Citations

Background— Recurrent functional mitral regurgitation (MR) has been reported after mitral valve repair with annuloplasty in patients with dilated cardiomyopathy, but the mechanism is not understood completely. The authors sought to identify abnormalities of the mitral valve and left ventricle that are associated with recurrent MR after mitral annuloplasty. Method and Results— In 104 patients with idiopathic dilated cardiomyopathy who underwent annuloplasty for functional MR, basal mitral anterior leaflet angle, distal mitral anterior leaflet angle (ALA tip ), posterior leaflet angle, coaptation depth, tenting area, mitral annular dimensions, left ventricular volumes, and MR severity were quantified by echocardiography before surgery and at 6-month intervals after it. Compared with patients without MR recurrence (n=79), patients with recurrent MR (defined as ≥2+) (n=25) had greater ALA tip ( P <0.001) and basal mitral anterior leaflet angle ( P <0.001), greater coaptation depth and tenting area ( P <0.001), larger left ventricular volumes ( P <0.001), and worse left ventricular ejection fraction ( P <0.05) but similar mitral annular dimensions and postoperative exaggeration in posterior leaflet angle. Multivariable analysis identified postoperative ALA tip as the major determinant of postoperative MR. Receiver operator characteristic curves identified preoperative ALA tip as the best predictor of MR recurrence (area under curve, 0.98). For ALA tip >25°, the sensitivity, specificity, and positive and negative predictive values in predicting recurrent MR were 88%, 94%, 82%, and 93%, respectively. Three distinct patterns of anterior leaflet tethering (minimal, basal, and distal) with an increasing risk of recurrent MR were identified. Conclusions— Posterior leaflet tethering is invariable after mitral annuloplasty, rendering postoperative mitral competence highly dependent on distal anterior leaflet mobility.

Abstract Detailed genomic studies have shown that cytogenetic abnormalities contribute to multiple myeloma (MM) pathogenesis and disease progression. Nevertheless, little is known about the characteristics of MM at the epigenetic level and specifically how microRNAs regulate MM progression in the context of the bone marrow milieu. Therefore, we performed microRNA expression profiling of bone marrow derived CD138+ MM cells versus their normal cellular counterparts and validated data by qRT-PCR. We identified a MM-specific microRNA signature characterized by down-expression of microRNA-15a/-16 and overexpression of microRNA-222/-221/-382/-181a/-181b (P < .01). We investigated the functional role of microRNA-15a and -16 and showed that they regulate proliferation and growth of MM cells in vitro and in vivo by inhibiting AKT serine/threonine-protein-kinase (AKT3), ribosomal-protein-S6, MAP-kinases, and NF-κB-activator MAP3KIP3. Moreover, miRNA-15a and -16 exerted their anti-MM activity even in the context of the bone marrow milieu in vitro and in vivo. These data indicate that microRNAs play a pivotal role in the biology of MM and represent important targets for novel therapies in MM.

Purpose Nonhormonal treatment options have been investigated as treatments for hot flashes, a major clinical problem in many women. Starting in 2000, a series of 10 individual double-blind placebo-controlled studies has evaluated newer antidepressants and gabapentin for treating hot flashes. This current project was developed to conduct an individual patient pooled analysis of the data from these published clinical trials. Patients and Methods Individual patient data were collected from the various study investigators who published their study results between 2000 and 2007. Between-study heterogeneity for study characteristics and patient populations was tested via χ2 tests before a pooled analysis. The primary end point, the change in hot flash activity from baseline to week 4, for each agent was calculated via both weighted and unweighted approaches, using the size of the study as the weight. Basic summary statistics were produced for hot flash score and frequency using the following three statistics: raw change, percent reduction, and whether or not a 50% reduction was achieved. Results This study included seven trials of newer antidepressants and three trials of gabapentin. The optimal doses (defined by individual study results) of the newer antidepressants paroxetine, venlafaxine, fluoxetine, and sertraline decreased hot flash scores by 41%, 33%, 13%, and 3% to 18% compared with the corresponding placebo arms, respectively. The three gabapentin trials decreased hot flashes by 35% to 38% compared with the corresponding placebo arms. Conclusion Some newer antidepressants and gabapentin, within 4 weeks of therapy initiation, decrease hot flashes more than placebo.

