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Toxins Apr 2020Centipedes are among the oldest venomous arthropods that use their venom to subdue the prey. The major components of centipede venom are a variety of...
Centipedes are among the oldest venomous arthropods that use their venom to subdue the prey. The major components of centipede venom are a variety of low-molecular-weight peptide toxins that have evolved to target voltage-gated ion channels to interfere with the central system of prey and produce pain or paralysis for efficient hunting. Peptide toxins usually contain several intramolecular disulfide bonds, which confer chemical, thermal and biological stability. In addition, centipede peptides generally have novel structures and high potency and specificity and therefore hold great promise both as diagnostic tools and in the treatment of human disease. Here, we review the centipede peptide toxins with reported effects on ion channels, including Nav, Kv, Cav and the nonselective cation channel polymodal transient receptor potential vanilloid 1 (TRPV1).
Topics: Animals; Arthropod Proteins; Arthropod Venoms; Bites and Stings; Chilopoda; Drug Discovery; Humans; Ion Channels; Membrane Transport Modulators; Protein Conformation; Signal Transduction; Structure-Activity Relationship
PubMed: 32260499
DOI: 10.3390/toxins12040230 -
Radiotherapy and Oncology : Journal of... Aug 2021Linear Energy Transfer (LET) is widely used to express the radiation quality of ion beams, when characterizing the biological effectiveness. However, averaged LET may be... (Review)
Review
Linear Energy Transfer (LET) is widely used to express the radiation quality of ion beams, when characterizing the biological effectiveness. However, averaged LET may be defined in multiple ways, and the chosen definition may impact the resulting reported value. We review averaged LET definitions found in the literature, and quantify which impact using these various definitions have for different reference setups. We recorded the averaged LET definitions used in 354 publications quantifying the relative biological effectiveness (RBE) of hadronic beams, and investigated how these various definitions impact the reported averaged LET using a Monte Carlo particle transport code. We find that the kind of averaged LET being applied is, generally, poorly defined. Some definitions of averaged LET may influence the reported averaged LET values up to an order of magnitude. For publications involving protons, most applied dose averaged LET when reporting RBE. The absence of what target medium is used and what secondary particles are included further contributes to an ill-defined averaged LET. We also found evidence of inconsistent usage of averaged LET definitions when deriving LET-based RBE models. To conclude, due to commonly ill-defined averaged LET and to the inherent problems of LET-based RBE models, averaged LET may only be used as a coarse indicator of radiation quality. We propose a more rigorous way of reporting LET values, and suggest that ideally the entire particle fluence spectra should be recorded and provided for future RBE studies, from which any type of averaged LET (or other quantities) may be inferred.
Topics: Humans; Linear Energy Transfer; Monte Carlo Method; Proton Therapy; Protons; Radiobiology; Relative Biological Effectiveness
PubMed: 33894298
DOI: 10.1016/j.radonc.2021.04.007 -
Clinical Journal of the American... Aug 2015Neutral-pH, low-glucose degradation products solutions were developed in an attempt to lessen the adverse effects of conventional peritoneal dialysis solutions. A... (Meta-Analysis)
Meta-Analysis Review
Effect of Neutral-pH, Low-Glucose Degradation Product Peritoneal Dialysis Solutions on Residual Renal Function, Urine Volume, and Ultrafiltration: A Systematic Review and Meta-Analysis.
BACKGROUND AND OBJECTIVES
Neutral-pH, low-glucose degradation products solutions were developed in an attempt to lessen the adverse effects of conventional peritoneal dialysis solutions. A systematic review was performed evaluating the effect of these solutions on residual renal function, urine volume, peritoneal ultrafiltration, and peritoneal small-solute transport (dialysate to plasma creatinine ratio) over time.
DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS
Multiple electronic databases were searched from January of 1995 to January of 2013. Randomized trials reporting on any of four prespecified outcomes were selected by consensus among multiple reviewers.
