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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 -
The Cochrane Database of Systematic... Oct 2018Biocompatible peritoneal dialysis (PD) solutions, including neutral pH, low glucose degradation product (GDP) solutions and icodextrin, have previously been shown to... (Meta-Analysis)
Meta-Analysis
BACKGROUND
Biocompatible peritoneal dialysis (PD) solutions, including neutral pH, low glucose degradation product (GDP) solutions and icodextrin, have previously been shown to favourably influence some patient-level outcomes, albeit based on generally sub-optimal quality studies. Several additional randomised controlled trials (RCT) evaluating biocompatible solutions in PD patients have been published recently. This is an update of a review first published in 2014.
OBJECTIVES
This review aimed to look at the benefits and harms of biocompatible PD solutions in comparison to standard PD solutions in patients receiving PD.
SEARCH METHODS
The Cochrane Kidney and Transplant Specialised Register was searched up to 12 February 2018 through contact with the Information Specialist using search terms relevant to this review. Studies in the Specialised Register are identified through searches of CENTRAL, MEDLINE, and EMBASE, conference proceedings, the International Clinical Trials Register Search Portal and ClinicalTrials.gov.
SELECTION CRITERIA
All RCTs and quasi-RCTs in adults and children comparing the effects of biocompatible PD solutions (neutral pH, lactate-buffered, low GDP; neutral pH, bicarbonate(± lactate)-buffered, low GDP; glucose polymer (icodextrin)) in PD were included. Studies of amino acid-based solutions were excluded.
DATA COLLECTION AND ANALYSIS
Two authors extracted data on study quality and outcomes. Summary effect estimates were obtained using a random-effects model, and results were expressed as risk ratios and 95% confidence intervals (CI) for categorical variables, and mean differences (MD) or standardised mean differences (SMD) and 95% CI for continuous variables.
MAIN RESULTS
This review update included 42 eligible studies (3262 participants), including six new studies (543 participants). Overall, 29 studies (1971 participants) compared neutral pH, low GDP PD solution with conventional PD solution, and 13 studies (1291 participants) compared icodextrin with conventional PD solution. Risk of bias was assessed as high for sequence generation in three studies, allocation concealment in three studies, attrition bias in 21 studies, and selective outcome reporting bias in 16 studies.Neutral pH, low GDP versus conventional glucose PD solutionUse of neutral pH, low GDP PD solutions improved residual renal function (RRF) preservation (15 studies, 835 participants: SMD 0.19, 95% CI 0.05 to 0.33; high certainty evidence). This approximated to a mean difference in glomerular filtration rate of 0.54 mL/min/1.73 m (95% CI 0.14 to 0.93). Better preservation of RRF was evident at all follow-up durations with progressively greater preservation observed with increasing follow up duration. Neutral pH, low GDP PD solution use also improved residual urine volume preservation (11 studies, 791 participants: MD 114.37 mL/day, 95% CI 47.09 to 181.65; high certainty evidence). In low certainty evidence, neutral pH, low GDP solutions may make little or no difference to 4-hour peritoneal ultrafiltration (9 studies, 414 participants: SMD -0.42, 95% CI -0.74 to -0.10) which approximated to a mean difference in peritoneal ultrafiltration of 69.72 mL (16.60 to 122.00 mL) lower, and may increase dialysate:plasma creatinine ratio (10 studies, 746 participants: MD 0.01, 95% CI 0.00 to 0.03), technique failure or death compared with conventional PD solutions. It is uncertain whether neutral pH, low GDP PD solution use led to any differences in peritonitis occurrence, hospitalisation, adverse events (6 studies, 519 participants) or inflow pain (1 study, 58 participants: RR 0.51, 95% CI 0.24 to 1.08).Glucose polymer (icodextrin) versus conventional glucose PD solutionIn moderate certainty evidence, icodextrin probably reduced episodes of uncontrolled fluid overload (2 studies, 100 participants: RR 0.30, 95% CI 0.15 to 0.59) and augmented peritoneal ultrafiltration (4 studies, 102 participants: MD 448.54 mL/d, 95% CI 289.28 to 607.80) without compromising RRF (4 studies, 114 participants: SMD 0.12, 95% CI -0.26 to 0.49; low certainty evidence) which approximated to a mean creatinine clearance of 0.30 mL/min/1.73m higher (0.65 lower to 1.23 higher) or urine output (3 studies, 69 participants: MD -88.88 mL/d, 95% CI -356.88 to 179.12; low certainty evidence). It is uncertain whether icodextrin use led to any differences in adverse events (5 studies, 816 participants) technique failure or death.
