Biomedical subjects
Publications and source records attributed to M Fiszman.
Explore the source record for details and available documents.
Explore the source record for details and available documents.
Post-ischemic heart failure is becoming a major issue for public health in occidental countries and therapeutical options are limited. Therefore cell transplantation was developed as an alternative strategy to improve cardiac structure and function. This review describes the multiple cell types and clinical trials considered for use in this indication. The transplantation of fetal or neonatal cardiomyocytes has proven to be functionally successful, but ethical as well as technical reasons make their clinical use limited. Recent reports, however, suggested that adult autologous cardiomyocytes could be prepared from stem cells present in various mesenchymal tissues. Alternatively, endothelial progenitors originating from bone marrow or peripheral blood could promote the neoangiogenesis within the scar tissue. Finally, the transplantation of skeletal muscle cells (SMC) in the infarcted area improved myocardial function, in correlation with the development of skeletal muscle tissue in various animal models. The latter results paved the way for the development of a first phase I clinical trial of SMC transplantation in patients with severe ischemic heart failure. It required the scale-up of human cell production according to Good Manufacturing Procedures, it started in June 2000 in Paris and was terminated in November 2001, and it was followed by several others. The results were encouraging and prompted the onset of a blinded, multicentric phase II clinical trial for SMC transplantation. Meanwhile, clinical trials also evaluate the safety and efficacy of various cells types originating from the bone marrow.
BACKGROUND: This study assessed the extent to which the initial degree of functional impairment and the number of injected cells may influence the functional improvement provided by autologous skeletal myoblast transplantation into infarcted myocardium. METHODS: One week after left coronary artery ligation, 44 rats received into the infarcted scar, autologous skeletal myoblasts expanded in vitro for 7 days (mean, 3.5 x 10(6), n = 21), or culture medium alone (controls, n = 23). Left ventricular function was assessed by two-dimensional echocardiography. RESULTS: When transplanted hearts were stratified according to their baseline ejection fraction, a significant improvement occurred at 2 months in the less than 25% (from 21.4% to 37%), 25% to 35% (from 29% to 43.8%), and in the 35% to 40% (from 37.2% to 41.7%) groups, compared to controls (p = 0.048, 0.0057, and 0.034, respectively), but not in the more than 40% stratum. A significant linear relationship was found between the improvement in ejection fraction and the number of injected myoblasts, both at 1 and 2 months after transplantation (p < 0.0001). CONCLUSIONS: Autologous myoblast transplantation is functionally effective over a wide range of postinfarct ejection fractions, including in the sickest hearts provided that they are injected with a sufficiently high number of cells.
Myosin-binding protein C (MyBP-C) is thought to play structural and/or regulatory role in striated muscles. The cardiac isoform of MyBP-C is one of the disease genes associated with familial hypertrophic cardiomyopathy and most of the mutations produce COOH truncated proteins. In order to determine the consequences of these mutations on myosin filament organization, we have characterized the effect of a 52-kDa NH2-terminal peptide of human cardiac MyBP-C on the alpha-myosin heavy chain (alpha-MyHC) filament organization. This peptide lacks the COOH-terminal MyHC-binding site and retains the two MyHC-binding domains located in the N-terminal part of MyBP-C. For this characterization, cDNA constructs (rat alpha-MyHC, full-length and truncated human cardiac MyBP-C) were transiently expressed singly or in pairwise combination in COS cells. In conformity with previous works performed on the skeletal isoform of MyBP-C, we observed that full-length cardiac MyBP-C organizes the MyHC into dense structures of uniform width. While the truncated protein is stable and can interact with MyHC in COS cells, it does not result in the same organization of sarcomeric MyHC that is seen with the full-length MyBP-C. These results suggest that the presence of truncated cardiac MyBP-C could, at least partly, disorganize the sarcomeric structure in patients with familial hypertrophic cardiomyopathy.
RATIONALE AND OBJECTIVES: The purpose of this study was to statistically identify some characteristics of unambiguous (ie, clear) chest radiography reports in the context of acute bacterial pneumonia. MATERIALS AND METHODS: Seven physicians individually read 292 chest radiography reports to determine if they contained radiologic evidence of pneumonia. Unambiguous reports were defined as those that physicians unanimously classified as supporting or not supporting the diagnosis of pneumonia. Ambiguous reports were assigned degrees of ambiguity on the basis of how much disagreement they caused among the physicians. Characteristics of unambiguous reports as described in the literature were manually quantified and assigned to every report. To identify characteristics that statistically distinguished unambiguous from ambiguous reports, the authors performed an ordinal logistic regression analysis for which the dependent variable was the number of dissenting votes the report received and the independent variables were the quantified characteristics of the report. RESULTS: Six independent variables were statistically significantly associated with unambiguous reports (P < .05). Three were positively associated: an interpretation of whether findings supported the diagnosis of pneumonia in reports with pneumonia-related observations, short sentences, and redundancy of pneumonia-related observations. Three were negatively associated: high use of uncertainty modifiers for pneumonia-related observations, use of only descriptive terms to describe pneumonia-related observations, and insufficient amount of pneumonia-related information. CONCLUSION: The most influential characteristic of an unambiguous chest radiography report was an interpretation of whether the radiograph supported the diagnosis of pneumonia when findings could be indicative.
