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International Journal of Clinical... Nov 2017Deutetrabenazine is a deuterated formulation of tetrabenazine. The aim of this systematic review is to describe the efficacy, tolerability and safety of deutetrabenazine... (Review)
Review
Deutetrabenazine for tardive dyskinesia: A systematic review of the efficacy and safety profile for this newly approved novel medication-What is the number needed to treat, number needed to harm and likelihood to be helped or harmed?
OBJECTIVE
Deutetrabenazine is a deuterated formulation of tetrabenazine. The aim of this systematic review is to describe the efficacy, tolerability and safety of deutetrabenazine for the treatment of tardive dyskinesia (TD).
DATA SOURCES
The pivotal registration trials were accessed by querying http://www.ncbi.nlm.nih.gov/pubmed/ and http://www.clinicaltrials.gov, for the search terms 'deutetrabenazine' OR 'SD-809', and by also querying the EMBASE (Elsevier) commercial database for clinical poster abstracts, and by asking the manufacturer for copies of posters presented at congresses. Product labelling provided additional information.
STUDY SELECTION
All available clinical reports of studies were identified.
DATA EXTRACTION
Descriptions of the principal results and calculation of number needed to treat (NNT) and number needed to harm (NNH) for relevant dichotomous outcomes were extracted from the available study reports and other sources of information.
DATA SYNTHESIS
Deutetrabenazine, a reversible inhibitor of vesicular monoamine transporter type 2 (VMAT2), received approval for the treatment of TD in adults based on a clinical trial development programme that included two 12-week parallel group, randomised and placebo-controlled studies. Deutetrabenazine dose is determined individually for each patient based on reduction of TD and tolerability. The recommended starting dose of deutetrabenazine for TD is 6 mg BID, administered with food, and can be increased at weekly intervals in increments of 6 mg/day to a maximum recommended daily dosage of 24 mg BID. The percentage of responders in the fixed-dose Phase III acute study, as defined by a rating of "much improved" or "very much improved" on the clinical global impression of change, was 46% for deutetrabenazine (pooled dose groups 12 and 18 mg BID) vs 26% for placebo, yielding a NNT of 5 (95% CI 3-19); the percentage of responders as defined by an improvement in Abnormal Involuntary Movement Scale (AIMS) severity score (sum of items 1-7) of 50% or more, was 34% for deutetrabenazine (pooled dose groups 12 and 18 mg BID) vs 12% for placebo, yielding a NNT of 5 (95% CI 3-11). Pooling the data across both short-term studies, NNT for AIMS response for the therapeutic doses of deutetrabenazine vs placebo was 7 (95% CI 4-18). Discontinuation because of an adverse event occurred among 3.6% of patients randomised to deutetrabenazine (any dose) vs 3.1% for placebo, yielding a NNH of 189 (not significant). The Likelihood to be Helped or Harmed comparing success (AIMS response) vs discontinuation because of an adverse event is 27. The most common adverse reactions (that occurred in ≥4% of deutetrabenazine-treated patients with TD and greater than placebo) were nasopharyngitis and insomnia, with NNH values of 50 (not significant) and 34 (95% CI 18-725), respectively.
CONCLUSIONS
Deutetrabenazine is the second FDA-approved agent specifically indicated for the treatment of TD. Head-to-head comparisons with other VMAT2 inhibitors among patients with TD in the "real world" are needed.
Topics: Adrenergic Uptake Inhibitors; Humans; Nasopharyngitis; Numbers Needed To Treat; Randomized Controlled Trials as Topic; Sleep Initiation and Maintenance Disorders; Tardive Dyskinesia; Tetrabenazine; Treatment Outcome; Vesicular Monoamine Transport Proteins
PubMed: 29024264
DOI: 10.1111/ijcp.13030 -
BMC Geriatrics Aug 2022Healthy aging relies on mitochondrial functioning because this organelle provides energy and diminishes oxidative stress. Single nucleotide polymorphisms (SNPs) in...