AUTHORS' CONCLUSIONS
This updated review strengthens evidence that neutral pH, low GDP PD solution improves RRF and urine volume preservation with high certainty. These effects may be related to increased peritoneal solute transport and reduced peritoneal ultrafiltration, although the evidence for these outcomes is of low certainty due to significant heterogeneity and suboptimal methodological quality. Icodextrin prescription increased peritoneal ultrafiltration and mitigated uncontrolled fluid overload with moderate certainty. The effects of either neutral pH, low GDP solution or icodextrin on peritonitis, technique survival and patient survival remain uncertain and require further high quality, adequately powered RCTs.
Topics: Adult; Bicarbonates; Child; Dialysis Solutions; Glucose; Humans; Hydrogen-Ion Concentration; Icodextrin; Kidney; Peritoneal Dialysis; Peritoneum; Pharmaceutical Solutions; Randomized Controlled Trials as Topic; Urine
PubMed: 30362116
DOI: 10.1002/14651858.CD007554.pub3 -
Physiological Reviews Apr 2007Triggered activity in cardiac muscle and intracellular Ca2+ have been linked in the past. However, today not only are there a number of cellular proteins that show clear... (Review)
Review
Triggered activity in cardiac muscle and intracellular Ca2+ have been linked in the past. However, today not only are there a number of cellular proteins that show clear Ca2+ dependence but also there are a number of arrhythmias whose mechanism appears to be linked to Ca2+-dependent processes. Thus we present a systematic review of the mechanisms of Ca2+ transport (forward excitation-contraction coupling) in the ventricular cell as well as what is known for other cardiac cell types. Second, we review the molecular nature of the proteins that are involved in this process as well as the functional consequences of both normal and abnormal Ca2+ cycling (e.g., Ca2+ waves). Finally, we review what we understand to be the role of Ca2+ cycling in various forms of arrhythmias, that is, those associated with inherited mutations and those that are acquired and resulting from reentrant excitation and/or abnormal impulse generation (e.g., triggered activity). Further solving the nature of these intricate and dynamic interactions promises to be an important area of research for a better recognition and understanding of the nature of Ca2+ and arrhythmias. Our solutions will provide a more complete understanding of the molecular basis for the targeted control of cellular calcium in the treatment and prevention of such.
Topics: Animals; Arrhythmias, Cardiac; Biological Transport, Active; Calcium; Calcium Signaling; Humans; Myocardial Contraction; Myocardium
PubMed: 17429038
DOI: 10.1152/physrev.00011.2006 -
American Journal of Physiology.... Apr 2016Inflammatory bowel disease (IBD) is a chronic inflammatory disorder with a complex pathogenesis. Diarrhea is a highly prevalent and often debilitating symptom of IBD... (Review)
Review
Inflammatory bowel disease (IBD) is a chronic inflammatory disorder with a complex pathogenesis. Diarrhea is a highly prevalent and often debilitating symptom of IBD patients that results, at least in part, from an intestinal hydroelectrolytic imbalance. Evidence suggests that reduced electrolyte absorption is more relevant than increased secretion to this disequilibrium. This systematic review analyses and integrates the current evidence on the roles of epithelial Na(+)-K(+)-ATPase (NKA), Na(+)/H(+) exchangers (NHEs), epithelial Na(+) channels (ENaC), and K(+) channels (KC) in IBD-associated diarrhea. NKA is the key driving force of the transepithelial ionic transport and its activity is decreased in IBD. In addition, the downregulation of apical NHE and ENaC and the upregulation of apical large-conductance KC all contribute to the IBD-associated diarrhea by lowering sodium absorption and/or increasing potassium secretion.
Topics: Animals; Epithelial Cells; Epithelial Sodium Channels; Gastrointestinal Absorption; Gastrointestinal Agents; Humans; Inflammatory Bowel Diseases; Intestinal Mucosa; Ion Transport; Membrane Transport Modulators; Potassium Channels; Signal Transduction; Sodium-Hydrogen Exchangers; Sodium-Potassium-Exchanging ATPase
PubMed: 26744474
DOI: 10.1152/ajpgi.00369.2015 -
La Clinica Terapeutica 2023Nutrigenomics - the study of the interactions between genetics and nutrition - has emerged as a pivotal field in personalized nutrition. Among various genetic... (Review)
Review
BACKGROUND
Nutrigenomics - the study of the interactions between genetics and nutrition - has emerged as a pivotal field in personalized nutrition. Among various genetic variations, single-nucleotide polymorphisms (SNPs) have been extensively studied for their probable relationship with metabolic traits.
