INHIBITION OF INTEGRIN VLA-3 AND TETRASPANIN CD151 PROTECTS AGAINST NEUTROPHIL-MEDIATED ENDOTHELIAL DAMAGE.

ABSTRACT: Background: The recruitment of neutrophils to sites of localized injury or infection is initiated by changes on the surface of endothelial cells located in proximity to tissue damage. Inflammatory mediators, such as TNF-α, increase surface expression of adhesive ligands and receptors on the endothelial surface to which neutrophils tether and adhere. Neutrophils then transit through the activated endothelium to reach sites of tissue injury with little lasting vascular injury. However, in cases of sepsis, the interaction of endothelial cells with highly activated neutrophils can cause damage vascular damage. The identification of molecules that are essential for neutrophil diapedesis may reveal targets of therapeutic opportunity for preservation of endothelial function in the presence of critical illness. We tested the hypothesis that inhibition of neutrophil ß1 integrin very late antigen-3 (VLA-3; α3ß1) and/or inhibition of the tetraspanin (TM4) family member CD151 would protect against neutrophil-mediated loss of endothelial function. Methods: Blood was obtained from septic patients or healthy donors. Neutrophils were purified, and aliquots were treated with/without proinflammatory molecules. Confluent human umbilical vascular endothelial cells were activated with TNF-α. Electric cell impedance sensing was used to determine monolayer resistance over time after the addition of neutrophils that were treated with blocking antibodies against VLA-3 and/or CD151 or isotype controls. Groups (depending on relevancy) were analyzed by Mann-Whitney U test, Wilcoxon test, or repeated-measures one-way ANOVA. Results: Neutrophils from septic patients and neutrophils activated ex vivo reduced endothelial monolayer resistance to a greater extent than neutrophils from healthy donors. Antibody blockade of VLA-3 and/or CD151 significantly reduced activation-associated endothelial damage. Similar findings were demonstrated on fibronectin, collagen I, collagen IV, and laminin, suggesting that neutrophil surface VLA-3 and CD151 are responsible for endothelial damage regardless of substrata and are likely to be operative in all bodily tissues. Conclusion: This report identifies VLA-3 and CD151 on the activated human neutrophil, which are responsible for damage to endothelial function. Targeting these molecules in vivo may demonstrate preservation of organ function during critical illness.

Radial Sided Triangular Fibrocartilage Complex Tears: A Comprehensive Review.

When evaluating the available literature on the diagnosis and management of triangular fibrocartilage complex tears (TFCC), ulnar tears comprise the major focus of TFCC literature. Radial-sided (Class 1D) tears are seldom researched or discussed. The purpose of this study was to review the methods for identifying and treating radial-sided TFCC lesions, by examining the anatomy of the TFCC, the pathology of its radial portion, diagnostic techniques, and both surgical and nonoperative treatments. The avascular nature of the radial TFCC may influence its healing potential. Magnetic resonance arthrogram is the gold standard for non-invasively diagnosing a radial-sided tear. Non-operative management should be exhausted prior to surgical intervention, which commonly involves an inside-out repair involving radial trans-osseous sutures. Still, the literature is limited by patient sample size and therefore requires a greater population of class 1-D tears to confirm optimal diagnostic and treatment methods.

Modeling response of water quality parameters to land-use and climate change in a temperate, mesotrophic lake.

Lake Auburn, Maine, USA, is a historically unproductive lake that has experienced multiple algal blooms since 2011. The lake is the water supply source for a population of ~60,000. We modeled past temperature, and concentrations of dissolved oxygen (DO) and phosphorus (P) in Lake Auburn by considering the catchment and internal contributions of P as well as atmospheric factors, and predicted the change in lake water quality in response to future climate and land-use changes. A stream hydrology and P-loading model (SimplyP) was used to generate input from two major tributaries into a lake model (MyLake-Sediment) to simulate physical mixing, chemical dynamics, and sediment geochemistry in Lake Auburn from 2013 to 2017. Simulations of future lake water quality were conducted using meteorological boundary conditions derived from recent historical data and climate model projections for high greenhouse-gas emission cases. The effects of future land development on lake water quality for the 2046 to 2055 time period under different land-use and climate change scenarios were also simulated. Our results indicate that lake P enrichment is more responsive to extreme storm events than increasing air temperatures, mean precipitation, or windstorms; loss of fish habitat is driven by windstorms, and to a lesser extent an increasing water temperature; and catchment development further leads to water quality decline. All simulations also show that the lake is susceptible to both internal and external P loadings. Simulation of temperature, DO, and P proved to be an effective means for predicting the loss of water quality under changing land-use and climate scenarios.