INTRODUCTION
Healthy aging relies on mitochondrial functioning because this organelle provides energy and diminishes oxidative stress. Single nucleotide polymorphisms (SNPs) in TOMM40, a critical gene that produces the outer membrane protein TOM40 of mitochondria, have been associated with mitochondrial dysfunction and neurodegenerative processes. Yet it is not clear whether or how the mitochondria may impact human longevity. We conducted this review to ascertain which SNPs have been associated with markers of healthy aging.
METHODS
Using the PRISMA methodology, we conducted a systematic review on PubMed and Embase databases to identify associations between TOMM40 SNPs and measures of longevity and healthy aging.
RESULTS
Twenty-four articles were selected. The TOMM40 SNPs rs2075650 and rs10524523 were the two most commonly identified and studied SNPs associated with longevity. The outcomes associated with the TOMM40 SNPs were changes in BMI, brain integrity, cognitive functions, altered inflammatory network, vulnerability to vascular risk factors, and longevity.
DISCUSSIONS
Our systematic review identified multiple TOMM40 SNPs potentially associated with healthy aging. Additional research can help to understand mechanisms in aging, including resilience, prevention of disease, and adaptation to the environment.
Topics: Aging; Healthy Aging; Humans; Longevity; Membrane Transport Proteins; Mitochondrial Precursor Protein Import Complex Proteins; Polymorphism, Single Nucleotide
PubMed: 35964003
DOI: 10.1186/s12877-022-03337-4 -
Pain Physician 2015Individual response to opioid analgesics varies among patients. (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
Individual response to opioid analgesics varies among patients.
OBJECTIVE
This study sought to clarify the impact of distinct genetic variations on pain, opioid consumption, and opioid side effects in patients with postoperative pain.
STUDY DESIGN
A systematic review and meta-analysis of associations between genetic single-nucleotide polymorphisms (SNPs) and opioids used for acute postoperative pain.
SETTING
This meta-analysis examined all studies involving an association between genetic polymorphisms and the analgesic efficacy or clinical outcome of opioid analgesics for postoperative pain.
METHODS
A literature search was performed up to January 31, 2014, using the PubMed, EMBase, ISI Web of Science, and Cochrane Library databases.
RESULTS
Fifty-nine studies were included in this systematic review, and 23 studies (a total of 5,902 patients) were included in the final meta-analysis. The results showed that human μ-opioid receptor gene (OPRM1) 118G allele variant carriers consumed more opioids for analgesia (SMD = -0.17, 95% CI = [-0.25, -0.10], P < 0.00001), but reported higher pain scores (MD = -0.11, 95% CI = [-0.17, -0.04], P = 0.002) and less nausea and vomiting (odds ratio = 1.30, 95% CI = [1.08, 1.55], P = 0.005) than the homozygous 118AA patients during the first 24 hour but not the 48 hour postoperative period. Moreover, CYP3A4*1G carriers consumed less opioids than homozygous CYP3A4*1/*1 patients during the first 24 hours postoperative period (MD = 45.12, 95% CI = [36.17, 54.06], P < 0.00001). No significant differences were found in CYP3A5*3, ABCB1 C3435T, and G2477T/A genetic polymorphisms.
LIMITATIONS
Some potential non-genetic factors can modify the effects of gene SNP on pain and opioid consumption during the postoperative period, such as age, gender, mood, anxiety, and drug-drug interactions. But further analyses could not be performed in the present meta-analysis due to limited information.
CONCLUSION
The results indicate that among the genetic SNPs we studied which include those affecting analgesic drug metabolism, transport of analgesic agents across the blood-brain barrier, and their activity at target receptors and ion channels and in the modulation of neurotransmitter pathways, the A118G allele variant of OPRM1 has the most potent influence on pain management of postoperative patients. Opioid receptor gene information may provide valuable information for clinicians to properly manage the analgesic use of opioids individually for better pain management.