RESULTS
Eleven trials of 643 patients were included. Trials were generally of poor quality. The meta-analysis was performed using a random effects model. The use of neutral-pH, low-glucose degradation products solutions resulted in better preserved residual renal function at various study durations, including >1 year (combined analysis: 11 studies; 643 patients; standardized mean difference =0.17 ml/min; 95% confidence interval, 0.01 to 0.32), and greater urine volumes (eight studies; 598 patients; mean difference =128 ml/d; 95% confidence interval, 58 to 198). There was no significant difference in peritoneal ultrafiltration (seven studies; 571 patients; mean difference =-110; 95% confidence interval, -312 to 91) or dialysate to plasma creatinine ratio (six studies; 432 patients; mean difference =0.03; 95% confidence interval, 0.00 to 0.06).
CONCLUSIONS
The use of neutral-pH, low-glucose degradation products solutions results in better preservation of residual renal function and greater urine volumes. The effect on residual renal function occurred early and persisted beyond 12 months. Additional studies are required to evaluate the use of neutral-pH, low-glucose degradation products solutions on hard clinical outcomes.
Topics: Biomarkers; Chi-Square Distribution; Creatinine; Dialysis Solutions; Glucose; Humans; Hydrogen-Ion Concentration; Kidney; Kidney Diseases; Peritoneal Dialysis; Randomized Controlled Trials as Topic; Risk Factors; Treatment Outcome; Urination; Urodynamics
PubMed: 26048890
DOI: 10.2215/CJN.05410514 -
Revista de Neurologia Jan 2015We conduct a systematic review of the preclinical studies published to date involving the use of latrepirdine (Dimebon ®). Latrepirdine is capable of modulating... (Review)
Review
We conduct a systematic review of the preclinical studies published to date involving the use of latrepirdine (Dimebon ®). Latrepirdine is capable of modulating different targets, such as those related with mitochondria, acetylcholinesterase activity or intraneuronal calcium levels, perhaps thanks to its action upon the N-methyl-D-aspartate-type receptor, which belongs to the glutamate family. The findings published on the possible effect of latrepirdine in protein aggregation processes in disorders such as Alzheimer's disease and Parkinson's disease are quite controversial. Likewise, the possible neuroprotective effect of latrepirdine has been evaluated in animal models of neurodegenerative diseases, again with heterogeneous results. Consequently, it can be concluded that no preclinical scientific evidence has been found to justify carrying out clinical trials.
Topics: Animals; Biological Availability; Calcium Signaling; Cholinesterase Inhibitors; Disease Models, Animal; Drug Evaluation, Preclinical; Excitatory Amino Acid Antagonists; Humans; Indoles; Mice; Mitochondria; Molecular Structure; Motor Neurons; Neurodegenerative Diseases; Neurons; Neuroprotective Agents; Parkinsonian Disorders; Protein Aggregation, Pathological; Rabbits; Rats; Receptors, N-Methyl-D-Aspartate; Tissue Distribution
PubMed: 25522862
DOI: No ID Found -
The Journal of Maternal-fetal &... Nov 2014Asthma is the most common chronic disease of childhood and the leading cause of childhood morbidity. When uncontrolled, asthma can place significant limits on daily... (Review)
Review
BACKGROUND
Asthma is the most common chronic disease of childhood and the leading cause of childhood morbidity. When uncontrolled, asthma can place significant limits on daily life, and is sometimes fatal. The use of magnesium sulphate (MgSO4) is one of numerous treatment options available during acute severe asthma in children. The efficacy of intravenous, or inhaled MgSO4 has been demonstrated, while little is known about the actual clinical use of either intravenous (IV) or inhaled MgSO4.
OBJECTIVE
To assess the effectiveness of intravenous (IV) and/or inhaled MgSO4 on hospital admissions and pulmonary function in children with asthma. This systematic review assessed the best available evidence for the use of either intravenous or inhaled MgSO4 in children with acute asthma. Magnesium deficiency is a common electrolyte disorder in children with acute severe asthma. Several authors reported that IV magnesium was effective in the treatment of moderate to acute asthma in children but evidence for nebulised magnesium was insufficient. In addition, it is used in severe, progressed cases to prevent respiratory failure and/or admission to the intensive care unit. It has bronchodilating and anti-inflammatory effects and modulates ion transport and influences intracellular calcium concentration. Intravenous MgSO4 therapy helps in achieving earlier improvement in clinical signs and symptoms of asthma, e.g. respiratory function and significantly reduced hospital admission, in children with acute severe asthma. The role of nebulised MgSO4 in asthmatic children requires further investigation.
