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Scientific Reports Jan 2018Results on the relationships between vitamin D receptor (VDR) gene polymorphisms and postmenopausal osteoporosis (PMOP) susceptibility and bone mineral density (BMD) are... (Meta-Analysis)
Meta-Analysis Review
Results on the relationships between vitamin D receptor (VDR) gene polymorphisms and postmenopausal osteoporosis (PMOP) susceptibility and bone mineral density (BMD) are conflicting. The aim of the study is to identify more eligible studies that calculated pooled OR and WMD with 95% CI to assess their associations. Overall, there were significant correlations between VDR ApaI, VDR FokI and PMOP susceptibility. Subgroup analysis showed that VDR ApaI polymorphism significantly decreased the osteoporosis risk in Caucasian postmenopausal women. In Asian populations, VDR BsmI and VDR FokI were associated with an increased risk of PMOP. As to the associations between VDR polymorphisms and BMD, Caucasian PMOP women carrying the ApaI aa genotype were at risk of high BMD in femoral neck, and low femoral neck BMD was observed in Caucasian PMOP women with FokI Ff genotype. PMOP women with the Cdx2 GA genotype had a lower lumbar spine BMD in overall and Caucasian populations compared with PMOP women with GG genotype. Different VDR gene polymorphisms have different impacts on PMOP risk and BMD.
Topics: Asian People; Bone Density; Bone and Bones; Deoxyribonucleases, Type II Site-Specific; Female; Gene Expression; Genetic Predisposition to Disease; Humans; Middle Aged; Osteoporosis, Postmenopausal; Polymorphism, Restriction Fragment Length; Postmenopause; Receptors, Calcitriol; White People
PubMed: 29343720
DOI: 10.1038/s41598-017-18670-7 -
International Forum of Allergy &... Jun 2018A major component of sputum in cystic fibrosis (CF) patients is polymerized DNA, a byproduct of degraded neutrophils. Dornase alfa (dornase) selectively cleaves...
BACKGROUND
A major component of sputum in cystic fibrosis (CF) patients is polymerized DNA, a byproduct of degraded neutrophils. Dornase alfa (dornase) selectively cleaves extracellular DNA and reduces the viscosity of sputum. It improves mucociliary clearance and pulmonary function. The benefit of dornase on CF-associated sinusitis is less clear. Therefore, the objective of this study was to systematically review the use of dornase on chronic rhinosinusitis (CRS) in CF patients.
METHODS
The Preferred Reporting Items for Systematic Reviews and Meta-Analyses statement was followed for this systematic review. Ovid Medline, EMBASE, PubMed, and the Cochrane Library were searched. The search terms "dornase alfa," "deoxyribonucleases," "rhinosinusitis," and "cystic fibrosis" were used to find articles published between 1990 and 2016. The articles were reviewed for study design, level of evidence, and clinical outcomes.
RESULTS
Sixty-two articles were identified; 6 met the inclusion criteria (104 patients). Improvement measured by sinonasal symptoms, endoscopic and radiographic findings, and pulmonary function was variably reported between the studies. Sinonasal symptoms were shown to improve in all studies with use of intranasal topical dornase. Three placebo-controlled studies showed that topical dornase significantly improved sinonasal symptoms more than saline alone. The impact on pulmonary function and radiographic and endoscopy findings was variable.
CONCLUSION
Topical intranasal dornase appears to improve sinonasal symptoms in CF patients to a greater degree than saline alone. The impact on other outcomes is less clear. Larger studies are needed to fully elucidate the true efficacy of dornase alfa in the treatment of CRS in CF patients.