BACKGROUND: In busy clinical settings, physicians often do not have enough time to identify patients for specific therapeutic guidelines. As a solution, decision support systems could automatically identify eligible patients and trigger computerized guidelines for specific diseases. Applying this idea to community-acquired pneumonia (CAP), we developed a Bayesian network (BN) and an artificial neural network (ANN) for identifying patients who have CAP and are eligible for a pneumonia guideline. OBJECTIVE: The aim of this study was to determine whether the diagnostic accuracy of these two decision support models differs in terms of identifying CAP patients. METHODS: We trained and tested the networks with a data set of 32,662 adult patients. For each network, we (1) calculated the specificity, the positive predictive value (PPV), and the negative predictive value (NPV) at a sensitivity of 95%, and (2) determined the area under the receiver operating characteristic curve (AUC) as a measure of overall accuracy. We tested for statistical difference between the AUCs using the correlated area z statistic. RESULTS: At a sensitivity of 95%, the respective values for specificity, PPV, and NPV were: 92.3%, 15.1%, and 99.9% for the BN, and 94.0%, 18.6%, and 99.9% for the ANN. The BN had an AUC of 0.9795 (95% CI: 0.9736, 0.9843), and the ANN had an AUC of 0.9855 (95% CI: 0.9805, 0.9894). The difference between the AUCs was statistically significant (p=0.0044). CONCLUSIONS: The networks achieved high overall accuracies on the testing data set. Because the difference in accuracies is statistically significant but not clinically significant, both networks are equally suited to drive a guideline.
OBJECTIVE: To evaluate the performance of a computerized decision support system that combines two different decision support methodologies (a Bayesian network and a natural language understanding system) for the diagnosis of patients with pneumonia. DESIGN: Evaluation study using data from a prospective, clinical study. PATIENTS: All patients 18 years and older who presented to the emergency department of a tertiary care setting and whose chest x-ray report was available during the encounter. METHODS: The computerized decision support system calculated a probability of pneumonia using information provided by the two systems. Outcome measures were the area under the receiver operating characteristic curve, sensitivity, specificity, predictive values, likelihood ratios, and test effectiveness. RESULTS: During the 3-month study period there were 742 patients (45 with pneumonia). The area under the receiver operating characteristic curve was 0.881 (95% CI: 0.822, 0.925) for the Bayesian network alone and 0.916 (95% CI: 0.869, 0.949) for the Bayesian network combined with the natural language understanding system (p=0.01). CONCLUSION: Combining decision support methodologies that process information stored in different data formats can increase the performance of a computerized decision support system.
BACKGROUND: Autologous skeletal myoblast (SM) transplantation improves function of infarcted myocardium, but pretransplantation cultures remain a complex process. This study assessed whether it could be optimized by muscle preconditioning with the local anesthetic bupivacaine or even bypassed with the use of the so-called mince technique. METHODS AND RESULTS: Muscle preconditioning consisted of intramuscular injections of the tibialis anterior of rats, 2 days before harvest. After 7 days of culture, the number of available myoblasts was significantly increased compared with nonconditioned controls (1 683 147 versus 85 300, P:=0.0013). The mince technique was then assessed. A myocardial infarction was created in 66 rats by coronary artery ligation. One week later, rats were reoperated on and intramyocardially injected with culture medium alone (controls, n=23), autologous cultured SM (3.5 x 10(6), n=21), or autologous muscle minced into a fine slurry, which was immediately transplanted (n=22). All muscles had been preconditioned. Left ventricular function was assessed by 2D echocardiography. Whereas end-diastolic volumes expanded over time in all groups, left ventricular ejection fraction (%, mean+/-SEM) was increased only in the cultured SM-transplanted group at 1 (P:=0. 0006) and 2 months (P:=0.0008) versus baseline (37.52+/-1.92 and 40. 92+/-2.17 versus 30.34+/-1.74), with a significant additional benefit between 1 and 2 months (P:=0.0069). CONCLUSIONS: Cell culture remains mandatory for SM transplantation to be successful but, in a clinical perspective, this process can be made more expeditious by preharvest muscle conditioning with bupivacaine, which greatly enhances the baseline cell yield.