The objective of this study was to determine the impact of lupus nephritis disease activity on maternal and foetal outcomes in pregnant patients with systemic lupus erythematosus (SLE). Medical records of all pregnant patients with SLE treated at our institution between 1976 and 2007 were reviewed. All patients met American College of Rheumatology classification criteria for SLE. Demographic data, history of lupus nephritis, nephritis disease activity and maternal and foetal outcomes of pregnancy were abstracted. Active lupus nephritis was defined as the presence of proteinuria >0.5 g/day and/or active urinary sediment with or without an elevation in serum creatinine (Cr). Quiescent lupus nephritis was confirmed in the presence of proteinuria <0.5 mg/day and inactive urinary sediment. We identified 58 patients with 90 pregnancies. Compared with pregnancies in SLE patients without renal involvement ( n = 47), pregnancies in patients with active lupus nephritis ( n = 23) were associated with a higher incidence of maternal complications (57% vs 11%, P < 0.001), whereas those with quiescent lupus nephritis ( n = 20) were not (35% vs 11%, P = 0.10). Women with active lupus nephritis were more likely to deliver preterm than women without lupus nephritis, median of 34 weeks vs 40 gestational weeks, respectively ( P = 0.002) and were more likely to suffer foetal loss (35% vs 9%, P = 0.031). Active, but not quiescent, lupus nephritis during pregnancy is associated with a higher incidence of maternal and foetal complications compared with pregnancies in SLE patients without renal involvement.

Rituximab improves outcomes for persons with lymphoproliferative disorders and is increasingly used to treat immune-mediated illnesses. Recent reports describe 2 patients with systemic lupus erythematosus and 1 with rheumatoid arthritis who developed progressive multifocal leukoencephalopathy (PML) after rituximab treatment. We reviewed PML case descriptions among patients treated with rituximab from the Food and Drug Administration, the manufacturer, physicians, and a literature review from 1997 to 2008. Overall, 52 patients with lymphoproliferative disorders, 2 patients with systemic lupus erythematosus, 1 patient with rheumatoid arthritis, 1 patient with an idiopathic autoimmune pancytopenia, and 1 patient with immune thrombocytopenia developed PML after treatment with rituximab and other agents. Other treatments included hematopoietic stem cell transplantation (7 patients), purine analogs (26 patients), or alkylating agents (39 patients). One patient with an autoimmune hemolytic anemia developed PML after treatment with corticosteroids and rituximab, and 1 patient with an autoimmune pancytopenia developed PML after treatment with corticosteroids, azathioprine, and rituximab. Median time from last rituximab dose to PML diagnosis was 5.5 months. Median time to death after PML diagnosis was 2.0 months. The case-fatality rate was 90%. Awareness is needed of the potential for PML among rituximab-treated persons.

ABSTRACT We analyzed surveillance cultures for vancomycin-resistant enterococci (VRE) and methicillin-resistant Staphylococcus aureus (MRSA) collected during a multicenter trial to determine if three negative cultures collected at weekly intervals would predict clearance of VRE or MRSA from colonized patients. Seventy-two percent of VRE-colonized patients and 94% of MRSA-colonized patients were culture negative after three consecutive negative cultures.

Background and Purpose— The risk of intracranial aneurysm (IA) rupture in asymptomatic members of families who have multiple affected individuals is not known. Methods— First-degree unaffected relatives of those with a familial history of IA who had a history of smoking or hypertension but no known IA were offered cerebral MR angiography (MRA) and followed yearly as part of a National Institute of Neurological Diseases and Stroke-funded study of familial IA (Familial Intracranial Aneurysm [FIA] Study). Results— A total of 2874 subjects from 542 FIA Study families were enrolled. After study enrollment, MRAs were performed in 548 FIA Study family members with no known history of IA. Of these 548 subjects, 113 subjects (20.6%) had 148 IAs by MRA of whom 5 subjects had IA ≥7 mm. Two subjects with an unruptured IA by MRA/CT angiography (3-mm and 4-mm anterior communicating artery) subsequently had rupture of their IA. This represents an annual rate of 1.2 ruptures per 100 subjects (1.2% per year; 95% CI, 0.14% to 4.3% per year). None of the 435 subjects with a negative MRA have had a ruptured IA. Survival curves between the MRA-positive and -negative cohorts were significantly different ( P =0.004). This rupture rate of unruptured IA in the FIA Study cohort of 1.2% per year is approximately 17 times higher than the rupture rate for subjects with an unruptured IA in the International Study of Unruptured Aneurysm Study with a matched distribution of IA size and location 0.069% per year. Conclusions— Small unruptured IAs in patients from FIA Study families may have a higher risk of rupture than sporadic unruptured IAs of similar size, which should be considered in the management of these patients.

