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Sports Medicine - Open Sep 2019There is abundant and mounting information related to the molecular and biological structure and function of the Aquaporin-1 (AQP1) gene and the AQP1-Aquaporin channel.... (Review)
Review
BACKGROUND
There is abundant and mounting information related to the molecular and biological structure and function of the Aquaporin-1 (AQP1) gene and the AQP1-Aquaporin channel. Regulation of water flow across cell membranes is essential for supporting inter- and intracellular fluid balance, which is critical for health and exercise performance. The transmembrane water channel AQP1 is important for cardiorespiratory endurance (CE) because it influences fluid transfers in erythrocytes, endothelial, and pulmonary cells and is vital for transport of ammonium, bicarbonate, carbon dioxide, glycerol, nitric oxide, potassium ion, water, and trans-epithelial and renal water. Very recent publications suggest the association between a DNA sequence variant, rs1049305 (C > G), in the 3'-untranslated region of the AQP1 gene and CE performance. Other reports indicate further significant associations between AQP1 channel and CE phenotypes. The purposes of this systematic review were to examine the extent of the associations between the AQP1 rs1049305 genotype and CE exercise performance and body fluid loss in long-distance runners and AQP1 channel associations with other CE phenotypes.
METHODS
Data sources: A comprehensive review was conducted using PubMed, EMBASE, CINAHL, and Cochrane electronic databases. The search ranged from January 1, 1988, to December 31, 2018. Studies reported in English, French, and Spanish were considered. Eligibility criteria: The criteria for inclusion in the review were (a) case-control study; (b) unequivocal definition of cases and controls; (c) CE was defined as performance in endurance events, laboratory tests, and/or maximal oxygen consumption; (d) exclusion criteria of known causes; (e) genotyping performed by PCR or sequencing; (f) genotype frequencies reported; and (g) no deviation of genotype frequencies from Hardy-Weinberg equilibrium in the control group. Study appraisal: The systematic review included studies examining the AQP1 gene and AQP1 channel structure and function, associations between the AQP1 gene sequence variant rs1049305 (C > G) and CE performance, body fluid loss in long-distance runners, and other studies reporting on the AQP1 gene and channel CE phenotype associations. Synthesis methods: For each selected study, the following data were extracted: authors, year of publication, sample size and number of cases and controls, CE definition, exclusion criteria, inclusion criteria for cases and controls, methods used for genotyping, genotype, allele frequencies and HWE for genotype frequencies in cases and control groups, and method of AQP1 gene and AQP1 channel analysis.
RESULTS
The initial databases search found 172 pertinent studies. Of those, 46 studies were utilized in the final synthesis of the systematic review. The most relevant findings were (a) the identification of an independent replication of the association between AQP1 gene sequence variant rs1049305 (C > G) and CE performance; (b) the association of the rs1049305 C-allele with faster CE running performance; (c) in knockout model, using a linear regression analysis of distance run as a function of Aqp1 status (Aqp1-null vs. wild-type mice) and conditions of hypoxia (ambient [O] = 16%), normoxia (21%), and hyperoxia (40%) indicated that the Aqp1 knockout ran less distance than the wild-type mice (p < 0.001); (d) in vitro, a reduced AQP1 expression was associated with the presence of the rs1049305 G-allele; (e) AQP1 null humans led normal lives and were entirely unaware of any physical limitations. However, they could not support fluid homeostasis when exposed to chronic fluid overload. The limited number of studies with "adequate sample sizes" in various racial and ethnic groups precluding to perform proper in-depth statistical analysis.
CONCLUSIONS
The AQP1 gene and AQP1 channel seems to support homeostatic mechanisms, yet to be totally understood, that are auxiliary in achieving an advantage during endurance exercise. AQP1 functions are vital during exercise and have a profound influence on endurance running performance. AQP1s are underappreciated structures that play vital roles in cellular homeostasis at rest and during CE endurance running exercise. The outcome of the present systematic review provide support to the statement of hypotheses and further research endeavors on the likely influence of AQP1 gene and AQP1 channel on CE performance. Registration: The protocol is not registered.
PubMed: 31486928
DOI: 10.1186/s40798-019-0213-0 -
Medicine Jun 2019Studies showed the controversial results about the effect of common genetic polymorphisms on the atrial fibrillation (AF) recurrence. We performed the systematic review... (Meta-Analysis)
Meta-Analysis
BACKGROUND
Studies showed the controversial results about the effect of common genetic polymorphisms on the atrial fibrillation (AF) recurrence. We performed the systematic review and meta-analysis to qualify the association between common genetic polymorphisms and AF recurrence.
