Citations

In this study, the first complexes of Zn(II) with the N-benzyloxycar- bonyl-S-alaninato ligand (N-Boc-S-ala) were synthesized. The new complexes were characterized by elemental analysis, conductometric measurements, IR, 1H-NMR, 13C-NMR and 2D-NMR spectroscopy. On the basis of the experimental data, tetrahedral geometry of the Zn(II) complexes was proposed. A very good agreement between the NMR and DFT calculated data was obtained. Investigation of antimicrobial activity of the newly synthesized complexes was also performed. It was established that [Zn(N-Boc-S-ala)2] was selective and acts only on Candida albicans.

Background— Hypertrophic cardiomyopathy (HCM) is the most common genetic heart disease characterized by a diverse clinical and phenotypic spectrum. This study reports the prevalence, morphology, clinical course, and management of an underrecognized subgroup of HCM patients with left ventricular apical aneurysms. Methods and Results— Of 1299 HCM patients, 28 (2%) were identified with left ventricular apical aneurysms, including a pair of identical twins. Aneurysms were recognized at a wide age range (26 to 83 years), including 12 patients (43%) who were ≤50 years of age. Apical aneurysms varied considerably in size (maximum dimension, 10 to 66 mm), were dyskinetic/akinetic with thin rims, and were associated with transmural (and often more extensive) myocardial scarring identified by late gadolinium enhancement cardiovascular magnetic resonance. Apical aneurysms were recognized by echocardiography in only 16 of 28 patients (57%) but by cardiovascular magnetic resonance in the 12 patients undetected by echocardiography. Left ventricular chamber morphology varied; however, 19 patients (68%) showed an “hourglass” contour, with midventricular hypertrophy producing muscular narrowing and intracavitary gradients in 9 patients (74±42 mm Hg). Sarcomeric protein missense mutations known to cause other phenotypic expressions of HCM were present in 3 patients. Over 4.1±3.7 years of follow-up, 12 patients (43%) with left ventricular apical aneurysms experienced adverse disease complications (event rate, 10.5%/y), including sudden death, appropriate implantable cardioverter-defibrillator discharges, nonfatal thromboembolic stroke, and progressive heart failure and death. Conclusions— Patients with left ventricular apical aneurysms represent an underappreciated subset in the heterogeneous HCM disease spectrum with important clinical implications, often requiring a high index of suspicion and cardiovascular magnetic resonance for identification. Apical aneurysms in HCM are associated with substantial cardiovascular morbidity and mortality and raise novel treatment considerations.

Background— There are few published data on the incidence of fatal and nonfatal stroke in American Indians. The aims of this observational study were to determine the incidence of stroke and to elucidate stroke risk factors among American Indians. Methods and Results— This report is based on 4549 participants aged 45 to 74 years at enrollment in the Strong Heart Study, the largest longitudinal, population-based study of cardiovascular disease and its risk factors in a diverse group of American Indians. At baseline examination in 1989 to 1992, 42 participants (age- and sex-adjusted prevalence proportion 1132/100 000, adjusted to the age and sex distribution of the US adult population in 1990) had prevalent stroke. Through December 2004, 306 (6.8%) of 4507 participants without prior stroke suffered a first stroke at a mean age of 66.5 years. The age- and sex-adjusted incidence was 679/100 000 person-years. Nonhemorrhagic cerebral infarction occurred in 86% of participants with incident strokes; 14% had hemorrhagic stroke. The overall age-adjusted 30-day case-fatality rate from first stroke was 18%, with a 1-year case-fatality rate of 32%. Age, diastolic blood pressure, fasting glucose, hemoglobin A 1c, smoking, albuminuria, hypertension, prehypertension, and diabetes mellitus were risk factors for incident stroke. Conclusions— Compared with US white and black populations, American Indians have a higher incidence of stroke. The case-fatality rate for first stroke is also higher in American Indians than in the US white or black population in the same age range. Our findings suggest that blood pressure and glucose control and smoking avoidance may be important avenues for stroke prevention in this population.