Topics: Administration, Intranasal; Chronic Disease; Cystic Fibrosis; Deoxyribonuclease I; Humans; Nasal Decongestants; Recombinant Proteins; Rhinitis; Sinusitis; Viscosity
PubMed: 29323796
DOI: 10.1002/alr.22082 -
Tumour Biology : the Journal of the... Oct 2017The purpose of this systemic review and meta-analysis was to examine the relationship between VDR gene polymorphisms and breast cancer. Literature was searched through... (Meta-Analysis)
Meta-Analysis Review
The purpose of this systemic review and meta-analysis was to examine the relationship between VDR gene polymorphisms and breast cancer. Literature was searched through PubMed database, Google scholar, and the web of knowledge from December 2015 to January 2017 and consists of 34 studies (26,372 cases and 32,883 controls). All statistical measures were done using STATA version 11.2. The heterogeneity among studies was tested using I statistics. Mantel-Haenszel method and DerSimonian-Laird method were used to combine data from studies using both random-effect model and fixed-effect model, respectively. Potential publication bias was evaluated by Egger's test. Sensitivity analysis was also performed to evaluate the quality and consistency in results. The results of this meta-analysis revealed that VDR gene polymorphisms (Bsm1 bb vs BB; SOR = 1.18, 95% CI = 1.054-1.322, Apa1 aa vs AA; SOR = 1.18, 95% CI = 0.87-1.59, Poly (A) LL vs SS; SOR = 1.41, 95% CI = 1.06-1.88, Fok1 ff + Ff vs FF; SOR = 1.25, 95% CI = 0.896-1.759, Apa1 aa+Aa vs AA; SOR = 1.13, 95% CI = 0.95-1.35, Poly (A) LL + LS vs SS; SOR = 1.19, 95% CI = 1.00-1.43, Poly (A) L vs S; SOR = 1.18, 95% CI = 1.03-1.35) are associated with the breast cancer. Cdx2, Bgl1, and Taq1 do not show association with breast cancer. Thus, the finding of this meta-analysis concluded that VDR Bsm1, Apa1, Fok1, and Poly (A) gene polymorphisms may be susceptible for breast cancer development.
Topics: Breast Neoplasms; DNA Restriction Enzymes; Female; Genetic Association Studies; Genetic Predisposition to Disease; Humans; Polymorphism, Genetic; Receptors, Calcitriol
PubMed: 29072133
DOI: 10.1177/1010428317731280 -
Respirology (Carlton, Vic.) Aug 2017Inhaled mucoactive agents are used in respiratory disease to improve mucus properties and enhance secretion clearance. The effect of mannitol, recombinant human... (Meta-Analysis)
Meta-Analysis Review
Inhaled mucoactive agents are used in respiratory disease to improve mucus properties and enhance secretion clearance. The effect of mannitol, recombinant human deoxyribonuclease/dornase alfa (rhDNase) and hypertonic saline (HS) or normal saline (NS) are not well described in chronic lung conditions other than cystic fibrosis (CF). The aim of this review was to determine the benefit and safety of inhaled mucoactive agents outside of CF. We searched Medline, Embase, CINAHL and CENTRAL for randomized controlled trials investigating the effects of mucoactive agents on lung function, adverse events (AEs), health-related quality of life (HRQOL), hospitalization, length of stay, exacerbations, sputum clearance and inflammation. There were detrimental effects of rhDNase in bronchiectasis, with average declines of 1.9-4.3% in forced expiratory volume in 1 s (FEV ) and 3.7-5.4% in forced vital capacity (FVC) (n = 410, two studies), and increased exacerbation risk (relative risk = 1.35, 95% CI = 1.01-1.79 n = 349, one study). Some participants exhibited a reduction in FEV (≥10-15%) with mucoactive agents on screening (mannitol = 158 of 1051 participants, rhDNase = 2 of 30, HS = 3 of 80). Most AEs were mild and transient, including bronchospasm, cough and breathlessness. NS eased symptomatic burden in COPD, while NS and HS improved spirometry, HRQOL and sputum burden in non-CF bronchiectasis. Mannitol improved mucociliary clearance in asthma and bronchiectasis, while the effects of N-acetylcysteine were unclear. In chronic lung diseases outside CF, there are small benefits of mannitol, NS and HS. Adverse effects of rhDNase suggest this should not be administered in non-CF bronchiectasis.
Topics: Acetylcysteine; Administration, Inhalation; Bronchiectasis; Chronic Disease; Deoxyribonuclease I; Expectorants; Forced Expiratory Volume; Humans; Lung Diseases; Mannitol; Mesna; Mucociliary Clearance; Quality of Life; Recombinant Proteins; Saline Solution, Hypertonic; Symptom Flare Up; Vital Capacity
PubMed: 28397992
DOI: 10.1111/resp.13047 -
Genetic Testing and Molecular Biomarkers Jan 2017Evidence supporting an association of intervertebral disc degeneration (DD) with polymorphisms of the vitamin D receptor (VDR) gene has been controversial. We performed... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
Evidence supporting an association of intervertebral disc degeneration (DD) with polymorphisms of the vitamin D receptor (VDR) gene has been controversial. We performed a meta-analysis of these studies to determine if there was substantial evidence to support such an association between the VDR polymorphisms and DD.
