Citations

Background— Caveolin-1 is a regulator of signaling events originating from plasma membrane microdomains termed caveolae. This study was performed to determine the regulatory role of caveolin-1 on the proliferative events induced by platelet-derived growth factor (PDGF) in vascular smooth muscle cells (VSMCs). Methods and Results— Treatment of VSMCs with PDGF for 24 hours resulted in a loss of caveolin-1 protein expression and plasma membrane–associated caveolae, despite a 3-fold increase in caveolin-1 mRNA. Pretreatment of VSMCs with chloroquine, an inhibitor of lysosomal function, inhibited the PDGF-induced loss of caveolin-1. These studies demonstrated that caveolin-1 was a target of PDGF signaling events. Adenoviral overexpression of caveolin-1 was associated with a switch in PDGF-induced signaling events from a proliferative response to an apoptotic response. This overexpression inhibited PDGF-induced expression of cyclin D1 in the presence of unaffected mitogen-activated protein kinase activation. Conclusions— Taken together, these studies suggest that caveolin-1 is an inhibitor of PDGF proliferative responses and might be capable of transforming PDGF-induced proliferative signals into death signals.

Background and Purpose— The magnitude of inherited risk of stroke may lessen with age, and this would have implications for optimizing genomic approaches to identifying genetic risk factors for stroke. We investigated the relationship between age and inherited risk of stroke. Methods— Family histories of stroke were obtained in systematic interviews with 310 adult men and women with recent CT- or MR-confirmed ischemic stroke. Probability of stroke in first-degree relatives was analyzed by logistic regression, adjusting for sibship size. Results— The probability of having a sibling with stroke increased as proband age at stroke presentation increased. Per decade increase in proband age, the odds ratio was 1.65 (95% confidence interval [CI], 1.20 to 2.28; P =0.002) for a concordant sibling and 1.69 (95% CI, 1.15 to 2.49; P =0.008) for ≥2 first-degree relatives with a history of stroke. Conclusions— Clustering of stroke was not greater in families with probands manifesting symptoms of stroke in earlier than later adulthood. The relationship between proband age and positive family history of stroke does not suggest an upper age-limit cutoff for genomewide linkage studies.

The inflammatory infiltrate in atherosclerotic plaque is composed of T cells and macrophages. CD4 + T cells with a unique phenotype, CD4 + CD28 null , are preferentially recruited into culprit lesions. These T cells are distinct from classic CD4 + CD28 + T cells in gene expression and function, including their ability to mediate cytolysis. In this study, we have investigated the regulation of CD4 + CD28 null T-cell cytolytic function. In patients with acute coronary syndromes (ACS), CD4 + CD28 null T cells express killer immunoglobulin-like receptors (KIRs). KIRs encompass a polymorphic family of receptors that recognize HLA class I molecules and have been implicated in self-tolerance. CD4 + CD28 null T-cell clones from patients with ACS and age-matched controls were compared for their KIR-expression profile. T-cell clones derived from the patients expressed a broader spectrum of KIRs ( P <0.001) with preference for the stimulatory variant, CD158j. Additionally, CD4 + T-cell clones from patients but not those from controls acquired de novo expression of the DAP12 molecule, an adapter chain that transmits CD158j-derived signals. Cumulative expression of CD158j and DAP12 endowed cytolytic competence on CD4 + CD28 null T cells, allowing them to kill in the absence of T-cell receptor triggering. Our data demonstrate that CD4 + CD28 null T cells in ACS are characterized by a unique gene expression profile. Consequently, these T cells acquire cytolytic capability that can bypass the need for T-cell receptor triggering and, thus, impose a threat to self-tolerance.

Three-dimensional kinematics of the ulnohumeral joint under simulated active elbow joint flexion-extension was obtained by using an electromagnetic tacking device. The joint motion was analyzed based on Eulerian angle description. In order to minimize the effect of "downstream cross-talk" on calculation of the three Eulerian angles, an optimal axis to best represent flexion-extension of the elbow joint was established. This axis, on average, is close to the line joining the centers of the capitellum and the trochlear groove. Furthermore, joint laxity under valgus-varus stress was also examined. With the weight of the forearm as the stress, maximums of 7.6° valgus-varus laxity and 5.3° axial rotation laxity were observed within a range of elbow flexion. The results of this study provide useful baseline information on joint laxity for the evaluation of elbow joints with implant replacements and other surgical treatment modalities.

