Application of the TIMI risk score for ST-elevation MI in the National Registry of Myocardial Infarction 3

CONTEXT: The Thrombolysis in Myocardial Infarction (TIMI) risk score for ST-elevation myocardial infarction (STEMI) is a simple integer score for bedside risk assessment of patients with STEMI. Developed and validated in multiple clinical trials of fibrinolysis, the risk score has not been validated in a community-based population. OBJECTIVE: To validate the TIMI risk score in a population of STEMI patients reflective of contemporary practice. DESIGN, SETTING, AND PARTICIPANTS: The risk score was evaluated among 84 029 patients with STEMI from the National Registry of Myocardial Infarction 3 (NRMI 3), which collected data on consecutive patients with myocardial infarction (MI) from 1529 US hospitals between April 1998 and June 2000. MAIN OUTCOME MEASURES: Ability of the TIMI risk score to correctly predict risk of death in terms of model discrimination (c statistic) and calibration (agreement of predicted and observed death rates). RESULTS: Patients in NRMI 3 tended to be older, to be more often female, and to have a history of coronary disease more often than those in the derivation set. Forty-eight percent received reperfusion therapy. The TIMI risk score revealed a significant graded increase in mortality with rising score (range, 1.1%-30.0%; P<.001 for trend). The risk score showed strong prognostic capacity overall (c = 0.74 vs 0.78 in derivation set) and among patients receiving acute reperfusion therapy (c = 0.79). Predictive behavior of the risk score was similar between fibrinolytic-treated patients (n = 23 960; c = 0.79) and primary percutaneous coronary intervention patients (n = 15 348; c = 0.80). In contrast, among patients not receiving reperfusion therapy, the risk score underestimated death rates and offered lower discriminatory capacity (c = 0.65). CONCLUSIONS: Sufficiently simple to be practical at the bedside and effective for risk assessment across a spectrum of patients, the TIMI risk score may be useful in triage and treatment of patients with STEMI who are treated with reperfusion therapy.     

The electrical stimulation of carbon nanotubes to provide a cardiomimetic cue to MSCs

Once damaged, cardiac muscle has little intrinsic repair capability due to the poor regeneration potential of remaining cardiomyocytes. One method of overcoming this issue is to deliver functional cells to the injured myocardium to promote repair. To address this limitation we sought to test the hypothesis that electroactive carbon nanotubes (CNT) could be employed to direct mesenchymal stem cell (MSC) differentiation towards a cardiomyocyte lineage. Using a two-pronged approach, MSCs exposed to medium containing CNT and MSCs seeded on CNT based polylactic acid scaffolds were electrically stimulated in an electrophysiological bioreactor. After electrical stimulation the cells reoriented perpendicular to the direction of the current and adopted an elongated morphology. Using qPCR, an upregulation in a range of cardiac markers was detected, the greatest of which was observed for cardiac myosin heavy chain (CMHC), where a 40-fold increase was observed for the electrically stimulated cells after 14 days, and a 12-fold increase was observed for the electrically stimulated cells seeded on the PLA scaffolds after 10 days. Differentiation towards a cardioprogenitor cell was more evident from the western blot analysis, where upregulation of Nkx2.5, GATA-4, cardiac troponin t (CTT) and connexin43 (C43) was seen to occur. This was echoed in immunofluorescent staining, where increased levels of CTT, CMHC and C43 protein expression were observed after electrical stimulation for both cells and cell-seeded scaffolds. More interestingly, there was evidence of increased cross talk between the cells as shown by the pattern of C43 staining after electrical stimulation. These results establish a paradigm for nanoscale biomimetic cues that can be readily translated to other electroactive tissue repair applications.     

Role of interleukin-6 in a glucan-induced model of granulomatous vasculitis

The role of interleukin-6 (IL-6) in granulomatous vasculitis is not well understood. To investigate its involvement in this type of vasculitis a model of glucan-induced pulmonary vasculitis employed interleukin-6 deficient (IL-6-/-) mice. Briefly, IL-6-/- mice and C57B/J6 wild type (IL-6+/+) mice were injected intravenously with a suspension of glucan isolated from the cell wall of bakers yeast which results in a granulomatous vasculitis primarily in the pulmonary vasculature. Histological examination demonstrated no significant difference in the number of infiltrating leukocytes between the IL-6+/+ and IL-6-/- glucan-injured mice. Similar numbers of granulomas were noted in both the IL-6+/+ and IL-6-/- injured animals, while no granulomas were seen in saline injected control mice. Cells recovered from the bronchoalveolar lavage (BAL) fluid were differentially stained and counted. While there was a significant increase in infiltrating leukocytes recovered from the BAL following glucan-induced injury, there was no significant difference between the IL-6+/+ and IL-6-/- mice. In addition, no difference was demonstrated in total protein content in the BAL fluid between IL-6+/+ and IL-6-/- mice. However, myeloperoxidase (MPO) activity in the lungs of the IL-6-/- mice was less than in their IL-6+/+ counterparts suggesting that these animals have a partial defect in their ability to recruit neutrophils in this model. Studies done to look for levels of other cytokines/chemokines in these animals to compensate for the loss of IL-6 revealed that only IL-10 in the sera (p<0.016) and BAL fluid (p<0.05) of IL-6-/- mice was significantly higher then their IL-6+/+-injured counterparts. These studies suggest that IL-6, while possibly involved in early neutrophil accumulation in this model does not appear critical to the development of the TH-2 mediated granulomatous vasculitis.     