Topics: Analgesics, Opioid; Female; Genetic Variation; Humans; Male; Middle Aged; Pain Management; Pain, Postoperative; Polymorphism, Single Nucleotide; Randomized Controlled Trials as Topic; Receptors, Opioid, mu
PubMed: 25794200
DOI: No ID Found -
Journal of Clinical Medicine Dec 2022Fatty acid translocase/cluster of differentiation 36 (FAT/CD36) is a multifunctional membrane protein activated by a high-fat diet, physical exercise, fatty acids (FAs),... (Review)
Review
Fatty acid translocase/cluster of differentiation 36 (FAT/CD36) is a multifunctional membrane protein activated by a high-fat diet, physical exercise, fatty acids (FAs), leptin, and insulin. The principal function of FAT/CD36 is to facilitate the transport of long-chain fatty acids through cell membranes such as myocytes, adipocytes, heart, and liver. Under high-energy expenditure, the different isoforms of FAT/CD36 in the plasma membrane and mitochondria bind to the mobilization and oxidation of FAs. Furthermore, FAT/CD36 is released in its soluble form and becomes a marker of metabolic dysfunction. Studies with healthy animals and humans show that physical exercise and a high-lipid diet increase FAT/CD36 expression and caloric expenditure. However, several aspects such as obesity, diabetes, Single Nucleotide polymorphisms (SNPs), and oxidative stress affect the normal FAs metabolism and function of FAT/CD36, inducing metabolic disease. Through a comprehensive systematic review of primary studies, this work aimed to document molecular mechanisms related to FAT/CD36 in FAs oxidation and trafficking in skeletal muscle under basal conditions, physical exercise, and diet in healthy individuals.
PubMed: 36615118
DOI: 10.3390/jcm12010318 -
Human Genetics Dec 2016Tooth agenesis and orofacial clefts represent the most common developmental anomalies and their co-occurrence is often reported in patients as well in animal models. The... (Review)
Review
Tooth agenesis and orofacial clefts represent the most common developmental anomalies and their co-occurrence is often reported in patients as well in animal models. The aim of the present systematic review is to thoroughly investigate the current literature (PubMed, EMBASE) to identify the genes and genomic loci contributing to syndromic or non-syndromic co-occurrence of tooth agenesis and orofacial clefts, to gain insight into the molecular mechanisms underlying their dual involvement in the development of teeth and facial primordia. Altogether, 84 articles including phenotype and genotype description provided 9 genomic loci and 26 gene candidates underlying the co-occurrence of the two congenital defects: MSX1, PAX9, IRF6, TP63, KMT2D, KDM6A, SATB2, TBX22, TGFα, TGFβ3, TGFβR1, TGFβR2, FGF8, FGFR1, KISS1R, WNT3, WNT5A, CDH1, CHD7, AXIN2, TWIST1, BCOR, OFD1, PTCH1, PITX2, and PVRL1. The molecular pathways, cellular functions, tissue-specific expression and disease association were investigated using publicly accessible databases (EntrezGene, UniProt, OMIM). The Gene Ontology terms of the biological processes mediated by the candidate genes were used to cluster them using the GOTermMapper (Lewis-Sigler Institute, Princeton University), speculating on six super-clusters: (a) anatomical development, (b) cell division, growth and motility, (c) cell metabolism and catabolism, (d) cell transport, (e) cell structure organization and (f) organ/system-specific processes. This review aims to increase the knowledge on the mechanisms underlying the co-occurrence of tooth agenesis and orofacial clefts, to pave the way for improving targeted (prenatal) molecular diagnosis and finally to reflect on therapeutic or ultimately preventive strategies for these disabling conditions in the future.