METHODS
Throughout this review, we have employed a targeted research approach, carefully handpicking the most representative and relevant articles on the subject. Our methodology involved a systematic review of the scientific literature to ensure a comprehensive and accurate overview of the available sources.
RESULTS
SNPs have demonstrated a significant influence on lipid metabolism, by impacting genes that encode for enzymes involved in lipid synthesis, transport, and storage. Furthermore, they have the ability to affect enzymes in glycolysis and insulin signaling pathways: in a way, they can influence the risk of type 2 diabetes. Thanks to recent advances in genotyping technologies, we now know numerous SNPs linked to lipid and carbohydrate metabolism. The large-scale studies on this topic have unveiled the potential of personalized dietary recommendations based on an individual's genetic makeup. Personalized nutritional interventions hold promise to mitigate the risk of various chronic diseases; however, translating these scientific insights into actionable dietary guidelines is still challenging.
CONCLUSIONS
As the field of nutrigenomics continues to evolve, collaborations between geneticists, nutritionists, and healthcare providers are essential to harness the power of genetic information for improving metabolic health. By unraveling the genetic basis of metabolic responses to diet, this field holds the potential to revolutionize how we approach dietary recommendations and preventive healthcare practices.
Topics: Humans; Nutrigenomics; Polymorphism, Single Nucleotide; Diabetes Mellitus, Type 2; Diet; Lipids; Carbohydrate Metabolism
PubMed: 37994765
DOI: 10.7417/CT.2023.2488 -
International Journal of Molecular... Jul 2023Aquaporins (AQPs) are a family of membrane proteins involved in the transport of water and ions across cell membranes. AQPs have been shown to be implicated in various... (Review)
Review
Aquaporins (AQPs) are a family of membrane proteins involved in the transport of water and ions across cell membranes. AQPs have been shown to be implicated in various physiological and pathological processes in the brain, including water homeostasis, cell migration, and inflammation, among others. Epileptogenesis is a complex and multifactorial process that involves alterations in the structure and function of neuronal networks. Recent evidence suggests that AQPs may also play a role in the pathogenesis of epilepsy. In animal models of epilepsy, AQPs have been shown to be upregulated in regions of the brain that are involved in seizure generation, suggesting that they may contribute to the hyperexcitability of neuronal networks. Moreover, genetic studies have identified mutations in AQP genes associated with an increased risk of developing epilepsy. Our review aims to investigate the role of AQPs in epilepsy and seizure onset from a pathophysiological point of view, pointing out the potential molecular mechanism and their clinical implications.
Topics: Animals; Aquaporins; Water; Homeostasis; Brain; Seizures
PubMed: 37569297
DOI: 10.3390/ijms241511923 -
Frontiers in Oncology 2022Cancer is a leading cause of death worldwide and novel prognostic factors are reported with increasing numbers. Systematic reviews and meta-analyses on cumulative...
Cancer is a leading cause of death worldwide and novel prognostic factors are reported with increasing numbers. Systematic reviews and meta-analyses on cumulative research data are crucial in estimating the true prognostic value of proposed factors. Dysadherin (FXYD Domain Containing Ion Transport Regulator 5; FXYD5) is a cell membrane glycoprotein that modulates Na+, K+-ATPase activity and cell-cell adhesion. It is abundantly expressed in a variety of cancer cells, but only in a limited number of normal cells and its levels are increased in many different tumor types. The expression or level of dysadherin has been suggested as an independent predictor for metastasis and poor prognosis by number of studies, yet we lack a definitive answer. In this study, we systematically evaluated the prognostic value of dysadherin in cancer and summarized the current knowledge on the subject. PubMed, Scopus, Web of Science and relevant clinical trial and preprint databases were searched for relevant publications and PRISMA and REMARK guidelines were applied in the process. After a careful review, a total of 23 original research articles were included. In each study, dysadherin was pointed as a marker for poor prognosis. Meta-analyses revealed 3- and 1.5-fold increases in the risk of death (fixed effects HR 3.08, 95% CI 1.88-5.06, RR 1.47, 95% CI 1.06-2.05 on overall survival, respectively) for patients with high (>50%) tumoral FXYD5 level. In many studies, a connection between dysadherin expression or level and metastatic behavior of the cancer as well as inverse correlation with E-cadherin level were reported. Thus, we conclude that dysadherin might be a useful prognostic biomarker in the assessment of disease survival of patients with solid tumors.
