy

Tendinopathy is a vexing clinical problem as its onset and development is often asymptomatic and unrecognized until tendon rupture. While extensively studied in the rotator cuff, Achilles, and patellar tendons, no study to date has examined the histological and molecular characteristics of the tendinopathic biceps long‐head (LHB). The anatomy of the LHB is unique in that it comprises intra‐ and extra‐articular portions, each exposed to differing loading patterns. Eleven LHBs post‐tenotomy were sectioned, fixed in formalin, and stained (H&E; Alcian Blue), and gross structural organization of collagen measured using polarized light microscopy. Protein expression of intra‐ and extra‐articular portions of the tenotomized biceps for IGF‐I, collagen III, and MMP‐1, ‐2, ‐3, and ‐13 was determined with Western blot analyses. The intra‐articular LHB exhibited significantly greater histological evidence of tendinopathy inclusive of increased proteoglycan (p < 0.05) and decreased organization as measured by polarized light microscopy (p < 0.01). The intra‐articular LHB also had significantly increased expression of collagen type III (p < 0.01) and of MMP‐1 and 3 (p < 0.01, p < 0.05 respectively). No significant differences were found for IGF‐I or for MMP‐2 and ‐13. The intra‐articular LHB exhibited histological characteristics of tendinopathy. Protein expression of the intra‐articular LHB did not universally display signs of tendinopathy in comparison to the extra‐articular portion of the tendon. © 2009 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 27:1379–1385, 2009     

Telangiectatic dedifferentiation of a parosteal osteosarcoma

A unique case of parosteal osteosarcoma (POS) of the proximal femur, with areas of telangiectatic dedifferentiation, in a 28-year-old woman is reported. The patient had a 7-week history of pain and swelling in her right thigh. A biopsy diagnosis of POS was established. The patient was treated with two cycles of intra-arterial chemotherapy, followed by limb salvage surgery. Histological examination of the resected specimen showed POS with areas of dedifferentiation composed of high-grade telangiectatic osteosarcoma with associated secondary aneurysmal bone cyst change. Received: 17 April 1998 Revision requested: 11 May 1998 Revision received: 9 May 2000 Accepted: 11 May 2000     

In situ radiotherapy with 111In-pentetreotide. State of the art and perspectives.

111In-pentetreotide (Octreoscan) and other radiolabeled somatostatin analogs are useful in the management of well differentiated neuroendocrine malignancies such as carcinoid or islet cell neoplasms. These radiopeptides bind to membrane bound somatostatin receptors (sst 1-5) which are over-expressed in a wide variety of neoplasms, especially those arising from the neuroectoderm. Imaging advances allow for the noninvasive determination of the presence of sst receptors by combining radioactivity [111Indium with a somatostatin analog, DTPA-D-phe1-octreotide (pentetreotide)]. Radiolabeled somatostatin analogs bind to membrane receptors and internalization of the complex occurs. Auger emitting somatostatin analogs offer a novel and significantly less toxic approach to controlling neoplastic diseases by delivering targeted radiation specifically to receptor bearing cells while sparing receptor negative cells. Responses of 62-69% in 85 patients with metastatic neuroendocrine tumors treated with high dose (6-19.6 GBq) 111In-pentetreotide, specifically targeting tumor somatostatin receptors, have been reported. Objective responses observed included biochemical and radiographic responses with prolonged survival. This article will discuss and review the multi-center data available to date, the mechanisms of action of radiolabeled somatostatin analogs, dosimetry, clinical response parameters, and toxicity.     

Preemptive Plasmapheresis and Recurrence of FSGS in High-Risk Renal Transplant Recipients

Recurrent focal segmental glomerulosclerosis (FSGS) following transplantation is ascribed to the presence of a circulating FSGS permeability factor (FSPF). Plasmapheresis (PP) can induce remission of proteinuria in recurrent FSGS. This study addressed the efficacy of pre-transplant PP in decreasing the incidence of recurrence in high-risk patients. Ten patients at high-risk for FSGS recurrence because of rapid progression to renal failure (n = 4) or prior transplant recurrence of FSGS (n = 6) underwent a course of 8 PP treatments in the peri-operative period. Recurrences were identified by proteinuria >3 g/day and confirmed by biopsy. Seven patients, including all 4 with first grafts and 3 of 6 with prior recurrence, were free of recurrence at follow-up (238-1258 days). Final serum creatinine in 8 patients with functioning kidneys averaged 1.53 mg/dL. FSGS recurred within 3 months in 3 patients, each of whom had lost prior transplants to recurrent FSGS. Two of these progressed to end-stage renal disease (ESRD) and the third has significant renal dysfunction. Based on inclusion criteria, recurrence rates of 60% were expected if no treatment was given. Therefore, PP may decrease the incidence of recurrent FSGS in high-risk patients. Definitive conclusions regarding optimal management can only be drawn from larger, randomized, controlled studies.     

A comparative study of adhesion formation and abdominal wall ingrowth after laparoscopic ventral hernia repair in a porcine model using multiple types of mesh

Background The ideal mesh for laparoscopic ventral hernia repair is not yet identified.Methods We laparoscopically placed polypropylene (PPM), expanded polytetrafluoroethylene (ePTFE), and polyester with antiadhesive collagen layer (PCO) in eight pigs using sutures and tacks for fixation. After 28-day survival, we compared adhesion formation, fibrous ingrowth, and shrinkage among the types of mesh.Results Mean area of adhesions to PCO (8.25%) was less than that to ePTFE (57.14%, p < 0.001) or PPM (79.38%, p < 0.001). Adhesions peel strength was less for PCO (2.3 N) than for PPM (16.1 N, p < 0.001) or ePTFE (8.8 N, p = 0.02). Peel strength of mesh from the abdominal wall was less for ePTFE (1.3 N/cm of mesh width) than for PCO (2.8 N/cm, p = 0.001) or PPM (2.1 N/cm, p = 0.05). ePTFE area (94.4 cm²) was less than that for PCO (118.6 cm², p < 0.001) or PPM (140.7 cm², p < 0.02).Conclusion PCO had fewer and less severe adhesions than ePTFE or PPM while facilitating excellent ingrowth of the adjacent parietal tissue.     

Postoperative epidural morphine for postpartum tubal ligation analgesia

Women undergoing postoperative postpartum tubal ligation (PPTL) often experience considerable pain. We hypothesized that epidural morphine, as part of a multi-modal analgesic regimen, would decrease postoperative pain and the need for systemic analgesia after PPTL. In a double-blinded study, patients were randomized to receive epidural saline or morphine 2 mg, 3 mg, or 4 mg after epidural anesthesia for PPTL. Postoperatively, ibuprofen 600 mg was administered every 6 h and patients could request acetaminophen 325 mg/hydrocodone 10 mg. The primary outcome variable was time to first request for supplemental analgesia. Verbal rating scores for pain and the incidence and severity of side effects were recorded for 24 h. Morphine group subjects requested supplemental analgesia later and received fewer doses compared with the saline group subjects. Peak cramping and incisional verbal rating scores for pain and the area under the verbal rating scores for pain x time curve for cramping pain were less after epidural morphine compared with saline, but there were no differences among morphine groups. Nausea, vomiting, and pruritus occurred more often in all morphine groups and subjects who received morphine 4 mg required treatment for these side effects more frequently than the saline or morphine 2 mg groups. In conclusion, epidural morphine 2 mg as part of a multi-modal analgesic regimen improved analgesia and decreased the need for supplemental analgesics after PPTL. The need to treat side effects with morphine 2 mg was not increased compared to a regimen of oral acetaminophen/opioid/nonsteroidal antiinflammatory analgesics.