METHODS
Articles were systematically retrieved PubMed, Web of Science, EMBASE, Wanfang, and CNKI database and 9 studies including 3204 patients were enrolled in our meta-analysis.
RESULTS
Results showed that the associations were significant under rs2200733 3 genetic models (TT vs CC: odds ratio [OR] [confidence interval [CI]] = 1.336 [1.061-1.683], P = .014; CT vs CC: OR [CI] = 0.759 [0.614-0.937], P = .01; TT vs CT + CC: OR [CI] = 2.308 [1.440-3.700], P = .001). The association was significant under rs10033464 genetic model (TT vs GG: OR [CI] = 1.517 [1.165-1.976], P = .002).
CONCLUSIONS
Rs13376333 on chromosome 1q21 (in KCNN3), rs7193343 and rs2106261 on chromosome 16q22 (in ZFHX3) were not associated with AF recurrence in our meta-analysis. In total, our meta-analysis found that rs2200733 and rs10033464 on chromosome 4q25 (near PITX2) were associated with the risk of AF recurrence.
Topics: Aged; Atrial Fibrillation; Chromosomes, Human; Female; Genetic Predisposition to Disease; Homeodomain Proteins; Humans; Male; Middle Aged; Odds Ratio; Polymorphism, Single Nucleotide; Recurrence; Small-Conductance Calcium-Activated Potassium Channels; Transcription Factors; Homeobox Protein PITX2
PubMed: 31169720
DOI: 10.1097/MD.0000000000015953 -
Medicine Jun 2019The K channel, subfamily J, member-11 (KCNJ11) E23K and β1 subunit of large-conductance Ca-activated K channel (KCNMB1) E65K polymorphisms were shown to be associated... (Meta-Analysis)
Meta-Analysis
BACKGROUND
The K channel, subfamily J, member-11 (KCNJ11) E23K and β1 subunit of large-conductance Ca-activated K channel (KCNMB1) E65K polymorphisms were shown to be associated with the risk of essential hypertension (EH). However, the results were inconclusive with relatively small sample size. Thus, we carried out a meta-analysis to investigate the genetic association between KCNJ11 E23K and KCNMB1 E65K polymorphisms and essential hypertension risk.
METHODS
Relative studies were collected using PubMed, Web of Science, the Cochrane Library databases, Chinese National Knowledge Infrastructure and Embase databases. Pooled odds ratios with 95% confidence intervals were used to assess the strength of associations.
RESULTS
The dominant models of KCNJ11 E23K (P = .006, OR [95%CI] = 0.45 [0.25, 0.79]) and KCNMB1 E65K (P = .04, OR [95%CI] = 0.91 [0.83, 1.00]) were significantly associated with essential hypertension risk. No significant association was detected between the allelic and recessive models of KCNJ11 E23K and KCNMB1 E65K and the susceptibility of EH. Subgroup analysis stratified by ethnicity showed that the dominant model of KCNMB1 E65K was associated with EH risk in Asian population (P = .003, OR [95%CI] = 0.83 [0.74, 0.94]), but not in Caucasian (P = .74, OR [95%CI] = 1.02 [0.89, 1.18]).
CONCLUSIONS
The dominant model of KCNJ11 E23K and KCNMB1 E65K might be susceptible factors for essential hypertension. To confirm this result, large-scale case-control studies with more subjects are necessary.
Topics: Adult; Aged; Asian People; Essential Hypertension; Female; Genetic Predisposition to Disease; Humans; Large-Conductance Calcium-Activated Potassium Channel beta Subunits; Male; Middle Aged; Potassium Channels, Inwardly Rectifying
PubMed: 31169684
DOI: 10.1097/MD.0000000000015828 -
Frontiers in Neuroscience 2019The exact mechanisms involved in the pathogenesis of neurodegenerative conditions are not fully known. The design of drugs that act on multiple targets represents a...