PubMed: 36119538
DOI: 10.3389/fonc.2022.945992 -
Cell Communication and Signaling : CCS Dec 2013Cell adhesion molecules (CAMs) play indispensable roles in the developing and mature brain by regulating neuronal migration and differentiation, neurite outgrowth,... (Review)
Review
Cell adhesion molecules (CAMs) play indispensable roles in the developing and mature brain by regulating neuronal migration and differentiation, neurite outgrowth, axonal fasciculation, synapse formation and synaptic plasticity. CAM-mediated changes in neuronal behavior depend on a number of intracellular signaling cascades including changes in various second messengers, among which CAM-dependent changes in intracellular Ca2+ levels play a prominent role. Ca2+ is an essential secondary intracellular signaling molecule that regulates fundamental cellular functions in various cell types, including neurons. We present a systematic review of the studies reporting changes in intracellular Ca2+ levels in response to activation of the immunoglobulin superfamily CAMs, cadherins and integrins in neurons. We also analyze current experimental evidence on the Ca2+ sources and channels involved in intracellular Ca2+ increases mediated by CAMs of these families, and systematically review the role of the voltage-dependent Ca2+ channels (VDCCs) in neurite outgrowth induced by activation of these CAMs. Molecular mechanisms linking CAMs to VDCCs and intracellular Ca2+ stores in neurons are discussed.
Topics: Animals; Calcium; Calcium Channels; Calcium Signaling; Cell Adhesion; Cell Adhesion Molecules; Neurons
PubMed: 24330678
DOI: 10.1186/1478-811X-11-94 -
Reproductive Biology and Endocrinology... Aug 2017The Catsper channel is a sperm-specific, Ca-permeable, pH-dependent, and low voltage-dependent channel that is essential for the hyperactivity of sperm flagellum,... (Review)
Review
The Catsper channel is a sperm-specific, Ca-permeable, pH-dependent, and low voltage-dependent channel that is essential for the hyperactivity of sperm flagellum, chemotaxis towards the egg, capacitation and acrosome reaction. All of these physiological events require calcium entry into sperm cells. Remarkably, Catsper genes are exclusively expressed in the testis during spermatogenesis, and are sensitive to ion channel-induced pH change, such as NHEs, CaATPase, K channel, Hv1 channel and HCO transporters. Furthermore, the Catsper channel is regulated by some physiological stimulants, such as progesterone, cyclic nucleotides (e.g., cAMP, cGMP), zona pellucida (ZP) glycoproteins and bovine serum albumin (BSA). All of these factors normally stimulate Ca entry into sperm through the Catsper channel. In addition, the Catsper channel may be a potential target for male infertility treatment or contraception. This review will focus on the structure, functions, regulation mechanisms and medicinal targets of the Catsper channel.
Topics: Animals; Calcium Channels; Calcium Signaling; Humans; Hydrogen-Ion Concentration; Infertility, Male; Male; Mice; Spermatozoa
PubMed: 28810916
DOI: 10.1186/s12958-017-0281-2 -
BioMed Research International 2014Copper (Cu) is an important trace element in humans; it plays a role as a cofactor for numerous enzymes and other proteins crucial for respiration, iron transport,... (Review)
Review
Copper (Cu) is an important trace element in humans; it plays a role as a cofactor for numerous enzymes and other proteins crucial for respiration, iron transport, metabolism, cell growth, and hemostasis. Natural copper comprises two stable isotopes, (63)Cu and (65)Cu, and 5 principal radioisotopes for molecular imaging applications ((60)Cu, (61)Cu, (62)Cu, and (64)Cu) and in vivo targeted radiation therapy ((64)Cu and (67)Cu). The two potential ways to produce Cu radioisotopes concern the use of the cyclotron or the reactor. A noncopper target is used to produce noncarrier-added Cu thanks to a chemical separation from the target material using ion exchange chromatography achieving a high amount of radioactivity with the lowest possible amount of nonradioactive isotopes. In recent years, Cu isotopes have been linked to antibodies, proteins, peptides, and nanoparticles for preclinical and clinical research; pathological conditions that influence Cu metabolism such as Menkes syndrome, Wilson disease, inflammation, tumor growth, metastasis, angiogenesis, and drug resistance have been studied. We aim to discuss all Cu radioisotopes application focusing on (64)Cu and in particular its form (64)CuCl2 that seems to be the most promising for its half-life, radiation emissions, and stability with chelators, allowing several applications in oncological and nononcological fields.
Topics: Copper Radioisotopes; Humans; Nuclear Medicine; Positron-Emission Tomography; Tomography, Emission-Computed, Single-Photon
PubMed: 24895611
DOI: 10.1155/2014/786463