CONCLUSION
According to the previous studies, the author recommends the use of intravenous MgSO4 as a safe and effective adjunct to conventional bronchodilator therapy in acute severe asthma in children.
Topics: Administration, Inhalation; Administration, Intravenous; Asthma; Bronchodilator Agents; Child; Health; Humans; Magnesium; Magnesium Sulfate; Treatment Outcome
PubMed: 24345031
DOI: 10.3109/14767058.2013.876620 -
Journal of the Science of Food and... Mar 2018Dairy milk consists of more than 85% water. Therefore, understanding the regulation of fluid absorption in the mammary gland is relevant to improving milk production. In... (Review)
Review
Dairy milk consists of more than 85% water. Therefore, understanding the regulation of fluid absorption in the mammary gland is relevant to improving milk production. In recent decades, studies using different approaches, including blood flow, transmembrane fluid flow, tight junction, fluid flow of the paracellular pathway and functional mammary epithelial cell state, have been conducted aiming to investigate how mammary gland fluid absorption is regulated. However, the relationship between regulation mechanisms of fluid flow and milk production has not been studied systematically. The present review summarizes a series of key milk yield regulatory factors mediated by whole-mammary fluid flow, including milk, mammary blood flow, blood/tissue fluid-cell fluid flow and cell-alveolus fluid flow. Whole-mammary fluid flow regulates milk production by altering transporter activity, ion channels, local microcirculation-related factors, driving force of fluid transport (osmotic pressure or electrochemical gradient), cellular connection state and a cell volume sensitive mechanism. In addition, whole-mammary fluid flow plays important roles in milk synthesis and secretion. Knowledge gained from fluid flow-mediated regulatory mechanisms of the dairy mammary gland will lead to a fundamental understanding of lactation biology and will be beneficial for the improvement of dairy productivity. © 2017 Society of Chemical Industry.
Topics: Animals; Biological Transport; Body Fluids; Cattle; Dairying; Female; Homeostasis; Humans; Lactation; Mammary Glands, Animal; Microcirculation; Milk; Regional Blood Flow; Tight Junctions
PubMed: 28758674
DOI: 10.1002/jsfa.8605 -
European Review For Medical and... Sep 2021Bipolar disorder (BD) is a severe disorder, and it is associated with an increased risk of mortality. About 25% of patients with BD have attempted and 11% have died by... (Meta-Analysis)
Meta-Analysis
OBJECTIVE
Bipolar disorder (BD) is a severe disorder, and it is associated with an increased risk of mortality. About 25% of patients with BD have attempted and 11% have died by suicide. All these characteristics suggest that the disorders within the bipolar spectrum are a crucial public health problem. With the development of molecular genetics in recent decades, it was possible to more easily detect risk genes associated with this disorder. This study aimed at summarizing the findings of systematic reviews and meta-analyses on the topic and assessing the quality of the available evidence.
MATERIALS AND METHODS
PubMed/Medline and Web of Science were searched to identify systematic reviews and meta-analyses published during 2013-2019. Standard methodology was applied to synthesize and assess the retrieved literature.
RESULTS
This systematic review identifies a number of potential risk genes associated with bipolar disorder whose mechanism of action has yet to be confirmed. They are divided into several groups: 1) a list of the most significant susceptibility genetic factors associated with BD; 2) the implication of the ZNF804A gene in BD; 3) the role of genes involved in calcium signaling in BD; 4) DNA methylation in BD; 5) BD and risk suicide genes; 6) susceptibility genes for early-onset BD; 7) candidate genes common to both BD and schizophrenia; 8) genes involved in cognitive status in BD cases; 9) genes involved in structural alteration in BD brain tissue; 10) genes involved in lithium response in BD.
CONCLUSIONS
Future research should concentrate on molecular mechanisms by which genetic variants play a major role in BD. Supplemental research is needed to replicate the applicable results.