Fabrication, mechanical and in vivo performance of polycaprolactone/tricalcium phosphate composite scaffolds

This paper explores the use of selective laser sintering (SLS) for the generation of bone tissue engineering scaffolds from polycaprolactone (PCL) and PCL/tricalcium phosphate (TCP). Different scaffold designs are generated, and assessed from the point of view of manufacturability, porosity and mechanical performance. Large scaffold specimens are produced, with a preferred design, and are assessed through an in vivo study of the critical size bone defect in sheep tibia with subsequent microscopic, histological and mechanical evaluation. Further explorations are performed to generate scaffolds with increasing TCP content. Scaffold fabrication from PCL and PCL/TCP mixtures with up to 50 mass% TCP is shown to be possible. With increasing macroporosity the stiffness of the scaffolds is seen to drop; however, the stiffness can be increased by minor geometrical changes, such as the addition of a cage around the scaffold. In the animal study the selected scaffold for implantation did not perform as well as the TCP control in terms of new bone formation and the resulting mechanical performance of the defect area. A possible cause for this is presented.     

Sexual Function and Quality of Life for Women with Mild‐to‐Moderate Stress Urinary Incontinence

Introduction: Sexual function is affected by stress urinary incontinence with or without pelvic organ prolapse. The aim of the study was to describe the sexual function of women with mild‐to‐moderate stress urinary incontinence, with or without pelvic organ prolapse (up to stage 2) and examine correlations with symptoms and quality of life. This investigation was part of a large, randomized, clinical trial of women with stress urinary incontinence who participated in an exercise intervention. Methods: Women included in the study suffered from stress urinary incontinence as measured by a pad test and were interested in an exercise intervention. All participants underwent assessment for prolapse staging. Instruments included: the Pelvic Organ Prolapse/Urinary Incontinence Sexual Questionnaire (PISQ‐12), Incontinence Quality of Life Questionnaire (I‐QOL), and a health and urinary leakage questionnaire. Results: One hundred and eighty‐seven ambulatory women, aged 20 to 65 years, had a mean sexual function score of 36.9 (standard deviation [SD] 5.9). No significant correlation was found between the sexual function scores and quantity of urinary leakage. A significant correlation existed between the sexual function and I‐QOL scores (P < .001). An additional finding was that women with urgency symptoms were older (P= .04) and had significantly lower sexual function scores (mean 35.7; SD 6.4) than those who did not report urgency (mean 38.7; SD 4.6; P < .001). Discussion: Women with mild‐to‐moderate stress urinary incontinence, without or with lower stages of pelvic organ prolapse, demonstrated good sexual function, which correlated with physical and psychosocial factors. Health professionals need to perform multifaceted intake assessments on women with urinary leakage to customize their health promotion regimen.     

On the biomechanical role of glycosaminoglycans in the aortic heart valve leaflet

While the role of collagen and elastin fibrous components in heart valve valvular biomechanics has been extensively investigated, the biomechanical role of the glycosaminoglycan (GAG) gelatinous-like material phase remains unclear. In the present study, we investigated the biomechanical role of GAGs in porcine aortic valve (AV) leaflets under tension utilizing enzymatic removal. Tissue specimens were removed from the belly region of porcine AVs and subsequently treated with either an enzyme solution for GAG removal or a control (buffer with no enzyme) solution. A dual stress level test methodology was used to determine the effects at low and high (physiological) stress levels. In addition, planar biaxial tests were conducted both on-axis (i.e. aligned to the circumferential and radial axes) and at 45° off-axis to induce maximum shear, to explore the effects of augmented fiber rotations on the fiber–fiber interactions. Changes in hysteresis were used as the primary metric of GAG functional assessment. A simulation of the low-force experimental setup was also conducted to clarify the internal stress system and provide viscoelastic model parameters for this loading range. Results indicated that under planar tension the removal of GAGs had no measureable affect extensional mechanical properties (either on- or 45° off-axis), including peak stretch, hysteresis and creep. Interestingly, in the low-force range, hysteresis was markedly reduced, from 35.96 ± 2.65% in control group to 25.00 ± 1.64% (p < 0.001) as a result of GAG removal. Collectively, these results suggest that GAGs do not play a direct role in modulating the time-dependent tensile properties of valvular tissues. Rather, they appear to be strongly connected with fiber–fiber and fiber–matrix interactions at low force levels. Thus, we speculate that GAGs may be important in providing a damping mechanism to reduce leaflet flutter when the leaflet is not under high tensile stress.