Matrix metalloproteinase abundance in human myocardial fibroblasts: effects of sustained pharmacologic matrix metalloproteinase inhibition

BACKGROUND: A cause-effect relationship has been established between matrix metalloproteinases (MMPs) and left ventricular (LV) myocardial remodeling through the use of pharmacologic MMP inhibitors. However, the direct effects of MMP inhibition on MMPs and endogenous tissue inhibitors of metalloproteinases (TIMPs) in LV human myocardial fibroblasts (LVHMFs) remain unknown. This study measured MMP-2, MMP-9, MMP-13, MT1-MMP, and TIMP-1 release in LVHMFs. METHODS AND RESULTS: LVHMF cultures were established from six individual patients (passages 2-5) and incubated with and without the broad-spectrum MMP inhibitor PD166793 (100 microM) for 12-36 h. While PD166793 did not influence MMP-2 release, MMP-9 levels based on substrate zymography increased at 36 h by over 30% (P < 0.05). TIMP-1 levels increased in a time-dependent manner with no effect from PD166793 incubation. However, the MMP-9/TIMP-1 ratio was increased by over 20% from time-matched values following 12-36 h of exposure to PD166793 (P < 0.05). Similar results obtained after incubation of LVHMF cultures with the broad-spectrum MMP inhibitor Batimastat (BB-94) suggest that these observations are due to a general class effect of broad-spectrum MMP inhibitors. CONCLUSIONS: This study is the first to demonstrate that a selective induction and release of an MMP species occurs with sustained exposure to pharmacologic MMP inhibition in LVHMFs. These observations may have particular importance with respect to controlling this proteolytic system in the context of LV myocardial remodeling.     

The Impact of the Good Behavior Game,a Universal Classroom-Based Preventive Intervention in First and Second Grades,on High-Risk Sexual Behaviors and Drug Abuse and Dependence Disorders into Young Adulthood

The Good Behavior Game (GBG), a method of teacher classroom behavior management, was tested in first- and second-grade classrooms in 19 Baltimore City Public Schools beginning in the 1985–1986 school year. The intervention was directed at the classroom as a whole to socialize children to the student role and reduce aggressive, disruptive behaviors, confirmed antecedents of a profile of externalizing problem outcomes. This article reports on the GBG impact on the courses and interrelationships among aggressive, disruptive behavior through middle school, risky sexual behaviors, and drug abuse and dependence disorders through ages 19–21. In five poor to lower-middle class, mainly African American urban areas, classrooms within matched schools were assigned randomly to either the GBG intervention or the control condition. Balanced assignment of children to classrooms was made, and teachers were randomly assigned to intervention or control. Analyses involved multilevel growth mixture modeling. By young adulthood, significant GBG impact was found in terms of reduced high-risk sexual behaviors and drug abuse and dependence disorders among males who in first grade and through middle school were more aggressive, disruptive. A replication with the next cohort of first-grade children with the same teachers occurred during the following school year, but with minimal teacher mentoring and monitoring. Findings were not significant but generally in the predicted direction. A universal classroom-based prevention intervention in first- and second-grade classrooms can reduce drug abuse and dependence disorders and risky sexual behaviors.     

A randomized phase II trial of tacrolimus,mycophenolate mofetil and sirolimus after non-myeloablative unrelated donor transplantation

The study is a randomized phase II trial investigating graft-versus-host disease prophylaxis after non-myeloablative (90 mg/m² fludarabine and 2 Gy total body irradiation) human leukocyte antigen matched unrelated donor transplantation. Patients were randomized as follows: arm 1 – tacrolimus 180 days and mycophenolate mofetil 95 days (n=69); arm 2 – tacrolimus 150 days and mycophenolate mofetil 180 days (n=71); arm 3 – tacrolimus 150 days, mycophenolate mofetil 180 days and sirolimus 80 days (n=68). All patients had sustained engraftment. Grade II-IV acute graft-versus-host disease rates in the 3 arms were 64%, 48% and 47% at Day 150, respectively (arm 3 vs. arm 1 (hazard ratio 0.62; P=0.04). Owing to the decreased incidence of acute graft-versus-host disease, systemic steroid use was lower at Day 150 in arm 3 (32% vs. 55% in arm 1 and 49% in arm 2; overall P=0.009 by hazard ratio analysis). The Day 150 incidence of cytomegalovirus reactivation was lower in arm 3 (arm 1, 54%; arm 2, 47%; arm 3, 22%; overall P=0.002 by hazard ratio analysis). Non-relapse mortality was comparable in the three arms at two years (arm 1, 26%; arm 2, 23%; arm 3, 18%). Toxicity rates and other outcome measures were similar between the three arms. The addition of sirolimus to tacrolimus and mycophenolate mofetil is safe and associated with lower incidence of acute graft-versus-host disease and cytomegalovirus reactivation. (clinicaltrials.gov identifier: 00105001).     

