The impact of patient–prosthesis mismatch on late outcomes after mitral valve replacement

ObjectivesThe incidence of patient–prosthesis mismatch after mitral valve replacement and its effect on late outcomes have remained unclear. This study was conducted to determine the impact of patient–prosthesis mismatch on recurrent congestive heart failure, postoperative pulmonary hypertension, and late survival after mitral valve replacement.MethodsBetween 1985 and 2005, 884 patients, with a mean age 63 ± 12 years, underwent mitral valve replacement (657 mechanical, 227 bioprosthesis) with contemporary prostheses. Mean clinical and echocardiographic follow-up was 5.1 ± 4.1 years (4344 patient-years). Patient–prosthesis mismatch was defined as an indexed effective orifice area of 1.25 cm2/m2 or less. Parametric and nonparametric analyses were used to determine predictors of outcomes.ResultsThe incidence of patient–prosthesis mismatch was 32%. Predictors of recurrent congestive heart failure included low indexed effective orifice area, low ejection fraction, elevated postoperative mean mitral gradient, and use of a bioprosthesis (P ≤ .05). Postoperative pulmonary hypertension was associated with small mitral size, elevated mean mitral gradient, low ejection fraction, and atrial fibrillation (P ≤ .05); indexed effective orifice area did not predict postoperative pulmonary hypertension (P = .89). Poor late survival was predicted by low indexed effective orifice area (≤1.25 cm2/m2), New York Heart Association class 3 or 4, elevated right ventricular pressure, stroke, older age, coronary artery disease, and bioprosthesis use (P ≤ .05). Survival for patients with patient–prosthesis mismatch versus those without patient–prosthesis mismatch at 1, 3, 5, and 10 years was 91% versus 95%, 85% versus 90%, 78% versus 86%, and 65% versus 75%, respectively (P = .05).ConclusionsPatient–prosthesis mismatch after mitral valve replacement is not uncommon; it is associated with recurrence of congestive heart failure and postoperative pulmonary hypertension and independently affected late survival. This study emphasizes the importance of implanting a sufficiently large prosthesis in adult patients undergoing mitral valve replacement

Bench to Bed Evidences for Pharmacokinetic and Pharmacodynamic Interactions Involving Oseltamivir and Chinese Medicine

Oseltamivir (OA), an ethyl ester prodrug of oseltamivir carboxylate (OC), is clinically used as a potent and selective inhibitor of neuraminidase. Chinese medicines have been advocated to combine with conventional drug for avian influenza. The current study aims to investigate the potential pharmacokinetic and pharmacodynamic interactions of a Chinese medicine formula, namely, Yin Qiao San and Sang Ju Yin (CMF1), commonly used for anti-influenza in combination with OA in both rat and human, and to reveal the underlined mechanisms. It was found that although Cmax, AUC and urinary recovery of OC, as well as metabolic ratio (AUCOC/AUCOA), were significantly decreased in a dose-dependent manner following combination use of CMF1 and OA in rat studies (P<0.01), such coadministration in 14 healthy volunteers only resulted in a trend of minor decrease in the related parameters. Further mechanistic studies found that although CMF1 could reduce absorption and metabolism of OA, it appears to enhance viral inhibition of OA (P<0.01). In summary, although there was potential interaction between OA and CMF1 found in rat studies, its clinical impact was expected to be minimal. The coadministration of OA and CMF1 at the clinical recommended dosages is, therefore, considered to be safe

IgG1 antibodies to acetylcholine receptors in ‘seronegative’ myasthenia gravis†

Only around 80% of patients with generalized myasthenia gravis (MG) have serum antibodies to acetylcholine receptor [AChR; acetylcholine receptor antibody positive myasthenia gravis (AChR-MG)] by the radioimmunoprecipitation assay used worldwide. Antibodies to muscle specific kinase [MuSK; MuSK antibody positive myasthenia gravis (MuSK-MG)] make up a variable proportion of the remaining 20%. The patients with neither AChR nor MuSK antibodies are often called seronegative (seronegative MG, SNMG). There is accumulating evidence that SNMG patients are similar to AChR-MG in clinical features and thymic pathology. We hypothesized that SNMG patients have low-affinity antibodies to AChR that cannot be detected in solution phase assays, but would be detected by binding to the AChRs on the cell membrane, particularly if they were clustered at the high density that is found at the neuromuscular junction. We expressed recombinant AChR subunits with the clustering protein, rapsyn, in human embryonic kidney cells and tested for binding of antibodies by immunofluorescence. To identify AChRs, we tagged either AChR or rapsyn with enhanced green fluorescence protein, and visualized human antibodies with Alexa Fluor-labelled secondary or tertiary antibodies, or by fluorescence-activated cell sorter (FACS). We correlated the results with the thymic pathology where available. We detected AChR antibodies to rapsyn-clustered AChR in 66% (25/38) of sera previously negative for binding to AChR in solution and confirmed the results with FACS. The antibodies were mainly IgG1 subclass and showed ability to activate complement. In addition, there was a correlation between serum binding to clustered AChR and complement deposition on myoid cells in patients’ thymus tissue. A similar approach was used to demonstrate that MuSK antibodies, although mainly IgG4, were partially IgG1 subclass and capable of activating complement when bound to MuSK on the cell surface. These observations throw new light on different forms of MG paving the way for improved diagnosis and management, and the approaches used have applicability to other antibody-mediated conditions

