1,720,998 research outputs found
Next Generation Sequencing: From Research Area to Clinical Practice
No full textTranslating the power of high-throughput sequencing technologies from research area into clinical medicine is one of the major goal for several researchers and health-care providers. One of the important advantages of these technologies is that they can be successfully used in a numerous range of clinical applications. The efficiency of sequencing, that can now be achieved, is leading impressive progress in the diagnostics of common and rare genetic disorders, inherited forms of cancer, prenatal testing or infectious diseases, to cite some examples. Despite several challenges and limitations still remain to overcome, the high-throughput sequencing technologies are leading to real and unprecedented benefits for the medical care of patients
Effect of carbamazepine and oxcarbazepine on wild-type and mutant neuronal nicotinic acetylcholine receptors linked to nocturnal frontal lobe epilepsy
No full textCarbamazepine (5H-dibenz[b,f]azepine-5-carboxamide) and oxcarbazepine (10,11-dihydro-10-oxo-5Hdibenz[b,f]azepine-5-carboxamide) are widely used for the treatment of partial epilepsy. Recent work
indicates that these drugs, in addition to targeting voltage-gated Na+ channels, can modulate ligand-gated channels. These compounds appear to be particularly effective for treatment of nocturnal frontal lobe epilepsy, which can be caused by mutant neuronal nicotinic receptors. We compared the effects of carbamazepine and oxcarbazepine on heteromeric nicotinic receptors to better understand the underlying
mechanism of the effect of these drugs in epileptic patients. Receptors were expressed in cell lines and studied by patch-clamp methods at −60 mV. For α2β4 receptors activated with 100 μM nicotine, IC50 for
carbamazepine was 49 μM. Receptors in which α2 was substituted with α2-I279N, linked to autosomal dominant nocturnal frontal lobe epilepsy, had an IC50 of 21 μM. For oxcarbazepine, the IC50 was larger than
500 μM for wild-type receptors and approximately 100 μM for mutant receptors. A similar inhibition was observed in the presence of 10 μM nicotine, indicating a non-competitive mechanism. The monohydroxy
derivative (MHD) of oxcarbazepine, clinically the most relevant compound, was tested on both α2β4 and α4β2 receptors, to obtain a broader view of its possible physiological effects. At the typical concentration present in blood (100 μM), MHD produced an approximate 40% channel block on α4β2, but no significant effect on α2β4 receptors. Oxcarbazepine and MHD retarded the channel deactivation, suggesting that these compounds produce open channel block. These results may explain the particular efficacy of these drugs in nocturnal frontal lobe epilepsy
Effect of carbamazepine and oxcarbazepine on wild-type and mutant neuronal nicotinic acetylcholine receptors linked to nocturnal frontal lobe epilepsy
No full textCarbamazepine (5H-dibenz[b,f]azepine-5-carboxamide) and oxcarbazepine (10,11-dihydro-10-oxo-5H-dibenz[b,f]azepine-5-carboxamide) are widely used for the treatment of partial epilepsy. Recent work indicates that these drugs, in addition to targeting voltage-gated Na(+) channels, can modulate ligand-gated channels. These compounds appear to be particularly effective for treatment of nocturnal frontal lobe epilepsy, which can be caused by mutant neuronal nicotinic receptors. We compared the effects of carbamazepine and oxcarbazepine on heteromeric nicotinic receptors to better understand the underlying mechanism of the effect of these drugs in epileptic patients. Receptors were expressed in cell lines and studied by patch-clamp methods at -60 mV. For alpha2beta4 receptors activated with 100 microM nicotine, IC(50) for carbamazepine was 49 microM. Receptors in which alpha2 was substituted with alpha2-I279 N, linked to autosomal dominant nocturnal frontal lobe epilepsy, had an IC(50) of 21 microM. For oxcarbazepine, the IC(50) was larger than 500 microM for wild-type receptors and approximately 100 microM for mutant receptors. A similar inhibition was observed in the presence of 10 microM nicotine, indicating a non-competitive mechanism. The monohydroxy derivative (MHD) of oxcarbazepine, clinically the most relevant compound, was tested on both alpha2beta4 and alpha4beta2 receptors, to obtain a broader view of its possible physiological effects. At the typical concentration present in blood (100 microM), MHD produced an approximate 40% channel block on alpha4beta2, but no significant effect on alpha2beta4 receptors. Oxcarbazepine and MHD retarded the channel deactivation, suggesting that these compounds produce open channel block. These results may explain the particular efficacy of these drugs in nocturnal frontal lobe epilepsy
Value-Based Health Care Implementation: The Case Study of mTBI Biomarkers
No full textTraumatic brain injury is a significant global health issue, affecting approximately 69 million people annually. Early diagnosis is crucial for effective management, and biomarkers provide a promising approach to identifying traumatic brain injury in various settings. This study investigates the perceived usefulness of biomarker testing in two distinct contexts: emergency departments and sports settings. Comprehensive interviews were conducted among healthcare professionals in emergency departments and sports-related medical staff. The interviews assessed their perceptions of the diagnostic accuracy, practicality, and overall value of traumatic brain injury biomarker testing. The findings indicate that the perceived usefulness of biomarker testing is high among professionals in both settings. However, significant differences emerged in the perceived barriers to implementation, with emergency department staff citing logistical issues and sports professionals expressing cost concerns. Addressing identified barriers could enhance the adoption and effectiveness of these tests, ultimately improving patient outcomes. Future research should focus on optimizing testing protocols and reducing implementation challenges. This study aims to evaluate the implementation of mild traumatic brain injury biomarkers within the framework of value-based health care, focusing on diagnostic accuracy and patient outcomes
Current Updates on Expanded Carrier Screening: New Insights in the Omics Era