Amyloid precursor protein (APP), associated with Alzheimer's disease plaques, is known to be present in synapses of the brain and in the adult neuromuscular junction (NMJ). In the present study we examined protein and gene expression of APP during the development of mouse skeletal muscle. Using immunocytochemical approaches, we found that APP is first detected in myotube cytoplasm at embryonic day 16 and becomes progressively concentrated at the NMJ beginning at birth until adulthood. The colocalization between APP and acetylcholine receptors at the NMJ is only partial at birth, but becomes complete upon reaching adulthood. We observed that all APP isoforms, including the Kunitz-containing (protease inhibitor or KPI) forms, are up-regulated from birth to postnatal day 5 and then decreased to reach the low levels observed in the adult. This suggests the involvement of APP during the events which lead to a mature mono-innervated synapse. A 92-kDa band, characteristic of a cleaved APP695 isoform and not due to a new muscle-specific alternative spliced form, was observed from postnatal day 15 following completion of polyneuronal synapse elimination. Taken together, these data suggest that skeletal muscle APP may well play a role in the differentiation of skeletal muscle and in the formation and maturation of NMJs.
The dystrophia muscularis dy2J/dy2J mouse is an animal model for one form of human congenital muscular dystrophy. A point mutation in the gene coding for the laminin-2 alpha 2 chain leads to the expression of a truncated, partially functional protein. We developed a simple assay for the detection of the dy2J allele, which contains a new NdeI restriction site. Genomic DNA was prepared from animals of known status and amplified by PCR. The digestion of the PCR product with the restriction enzyme resulted in characteristic profiles. Then, this technique was used to identify heterozygous mice among unaffected animals of unknown status. Subsequently, the heterozygous genotype of these mice was confirmed by the birth of dystrophic offspring after mating. This technique allows the detection of the dy2J allele in heterozygous and homozygous animals at any age.
OBJECTIVES: Transplantation of fetal cardiomyocytes improves function of infarcted myocardium but raises availability, immunologic, and ethical issues that justify the investigation of alternate cell types, among which skeletal myoblasts are attractive candidates. METHODS: Myocardial infarction was created in rats by means of coronary artery ligation. One week later, the animals were reoperated on and intramyocardially injected with culture growth medium alone (controls, n = 15), fetal cardiomyocytes (5 x 10(6) cells, n = 11), or neonatal skeletal myoblasts (5 x 10(6) cells, n = 16). The injections consisted of a 150-microL volume and were made in the core of the infarct, and the animals were immunosuppressed. Left ventricular function was assessed by echocardiography immediately before transplantation and 1 month thereafter. Myoblast-transplanted hearts were then immunohistologically processed for the expression of skeletal muscle-specific embryonic myosin heavy chain and cardiac-specific connexin 43. RESULTS: The left ventricular ejection fraction markedly increased in the fetal and myoblast groups from 39.3% +/- 3.9% to 45% +/- 3.4% (P =.086) and from 40.4% +/- 3.6% to 47.3% +/- 4.4% (P =.034), respectively, whereas it decreased in untreated animals from 40.6% +/- 4% to 36.7% +/- 2.7%. Transplanted myoblasts could be identified in all animals by the positive staining for skeletal muscle myosin. Conversely, clusters of connexin 43 were not observed on these skeletal muscle cells. CONCLUSIONS: These results support the hypothesis that skeletal myoblasts are as effective as fetal cardiomyocytes for improving postinfarction left ventricular function. The clinical relevance of these findings is based on the possibility for skeletal myoblasts to be harvested from the patient himself.
OBJECTIVE: Evaluate the effect of a radiology speech recognition system on a real-time computerized guideline in the emergency department. METHODS: We collected all chest x-ray reports (n = 727) generated for patients in the emergency department during a six-week period. We divided the concurrently generated reports into those generated with speech recognition and those generated by traditional dictation. We compared the two sets of reports for availability during the patient's emergency department encounter and for readability. RESULTS: Reports generated by speech recognition were available seven times more often during the patients' encounters than reports generated by traditional dictation. Using speech recognition reduced the turnover time of reports from 12 hours 33 minutes to 2 hours 13 minutes. Readability scores were identical for both kinds of reports. CONCLUSION: Using speech recognition to generate chest x-ray reports reduces turnover time so reports are available while patients are in the emergency department.