Abstract Bladder cancer is the fifth most commonly diagnosed malignancy in the United States and one of the most prevalent worldwide. It harbors a probability of recurrence of &gt;50%; thus, rigorous, long-term surveillance of patients is advocated. Flexible cystoscopy coupled with voided urine cytology is the primary diagnostic approach, but cystoscopy is an uncomfortable, invasive procedure and the sensitivity of voided urine cytology is poor in all but high-grade tumors. Thus, improvements in noninvasive urinalysis assessment strategies would benefit patients. We applied gene expression microarray analysis to exfoliated urothelia recovered from bladder washes obtained prospectively from 46 patients with subsequently confirmed presence or absence of bladder cancer. Data from microarrays containing 56,000 targets was subjected to a panel of statistical analyses to identify bladder cancer-associated gene signatures. Hierarchical clustering and supervised learning algorithms were used to classify samples on the basis of tumor burden. A differentially expressed geneset of 319 gene probes was associated with the presence of bladder cancer (P &lt; 0.01), and visualization of protein interaction networks revealed vascular endothelial growth factor and angiotensinogen as pivotal factors in tumor cells. Supervised machine learning and a cross-validation approach were used to build a 14-gene molecular classifier that was able to classify patients with and without bladder cancer with an overall accuracy of 76%. Our results show that it is possible to achieve the detection of bladder cancer using molecular signatures present in exfoliated tumor urothelia. Further investigation and validation of the cancer-associated profiles may reveal important biomarkers for the noninvasive detection and surveillance of bladder cancer. (Cancer Epidemiol Biomarkers Prev 2009;18(2):444–53)

Purpose Optimal therapy of follicular lymphoma (FL) is not defined. We analyzed a large prospective cohort study to identify current demographics and patterns of care of FL in the United States. Patients and Methods The National LymphoCare Study is a multicenter, longitudinal, observational study designed to collect information on treatment regimens and outcomes for patients with newly diagnosed FL in the United States. Patients were enrolled between 2004 and 2007. There is no study-specific prescribed treatment regimen or intervention. Results Two thousand seven hundred twenty-eight subjects were enrolled at 265 sites, including the 80% of patients enrolled from nonacademic sites. Using the Follicular Lymphoma International Prognostic Index (FLIPI), three distinct groups independent of histologic grade could be defined. Initial therapeutic strategy was: observation, 17.7%; rituximab monotherapy, 13.9%; clinical trial 6.1%; radiation therapy, 5.6%; chemotherapy only, 3.2%; chemotherapy plus rituximab, 51.9%. Chemotherapy plus rituximab regimens were: rituximab plus cyclophosphamide, doxorubicin, vincristine, prednisone, 55.0%; rituximab plus cyclophosphamide, vincristine, and prednisone, 23.1%; rituximab plus fludarabine based, 15.5%; other, 6.4%. The choice to initiate therapy rather than observe was associated with age, FLIPI, stage, and grade (P < .01). Significant differences in treatment (P < .01) across regions of the United States were noted. Contrary to practice guidelines, treatment of stage I FL frequently omits radiation therapy. Conclusion Widely disparate therapeutic approaches are utilized for FL. Initial therapy is deferred in a small subset of patients. There is no single standard of care for the treatment of de novo FL, although antibody use is ubiquitous when therapy is initiated. These disparate approaches to the initial care of patients with FL render a heterogeneous group of patients at relapse.