Topics: Anodontia; Brain; Cleft Lip; Cleft Palate; Gene Expression Regulation; Gene Ontology; Genetic Association Studies; Genotype; Humans; Organ Specificity; Phenotype; Protein Biosynthesis
PubMed: 27699475
DOI: 10.1007/s00439-016-1733-z -
Journal of Dairy Science Jan 2021Development of ketosis in high-producing dairy cows contributes to several animal health issues and highlights the need for a better understanding of the genetic basis... (Meta-Analysis)
Meta-Analysis
Development of ketosis in high-producing dairy cows contributes to several animal health issues and highlights the need for a better understanding of the genetic basis of metabolic diseases. To evaluate the pattern of differential gene expression in the liver of cows under negative energy balance (NEB), and under subclinical and clinical ketosis, a meta-analysis of gene expression and genome-wide association studies results was performed. An initial systematic review identified 118 articles based on the key words "cow," "liver," "negative energy balance," "ketosis," "expression," "qPCR," "microarray," "proteomic," "RNA-Seq," and "GWAS." After further screening for only peer-reviewed and pertinent articles for gene expression during NEB and clinical and subclinical ketosis (considering plasma levels of β-hydroxybutyrate), 20 articles were included in the analysis. From the systematic review, 430 significant SNPs identified by genome-wide association studies (GWAS) were assigned to genes reported in gene expression studies by considering chromosome and base pair positions in the ARS-UCD 1.2 bovine assembly. Venn diagrams were created to integrate the data obtained in the systematic review, and Gene Ontology enrichment analysis was carried out using official gene names. A QTL enrichment analysis was also performed to identify potential positional candidate loci. Twenty-four significant SNPs were located within the coordinates of differentially expressed genes located on chromosomes 2, 3, 6, 9, 11, 14, 27, and 29. Three significant metabolic pathways were associated with NEB and subclinical and clinical ketosis. In addition, 2 important genes, PPARA (peroxisome proliferator activated receptor alpha) and ACACA (acetyl-coenzyme A carboxylase α), were identified, which were differentially expressed in the 3 metabolic conditions. The PPARA gene is involved in the regulation of lipid metabolism and fatty liver disease and the ACACA gene encodes an enzyme that catalyzes the carboxylation of acetyl-coenzyme A to malonyl-coenzyme A, which is a rate-limiting step in fatty acid synthesis. Gene network analysis revealed co-expression interactions among 34 genes associated with functions involving fatty acid transport and fatty acid metabolism. For the annotated QTL, 9 QTL were identified for ketosis. The genes FN1 (fibronectin 1) and PTK2 (protein tyrosine kinase 2), which are mainly involved in cell adhesion and formation of extracellular matrix constituents, were enriched for QTL previously associated with the trait "ketosis" on chromosome 2 and for the trait "milk iron content" on chromosome 14, respectively. This integration of gene expression and GWAS data provides an additional understanding of the genetic background of NEB and subclinical and clinical ketosis in dairy cattle. Thus, it is a useful approach to identify biological mechanisms underlying these metabolic conditions in dairy cattle.
Topics: Animals; Cattle; Cattle Diseases; Energy Metabolism; Female; Gene Expression
PubMed: 33189279
DOI: 10.3168/jds.2020-18883 -
Cureus May 2022Somatic () mutations are the most common mutations in various hematological malignancies, such as myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML).... (Review)
Review
A Systematic Review of the Role of Runt-Related Transcription Factor 1 (RUNX1) in the Pathogenesis of Hematological Malignancies in Patients With Inherited Bone Marrow Failure Syndromes.