METHODS
PubMed, Embase, and Science Direct databases were searched for studies that investigated associations of the FokI (rs2228570, rs10735810), and ApaI (rs7975253) polymorphisms of the VDR gene with DD. From the extracted genotype data from 14 publications, we estimated risk (odds ratio [OR] with 95% confidence intervals).
RESULTS
Overall associations of FokI with DD were absent (OR 0.96-1.04, p = 0.73-0.95) with heterogeneity in the dominant and codominant models (p <0.10, I = 47-57%). Post-outlier pooled effects yielded dominant significance indicating reduced risk (OR 0.77, p = 0.01) with concomitant zero heterogeneity (I = 0%). ApaI effects pointed to reduced risks, with overall dominant significance (OR 0.69, p = 0.04) and Asian subgroup nonsignificance (OR 0.75-0.93, p = 0.17-0.74). In FokI, Non-Hispanic Caucasians (OR 0.77, p = 0.01) and males (OR 0.36-0.66, p = 0.001-0.04) were protected but not Hispanic Caucasians (OR 1.39-1.85, p = 0.006-0.05) and females (OR 1.72, p = 0.05). Tests of interaction between the genders highlighted female susceptibility and male protection (p = 0.001-0.005). Zero heterogeneity (I = 0%) is a key strength of these significant effects.
CONCLUSION
This meta-analysis confirmed the protective role of the ApaI polymorphism, however, susceptibility and protective effects of the FokI polymorphism may be ethnic and gender specific.
Topics: Case-Control Studies; Deoxyribonucleases, Type II Site-Specific; Female; Genetic Predisposition to Disease; Humans; Intervertebral Disc Degeneration; Male; Polymorphism, Single Nucleotide; Receptors, Calcitriol
PubMed: 27797588
DOI: 10.1089/gtmb.2016.0054 -
Gastroenterology Jan 2017High-throughput sequencing analysis has accelerated searches for genes associated with risk for colorectal cancer (CRC); germline mutations in NTHL1, RPS20, FANCM, FAN1,... (Review)
Review
High-throughput sequencing analysis has accelerated searches for genes associated with risk for colorectal cancer (CRC); germline mutations in NTHL1, RPS20, FANCM, FAN1, TP53, BUB1, BUB3, LRP6, and PTPN12 have been recently proposed to increase CRC risk. We attempted to validate the association between variants in these genes and development of CRC in a systematic review of 11 publications, using sequence data from 863 familial CRC cases and 1604 individuals without CRC (controls). All cases were diagnosed at an age of 55 years or younger and did not carry mutations in an established CRC predisposition gene. We found sufficient evidence for NTHL1 to be considered a CRC predisposition gene-members of 3 unrelated Dutch families were homozygous for inactivating p.Gln90Ter mutations; a Canadian woman with polyposis, CRC, and multiple tumors was reported to be heterozygous for the inactivating NTHL1 p.Gln90Ter/c.709+1G>A mutations; and a man with polyposis was reported to carry p.Gln90Ter/p.Gln287Ter; whereas no inactivating homozygous or compound heterozygous mutations were detected in controls. Variants that disrupted RPS20 were detected in a Finnish family with early-onset CRC (p.Val50SerfsTer23), a 39-year old individual with metachronous CRC (p.Leu61GlufsTer11 mutation), and a 41-year-old individual with CRC (missense p.Val54Leu), but not in controls. We therefore found published evidence to support the association between variants in NTHL1 and RPS20 with CRC, but not of other recently reported CRC susceptibility variants. We urge the research community to adopt rigorous statistical and biological approaches coupled with independent replication before making claims of pathogenicity.
