P38 MAPK inhibitors suppress biomarkers of hypertension end-organ damage, osteopontin and plasminogen activator inhibitor-1.

The assessment of target organ damage is important in defining the optimal treatment of hypertension and blood pressure-related cardiovascular disease. The aims of the present study were (1) to investigate candidate biomarkers of target organ damage, osteopontin (OPN) and plasminogen activator inhibitor-1 (PAI-1), in models of malignant hypertension with well characterized end-organ pathology; and (2) to evaluate the effects of chronic treatment with a p38 MAPK inhibitor. Gene expression, plasma concentrations, and renal immunohistochemical localization of OPN and PAI-1 were measured in stroke-prone spontaneously hypertensive rats on a salt-fat diet (SFD SHR-SP) and in spontaneously hypertensive rats receiving N(omega)-nitro-L-arginine methyl ester (L-NAME SHR). Plasma concentrations of OPN and PAI-1 increased significantly in SFD SHR-SP and L-NAME SHR as compared with controls, (2.5-4.5-fold for OPN and 2.0-9.0-fold for PAI-1). The plasma levels of OPN and PAI-1 were significantly correlated with the urinary excretion of albumin (p < 0.0001). Elevations in urinary albumin, plasma OPN and PAI-1 were abolished by chronic treatment (4-8 weeks) with a specific p38 MAPK inhibitor, SB-239063AN. OPN immunoreactivity was localized predominantly in the apical portion of tubule epithelium, while PAI-1 immunoreactivity was robust in glomeruli, tubules and renal artery endothelium. Treatment with the p38 MAPK inhibitor significantly reduced OPN and PAI-1 protein expression in target organs. Kidney gene expression was increased for OPN (4.9- and 7.9-fold) and PAI-1 (2.8- and 11.5-fold) in SFD SHR-SP and L-NAME SHR, respectively. In-silico pathway analysis revealed that activation of p38 MAPK was linked to OPN and PAI-1 via SPI, c-fos and c-jun; suggesting that these pathways may play an important role in p38 MAPK-dependent hypertensive renal dysfunction. The results suggest that enhanced OPN and PAI-1 expression reflects end-organ damage in hypertension and that suppression correlates with end-organ protection regardless of overt antihypertensive action.

Differential alterations in 5alpha-reductase type 1 and type 2 levels during development and progression of prostate cancer.

BACKGROUND: In the prostate, conversion of testosterone to dihydrotestosterone (DHT), by the enzymes 5alpha-reductase types 1 and 2 (5alphaR1, 5alphaR2) is required for normal growth and probably also for development of prostate cancer (PCa). Finasteride, a 5alphaR2 inhibitor, was shown to reduce the prevalence of PCa in the Prostate Cancer Prevention Trial. However, inhibition of both 5alphaR isoenzymes causes a greater decrease in serum DHT. The aim of this study was to assess differential expression of these enzymes at various stages of PCa development. METHODS: Immunostaining for 5alphaR1 and 5alphaR2, using specific, well-validated antibodies, was evaluated in 26 benign prostatic hyperplasia (BPH) (16 for 5alphaR2), 53 primary PCa (21 for 5alphaR2), 18 prostatic intraepithelial neoplasia (PIN), 12 primary PCa treated with neoadjuvant androgen ablation, 15 locally recurrent PCa specimens, and 18 PCa metastases. RESULTS: The mean area of moderate plus high intensity staining for 5alphaR1 increased from 4.8 +/- 2.8% of total epithelial area in BPH, to 18.9 +/- 5.7% in PIN, 17.0 +/- 3.2% in primary cancer, 38.0 +/- 7.3% in recurrent cancer, and 55.8 +/- 8.5% in PCa metastases. The mean staining area for 5alphaR2 decreased from 58.8 +/- 7.2% in BPH, to 21.1 +/- 5.5% in PIN and 34.8 +/- 6.7% in primary PCa. Staining for 5alphaR2 was increased in recurrent cancer and PCa metastases compared to primary PCa, at 58.7 +/- 5.2% and 69.2 +/- 8.7%, respectively. CONCLUSIONS: 5alphaR1 immunostaining is increased and 5alphaR2 immunostaining is decreased during development of PCa. In addition, there is increased expression of both 5alphaR isozymes in recurrent and metastatic cancers, suggesting that both isozymes may be important in the development and progression of PCa.