The exact mechanisms involved in the pathogenesis of neurodegenerative conditions are not fully known. The design of drugs that act on multiple targets represents a promising approach that should be explored for more effective clinical options for neurodegenerative disorders. B7C is s synthetic drug that has been studied for over 20 years and represents a promising multi-target drug for the treatment of neurodegenerative disorders, such as AD. The present systematic review, thus, aims at examining existing studies on the effect of B7C on different molecular targets and at discussing the relevance of B7C in neurological disorders. A list of predefined search terms was used to retrieve relevant articles from the databases of Embase, Pubmed, Scopus, and Web of Science. The selection of articles was done by two independent authors, who were considering articles concerned primarily with the evaluation of the effect of B7C on neurological disorders. Only full-text articles written in English were included; whereas, systematic reviews, meta-analyses, book chapters, conference subtracts, and computational studies were excluded. A total of 2,266 articles were retrieved out of which 41 articles were included in the present systematic review. The effect of B7C on molecular targets, including AChE, BChE, BACE-1, NMDA receptor, GABA receptor, NOS, and Kv4.2 potassium channels was evaluated. Moreover, the studies that were included assessed the effect of B7C on biological processes, such as apoptosis, neuritogenesis, and amyloid beta aggregation. The animal studies examined in the review focused on the effect of B7C on cognition and memory. The beneficial effects observed on different molecular targets and biological processes relevant to neurological conditions confirm that B7C is a promising multi-target drug with the potential to treat neurological disorders.
PubMed: 31143096
DOI: 10.3389/fnins.2019.00445 -
The Journal of Pain 2020Chronic postsurgical pain (CPSP) is a significant detriment to postsurgical recovery and a risk factor for prolonged opioid use. Emerging evidence suggests the estimated... (Meta-Analysis)
Meta-Analysis
Chronic postsurgical pain (CPSP) is a significant detriment to postsurgical recovery and a risk factor for prolonged opioid use. Emerging evidence suggests the estimated heritability for chronic pain is 45% and that genetic factors partially explain individual susceptibility to CPSP. The aim of this study was to systematically review, assess quality, and summarize the studies in humans that have investigated genetic factors associated with CPSP. We also conducted a meta-analysis to derive a single effect size for evaluable genetic associations with CPSP. Our comprehensive literature search included review of 21 full-text articles evaluating variants of 69 genes for association with CPSP. We found significant gene variant associations reported for variants/haplotypes of 26 genes involved in neurotransmission, pain signaling, immune responses and neuroactive ligand-receptor interaction, with CPSP. Six variants of 5 genes (COMT: rs4680 and rs6269, OPRM1: rs1799971, GCH1: rs3783641, KCNS1: rs734784 and TNFA: rs1800629), were evaluated by more than one study and were included in the meta-analysis. At rs734784 (A>G) of KCNS1, presence of G allele marginally increased risk of CPSP (Additive genetic model; Odds ratio: 1.511; 95% CI 1-2.284; P value: .050), while the other variants did not withstand meta-analyses criteria. Our findings demonstrate the role of genetic factors with different functions in CPSP, and also emphasize that single genetic factors have small effect sizes in explaining complex conditions like CPSP. Heterogeneity in surgical cohorts, population structure, and outcome definitions, as well as small number of available studies evaluating same variants, limit the meta-analysis. There is a need for large-scale, homogenous, replication studies to validate candidate genes, and understand the underlying biological networks underpinning CPSP. PERSPECTIVE: Our systematic review comprehensively describes 21 studies evaluating genetic association with CPSP, and limitations thereof. A meta-analysis of 6 variants (5 genes) found marginally increased risk for CPSP associated with rs734784 A>G of the potassium voltage-gated channel gene (KCNS1). Understanding genetic predisposition for CPSP will enable prediction and personalized management.
Topics: Genetic Predisposition to Disease; Humans; Pain, Postoperative
PubMed: 31129315
DOI: 10.1016/j.jpain.2019.05.008 -
Topics in Spinal Cord Injury... 2018Spasticity is a common secondary complication of spinal cord injury (SCI), which can severely impact functional independence and quality of life. 4-Aminopyridine (4-AP)...
Spasticity is a common secondary complication of spinal cord injury (SCI), which can severely impact functional independence and quality of life. 4-Aminopyridine (4-AP) is a potassium channel blocker that has been studied as an intervention for spasticity in individuals with SCI. To conduct a systematic review of the available evidence regarding the effectiveness of 4-AP for the management of spasticity in individuals with SCI. A comprehensive literature search was conducted on five electronic databases for articles published in English up to January 2017. Studies were included if (1) the sample size was three or more subjects, (2) the population was ≥50% SCI, (3) the subjects were ≥18 years old, (4) the treatment was 4-AP via any route, and (5) spasticity was assessed before and after the intervention. Subject characteristics, study design, intervention protocol, assessment methods, side effects, adverse events, and outcomes were extracted from selected studies. Randomized controlled trials (RCTs) were evaluated for methodological quality using the Physiotherapy Evidence Database (PEDro) tool. Levels of evidence were assigned using a modified Sackett scale. Nine studies met inclusion criteria with a pooled sample size of 591 subjects. Six studies were RCTs (PEDro = 6-10, Level 1 evidence) and three studies were pre-post tests (Level 4 evidence). There was a wide range in duration, severity, and level of SCI across subjects. Oral 4-AP was investigated in five studies; one study reported significant improvements on the Ashworth Scale (AS), while the remaining four studies found no improvement. Three studies found no significant improvements on the Spasm Frequency Scale. Intravenous 4-AP was investigated in three studies; no significant improvements were found on the AS or in the Reflex Score. Intrathecal 4-AP was investigated in one study, which did not find significant improvements on the AS. There is weak evidence supporting the effectiveness of 4-AP in reducing spasticity post SCI. Future research should utilize contemporary measures of spasticity and address methodological limitations such as small sample sizes.