A comparison of the analgesic efficacy of Tramadol Contramid OAD versus placebo in patients with pain due to osteoarthritis.

One thousand twenty-eight (1,028) patients with pain due to osteoarthritis (OA) of the knee were enrolled in this multicenter, randomized, double-blind, parallel study designed to assess the analgesic efficacy and safety of Tramadol Contramid OAD compared to placebo. An open-label phase was followed by a double-blind phase, in which a total of 646 patients were randomized to double-blind treatment with placebo or Tramadol Contramid OAD. Patients were titrated to their optimal dose (200mg or 300 mg), which was maintained for 12 weeks. An absolute mean reduction of 3.0+/-2.1 on a Pain Intensity Numerical Rating Scale (PI-NRS) was noted in the Tramadol Contramid OAD treatment group. The difference between active and placebo groups regarding this absolute mean reduction was statistically significant (P<0.001) throughout the study. The responder analysis demonstrated that a significantly greater percentage of patients in the active treatment arm achieved a reduction of >or=1 and >or=2 points on the PI-NRS score by the end of the study (P=0.035). A significantly greater percentage of respondents in the Tramadol Contramid OAD group indicated improvement on both the Patient and Physician Global Impressions of Change (P=0.0002). Both the 200mg and 300 mg doses contributed to the overall superiority of Tramadol Contramid OAD. The most frequent adverse events were consistent with the known side effects of tramadol and were generally mild to moderate in intensity. These results confirm that Tramadol Contramid OAD given once daily is an efficacious and safe treatment for pain due to OA.

Venlafaxine extended release in the short-term treatment of depressed and anxious primary care patients with multisomatoform disorder.

OBJECTIVE: This pilot study explored the efficacy and tolerability of extended-release venlafaxine (venlafaxine ER) in anxious and/or depressed patients with multisomatoform disorder (MSD). METHOD: This 12-week, multicenter, randomized, double-blind study evaluated adult primary care outpatients with MSD and comorbid major depressive disorder, generalized anxiety disorder, or social anxiety disorder (DSM-IV criteria). The intent-to-treat population included 112 patients (venlafaxine ER, N = 55; placebo, N = 57). The primary efficacy variable was the change in the 15-item Patient Health Questionnaire (PHQ-15) somatic symptom severity score. Secondary outcomes included the Hamilton Rating Scale for Depression (HAM-D-17) and for Anxiety (HAM-A), Clinical Global Impressions-Severity of Illness (CGI-S) and -Improvement (CGI-I) scales, McGill Quality of Life Questionnaire Physical Symptoms Scale (MQOL-PS), and Medical Outcomes Study Short-Form 36-Item questionnaire (MOS SF-36). Data were collected from April 2003 to December 2003. RESULTS: The decline by week 12 in PHQ-15 scores was significant (p < .0001) in both groups; however, the difference between the venlafaxine ER and placebo groups (-8.3 vs. -6.6, respectively) was not (p = .097). Improvement was greater with venlafaxine ER than placebo on the PHQ-15 pain subscale (p = .03), SF-36 bodily pain scale (26.1 vs. 14.5, p = .03), MQOL-PS (-11.7 vs. -6.0, p = .02), HAM-A psychic anxiety subscale (p = .02), SF-36 mental component summary (p = .03), time to response (54 vs. 71 days, p = .01), and CGI-I scale (p = .009). Venlafaxine ER was generally well tolerated. CONCLUSION: These results suggest that venlafaxine ER may be effective in relieving some types of somatic physical symptoms, particularly pain, in patients with depression and/or anxiety disorders.