Citations

Background and Purpose— Epidemiological studies have found strong correlations between elevated plasma fibrinogen levels and both ischemic stroke incidence and stroke mortality. Little is known about the influence of fibrinogen levels on functional stroke outcome. Methods— Placebo data from the Stroke Treatment with Ancrod Trial (STAT) and European Stroke Treatment with Ancrod Trial (ESTAT) were analyzed. Fibrinogen levels were determined within 3 hours (STAT) or 6 hours (ESTAT) of stroke onset and at preset intervals throughout 5 days of intravenous infusions. Barthel Index scores at 90 days quantified functional outcomes. The association between initial fibrinogen levels and functional outcomes was evaluated using a multiple logistic regression analysis. Results— Fibrinogen levels increased gradually over the first 24 hours from a pretreatment median value of 340 mg/dL to a 24-hour median value of 376 mg/dL. In a univariate analysis, the proportion of patients with good functional outcome decreased with increasing quartiles of initial fibrinogen levels in both STAT (36.0% to 26.2%) and ESTAT (53.8% to 24.8%). In a multifactorial analysis, the same trend was observed. Patients with initial fibrinogen levels <450 mg/dL had better outcomes in both studies; the difference (42.0% versus 21.6%) was significant in ESTAT ( P =0.0006), even when corrected for age and initial stroke severity. Conclusion— The independent association of higher initial fibrinogen levels with poor outcome needs to be verified using a larger acute stroke dataset. Even in the present small populations, the apparent association of these 2 variables suggests that treatments designed to reduce fibrinogen levels could potentially be important in treating acute ischemic stroke.

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.

Over the past 50 years, survival has improved in patients with systemic lupus erythematosus and associated nephritis. Yet, there are few long-term outcome studies in patients with well-defined nephropathy. We examinbed the outcome of 439 patients with lupus nephritis who were seen at the Mayo Clinic between 1964 and 1986 in whom renal biopsies were assessed using the World Health Organization (WHO) classification. There were 341 women and 98 men (mean ± s.d., age 33.5 ± 14 years); 200 (46%) patients were hypertensive and 249 (57%) had impaired renal function at renal biopsy. All WHO morphologic classes were represented and 339 (77%) patients had class III, IV and V (the more severe forms of nephritis). Follow-up averaged 10.2 years per patient. At last contact, 286 (65%) patients were alive and 153 (35%) were dead. Overall patient survival was 80%, 69% and 53% at 5, 10 and 20 years after biopsy that was significantly worse than expected survival (P < 0.001). Ten-year cumulative patient survival improved comparing earlier to more recent time spans: 64% in 231 patients seen during 1964-75; 76% in 2089 patients studied during 1976-86 (P = 0.03). Survival free of renal failure was 83%, 74% and 64% at 5, 10 and 20 years, and survival was unfavorably influenced by progressive WHO class, hypertension, impaired renal function, nephrotic range proteinuria, hypoalbuminemia and anemia. Multivariate analysis found impaired renal function, increased urine protein, anemia and younger age to be independent predictors of renal failure. WHO class was not a significant predictor when adjusted for these four factors. Cardiovascular events accounted for 48% of the known deaths and were equally distributed across all WHO classes, followed by infections, renal failure, malignancy, respiratory failure and gastrointestinal bleeding. Severe nephritis, nephrotic syndrome, hypertension and anemia remain strong predictors of a poor renal outcome. Prospective randomized studies stratifying for these factors are needed to find optimal immunosuppressive regimens to improve renal survival.

ABSTRACT Human immunodeficiency virus type 1 (HIV-1) infection causes apoptosis of infected CD4 T cells as well as uninfected (bystander) CD4 and CD8 T cells. It remains unknown what signals cause infected cells to die. We demonstrate that HIV-1 protease specifically cleaves procaspase 8 to create a novel fragment termed casp8p41, which independently induces apoptosis. casp8p41 is specific to HIV-1 protease-induced death but not other caspase 8-dependent death stimuli. In HIV-1-infected patients, casp8p41 is detected only in CD4 + T cells, predominantly in the CD27 + memory subset, its presence increases with increasing viral load, and it colocalizes with both infected and apoptotic cells. These data indicate that casp8p41 independently induces apoptosis and is a specific product of HIV-1 protease which may contribute to death of HIV-1-infected cells.

