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Nutrients Mar 2023The inter-individual variability of metabolic response to foods may be partly due to genetic variation. This systematic review aims to assess the associations between... (Review)
Review
The inter-individual variability of metabolic response to foods may be partly due to genetic variation. This systematic review aims to assess the associations between genetic variants and glucose response to an oral glucose tolerance test (OGTT). Three databases (PubMed, Web of Science, Embase) were searched for keywords in the field of genetics, OGTT, and metabolic response (PROSPERO: CRD42021231203). Inclusion criteria were available data on single nucleotide polymorphisms (SNPs) and glucose area under the curve (gAUC) in a healthy study cohort. In total, 33,219 records were identified, of which 139 reports met the inclusion criteria. This narrative synthesis focused on 49 reports describing gene loci for which several reports were available. An association between SNPs and the gAUC was described for 13 gene loci with 53 different SNPs. Three gene loci were mostly investigated: (), (), and (). In most reports, the associations were not significant or single findings were not replicated. No robust evidence for an association between SNPs and gAUC after an OGTT in healthy persons was found across the identified studies. Future studies should investigate the effect of polygenic risk scores on postprandial glucose levels.
Topics: Humans; Glucose Tolerance Test; Diabetes Mellitus, Type 2; Genotype; Risk Factors; Glucose; Polymorphism, Single Nucleotide; Genetic Predisposition to Disease
PubMed: 37049537
DOI: 10.3390/nu15071695 -
Neuropediatrics Oct 2023Autosomal dominant mutations of the gene can cause two epileptic disorders: benign familial neonatal seizures (BFNS) and developmental epileptic encephalopathy (DEE)....
BACKGROUND
Autosomal dominant mutations of the gene can cause two epileptic disorders: benign familial neonatal seizures (BFNS) and developmental epileptic encephalopathy (DEE). This systematic review aims to identify the best reported therapy for these patients, relating to phenotype, neurodevelopmental outcome, and an eventual correlation between phenotype and genotype.
METHODS
We searched on PubMed using the search terms "" AND "therapy" and "" AND "treatment"; we found 304 articles. Of these, 29 met our criteria. We collected the data from 194 patients. All 29 articles were retrospective studies.
RESULTS
In all, 104 patients were classified as DEE and 90 as BFNS. After treatment began, 95% of BFNS patients became seizure free, whereas the seizures stopped only in 73% of those with DEE. Phenobarbital and sodium channel blockers were the most used treatment in BFNS. Most of the DEE patients (95%) needed polytherapy for seizure control and even that did not prevent subsequent developmental impairment (77%).Missense mutations were discovered in 96% of DEE patients; these were less common in BFNS (50%), followed by large deletion (16%), truncation (16%), splice donor site (10%), and frameshift (7%).
CONCLUSION
Phenobarbital or carbamazepine appears to be the most effective antiseizure medication for children with a "benign" variant. On the contrary, polytherapy is often needed for DEE patients, even if it does not seem to improve neurological outcomes. In DEE patients, most mutations were located in S4 and S6 helix, which could serve as a potential target for the development of more specific treatment in the future.
Topics: Child; Infant, Newborn; Humans; Retrospective Studies; KCNQ2 Potassium Channel; Epilepsy, Benign Neonatal; Mutation; Seizures; Phenotype; Genotype; Phenobarbital
PubMed: 36948217
DOI: 10.1055/a-2060-4576 -
Neurological Sciences : Official... Apr 2023KCNT1 has been known to encode a subunit of the tetrameric sodium activated potassium channel (K1.1). Pathogenic variants of KCNT1, especially gain-of-function (GOF)... (Review)
Review
KCNT1 has been known to encode a subunit of the tetrameric sodium activated potassium channel (K1.1). Pathogenic variants of KCNT1, especially gain-of-function (GOF) variants, are associated with multiple epileptic disorders which are often refractory to conventional anti-seizure medications and summarized as KCNT1-related epilepsy. Although the detailed pathogenic mechanisms of KCNT1-related epilepsy remain unknown, increasing studies attempt to find effective medications for those patients by utilizing quinidine to inhibit hyperexcitable K1.1. However, it has been shown that controversial outcomes among studies and partial success in some individuals may be due to multiple factors, such as poor blood-brain barrier (BBB) penetration, mutation-dependent manner, phenotype-genotype associations, and rational therapeutic schedule. In recent years, with higher resolution of K1.1 structure in different activation states and advanced synthetic techniques, it improves the process performance of therapy targeting at K1.1 channel to achieve more effective outcomes. Here, we systematically reviewed the study history of quinidine on KCNT1-related epilepsy and its corresponding therapeutic effects. Then, we analyzed and summarized the possible causes behind the different outcomes of the application of quinidine. Finally, we outlooked the recent advances in precision medicine treatment for KCNT1-related epilepsy.