Somatic () mutations are the most common mutations in various hematological malignancies, such as myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML). Mono-allelic mutations in germline cells may cause familial platelet disorder (FPD), an inherited bone marrow failure syndrome (IBMFS) associated with an increased lifetime risk of AML. It is suspected that additional mutations may play a role in the pathogenesis of hematological malignancies in IBMFS. This review aims to study the role of mutations in the pathogenesis of hematological malignancies in patients with IBMFS. A PubMed database search was conducted using the following medical subject heading (MeSH) terms: "inherited bone marrow failure syndromes," "hematological neoplasms," "gene expression regulation, leukemic," "RUNX1 protein, human," "RUNX1 protein, mouse," and "Neutropenia, Severe Congenital, Autosomal recessive." Three studies published in 2020 were identified as meeting our inclusion and exclusion criteria. Leukemic progression in severe congenital neutropenia was used as a disease model to evaluate the clinical, molecular, and mechanistic basis of mutations identified in hematological malignancies. Studies in mice and genetically reprogrammed or induced pluripotent stem cells (iPSCs) have shown that isolated mutations are weakly leukemogenic and only initiate hyperproduction of immature hematopoietic cells when in combination with () mutations. Despite this, whole-exome sequencing (WES) performed on leukemogenic transformed cells revealed that all AML cells had an additional mutation in the () gene that caused hyperproduction of the ten-eleven translocation (TET2) protein. This protein causes inflammation in cells with mutations. This process is thought to be critical for clonal myeloid malignant transformation (CMMT) of leukemogenic cells. In conclusion, the combinations of and mutations have a prominent effect on myeloid differentiation resulting in the hyperproduction of myeloblasts. In other studies, it has been noted that the mutations in and genes are not sufficient for the full transformation of leukemogenic cells to AML, and an additional clonal mutation in the gene is essential for full transformation to occur. These data have implicitly demonstrated that mutations are critical in the pathogenesis of various hematological malignancies, and further investigations into the role of are paramount for the development of new cancer treatments.
PubMed: 35765406
DOI: 10.7759/cureus.25372 -
Current Oncology Reports Mar 2020Burkitt's lymphoma and its leukemic form (Burkitt cell acute lymphoblastic leukemia) are a highly aggressive disease. We review the classification, clinical...
PURPOSE OF REVIEW
Burkitt's lymphoma and its leukemic form (Burkitt cell acute lymphoblastic leukemia) are a highly aggressive disease. We review the classification, clinical presentation, histology, cytogenetics, and the treatment of the disease.
RECENT FINDINGS
Burkitt's lymphoma might be associated with tumor lysis syndrome which is a potentially fatal complication that occurs spontaneously or upon initiation of chemotherapy. Major improvements were made in the treatment of pediatric and adults population using short-course dose-intensive chemotherapy regimens, usually 1 week after a prephase induction. Addition of Rituximab to chemotherapy has become a standard of care. Relapsed/refractory disease has a very poor prognosis and the benefit from autologous/allogeneic hematopoietic stem cell transplant remains uncertain. Rituximab-based short-course dose-intensive chemotherapy is the standard of care of Burkitt's lymphoma even in the immunodeficiency-related form.
Topics: Antigens, CD20; Antineoplastic Combined Chemotherapy Protocols; Burkitt Lymphoma; Chromosomes, Human, Pair 14; Chromosomes, Human, Pair 8; Hematopoietic Stem Cell Transplantation; Humans; Proto-Oncogene Proteins c-bcl-6; Rituximab; Translocation, Genetic
PubMed: 32144513
DOI: 10.1007/s11912-020-0898-8 -
American Journal of Reproductive... Dec 2021A homeostatic balance between reactive oxygen species production and the antioxidant redox system is an important component of normal pregnancy. Nuclear Factor Erythroid... (Review)
Review
OBJECTIVE
A homeostatic balance between reactive oxygen species production and the antioxidant redox system is an important component of normal pregnancy. Nuclear Factor Erythroid 2-Related Factor 2 (Nrf2) preserves cellular homeostasis by enhancing the cell's innate antioxidant status to reduce oxidative stress and inflammatory damage to the cell during pregnancy. Active Nrf2, in the nucleus of the cell, transactivates various antioxidant genes. The objective of this systematic review was to synthesize evidence on the role of Nrf2 in various adverse pregnancy outcomes (APOs).
METHODS
We conducted a systematic review of the role of Nrf2 in pregnancy. Articles written in English, Portuguese, and Spanish were obtained from three different databases from inception until January 2021. The titles, abstracts and full text were reviewed independently by six reviewers. The quality of the included studies was assessed using a quality assessment tool developed to assess basic science and clinical studies. Nrf2 expression (gene and protein), functional contributions, and association with APOs were assessed.