Risk Selection into Consumer‐Directed Health Plans: An Analysis of Family Choices within Large Employers

Objective

To identify the degree of selection into consumer-directed health plans (CDHPs) versus traditional plans over time, and factors that influence choice and temper risk selection.

Data Sources/Study Setting

Sixteen large employers offering both CDHP and traditional plans during the 2004–2007 period, more than 200,000 families.

Study Design

We model CDHP choice with logistic regression; predictors include risk scores, in addition to family, choice setting, and plan characteristics. Additional models stratify by account type or single enrollee versus family.

Data Collection/Extraction Methods

Risk scores, family characteristics, and enrollment decisions are derived from medical claims and enrollment files. Interviews with human resources executives provide additional data.

Principal Findings

CDHP risk scores were 74 percent of traditional plan scores in the first year, and this difference declined over time. Employer contributions to accounts and employee premium savings fostered CDHP enrollment and reduced risk selection. Having to make an active choice of plan increased CDHP enrollment but also increased risk selection. Risk selection was greater for singles than families and did not differ between HRA and HSA-based CDHPs.

Conclusions

Risk selection was not severe and it was well managed. Employers have effective methods to encourage CDHP enrollment and temper selection against traditional plans.     

Association of sleep apnea with clinically silent microvascular brain tissue changes in acute cerebral ischemia

The aim of this study was to determine the importance of sleep apnea in relation to clinically silent microvascular brain tissue changes in patients with acute cerebral ischemia. Patients with acute cerebral ischemia prospectively underwent nocturnal respiratory polygraphy within 5 days from symptom-onset. Sleep apnea was defined as apnea–hypopnea-index (AHI) ≥5/h. Experienced readers blinded to clinical and sleep-related data reviewed brain computed tomography and magnetic resonance imaging scans for leukoaraiosis and chronic lacunar infarctions. Ischemic lesions were considered clinically silent when patients did not recall associated stroke-like symptoms. Functional outcome was assessed with modified Rankin Scale at discharge, 6 and 12 months. Fifty-one of 56 (91 %) patients had sleep apnea of any degree. Patients with moderate-to-severe leukoaraiosis (Wahlund score ≥5) were found to have higher mean AHI than those with none or mild leukoaraiosis (34.4 vs. 12.8/h, p < 0.001). Moderate-to-severe sleep apnea (AHI ≥15/h) was found to be an independent predictor of moderate-to-severe leukoaraiosis (adjusted OR 6.03, 95 % CI 1.76–20.6, p = 0.0042) and of moderate-to-severe leukoaraiosis associated with clinically silent chronic lacunar infarctions (adjusted OR 10.5, 95 % CI 2.19–50.6, p = 0.003). The higher the Wahlund score and the AHI, the more likely unfavorable functional outcome resulted over time (p = 0.0373). In acute cerebral ischemia, sleep apnea is associated with clinically silent microvascular brain tissue changes and may negatively influence functional outcome. Routine sleep apnea screening and further investigation of possible long-term effects of non-invasive ventilatory treatment of sleep apnea appear warranted in this at-risk population.     

Peripheral nerve morphogenesis induced by scaffold micropatterning

Several bioengineering approaches have been proposed for peripheral nervous system repair, with limited results and still open questions about the underlying molecular mechanisms. We assessed the biological processes that occur after the implantation of collagen scaffold with a peculiar porous micro-structure of the wall in a rat sciatic nerve transection model compared to commercial collagen conduits and nerve crush injury using functional, histological and genome wide analyses. We demonstrated that within 60 days, our conduit had been completely substituted by a normal nerve. Gene expression analysis documented a precise sequential regulation of known genes involved in angiogenesis, Schwann cells/axons interactions and myelination, together with a selective modulation of key biological pathways for nerve morphogenesis induced by porous matrices. These data suggest that the scaffold's micro-structure profoundly influences cell behaviors and creates an instructive micro-environment to enhance nerve morphogenesis that can be exploited to improve recovery and understand the molecular differences between repair and regeneration.