Topics: Adenomatous Polyposis Coli; Colorectal Neoplasms; Deoxyribonuclease (Pyrimidine Dimer); Genetic Predisposition to Disease; Germ-Line Mutation; Humans; Ribosomal Proteins
PubMed: 27713038
DOI: 10.1053/j.gastro.2016.09.041 -
The Cochrane Database of Systematic... Jul 2016Inhalation of the enzyme dornase alfa reduces sputum viscosity and improves clinical outcomes of people with cystic fibrosis. This is an update of a previously published... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
Inhalation of the enzyme dornase alfa reduces sputum viscosity and improves clinical outcomes of people with cystic fibrosis. This is an update of a previously published Cochrane review.
OBJECTIVES
To determine the effect of timing of dornase alfa inhalation on measures of clinical efficacy in people with cystic fibrosis (in relation to airway clearance techniques or time of day).
SEARCH METHODS
Relevant randomised and quasi-randomised controlled trials were identified from the Cochrane Cystic Fibrosis Trials Register, Physiotherapy Evidence Database (PEDro), and international cystic fibrosis conference proceedings.Date of the most recent search: 25 April 2016.
SELECTION CRITERIA
Any trial of dornase alfa in people with cystic fibrosis where timing of inhalation was the randomised element in the study with either: inhalation before compared to after airway clearance techniques; or morning compared to evening inhalation.
DATA COLLECTION AND ANALYSIS
Both authors independently selected trials, assessed risk of bias and extracted data with disagreements resolved by discussion. Relevant data were extracted and, where possible, meta-analysed.
MAIN RESULTS
We identified 115 trial reports representing 55 studies, of which five studies (providing data on 122 participants) met our inclusion criteria. All five studies used a cross-over design. Intervention periods ranged from two to eight weeks. Four trials compared dornase alfa inhalation before versus after airway clearance techniques. Inhalation after instead of before airway clearance did not significantly change forced expiratory volume at one second. Similarly, forced vital capacity and quality of life were not significantly affected; forced expiratory flow at 25% was significantly worse with dornase alfa inhalation after airway clearance, mean difference -0.17 litres (95% confidence interval -0.28 to -0.05), based on the pooled data from two small studies in children (seven to 19 years) with well-preserved lung function. All other secondary outcomes were statistically non-significant.In one trial, morning versus evening inhalation had no impact on lung function or symptoms.
AUTHORS' CONCLUSIONS
The current evidence derived from a small number of participants does not indicate that inhalation of dornase alfa after airway clearance techniques is more or less effective than the traditional recommendation to inhale nebulised dornase alfa 30 minutes prior to airway clearance techniques, for most outcomes. For children with well-preserved lung function, inhalation before airway clearance may be more beneficial for small airway function than inhalation after. However, this result relied on a measure with high variability and studies with variable follow up. In the absence of strong evidence to indicate that one timing regimen is better than another, the timing of dornase alpha inhalation can be largely based on pragmatic reasons or individual preference with respect to the time of airway clearance and time of day. Further research is warranted.
Topics: Administration, Inhalation; Adolescent; Child; Combined Modality Therapy; Cystic Fibrosis; Deoxyribonuclease I; Drug Administration Schedule; Humans; Quality of Life; Randomized Controlled Trials as Topic; Recombinant Proteins; Respiratory Therapy; Time Factors; Young Adult
PubMed: 27457496
DOI: 10.1002/14651858.CD007923.pub4 -
Scientific Reports Jul 2016An increasing number of studies have highlighted the potential link between EXO1 polymorphisms and cancer risk, although no consensus has yet been obtained. Thus, we... (Meta-Analysis)
Meta-Analysis
An increasing number of studies have highlighted the potential link between EXO1 polymorphisms and cancer risk, although no consensus has yet been obtained. Thus, we aimed to obtain a thorough and current assessment of EXO1 polymorphisms and cancer susceptibility by performing a meta-analysis. A comprehensive literature retrieval was performed on PubMed, EMbase, Web of Science and Wanfang databases. The odds ratio (OR) and 95% confidence interval (CI) were applied to assess the results. Finally, 39 case-control studies of the nine EXO1 polymorphisms that involved 21,651 cases and 21,348 controls met our inclusion criteria. The pooled analysis indicated that the rs1047840 polymorphism conferred a significantly increased susceptibility to cancer in an allelic model. Similarly, the rs3754093, rs1776177, rs9350, rs10802996, rs1635498, rs1776148 and rs851797 polymorphisms were also associated with an increased susceptibility to cancer in an allelic model, respectively, while no significant association was identified for rs1635517 polymorphism. For the rs1047840 polymorphism, in an ethnicity subgroup analysis, a significantly increased susceptibility to cancer for Asians was identified in all the genetic models, and for Caucasians in an allelic model. Our findings provide the evidence that the rs1047840, rs9350, rs10802996, rs1635498, rs1776148, rs1776177, rs3754093 and rs851797 polymorphisms may act as risk factors for cancer.