No full textGenetic carrier screening has been successfully used over the last decades to identify individuals at risk of transmitting specific DNA variants to their newborns, thus having an affected child. Traditional testing has been offered based on familial and/or ethnic backgrounds. The development of high-throughput technologies, such as next-generations sequencing, able to allow the study of large genomic regions in a time and cost-affordable way, has moved carrier screening toward a more comprehensive and extensive approach, i.e., expanded carrier screening (ECS). ECS simultaneously analyses several disease-related genes and better estimates individuals’ carrier status. Indeed, it is not influenced by ethnicity and is not limited to a subset of mutations that may arise from poor information in some populations. Moreover, if couples carry out ECS before conceiving a baby, it allows them to obtain a complete estimation of their genetic risk and the possibility to make an informed decision regarding their reproductive life. Despite these advantages, some weakness still exists regarding, for example, the number of genes and the kind of diseases to be analyzed and the interpretation and communication of the obtained results. Once these points are fixed, it is expectable that ECS will become an ever more frequent practice in clinical settings
Cardiac magneti resonance and arrhythmic risk stratification of cardiomyopathy associated with lamin A/C mutations: results from a 5 years study
No full textLinks between accuracy and effectiveness of laboratory medicine equipment: use of the EUnetHTA core model to compare two analyzers by measuring HbA1c
Full text linkObjectives: In the field of Laboratory Medicine, the evolution of knowledge and the innovation of technologies are the basis of analytical and diagnostic progress, leading to the development of new solutions based on innovative technologies. However, these advances must be accompanied by evidence of appropriateness, diagnostic effectiveness, and organizational efficiency, considering the test’s first impact on patient outcomes. Methods: The Health Technology Assessment (HTA) is a valid management tool to support Laboratory Medicine professionals in assessing technologies and which is the most appropriate to adopt. This study is an illustrative case of the application of HTA, exploiting the EUnetHTA Core Model, on two analyzers able to determine the glycated hemoglobin (Hemoglobin A1c, HbA1c), the Capillarys 2 Flex piercing analyzer and the HLC-723G11 analyzer in the Laboratory Medicine Service of the IRCCS San Raffaele Hospital (Milan, IT). The main focus is related to potential differences in methods, organizational aspects, and clinical effectiveness of these approaches for measuring HbA1c. Results: The EUnetHTA Core Model has proven to be the optimal method for HTA in the field of Laboratory Medicine, as it allows to highlight both the peculiarities of the methods on which the analyzers are based and the clinical efficacy of the laboratory test on specific patient populations, considering individual variations in treatment responses, assessing the potential benefits for individual patients or small groups. Conclusions: This granular analysis helps provide insights into the effectiveness and value of healthcare interventions at the patient level, contributing to evidence-based decision-making in clinical practice and healthcare policy
Evaluation of damaging effects of splicing mutations: validation of an in vitro method for diagnostic laboratories
No full textBackground: Pre-mRNA splicing defects may have an important impact on clinical phenotype in several diseases, but often their pathogenic role is difficult to demonstrate. The aim of this study was to validate an in vitro method to assess the effects of putative splicing variants. Materials and methods: We studied three novel variants in vitro using a novel minigene approach and compared results with in silico and ex vivo strategies from patient samples. Results: For the c.1146C>T variant in the LMNA gene, in vitro and ex vivo studies were concordant with the prediction obtained by in silico tools, confirming the loss of 13. bp at the end of exon 6. In the second case (c.1140+1G>A, SCN5A gene), in vitro experiments identified the insertion of 94 intronic bp in exon 9 as well as exon 9 skipping, but these results were not correctly predicted by ex vivo data and in silico tools. In the third case (c.1608+1C>T, LMNA gene) in vitro and ex vivo studies suggested the recognition of an exonic cryptic site leading to the loss of 29. bp in exon 9, not predicted by in silico analysis. Conclusion: Our results revealed how in silico tools are often unreliable requiring wetRNA analysis. Since ex vivo studies are not always feasible, the use of an in vitro construct represents an efficient and useful method for the evaluation of damaging effects of unknown splicing variants, especially in diagnostic laboratories. � 2014 Elsevier B.V
Evaluation of damaging effects of splicing mutations: Validation of an in vitro method for diagnostic laboratories
No full textBackground: Pre-mRNA splicing defects may have an important impact on clinical phenotype in several diseases, but often their pathogenic role is difficult to demonstrate. The aim of this study was to validate an in vitro method to assess the effects of putative splicing variants. Materials and methods: We studied three novel variants in vitro using a novel minigene approach and compared results with in silico and ex vivo strategies from patient samples. Results: For the c.1146C>T variant in the LMNA gene, in vitro and ex vivo studies were concordant with the prediction obtained by in silico tools, confirming the loss of 13. bp at the end of exon 6. In the second case (c.1140+1G>A, SCN5A gene), in vitro experiments identified the insertion of 94 intronic bp in exon 9 as well as exon 9 skipping, but these results were not correctly predicted by ex vivo data and in silico tools. In the third case (c.1608+1C>T, LMNA gene) in vitro and ex vivo studies suggested the recognition of an exonic cryptic site leading to the loss of 29. bp in exon 9, not predicted by in silico analysis. Conclusion: Our results revealed how in silico tools are often unreliable requiring wetRNA analysis. Since ex vivo studies are not always feasible, the use of an in vitro construct represents an efficient and useful method for the evaluation of damaging effects of unknown splicing variants, especially in diagnostic laboratories. © 2014 Elsevier B.V
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