Topics: 4-Aminopyridine; Humans; Muscle Relaxants, Central; Muscle Spasticity; Potassium Channel Blockers; Spinal Cord Injuries; Treatment Outcome
PubMed: 30459498
DOI: 10.1310/sci17-00048 -
Circulation Oct 2018Among his major cardiac electrophysiological contributions, Miles Vaughan Williams (1918-2016) provided a classification of antiarrhythmic drugs that remains central to...
BACKGROUND
Among his major cardiac electrophysiological contributions, Miles Vaughan Williams (1918-2016) provided a classification of antiarrhythmic drugs that remains central to their clinical use.
METHODS
We survey implications of subsequent discoveries concerning sarcolemmal, sarcoplasmic reticular, and cytosolic biomolecules, developing an expanded but pragmatic classification that encompasses approved and potential antiarrhythmic drugs on this centenary of his birth.
RESULTS
We first consider the range of pharmacological targets, tracking these through to cellular electrophysiological effects. We retain the original Vaughan Williams Classes I through IV but subcategorize these divisions in light of more recent developments, including the existence of Na current components (for Class I), advances in autonomic (often G protein-mediated) signaling (for Class II), K channel subspecies (for Class III), and novel molecular targets related to Ca homeostasis (for Class IV). We introduce new classes based on additional targets, including channels involved in automaticity, mechanically sensitive ion channels, connexins controlling electrotonic cell coupling, and molecules underlying longer-term signaling processes affecting structural remodeling. Inclusion of this widened range of targets and their physiological sequelae provides a framework for a modernized classification of established antiarrhythmic drugs based on their pharmacological targets. The revised classification allows for the existence of multiple drug targets/actions and for adverse, sometimes actually proarrhythmic, effects. The new scheme also aids classification of novel drugs under investigation.
CONCLUSIONS
We emerge with a modernized classification preserving the simplicity of the original Vaughan Williams framework while aiding our understanding and clinical management of cardiac arrhythmic events and facilitating future developments in this area.
Topics: Action Potentials; Animals; Anti-Arrhythmia Agents; Arrhythmias, Cardiac; Calcium Channel Blockers; Heart Conduction System; Heart Rate; Humans; Ion Channels; Membrane Transport Modulators; Neurotransmitter Agents; Potassium Channel Blockers; Terminology as Topic; Voltage-Gated Sodium Channel Blockers
PubMed: 30354657
DOI: 10.1161/CIRCULATIONAHA.118.035455 -
Medicine Sep 2018We sought to identify common ion channel single nucleotide polymorphisms (SNPs) associated with the occurrence of sudden cardiac death (SCD) to predict the incidence of... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
We sought to identify common ion channel single nucleotide polymorphisms (SNPs) associated with the occurrence of sudden cardiac death (SCD) to predict the incidence of SCD in clinical settings.
METHODS
This study involved a systematic review and meta-analysis of ion channel SNPs and risk of SCD in adults. We searched public databases for studies published up to September 19, 2017. We examined relationships between SNPs in common ion channel genes and the incidence of SCD.
RESULTS
We collected data for 22 trials that included a total of 4149 patients who experienced SCD or had a high risk of SCD and assessed these data in our meta-analysis. An allelic model showed that rs11720524 in SCN5A clearly protected against SCD (odds ratio [OR]: 0.76; 95% confidence interval [95% CI]: 0.67-0.85; P < .001). Subgroup analysis showed that rs11720524 in SCN5A protected against SCD in Europeans and Caucasians but not in Koreans. The allelic model indicated that rs12296050 in KCNQ1 also had significant protective effects against SCD (OR: 0.85; 95% CI: 0.76-0.96; P = .007). Moreover, this model demonstrated that rs2283222 in KCNQ1 had a significant negative relationship with SCD (OR: 0.73; 95% CI: 0.62-0.85; P < .001). Rs12296050 in KCNQ1 protected against SCD in Koreans and Americans. Our results also showed that rs790896 in RYR2 was negatively associated with SCD in a dominant model (OR: 0.66; 95% CI: 0.45-0.97; P = .033).
