Citations

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.

OBJECTIVE. The aim of this study was to report the incidence rates and other epidemiologic characterizations of written-language disorder. There have been no epidemiologic studies on the incidence of written-language disorder in the United States, and the use of a population-based birth cohort, longitudinally followed, is the most powerful method for reaching this objective.METHODS. In this population-based, retrospective birth cohort study, subjects included 5718 children born between 1976 and 1982 in Rochester, Minnesota, who remained in the community after 5 years of age. Records from all public and nonpublic schools, medical facilities, and private tutorial services were reviewed and results of all individually administered IQ and achievement tests, and extensive medical, educational, and socioeconomic information, were collected. The essential features of writing problems from the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision were included in our operationalized definition of written-language disorder. Written-language disorder incident cases were established by using research criteria based on 3 formulas (regression-based discrepancy, nonregression-based discrepancy, and low achievement).RESULTS. Cumulative incidence rates of written-language disorder varied from 6.9% to 14.7% depending on the formula. Boys were 2 to 3 times more likely to be affected than girls regardless of the formula. Among all written-language disorder cases (N = 806), 25% (n = 203) had written-language disorder without a reading disability. Specifics of the writing problems were identified for 87% (n = 702) of written-language disorder cases.CONCLUSIONS. In this population-based birth cohort of school-aged children, written-language disorder was at least as frequent as reading disabilities and significantly more frequent among boys than girls.

Object The pathophysiology of myocardial dysfunction after subarachnoid hemorrhage (SAH) remains unclear. Using myocardial real-time perfusion contrast echocardiography (RTP-CE), the authors evaluated microvascular function in patients with acute SAH. Methods Over a 15-month period, 10 patients with acute SAH and evidence of cardiac dysfunction were prospectively enrolled. The authors performed RTP-CE within 48 hours of SAH diagnosis. Wall motion and myocardial perfusion were evaluated in 16 left ventricle segments. Qualitative and quantitative RTP-CE analyses were conducted to compare patients with and without regional wall motion abnormalities (RWMAs). Follow-up RTP-CE at a mean of 53.7 ± 43 days was undertaken in patients with baseline RWMAs. Results Ten patients with SAH and evidence of cardiac dysfunction were prospectively enrolled. There were 3 men and 7 women whose mean age was 63.5 ± 10.1 years. The authors documented evidence of RWMAs in 6 patients. Normal perfusion was demonstrated by RTP-CE in all patients at baseline and follow-up, despite the presence of RWMAs. Compared with patients presenting with normal wall motion, in patients with RWMAs there was a trend for higher quantitative RTP-CE parameters, suggesting hyperemia with mean myocardial blood flow velocity (β, s−1) of 1.08 ± 0.61 (95% CI 0–2.61) compared with 1.62 ± 0.64 (95% CI 0.94–2.29) and myocardial blood flow (A × β, dB/s) of 0.99 ± 0.41 (95% CI 0–2.0) versus 1.63 ± 0.86 (95% CI 0.72–2.53). Follow-up RTP-CE was feasible in 3 patients with RWMAs. Regional systolic function was restored in those who completed follow-up. Conclusions The authors found that RTP-CE readily evaluates microvascular function in patients with SAH. Wall motion and perfusion dissociation were observed. Quantitative RTP-CE showed a trend for microvascular hyperemia in patients with RWMAs, suggesting that post-SAH myocardial dysfunction could occur in the absence of microvascular dysfunction.

ABSTRACTWe previously reported that mitogenic activation of porcine peripheral blood mononuclear cells resulted in production of porcine endogenous retrovirus(es) (PERV[s]) capable of productively infecting human cells (C. Wilson et al., J. Virol. 72:3082–3087, 1998). We now extend that analysis to show that additional passage of isolated virus, named here PERV-NIH, through a human cell line yielded a viral population with a higher titer of infectious virus on human cells than the initial isolate. We show that in a single additional passage on a human cell line, the increase in infectivity for human cells is accounted for by selection against variants carrying pig-tropic envelope sequences (PERV-C) as well as by enrichment for replication-competent genomes. Sequence analysis of the envelope cDNA present in virions demonstrated that the envelope sequence of PERV-NIH is related to but distinct from previously reported PERV envelopes. The in vitro host range of PERV was studied in human primary cells and cell lines, as well as in cell lines from nonhuman primate and other species. This analysis reveals three patterns of susceptibility to infection among these host cells: (i) cells are resistant to infection in our assay; (ii) cells are infected by virus, as viral RNA is detected in the supernatant by reverse transcription-PCR, but the cells are not permissive to productive replication and spread; and (iii) cells are permissive to low-level productive replication. Certain cell lines were permissive for efficient productive infection and spread. These results may prove useful in designing appropriate animal models to assess the in vivo infectivity properties of PERV.