Topics: Humans; Quinidine; Anticonvulsants; Potassium Channels, Sodium-Activated; Epilepsy; Potassium Channels; Mutation; Nerve Tissue Proteins
PubMed: 36437393
DOI: 10.1007/s10072-022-06521-x -
Biomedicines Nov 2022The endothelium plays a pivotal role in homeostatic mechanisms. It specifically modulates vascular tone by releasing vasodilatory mediators, which act on the vascular... (Review)
Review
BACKGROUND
The endothelium plays a pivotal role in homeostatic mechanisms. It specifically modulates vascular tone by releasing vasodilatory mediators, which act on the vascular smooth muscle. Large amounts of work have been dedicated towards identifying mediators of vasodilation and vasoconstriction alongside the deleterious effects of reactive oxygen species on the endothelium. We conducted a systematic review to study the role of the factors released by the endothelium and the effects on the vessels alongside its role in atherosclerosis.
METHODS
A search was conducted with appropriate search terms. Specific attention was offered to the effects of emerging modulators of endothelial functions focusing the analysis on studies that investigated the role of reactive oxygen species (ROS), perivascular adipose tissue, shear stress, AMP-activated protein kinase, potassium channels, bone morphogenic protein 4, and P2Y2 receptor.
RESULTS
530 citations were reviewed, with 35 studies included in the final systematic review. The endpoints were evaluated in these studies which offered an extensive discussion on emerging modulators of endothelial functions. Specific factors such as reactive oxygen species had deleterious effects, especially in the obese and elderly. Another important finding included the shear stress-induced endothelial nitric oxide (NO), which may delay development of atherosclerosis. Perivascular Adipose Tissue (PVAT) also contributes to reparative measures against atherosclerosis, although this may turn pathological in obese subjects. Some of these factors may be targets for pharmaceutical agents in the near future.
CONCLUSION
The complex role and function of the endothelium is vital for regular homeostasis. Dysregulation may drive atherogenesis; thus, efforts should be placed at considering therapeutic options by targeting some of the factors noted.
PubMed: 36359402
DOI: 10.3390/biomedicines10112884 -
Pharmacology Research & Perspectives Oct 2022The misattribution of an adverse drug reaction (ADR) as a symptom or illness can lead to the prescribing of additional medication, referred to as a prescribing cascade....
The misattribution of an adverse drug reaction (ADR) as a symptom or illness can lead to the prescribing of additional medication, referred to as a prescribing cascade. The aim of this systematic review is to identify published prescribing cascades in community-dwelling adults. A systematic review was reported in line with the PRISMA guidelines and pre-registered with PROSPERO. Electronic databases (Medline [Ovid], EMBASE, PsycINFO, CINAHL, Cochrane Library) and grey literature sources were searched. Inclusion criteria: community-dwelling adults; risk-prescription medication; outcomes-initiation of new medicine to "treat" or reduce ADR risk; study type-cohort, cross-sectional, case-control, and case-series studies. Title/abstract screening, full-text screening, data extraction, and methodological quality assessment were conducted independently in duplicate. A narrative synthesis was conducted. A total of 101 studies (reported in 103 publications) were included. Study sample sizes ranged from 126 to 11 593 989 participants and 15 studies examined older adults specifically (≥60 years). Seventy-eight of 101 studies reported a potential prescribing cascade including calcium channel blockers to loop diuretic (n = 5), amiodarone to levothyroxine (n = 5), inhaled corticosteroid to topical antifungal (n = 4), antipsychotic to anti-Parkinson drug (n = 4), and acetylcholinesterase inhibitor to urinary incontinence drugs (n = 4). Identified prescribing cascades occurred within three months to one year following initial medication. Methodological quality varied across included studies. Prescribing cascades occur for a broad range of medications. ADRs should be included in the differential diagnosis for patients presenting with new symptoms, particularly older adults and those who started a new medication in the preceding 12 months.