Topics: Bipolar Disorder; Calcium Signaling; DNA Methylation; Genes, Transgenic, Suicide; Genetic Association Studies; Genetic Predisposition to Disease; Humans; Kruppel-Like Transcription Factors; Schizophrenia
PubMed: 34604962
DOI: 10.26355/eurrev_202109_26789 -
The Cochrane Database of Systematic... Nov 2013Cystic fibrosis is caused by a defective gene encoding a protein called the cystic fibrosis transmembrane conductance regulator (CFTR), and is characterised by chronic... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
Cystic fibrosis is caused by a defective gene encoding a protein called the cystic fibrosis transmembrane conductance regulator (CFTR), and is characterised by chronic lung infection resulting in inflammation and progressive lung damage that results in a reduced life expectancy.
OBJECTIVES
To determine whether topical CFTR gene replacement therapy to the lungs in people with cystic fibrosis is associated with improvements in clinical outcomes, and to assess any adverse effects.
SEARCH METHODS
We searched the Cochrane Cystic Fibrosis and Genetic Disorders Group Trials Register comprising references identified from comprehensive electronic database searches, handsearching relevant journals and abstract books of conference proceedings.Date of most recent search: 22 August 2013.An additional search of the National Institutes for Health (NIH) Genetic Modification Clinical Research Information System (GeMCRIS) was also performed for the years 1992 to 2013.Date of most recent search: 04 September 2013.
SELECTION CRITERIA
Randomised controlled trials comparing topical CFTR gene delivery to the lung, using either viral or non-viral delivery systems, with placebo or an alternative delivery system in people with confirmed cystic fibrosis.
DATA COLLECTION AND ANALYSIS
The authors independently extracted data and assessed study quality. Authors of included studies were contacted and asked for any available additional data. Meta-analysis was limited due to differing study designs.
MAIN RESULTS
Three randomised controlled trials met the inclusion criteria for this review, involving a total of 155 participants. Fourteen studies were excluded. The included studies differed in terms of CFTR gene replacement agent and study design, which limited the meta-analysis.Although the first Moss study reported a significant improvement in respiratory function (forced expiratory volume at one second) 30 days after participants had received their first dose of gene therapy agent, this finding was not confirmed in their larger second study or in our meta-analysis.In participants who received the CFTR gene transfer agents in the Alton study, "influenza-like" symptoms were found (risk ratio 7.00 (95% confidence interval 1.10 to 44.61)). There were no other significant increases in adverse events in any of the studies.Alton measured ion transport in the lower airways and demonstrated significant changes toward normal values in the participants who received gene transfer agents (P < 0.0001), mean difference 6.86 (95% confidence interval 3.77 to 9.95). In these participants there was also evidence of increased salt transport in cells obtained by brushing the lower airway. These outcomes, whilst important, are not of direct clinical relevance.
AUTHORS' CONCLUSIONS
There is currently no evidence to support the use of CFTR gene transfer agents as a treatment for lung disease in people with cystic fibrosis. Future studies need to investigate clinically important outcome measures.
Topics: Cystic Fibrosis; Cystic Fibrosis Transmembrane Conductance Regulator; Gene Transfer Techniques; Genetic Therapy; Humans; Randomized Controlled Trials as Topic; Respiratory Function Tests; Targeted Gene Repair
PubMed: 24282073
DOI: 10.1002/14651858.CD005599.pub4 -
The Cochrane Database of Systematic... Apr 2014People with cystic fibrosis (CF) have increased transport of the salt, sodium across their airway lining. Over-absorption of sodium results in the dehydration of the... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
People with cystic fibrosis (CF) have increased transport of the salt, sodium across their airway lining. Over-absorption of sodium results in the dehydration of the liquid that lines the airway surface and (along with defective chloride secretion) is a primary defect in people with CF.
OBJECTIVES
To determine whether the topical administration of drugs that block sodium transport improves the respiratory condition of people with CF.
SEARCH METHODS
We searched the Cochrane Cystic Fibrosis and Genetic Disorders Group Trials Register comprising references identified from comprehensive electronic database searches, handsearching relevant journals and abstract books of conference proceedings. We contacted principal investigators known to work in the field, previous authors and pharmaceutical companies who manufacture ion transport agents for unpublished or follow-up data.Most recent search of the Group's register: 19 December 2013.
SELECTION CRITERIA
Published or unpublished randomised controlled trials (RCTs) or quasi-randomised controlled trials of sodium channel blockers compared to placebo or another sodium channel blocker or the same sodium channel blocker at a different dosing regimen.
DATA COLLECTION AND ANALYSIS
Two authors independently extracted data. Meta-analysis was limited due to differing study designs.