Purpose: To determine if increasing the dose of paclitaxel increases the probability of clinical response, progression-free survival, or overall survival in women who have persistent or recurrent ovarian cancer, and whether doubling the dose of prophylactic filgrastim accompanying the higher paclitaxel dose decreases the frequency of neutropenic fever. Patients and Methods: Consenting patients with persistent, recurrent, or progressing ovarian cancer, despite first-line platinum therapy (but no prior taxane), were randomly assigned to paclitaxel 135 mg/m2, 175 mg/m2, or 250 mg/m2 over 24 hours every 3 weeks. Patients receiving paclitaxel 250 mg/m2 were also randomly assigned to 5 or 10 μg/kg of filgrastim per day subcutaneously. Results: Accession to the paclitaxel 135-mg/m2 arm was closed early. Among the 271 patients on the other regimens with measurable disease, partial and complete response on paclitaxel 250 mg/m2 (36%) was significantly higher than on 175 mg/m2 (27%, P = .027). This difference was more evident among patients who never responded to prior platinum. However, progression-free and overall survival results were similar. The median durations of overall survival were 13.1 and 12.3 months for paclitaxel 175 mg/m2 and 250 mg/m2, respectively. Thrombocytopenia, neuropathy, and myalgia were greater with paclitaxel 250 mg/m2 (P < .05). The incidence of neutropenic fever after the first cycle of paclitaxel 250 mg/m2 was 19% and 18% on the 5-μg/kg and 10-μg/kg filgrastim dose, respectively (22% for paclitaxel 175 mg/m2 without filgrastim). Conclusion: Paclitaxel exhibits a dose effect with regard to response rate, but there is more toxicity and no survival benefit to justify paclitaxel 250 mg/m2 plus filgrastim. Doubling the filgrastim dose from 5 to 10 μg/kg did not reduce the probability of neutropenic fever after high-dose paclitaxel.

Abstract Aneuploid is ubiquitous in multiple myeloma (MM), and 4 cytogenetic subcategories are recognized: hypodiploid (associated with a shorter survival), pseudodiploid, hyperdiploid, and near-tetraploid MM. The hypodiploid, pseudodiploid, and near-tetraploid karyotypes can be referred to as the nonhyperdiploid MM. Immunoglobulin heavy-chain (IgH) translocations are seen in 60% of patients. We studied the relation between aneuploidy and IgH translocations in MM. Eighty patients with MM and abnormal metaphases were studied by means of interphase fluorescent in situ hybridization (FISH) to detect IgH translocations. We also studied a second cohort of 199 patients (Eastern Cooperative Oncology Group [ECOG]) for IgH translocations, chromosome 13 monosomy/deletions (Δ13), and ploidy by DNA content. Mayo Clinic patients with abnormal karyotypes and FISH-detected IgH translocation were more likely to be nonhyperdiploid (89% versus 39%, P &lt; .0001). Remarkably, 88% of tested patients with hypodiploidy (16 of 18) and 90% of tested patients with tetraploidy (9 of 10) had an IgH translocation. ECOG patients with IgH translocations were more likely to have nonhyperdiploid MM by DNA content (68% versus 21%, P &lt; .001). This association was seen predominantly in patients with recurrent chromosome partners to the IgH translocation (11q13, 4p16, and 16q23). The classification of MM into hyperdiploidy and nonhyperdiploidy is dictated largely by the recurrent (primary) IgH translocations in the latter. (Blood. 2003;102:2562-2567)

Abstract Survival is linked to the histopathologic distinction between usual interstitial pneumonia (UIP) and nonspecific interstitial pneumonia (NSIP), the most commonly encountered fibrotic idiopathic interstitial pneumonia. We retrospectively compared the prognostic significance of histopathologic diagnoses, baseline pulmonary function indices, and serial trends in pulmonary function indices (diffusing capacity, FVC, FEV1, the recently defined composite physiologic index) at 6 and 12 months in 104 patients (UIP, n = 63; fibrotic NSIP, n = 41). Survival was lower in UIP than in fibrotic NSIP (p = 0.001) but not in patients with severe functional impairment; mortality during the first 2 years was linked solely to the severity of functional impairment at presentation. The composite physiologic index was the strongest determinant of outcome (p &lt; 0.001). At 6 months, serial diffusing capacity levels (p = 0.003) and histopathologic diagnosis (p = 0.002) were prognostically equivalent. At 12 months, serial pulmonary function trends were the only major prognostic determinant (p &lt; 0.0005 for all variables), with no independent significance associated with the distinction between UIP and fibrotic NSIP. We conclude that at 12 months, serial pulmonary function trends have considerable prognostic value in UIP and NSIP. Their histologic distinction provides no additional prognostic information when pulmonary function trends are clear cut or when functional impairment is severe.