Background— Papillary muscle rupture (PMR) is an infrequent but catastrophic complication of acute myocardial infarction (MI). Although always considered, surgical treatment is often denied because of high operative mortality. Moreover, the effects of surgery for PMR on long-term outcome, particularly compared with expected outcome after MI, are undefined. Methods and Results— Fifty-four consecutive patients (age, 70±8 years; 74% male) underwent mitral surgery for post-MI PMR from January 1980 through December 2000. Severe presentation (cardiogenic shock, pulmonary edema, or cardiac arrest) was noted in 91% preoperatively. Performance of coronary artery bypass graft was associated with lower operative mortality (odds ratio, 0.18; 95% CI, 0.04 to 0.83; P =0.011), whereas there was a trend for lower mortality after surgery after 1990 (odds ratio, 0.28; 95% CI, 0.06 to 1.3). Thus, operative mortality (overall, 18.5%) decreased from 67% up to 1990 without coronary artery bypass graft to 8.7% after 1990 with coronary artery bypass graft. Overall 5-year survival was 65±7%, and survival free of congestive heart failure was 52±7%. Five-year survival of 30-day operative survivors was 79±4%, identical ( P =0.24) to that of matched controls with MI (similar age, sex, ejection fraction, MI location, and MI year). Survival free of congestive heart failure was similar in PMR cases and MI controls (10-year survival, 28±8% versus 36±6%; P =0.46). Conclusions— Surgery for post-MI PMR involves a notable operative mortality, but there are recent trends for lower operative risk, particularly with associated coronary artery bypass graft. Long term after surgery, outcome is restored to that of similar MI without PMR. These encouraging observations emphasize the importance of prompt diagnosis and aggressive therapeutic approach for patients incurring PMR after MI.

OBJECTIVE—The purpose of this study was to determine whether implementation of a multicomponent organizational intervention can produce significant change in diabetes care and outcomes in community primary care practices. RESEARCH DESIGN AND METHODS—This was a group-randomized, controlled clinical trial evaluating the practical effectiveness of a multicomponent intervention (TRANSLATE) in 24 practices. The intervention included implementation of an electronic diabetes registry, visit reminders, and patient-specific physician alerts. A site coordinator facilitated previsit planning and a monthly review of performance with a local physician champion. The principle outcomes were the percentage of patients achieving target values for the composite of systolic blood pressure (SBP) <130 mmHg, LDL cholesterol <100 mg/dl, and A1C <7.0% at baseline and 12 months. Six process measures were also followed. RESULTS—Over 24 months, 69,965 visits from 8,405 adult patients with type 2 diabetes were recorded from 238 health care providers in 24 practices from 17 health systems. Diabetes process measures increased significantly more in intervention than in control practices, giving net increases as follows: foot examinations 35.0% (P < 0.0.001); annual eye examinations 25.9% (P < 0.001); renal testing 28.5% (P < 0.001); A1C testing 8.1%(P < 0.001); blood pressure monitoring 3.5% (P = 0.05); and LDL testing 8.6% (P < 0.001). Mean A1C adjusted for age, sex, and comorbidity decreased significantly in intervention practices (P < 0.02). At 12 months, intervention practices had significantly greater improvement in achieving recommended clinical values for SBP, A1C, and LDL than control clinics (P = 0.002). CONCLUSIONS—Introduction of a multicomponent organizational intervention in the primary care setting significantly increases the percentage of type 2 diabetic patients achieving recommended clinical outcomes.