CONCLUSIONS
Rs11720524 in SCN5A is negatively related to SCD in Europeans and Caucasians, and rs12296050 and rs2283222 in KCNQ1 and rs790896 in RYR2 clearly have protective effects against SCD.
Topics: Adult; Alleles; Asian People; Death, Sudden, Cardiac; Female; Humans; Incidence; Ion Channels; KCNQ1 Potassium Channel; Male; NAV1.5 Voltage-Gated Sodium Channel; Observational Studies as Topic; Polymorphism, Single Nucleotide; Predictive Value of Tests; Ryanodine Receptor Calcium Release Channel; White People
PubMed: 30235722
DOI: 10.1097/MD.0000000000012428 -
European Neurology 2017Gait impairment is one of the most disabling symptoms in people with multiple sclerosis (PwMS). Fampridine, has demonstrated a positive effect on gait speed in PwMS... (Review)
Review
BACKGROUND
Gait impairment is one of the most disabling symptoms in people with multiple sclerosis (PwMS). Fampridine, has demonstrated a positive effect on gait speed in PwMS after 14 days of treatment but the long-term effects have not yet been demonstrated. This study reviews the long-term effects of fampridine on gait in PwMS.
SUMMARY
This systematic review was conducted according to the PRISMA statement. Studies were considered long term if treatment exceeded 28 days. From the 498 studies identified, 18 (2,200 patients) fulfilled all eligibility criteria. Only 3 studies followed-up patients for >1 year and one of these showed a non-significant improvement in the gait speed. Key Messages: Fampridine seems to be beneficial at improving gait speed in PwMS in the long term. Further long-term studies are needed on related gait and functional parameters.
Topics: 4-Aminopyridine; Adult; Female; Gait; Gait Disorders, Neurologic; Humans; Male; Middle Aged; Multiple Sclerosis; Potassium Channel Blockers
PubMed: 28992626
DOI: 10.1159/000480729 -
Psychiatry and Clinical Neurosciences Oct 2017Antibodies to the voltage-gated potassium channel (VGKC) complex and glutamic acid decarboxylase (GAD) have been reported in some cases of psychosis. We conducted the... (Meta-Analysis)
Meta-Analysis Review
Antibodies to the voltage-gated potassium channel (VGKC) complex and glutamic acid decarboxylase (GAD) have been reported in some cases of psychosis. We conducted the first systematic review and meta-analysis to investigate their prevalence in people with psychosis and report a case series of VGKC-complex antibodies in refractory psychosis. Only five studies presenting prevalence rates of VGKC seropositivity in psychosis were identified, in addition to our case series, with an overall prevalence of 1.5% (25/1720) compared to 0.7% in healthy controls (12/1753). Meta-analysis established that the pooled prevalence of GAD65 autoantibodies was 5.8% (95% confidence interval [CI]: 2.0-15.6%; I = 91%; nine studies) in psychotic disorders, with a prevalence of 4.6% (95%CI: 1.2-15.9%; nine studies; I = 89%) and 6.2% (95%CI: 1.2-27.0%; two studies; I = 69%) in schizophrenia and bipolar disorder, respectively. People with psychosis were more likely to have GAD65 antibodies than controls (odds ratio [OR], 2.24; 95%CI: 1.28-3.92%; P = 0.005; eight studies; I = 0%). Among 21 participants with treatment-resistant psychosis, none had VGKC antibodies. The prevalence of VGKC antibodies is low in psychosis. Our preliminary meta-analysis suggests that GAD autoantibodies are more common in people with psychosis than in controls, although few studies accounted for the possibility of co-existing type 1 diabetes mellitus and the clinical significance of reported GAD titers remains unclear. The paucity of studies reporting thresholds for defining GAD abnormality and rates of comorbid type 1 diabetes mellitus precludes interpretations regarding the influence of GAD antibodies on the development of psychotic disorders and may have led to an overestimate of the prevalence of GAD. Our case series fails to support the hypothesis that VGKC antibodies are linked to treatment resistance in psychosis, but the literature to date is remarkably sparse.
Topics: Autoantibodies; Glutamate Decarboxylase; Humans; Potassium Channels, Voltage-Gated; Psychotic Disorders
PubMed: 28573688
DOI: 10.1111/pcn.12543