OBJECTIVE: To evaluate if a medical language processing (MLP) system is able to support real-time computerization of community-acquired pneumonia (CAP) guidelines. METHODS: Prospective validation study in the emergency department of a tertiary care facility. All the chest x-ray reports available in real-time for an admission decision during a five-week period were included. The MLP system was compared to a physician for the automatic selection of eligible patients and on the extraction of radiographic findings required by five different CAP guidelines. The gold standard comprised of three independent physicians and reliability measures were calculated. The outcome measures were the area under the receiver operated characteristic curve (AUC) for selecting eligible patients, sensitivity, positive predictive value (PPV), and specificity for the extraction of radiographic findings. RESULTS: During the five-week period, 243 reports were available in real-time. The AUCs on selecting eligible CAP patients were 89.7% (CI: 84.2%, 93.7%) for the MLP system, and 93.3% (CI: 83.9%, 97.8%) for the physician. The average sensitivity, PPV, and specificity for radiographic findings that assessed localization and extension of CAP were respectively: 94%, 87%, 96% (physician); and 34%, 90%, 95% (MLP system). Both, the MLP system and the physician had average sensitivity, PPV, and specificity of 97%, 97%, and 99%, respectively, when localization was not an issue. Reliability measures for the gold standard were above 70%. CONCLUSION: The MLP system was able to support real-time computerization of guidelines by selecting eligible patients and extracting radiographic findings that do not assess localization and extension of CAP.
Laminin-2 is part of the basement membrane of the skeletal muscle fibers. The laminin alpha 2 chain is absent or drastically reduced in a subgroup of congenital muscular dystrophy patients, and in the severely affected dystrophic dy/dy mouse. We previously reported that heterogeneous primary mouse muscle cell cultures conferred laminin alpha 2 chain expression in dy/dy mice muscles upon cell transplantation. In the present study we investigated whether pure myoblast cell lines were able to confer laminin alpha 2 chain expression in vivo. We observed that: (1) xeno-transplantation of non-immortalized human myoblast in SCID mouse muscles allows human laminin alpha 2 chain expression; (2) allotransplantation of the permanent G8 mouse myoblast cell line in dy/dy muscles allows the expression of the murine laminin alpha 2 chain; and (3) allo-transplantation of the D7 dystrophic dy/dy cell line allows the formation of new and hybrid muscle fibers in dy/dy muscle in the absence of laminin alpha 2 chain expression. We conclude that normal myoblasts are able to restore the expression of an extracellular skeletal muscle protein and that the absence of laminin-2 does not prevent transplanted muscle cells from participating in the formation of myofibers. Myoblasts are, therefore, attractive tools for further exploration of gene complementation strategies in the animal models of congenital muscular dystrophy.
A medical language processing system called SymText, two other automated methods, and a lay person were compared against an internal medicine resident for their ability to identify pneumonia related concepts on chest x-ray reports. Sensitivity (recall), specificity, and positive predictive value (precision) are reported with respect to an independent panel of physicians. Overall the performance of SymText was similar to the physician and superior to the other methods. The automatic encoding of pneumonia concepts will support clinical research, decision making, computerized clinical protocols, and quality assurance in a radiology department.
Troponin T (TnT) is a component of the troponin complex which regulates muscle contraction in response to alterations in intracellular calcium ion concentration. In human heart, multiple isoforms of cardiac TnT have been described on the basis of antibody studies and molecular cloning of corresponding cDNAs. These isoforms are all derived from the transcription of a single gene, TNNT2, located on chromosome 1q32, and generated by alternative splicing. We show here that isoform diversity is achieved by the use of both alternative exons and alternative acceptor sites and present the organisation of the human TNNT2 gene, which is composed of 17 exons spread over 17 kb. A potential structure of the promoter region is also presented. Several polymorphisms in both the exonic and intronic regions were identified, some of which may act as modulators of the expression of this gene.
Free-text documents are the main type of data produced by a radiology department in a hospital information system. While this type of data is readily accessible for clinical data review it can not be accessed by other applications to perform medical decision support, quality assurance, and outcome studies. In an attempt to solve this problem, natural language processing systems have been developed and tested against chest x-rays reports to extract relevant clinical information and make it accessible to other computer applications. We have used a natural language processing tool called SymText to extract relevant clinical information from a different type of radiology report, the Ventilation/Perfusion lung scan report. Results of this effort can be analyzed in terms of precision and recall. The overall precision was 0.88 and recall was 0.92. In addition, the natural language processing system functions differently in reports with and without an impression section. If this type of information can be successfully extracted from radiology reports, one can develop quality monitors for the diagnostic performance of the radiologist by correlating the impressions with gold standard data present in a hospital information system. Avoiding the manual effort previously necessary to create quality assurance data, can lead to a higher frequency of quality review in a radiology department.