RESULTS
A total of 747 citations were identified; 80 were retained for full review. Most studies on Nrf2 have been carried out using placental tissues and placenta-derived cells. Limited studies have been conducted using fetal membranes, uterus, and cervix. Nuclear translocation of Nrf2 results in transactivation of antioxidant enzymes, including glutathione peroxidase, hemeoxygenase-1, and superoxide dismutase in gestational cells during pregnancy. This antioxidant response maintains cellular homeostasis during pregnancy. This promotes trophoblast cell survival and prevents cell death and abnormal angiogenesis in the placenta. Excessive and insufficient Nrf2 response may promote oxidative and reductive stress, respectively. This Nrf2 dysregulation has been associated with APOs including gestational diabetes mellitus, intrauterine growth restriction, reproductive toxicity, preeclampsia, and preterm birth.
CONCLUSION
Several studies have localized and reported an association between Nrf2's differential expression in reproductive tissues and the pathogenesis of APOs. However, a comprehensive functional understanding of Nrf2 in reproductive tissues is still lacking. Nrf2's activation and functions are complex, and therefore, current in vitro and in vivo studies are limited in their experimental approaches. We have identified key areas for future Nrf2 research that is needed to fill knowledge gaps.
Topics: Female; Humans; NF-E2-Related Factor 2; Oxidative Stress; Placenta; Pregnancy; Premature Birth; Reactive Oxygen Species; Superoxide Dismutase; Trophoblasts
PubMed: 34467607
DOI: 10.1111/aji.13496 -
Cureus Dec 2020Alzheimer's disease (AD) is caused by several risk factors leading to dementia. It's diagnosis usually depends on clinical presentation and certain biomarkers in the... (Review)
Review
Alzheimer's disease (AD) is caused by several risk factors leading to dementia. It's diagnosis usually depends on clinical presentation and certain biomarkers in the cerebrospinal fluid (CSF). The brain has a high content of cholesterol and the metabolism of cholesterol in the brain can be associated with beta-amyloid plaques formation, which is seen in Alzheimer's disease. Given these implications, we studied if plasma lipid levels can vary in Alzheimer's disease and if these can be used as biomarkers to diagnose and predict the progression of Alzheimer's disease. Certain mutations in the brain cholesterol transport receptors and proteins and their association with Alzheimer's were also studied. This systematic review abides by the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. We searched multiple databases, such as Pubmed, Google Scholar, Pubmed central, ScienceDirect, Web of Science, and Medline with the help of keywords like Alzheimer's disease, cognitive impairment, plasma lipid biomarkers, cholesterol, brain cholesterol metabolism separately and in combination with each other. We collected 49 quality appraised articles on the association between plasma lipids and Alzheimer's disease and the genetic mutations in alleles related to cholesterol metabolism and Alzheimer's disease by applying the inclusion and exclusion criteria. Based on the finding of the studies reviewed, we found an association between plasma lipids, polymorphisms in genes associated with cholesterol transport, and Alzheimer's disease. Increased serum low-density lipoprotein (LDL-C), triglycerides (TG), total cholesterol (TC), sphingolipids, 24S hydroxycholesterol (24S-HC), 27O hydroxycholesterol (27O-HC) was associated with Alzheimer's. Decreased high-density lipoprotein (HDL-C) and phospholipids were noticed. Genetic mutations in apolipoprotein E (ApoE), apolipoprotein B (ApoB), apolipoprotein A (ApoA), ATP binding cassette transporter 1 (ABCA1), ATP binding cassette transporter 7 (ABCA7), amyloid precursor protein (APP), cytochrome P450 family 46 subfamilies A member 1 (CYP46A1), presenilin 1 (PSEN1), presenilin 2 (PSEN2) are also associated with increased risk of Alzheimer's disease. This study found an association between plasma lipids and Alzheimer's, proving that plasma lipids can be used as biomarkers for early diagnosis of Alzheimer's disease. It may also help predict the prognosis and stage the disease severity. Further studies are needed to find out the exact mechanism behind these changes.
PubMed: 33457117
DOI: 10.7759/cureus.12008