Topics: Acetylcholinesterase; Aged; Antifungal Agents; Antipsychotic Agents; Calcium Channel Blockers; Cholinesterase Inhibitors; Cross-Sectional Studies; Drug-Related Side Effects and Adverse Reactions; Humans; Independent Living; Sodium Potassium Chloride Symporter Inhibitors; Thyroxine
PubMed: 36123967
DOI: 10.1002/prp2.1008 -
Journal of Clinical Medicine Aug 2022: In the last 40 years, assisted reproductive techniques (ARTs) have emerged as potentially resolving procedures for couple infertility. This study aims to evaluate... (Review)
Review
: In the last 40 years, assisted reproductive techniques (ARTs) have emerged as potentially resolving procedures for couple infertility. This study aims to evaluate whether ART is associated with epigenetic dysregulation in the offspring. . To accomplish this, we collected all available data on methylation patterns in offspring conceived after ART and in spontaneously conceived (SC) offspring. We extracted 949 records. Of these, 50 were considered eligible; 12 were included in the quantitative synthesis. Methylation levels of CCCTC-binding factor 3 (CTCF3) were significantly lower in the ART group compared to controls (SMD -0.81 (-1.53; -0.09), I = 89%, = 0.03). In contrast, CCCTC-binding factor 6 (CTCF6), (), (), and () were not differently methylated in ART vs. SC offspring. : The methylation pattern of the offspring conceived after ART may be different compared to spontaneous conception. Due to the lack of studies and the heterogeneity of the data, further prospective and well-sized population studies are needed to evaluate the impact of ART on the epigenome of the offspring.
PubMed: 36078985
DOI: 10.3390/jcm11175056 -
British Journal of Clinical Pharmacology Dec 2022Despite numerous studies on quinidine therapies for epilepsies associated with KCNT1 gene mutations, there is no consensus on its clinical utility. Thus, we reviewed... (Review)
Review
AIMS
Despite numerous studies on quinidine therapies for epilepsies associated with KCNT1 gene mutations, there is no consensus on its clinical utility. Thus, we reviewed studies evaluating the efficacy and safety of quinidine in KCNT1-related epileptic disorders.
METHODS
Electronic databases were queried for in vivo and in vitro studies on quinidine therapy in KCNT1-related epilepsies published on or before 1 May 2022. The evaluation of evidence was done as per the American Academy of Neurology's classification scheme. Identification of significant factors that possibly influenced therapeutic effects of quinidine were performed using χ tests.
RESULTS
Twenty-seven studies containing 82 patient records were reviewed. Records of 80 patients with 33 KCNT1 mutations were analysed, of which 20 patients had gained ≥50% seizure reduction due to quinidine therapy. However, quinidine therapy often had different effects on patients with the same KCNT1 mutation. Age, genotypes of KCNT1 mutations, seizure types and brain MRI did not significantly influence the therapeutic effect of quinidine. Prolonged QTc was the most common among all adverse events with quinidine. Notably, results of in vitro quinidine tests did not correspond with in vivo tests.
CONCLUSIONS
Therapeutic effects of quinidine on KCNT1-related epilepsies remained indefinite as contradictory results were detected in similar patients. Age, seizure types, genotypes of KCNT1 mutations and brain MRI did not influence the therapeutic effects of quinidine. Insensitivity to quinidine by a certain Kcnt1 genotype in molecular tests is predictive of its inefficacy in human populations of the respective mutation.
Topics: Humans; Quinidine; Potassium Channels, Sodium-Activated; Anticonvulsants; Nerve Tissue Proteins; Epilepsy; Seizures; Mutation
PubMed: 35940594
DOI: 10.1111/bcp.15479 -
International Journal of Clinical... 2022The purpose of this study was to clarify the role of genetic factors on posttransplant diabetes mellitus (PTDM) risk. (Meta-Analysis)
Meta-Analysis Review
OBJECTIVES
The purpose of this study was to clarify the role of genetic factors on posttransplant diabetes mellitus (PTDM) risk.
METHODS
Relevant publications were systematically retrieved from PubMed, EMBASE, and the Cochrane Library up to December 2020. Data from eligible case-control and cohort studies were extracted for qualitative and quantitative analyses. Odds ratios (ORs) and 95% confidence intervals (CIs) were used to estimate the association between gene polymorphisms and PTDM in the quantitative meta-analysis.