Purpose Adjuvant chemotherapy for resected non–small-cell lung cancer (NSCLC) is now accepted on the basis of several randomized clinical trials (RCTs) that demonstrated improved survival. Although there is strong evidence that adjuvant chemotherapy is effective in stages II and IIIA NSCLC, its utility in stage IB disease is unclear. This report provides a mature analysis of Cancer and Leukemia Group B (CALGB) 9633, the only RCT designed specifically for stage IB NSCLC. Patients and Methods Within 4 to 8 weeks of resection, patients were randomly assigned to adjuvant chemotherapy or observation. Eligible patients had pathologically confirmed T2N0 NSCLC and had undergone lobectomy or pneumonectomy. Chemotherapy consisted of paclitaxel 200 mg/m 2 intravenously over 3 hours and carboplatin at an area under the curve dose of 6 mg/mL per minute intravenously over 45 to 60 minutes every 3 weeks for four cycles. The primary end point was overall survival. Results Three hundred-forty-four patients were randomly assigned. Median follow-up was 74 months. Groups were well-balanced with regard to demographics, histology, and extent of surgery. Grades 3 to 4 neutropenia were the predominant toxicity; there were no treatment-related deaths. Survival was not significantly different (hazard ratio [HR], 0.83; CI, 0.64 to 1.08; P = .12). However, exploratory analysis demonstrated a significant survival difference in favor of adjuvant chemotherapy for patients who had tumors ≥ 4 cm in diameter (HR, 0.69; CI, 0.48 to 0.99; P = .043). Conclusion Because a significant survival advantage was not observed across the entire cohort, adjuvant chemotherapy should not be considered standard care in stage IB NSCLC. Given the magnitude of observed survival differences, CALGB 9633 was underpowered to detect small but clinically meaningful improvements. A statistically significant survival advantage for patients who had tumors ≥ 4 cm supports consideration of adjuvant paclitaxel/carboplatin for stage IB patients who have large tumors.

WAVE2 regulates T cell receptor (TCR)–stimulated actin cytoskeletal dynamics leading to both integrin clustering and affinity maturation. Although WAVE2 mediates integrin affinity maturation by recruiting vinculin and talin to the immunological synapse in an Arp2/3-dependent manner, the mechanism by which it regulates integrin clustering is unclear. We show that the Abl tyrosine kinase associates with the WAVE2 complex and TCR ligation induces WAVE2-dependent membrane recruitment of Abl. Furthermore, we show that WAVE2 regulates TCR-mediated activation of the integrin regulatory guanosine triphosphatase Rap1 via the recruitment and activation of the CrkL–C3G exchange complex. Moreover, we demonstrate that although Abl does not regulate the recruitment of CrkL–C3G into the membrane, it does affect the tyrosine phosphorylation of C3G, which is required for its guanine nucleotide exchange factor activity toward Rap1. This signaling node regulates not only TCR-stimulated integrin clustering but also affinity maturation. These findings identify a previously unknown mechanism by which the WAVE2 complex regulates TCR signaling to Rap1 and integrin activation.

AbstractA venous thromboembolism (VTE) with the subsequent risk of pulmonary embolism is a major concern in the treatment of patients with multiple myeloma with thalidomide. The susceptibility to developing a VTE in response to thalidomide therapy is likely to be influenced by both genetic and environmental factors. To test genetic variation associated with treatment related VTE in patient peripheral blood DNA, we used a custom-built molecular inversion probe (MIP)–based single nucleotide polymorphism (SNP) chip containing 3404 SNPs. SNPs on the chip were selected in “functional regions” within 964 genes spanning 67 molecular pathways thought to be involved in the pathogenesis, treatment response, and side effects associated with myeloma therapy. Patients and controls were taken from 3 large clinical trials: Medical Research Council (MRC) Myeloma IX, Hovon-50, and Eastern Cooperative Oncology Group (ECOG) EA100, which compared conventional treatments with thalidomide in patients with myeloma. Our analysis showed that the set of SNPs associated with thalidomide-related VTE were enriched in genes and pathways important in drug transport/metabolism, DNA repair, and cytokine balance. The effects of the SNPs associated with thalidomide-related VTE may be functional at the level of the tumor cell, the tumor-related microenvironment, and the endothelium. The clinical trials described in this paper have been registered as follows: MRC Myeloma IX: ISRCTN68454111; Hovon-50: NCT00028886; and ECOG EA100: NCT00033332.

Abstract Polarizing effects of productive dendritic cell (DC)–T-cell interactions on DC cytoskeleton have been known in some detail, but the effects on DC membrane have been studied to a lesser extent. We found that T-cell incubation led to DC elongation and segregation of characteristic DC veils to the broader pole of the cell. On the opposite DC pole, we observed a novel membrane feature in the form of bundled microvilli. Each villus was approximately 100 nm in diameter and 600 to 1200 nm long. Microvilli exhibited high density of antigen-presenting molecules and costimulatory molecules and provided the physical basis for the multifocal immune synapse we observed during human DC and T-cell interactions. T cells preferentially bound to this site in clusters often contained both CD4+ and CD8+ T cells.