Abstract This multicenter, open-label, randomized phase 2 study evaluated 2 dose regimens of lenalidomide for relapsed, refractory myeloma. Seventy patients were randomized to receive either 30 mg once-daily or 15 mg twice-daily oral lenalidomide for 21 days of every 28-day cycle. Patients with progressive or stable disease after 2 cycles received dexamethasone. Analysis of the first 70 patients showed increased grade 3/4 myelo-suppression in patients receiving 15 mg twice daily (41% versus 13%, P = .03). An additional 32 patients received 30 mg once daily. Responses were evaluated according to European Group for Blood and Marrow Transplantation (EBMT) criteria. Overall response rate (complete, partial, or minor) to lenalidomide alone was 25% (24% for once-daily and 29% for twice-daily lenalidomide). Median overall survival in 30-mg once-daily and twice-daily groups was 28 and 27 months, respectively. Median progression-free survival was 7.7 months on once-daily versus 3.9 months on twice-daily lenalidomide (P = .2). Dexamethasone was added in 68 patients and 29% responded. Time to first occurrence of clinically significant grade 3/4 myelosuppression was shorter in the twice-daily group (1.8 vs 5.5 months, P = .05). Significant peripheral neuropathy and deep vein thrombosis each occurred in only 3%. Lenalidomide is active and well tolerated in relapsed, refractory myeloma, with the 30-mg once-daily regimen providing the basis for future studies as monotherapy and with dexamethasone.

Background The triceps tendon has been described as a single unit with contribution from each of the 3 heads of the muscle. An observation at the time of surgical repair of a triceps tendon injury led to an anatomical study to further define the anatomy of this tendon as it inserts on the olecranon. Hypothesis The medial head of the triceps has a tendon that is distinct from, and deep to, the common tendon of the long and lateral heads. Study Design Descriptive laboratory study and case report. Methods Eight cadaveric elbows were dissected to examine the triceps tendon. None of the specimens had any evidence of prior injury or surgery to the elbow. All specimens were fresh-frozen and stored at–4°C until they were thawed for use. Skin and subcutaneous tissue were removed, and the tendon of each head of the triceps was explored from the muscle to its bony insertion. Results In all 8 specimens, on gross inspection, the medial head had a separate insertion deep to the common insertion of the lateral and long heads. The muscle of the medial head extended further distally than did the long and lateral heads. The medial head was muscular to its deep insertion, with a small amount of tendon blended with the muscle distally. Histologic analysis demonstrated that the tendon of the medial head and that of the other 2 heads are confluent distally at their olecranon insertion. Conclusion The medial head of the triceps has a tendon that is distinct from, and deep to, the common tendon of the long and lateral heads on gross inspection. Histologic studies show the insertion of these 2 tendons is confluent. Clinical Relevance This anatomy has important implications for surgical repair of these tendon injuries. Rupture of the deep triceps insertion alone can occur and lead to weakness of elbow extension with the elbow flexed beyond 90°. Triceps strength should be tested with the elbow fully flexed when injury to the tendinous insertion is suspected.

AbstractPrevious studies have demonstrated the in vitro and in vivo activity of CC-5013 (Revlimid), an immunomodulatory analog (IMiD) of thalidomide, in multiple myeloma (MM). In the present study, we have examined the anti-MM activity of rapamycin (Rapamune), a specific mTOR inhibitor, combined with CC-5013. Based on the Chou-Talalay method, combination indices of less than 1 were obtained for all dose ranges of CC-5013 when combined with rapamycin, suggesting strong synergism. Importantly, this combination was able to overcome drug resistance when tested against MM cell lines resistant to conventional chemotherapy. Moreover, the combination, but not rapamycin alone, was able to overcome the growth advantage conferred on MM cells by interleukin-6 (IL-6), insulin-like growth factor-1 (IGF-1), or adherence to bone marrow stromal cells (BMSCs). Combining rapamycin and CC-5013 induced apoptosis of MM cells. Differential signaling cascades, including the mitogen-activated protein kinase (MAPK) and the phosphatidylinositol 3′-kinase/Akt kinase (PI3K/Akt) pathways, were targeted by these drugs individually and in combination, suggesting the molecular mechanism by which they interfere with MM growth and survival. These studies, therefore, provide the framework for clinical evaluation of mTOR inhibitors combined with IMiDs to improve patient outcome in MM.