The trio guanine nucleotide exchange factor is a RhoA target. Binding of RhoA to the trio immunoglobulin-like domain.

Trio is a complex protein containing two guanine nucleotide exchange factor domains each with associated pleckstrin homology domains, a serine/threonine kinase domain, two SH3 domains, an immunoglobulin-like domain, and spectrin-like repeats. Trio was originally identified as a LAR tyrosine phosphatase-binding protein and is involved in actin remodeling, cell migration, and cell growth. Herein we provide evidence that Trio not only activates RhoA but is also a RhoA target. The RhoA-binding site was mapped to the Trio immunoglobulin-like domain. RhoA isoprenylation is necessary for the RhoA-Trio interaction, because mutation of the RhoA carboxyl-terminal cysteine residue blocked binding. The existence of an intramolecular functional link between RhoA activation and RhoA binding is suggested by the finding that Trio exchange activity enhanced RhoA binding to Trio. Furthermore, immunofluorescence studies of HeLa cells showed that although ectopically expressed Trio was evenly distributed within the cell, co-expression of Trio with RhoA resulted in relocalization of Trio into punctate structures. Relocalization was not observed with Trio constructs lacking the immunoglobulin-like domain, indicating that RhoA acts to regulate Trio localization via binding to the immunoglobulin-like domain. We propose that Trio-mediated RhoA activation and subsequent RhoA-mediated relocalization of Trio functions to modulate and coordinate Trio signaling.

What is the paradigm: hospital or home health care for pressure ulcers?

A home health care (HHC) referral should link the patient in a cost-effective fashion to the physician, home care, and instructions regarding ulcer management. Twenty-one patients (mean age, 74.6 years) had stage III pressure ulcers (<100 cm2) and an involved family member at home. Risk and contributing factors included cardiac disease (n = 9), hypertension (n = 14), end-stage renal disease (n = 7), smoking (n = 11), diabetes (n = 8), chronic brain syndrome (n = 14), cerebrovascular accident (n = 5), and above-the-knee amputation (n = 2). Treatment regimens included standard wound care, pressure relief and, where appropriate, culture-specific antibiotics, as well as a rehabilitation program. Home care progressively decreased the frequency of the nurse HHC and physician office visits. Resolution of the pressure ulcer varied from 6 to 32 weeks. Only two patients had progression of their wound and required hospital readmission. The billable fees included: 1) an office visit, $30.00 (medicare reimbursement, $14.00); 2) the HHC nurse visit, $159.00 (medicare reimbursement, $105.00); 3) supplies, $75.00 to $150.00/week (variable reimbursement); 4) hospitalization, $400.00 to $900.00/day; and 5) a chronic-care bed, $400.00 to $750.00/day. HHC, given a responsible support team and an involved family member, was more socially and financially acceptable than an inpatient facility. Intermittent physician visits with HHC proved safe and reliable, with 90 per cent successfully healing their wounds.

Epidemiology, risk factors, and management of peripheral vascular disease.

Peripheral vascular occlusive disease is initiated with a genetic risk factor component compounded by patient-controlled contributions including obesity, diabetes, hypertension, and smoking. Medical management of these factors may delay or obviate surgical intervention. Angiography may be used to perform angioplasty (+/- stents) or to guide various interventional procedures. The major contribution to pre- and post-operative assessment is the noninvasive laboratory.

Axillobifemoral bypass: elective versus emergent operation.

Axillobifemoral bypass (AxBFB) is considered an inferior operation because of comparatively poor long-term results. One factor that has not been considered in the literature is whether or not the operation is performed electively or for acute ischemia (< 24 hours duration). This may be a more important predictor of poor results than previously recognized. During the last 10 years, we have performed 59 AxBFB. In Group A, 41 patients (mean age 71) underwent elective AxBFB and in Group B, 18 patients (mean age 65) had emergency AxBFB. Indications for surgery in Group A were limb-threatening ischemia (30), infected aortic graft (5), and severe claudication (6); in Group B, indications for surgery were acute limb ischemia (16), and aortoduodenal fistula (2). Primary patency (p < 0.002), limb salvage (p < 0.002), and survival (p < 0.03) were significantly better in Group A versus Group B. We conclude that an AxBFB performed electively provides satisfactory palliation of severe vascular disease in high-risk patients. The indications for operation and timing of the operation may explain the widely disparate clinical results reported in the literature.