MAIN RESULTS
Five RCTs, with a total of 226 participants, examining the topical administration of the short-acting sodium channel blocker, amiloride, compared to placebo were identified as eligible for inclusion in the review. In three studies over six months, there was a significant difference found in the difference in relative change in FVC in favour of placebo (weighted mean difference 1.51% (95% confidence interval -2.77 to -0.25), although heterogeneity was evident. A two-week study demonstrated that hypertonic saline with amiloride pre-treatment did not result in a significant improvement in respiratory function or mucus clearance, in contrast to pre-treatment with placebo. There were no significant differences identified in other clinically relevant outcomes.
AUTHORS' CONCLUSIONS
We found no evidence that the topical administration of a short-acting sodium channel blocker improves respiratory condition in people with cystic fibrosis and some limited evidence of deterioration in lung function.
Topics: Amiloride; Anti-Bacterial Agents; Cystic Fibrosis; Forced Expiratory Volume; Humans; Mucus; Randomized Controlled Trials as Topic; Respiration; Saline Solution, Hypertonic; Sodium Channel Blockers; Vital Capacity
PubMed: 24715704
DOI: 10.1002/14651858.CD005087.pub4 -
The Cochrane Database of Systematic... Oct 2012Cystic fibrosis is caused by a defective gene encoding a protein called the cystic fibrosis transmembrane conductance regulator (CFTR), and is characterised by chronic... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
Cystic fibrosis is caused by a defective gene encoding a protein called the cystic fibrosis transmembrane conductance regulator (CFTR), and is characterised by chronic lung infection resulting in inflammation and progressive lung damage that results in a reduced life expectancy.
OBJECTIVES
To determine whether topical CFTR gene replacement therapy to the lungs in people with cystic fibrosis is associated with improvements in clinical outcomes, and to assess any adverse effects.
SEARCH METHODS
We searched the Cochrane Cystic Fibrosis and Genetic Disorders Group Trials Register comprising references identified from comprehensive electronic database searches, handsearching relevant journals and abstract books of conference proceedings.Date of most recent search: 19 July 2012.An additional search of the National Institutes for Health (NIH) Genetic Modification Clinical Research Information System (GeMCRIS) was also performed for the years 1992 to 2012.Date of most recent search: 25 July 2012.
SELECTION CRITERIA
Randomised controlled trials comparing topical CFTR gene delivery to the lung, using either viral or non-viral delivery systems, with placebo or an alternative delivery system in people with confirmed cystic fibrosis.
DATA COLLECTION AND ANALYSIS
The authors independently extracted data and assessed study quality. Authors of included studies were contacted and asked for any available additional data. Meta-analysis was limited due to differing study designs.
MAIN RESULTS
Three randomised controlled trials met the inclusion criteria for this review, involving a total of 155 participants. Fourteen studies were excluded. The included studies differed in terms of CFTR gene replacement agent and study design, which limited the meta-analysis.Although the first Moss study reported a significant improvement in respiratory function (forced expiratory volume at one second) 30 days after participants had received their first dose of gene therapy agent, this finding was not confirmed in their larger second study or in our meta-analysis.In participants who received the CFTR gene transfer agents in the Alton study, "influenza-like" symptoms were found (risk ratio 7.00 (95% confidence interval 1.10 to 44.61)). There were no other significant increases in adverse events in any of the studies.Alton measured ion transport in the lower airways and demonstrated significant changes toward normal values in the participants who received gene transfer agents (P < 0.0001), mean difference 6.86 (95% CI of 3.77 to 9.95). In these participants there was also evidence of increased salt transport in cells obtained by brushing the lower airway. These outcomes, whilst important, are not of direct clinical relevance.
AUTHORS' CONCLUSIONS
There is currently no evidence to support the use of CFTR gene transfer reagents as a treatment for lung disease in people with cystic fibrosis. Future studies need to investigate clinically important outcome measures.
Topics: Cystic Fibrosis; Cystic Fibrosis Transmembrane Conductance Regulator; Gene Transfer Techniques; Humans; Randomized Controlled Trials as Topic; Respiratory Function Tests; Targeted Gene Repair
PubMed: 23076917
DOI: 10.1002/14651858.CD005599.pub3