RESULTS
A total of 43 eligible articles were identified, and 16 studies on 9 DNA variants from 8 genes were included in the meta-analysis. rs7903146 was significantly associated with PTDM risk in 5 genetic models (OR (95% CI): allelic: 1.59 (1.17-2.16), =0.003; dominant recessive: 1.62 (1.14, 2.31), =0.007; recessive: 1.87 (1.18, 2.94), =0.007; homozygote: 2.21 (1.23, 3.94), =0.008; and heterozygote 1.50 (1.08, 2.10), =0.017). rs2237892 was significantly correlated with PTDM risk in 3 genetic models (allelic: 0.68 (0.58, 0.81), < 0.001; dominant: 0.6 (049, 0.74), < 0.001; and heterozygote: 0.61 (0.48, 0.76), < 0.001). rs5219 was significantly linked with PTDM in the recessive genetic model (1.59 (1.01, 2.50), =0.047). No significant correlations of PTDM with rs12255372, rs13266634, rs1801282, rs10811661, rs1111875, and rs4402960 polymorphisms were found.
CONCLUSIONS
The gene polymorphisms of rs7903146, rs2237892, and rs5219 may predispose kidney transplant recipients to PTDM. Large sample size studies on diverse ethnic populations were warranted to confirm our findings.
Topics: Diabetes Mellitus, Type 2; Genetic Predisposition to Disease; Humans; KCNQ1 Potassium Channel; Kidney; Polymorphism, Single Nucleotide; RNA-Binding Proteins
PubMed: 35685576
DOI: 10.1155/2022/7140024 -
Pediatric Diabetes Sep 2022In monogenic diabetes due to KCNJ11 and ABCC8 mutations that impair KATP- channel function, sulfonylureas improve long-term glycemic control. Although KATP channels are... (Meta-Analysis)
Meta-Analysis
OBJECTIVE
In monogenic diabetes due to KCNJ11 and ABCC8 mutations that impair KATP- channel function, sulfonylureas improve long-term glycemic control. Although KATP channels are extensively expressed in the brain, the effect of sulfonylureas on neurological function has varied widely. We evaluated published evidence about potential effects of sulfonylureas on neurological features, especially epilepsy, cognition, motor function and muscular tone, visuo-motor integration, and attention deficits in children and adults with KCNJ11 and ABCC8-related neonatal-onset diabetes mellitus.
RESEARCH DESIGN AND METHODS
We conducted a systematic review and meta-analyses of the literature (PROSPERO, CRD42021254782), including individual-patient data, according to PRISMA, using RevMan software. We also graded the level of evidence.
RESULTS
We selected 34 of 776 publications. The evaluation of global neurological function before and after sulfonylurea (glibenclamide) treatment in 114 patients yielded a risk difference (RD) of 58% (95%CI, 43%-74%; I = 54%) overall and 73% (95%CI, 32%-113%; I = 0%) in the subgroup younger than 4 years; the level of evidence was moderate and high, respectively. EEG studies of epilepsy showed a RD of 56% (95%CI, 23%-89%; I = 34%) in patients with KCNJ11 mutations, with a high quality of evidence. For hypotonia and motor function, the RDs were 90% (95%CI, 69%-111%; I = 0%) and 73% (95%CI, 35%-111%; I = 0%), respectively, with a high level of evidence.
CONCLUSIONS
Glibenclamide significantly improved neurological abnormalities in patients with neonatal-onset diabetes due to KCNJ11 or ABCC8 mutations. Hypotonia was the symptom that responded best. Earlier treatment initiation was associated with greater benefits.
Topics: Adult; Child; Diabetes Mellitus; Epilepsy; Glyburide; Humans; Infant, Newborn; Infant, Newborn, Diseases; KATP Channels; Muscle Hypotonia; Mutation; Potassium Channels, Inwardly Rectifying; Sulfonylurea Compounds; Sulfonylurea Receptors
PubMed: 35657808
DOI: 10.1111/pedi.13376 -
Biomedicines Mar 2022The neurologic complications of COVID-19 infection are frequent in hospitalized patients; a high percentage of them present neurologic manifestations at some point... (Review)
Review
The neurologic complications of COVID-19 infection are frequent in hospitalized patients; a high percentage of them present neurologic manifestations at some point during the course of their disease. Headache, muscle pain, encephalopathy and dizziness are among the most common complications. Encephalitis is an inflammatory condition with many etiologies. There are several forms of encephalitis associated with antibodies against intracellular neuronal proteins, cell surfaces or synaptic proteins, referred to as autoimmune encephalitis. Several case reports published in the literature document autoimmune encephalitis cases triggered by COVID-19 infection. Our paper first presents our experience in this issue and then systematically reviews the literature on autoimmune encephalitis that developed in the background of SARS-CoV-2 infections and also discusses the possible pathophysiological mechanisms of auto-immune-mediated damage to the nervous system. This review contributes to improve the management and prognosis of COVID-19-related autoimmune encephalitis.
PubMed: 35453524
DOI: 10.3390/biomedicines10040774