Satellite communications systems and technology. Executive Summary

NASA and the National Science Foundation (NSF) commissioned a panel of US experts to study the international status of satellite communications systems and technology. The study covers emerging systems concepts, applications, services, and the attendant technologies. The panel members travelled to Europe, Japan, and Russia to gather information first-hand. They visited 17 sites in Europe, 20 sites in Japan, and four in Russia. These included major manufacturers, government organizations, service providers, and associated R&D facilities. The panel's report was reviewed by the sites visited, by the panel, and by representatives of US industry. The report details the information collected and compares it to US activities

Information and communication technology

NASA and the National Science Foundation (NSF) commissioned a panel of U.S. experts to study the international status of satellite communications systems and technology. The study covers emerging systems concepts, applications, services, and the attendant technologies. The panel members traveled to Europe, Japan, and Russia to gather information firsthand. They visited 17 sites in Europe, 20 in Japan, and 4 in Russia. These included major manufacturers, government organizations, service providers, and associated research and development facilities. The panel's report was reviewed by the sites visited, by the panel, and by representatives of U.S. industry. The report details the information collected and compares it to U.S. activities

Focal CA3 hippocampal subfield atrophy following LGI1 VGKC-complex antibody limbic encephalitis

Magnetic resonance imaging has linked chronic voltage-gated potassium channel (VGKC) complex antibody-mediated limbic encephalitis with generalized hippocampal atrophy. However, autoantibodies bind to specific rodent hippocampal subfields. Here, human hippocampal subfield (subiculum, cornu ammonis 1-3, and dentate gyrus) targets of immunomodulation-treated LGI1 VGKC-complex antibody-mediated limbic encephalitis were investigated using in vivo ultra-high resolution (0.39 x 0.39 x 1.0 mm³) 7.0T magnetic resonance imaging [n = 18 patients, 17 patients (94%) positive for LGI1 antibody and one patient negative for LGI1/CASPR2 but positive for VGKC-complex antibodies, mean age: 64.0 ± 2.55 years, median 4 years post-limbic encephalitis onset; n = 18 controls]. First, hippocampal subfield quantitative morphometry indicated significant volume loss confined to bilateral CA3 [F(1,34) = 16.87, P 3 months from symptom onset) were associated with CA3 atrophy. Third, whole-brain voxel-by-voxel morphometry revealed no significant grey matter loss. Fourth, CA3 subfield atrophy was associated with severe episodic but not semantic amnesia for postmorbid autobiographical events that was predicted by variability in CA3 volume. The results raise important questions about the links with histopathology, the impact of the observed focal atrophy on other CA3-mediated reconstructive and episodic mechanisms, and the role of potential antibody-mediated pathogenicity as part of the pathophysiology cascade in humans

Carboxyl-terminal truncated HBx regulates a distinct microRNA transcription program in Hepatocellular carcinoma development

Background: The biological pathways and functional properties by which misexpressed microRNAs (miRNAs) contribute to liver carcinogenesis have been intensively investigated. However, little is known about the upstream mechanisms that deregulate miRNA expressions in this process. In hepatocellular carcinoma (HCC), hepatitis B virus (HBV) X protein (HBx), a transcriptional trans-activator, is frequently expressed in truncated form without carboxyl-terminus but its role in miRNA expression and HCC development is unclear. Methods: Human non-tumorigenic hepatocytes were infected with lentivirus-expressing full-length and carboxyl-terminal truncated HBx (Ct-HBx) for cell growth assay and miRNA profiling. Chromatin immunoprecipitation microarray was performed to identify the miRNA promoters directly associated with HBx. Direct transcriptional control was verified by luciferase reporter assay. The differential miRNA expressions were further validated in a cohort of HBV-associated HCC tissues using real-time PCR. Results: Hepatocytes expressing Ct-HBx grew significantly faster than the full-length HBx counterparts. Ct-HBx decreased while full-length HBx increased the expression of a set of miRNAs with growth-suppressive functions. Interestingly, Ct-HBx bound to and inhibited the transcriptional activity of some of these miRNA promoters. Notably, some of the examined repressed-miRNAs (miR-26a, -29c, -146a and -190) were also significantly down-regulated in a subset of HCC tissues with carboxyl-terminal HBx truncation compared to their matching non-tumor tissues, highlighting the clinical relevance of our data. Conclusion: Our results suggest that Ct-HBx directly regulates miRNA transcription and in turn promotes hepatocellular proliferation, thus revealing a viral contribution of miRNA deregulation during hepatocarcinogenesis. © 2011 Yip et al.published_or_final_versio