ABSTRACT Mutations that negatively or positively affect the fusion properties of murine leukemia viruses (MLVs) have been found within all subdomains of their SU (surface) and TM (transmembrane) envelope units. Yet, the interrelations between these different regions of the envelope complex during the cell entry process are still elusive. Deletion of the histidine residue of the conserved PHQV motif at the amino terminus of the amphotropic or the ecotropic MLV SU resulted in the AdelH or the MOdelH fusion-defective mutant envelope, respectively. These delH mutant envelopes are incorporated on retroviral particles at normal densities and normally mediate virion binding to cells expressing the retroviral receptors. However, both their cell-cell and virus-cell fusogenicities were fully prevented at an early postbinding stage. We show here that the fusion defect of AdelH or MOdelH envelopes was also almost completely reverted by providing either soluble SU or a polypeptide encompassing the receptor-binding domain (RBD) to the target cells, provided that the integrity of the amino-terminal end of either polypeptide was preserved. Restoration of delH envelope fusogenicity was caused by activation of the target cells via specific interaction of the latter polypeptides with the retrovirus receptor rather than by their association with the delH envelope complexes. Moreover crossactivation of the target cells, leading to fusion activation of AdelH or MOdelH envelopes, was achieved by polypeptides containing various type C mammalian retrovirus RBDs, irrespective of the type of entry-defective glycoprotein that was used for infection. Our results indicate that although they recognize different receptors for binding to the cell surface, type C mammalian retroviruses use a common entry pathway which is activated by a conserved feature of their envelope glycoproteins.

ABSTRACT Introduction Personal digital assistant (PDA)-based continuing medical education (CME) activities have become widely available. Aims To evaluate the effectiveness of print- and PDA-based CME materials in erectile dysfunction (ED). Methods CME materials describing links between ED and comorbid medical conditions, effects of certain lifestyle modifications on ED, and treatment of ED with phosphodiesterase 5 (PDE5) inhibitors were distributed as a print supplement and as electronic modules, viewed with PDAs. We evaluated how effectively these materials improved evidence-based clinical choices, using survey questions about case vignettes and comparing responses of CME participants (N = 85) and matched nonparticipants (N = 94). Main Outcome Measures Effect size, measuring the difference in evidence-based clinical scores between participants and nonparticipants. Results CME certificates were awarded to 3,557 participants (459 print, 3,098 PDA). Among survey respondents, significantly more CME participants recognized that ED was associated with greater risk for myocardial infarction (61% participants; 34% nonparticipants; P ≤ 0.001) and was a strong marker for diabetes mellitus (37% participants; 9% nonparticipants; P ≤ 0.001). In contrast, participants and nonparticipants both displayed a good understanding of the relationships of smoking, obesity, and sedentary lifestyle with ED and of using PDE5 inhibitors to treat ED in patients with prostate cancer or benign prostatic hyperplasia; this likely reflects a good baseline understanding of these topics. Participants and nonparticipants each displayed a poor understanding of the recommendations regarding nonarteritic anterior ischemic optic neuropathy and PDE5 inhibitor use. Patient reluctance to discuss sexual concerns was perceived as the most significant barrier to optimal ED management. Conclusions. Given patient reluctance to discuss sexual concerns, future CME activities should focus on educating health-care providers and patients that ED is a risk factor for cardiovascular disease and diabetes. Both print- and PDA-based CME on ED were effective; the large number of lesson completers suggests a trend toward on-demand, self-selected CME is positive.