Topics: Case-Control Studies; DNA Repair Enzymes; Ethnicity; Exodeoxyribonucleases; Genetic Predisposition to Disease; Humans; Neoplasms; Polymorphism, Single Nucleotide
PubMed: 27387683
DOI: 10.1038/srep29270 -
The Cochrane Database of Systematic... Apr 2016Dornase alfa is currently used as a mucolytic to treat pulmonary disease (the major cause of morbidity and mortality) in cystic fibrosis. It reduces mucus viscosity in... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
Dornase alfa is currently used as a mucolytic to treat pulmonary disease (the major cause of morbidity and mortality) in cystic fibrosis. It reduces mucus viscosity in the lungs, promoting improved clearance of secretions. This is an update of a previously published review.
OBJECTIVES
To determine whether the use of dornase alfa in cystic fibrosis is associated with improved mortality and morbidity compared to placebo or other medications that improve airway clearance, and to identify any adverse events associated with its use.
SEARCH METHODS
We searched the Cochrane Cystic Fibrosis and Genetic Disorders Group Trials Register which comprises references identified from comprehensive electronic database searches, handsearching relevant journals and abstracts from conferences. Date of the most recent search of the Group's Cystic Fibrosis Register: 30 November 2015.Clinicaltrials.gov was also searched to identify unpublished or ongoing trials. Date of most recent search: 28 November 2015.
SELECTION CRITERIA
All randomised and quasi-randomised controlled trials comparing dornase alfa to placebo, standard therapy or other medications that improve airway clearance.
DATA COLLECTION AND ANALYSIS
Authors independently assessed trials against the inclusion criteria; two authors carried out analysis of methodological quality and data extraction.
MAIN RESULTS
The searches identified 54 trials, of which 19 (including a total of 2565 participants) met our inclusion criteria. Three additional papers examined the healthcare cost from one of the clinical trials. Fifteen trials compared dornase alfa to placebo or no dornase alfa treatment (2447 participants); two compared daily dornase to hypertonic saline (32 participants); one compared daily dornase alfa with hypertonic saline and alternate day dornase alfa (48 participants); one compared dornase alfa to mannitol and the combination of both drugs (38 participants). Trial duration varied from six days to three years.Compared to placebo, forced expiratory volume at one second improved in the intervention groups, with significant differences at one, three, six months and two years. There was also a significant improvement in lung clearance index at one month. There was a decrease in pulmonary exacerbations compared to placebo in trials of longer duration. The quality of the evidence from placebo-controlled trials was moderate to high for outcomes of lung function and pulmonary exacerbations. Limited, low quality evidence was available for changes in quality of life from baseline. One trial that examined the cost of care, including the cost of dornase alfa, found that the cost savings from dornase alfa offset 18% to 38% of the medication costs.The results for trials comparing dornase alfa to other medications that improve airway clearance (hypertonic saline or mannitol) were mixed, with one trial showing a greater improvement in forced expiratory volume at one second for dornase alfa compared to hypertonic saline, and three trials finding no difference between medications. In the only trial to assess the combination of dornase alfa with another medication compared to dornase alone, there was no benefit seen with the combination of dornase alfa and mannitol. Evidence of dornase alfa compared to other medications was limited and the open-label design of the trials may have induced bias, therefore the quality of the evidence was judged to be low.Dornase alfa did not cause significantly more adverse effects, except voice alteration and rash.
AUTHORS' CONCLUSIONS
There is evidence to show that, compared with placebo, therapy with dornase alfa improves lung function in people with cystic fibrosis in trials lasting one month to two years. There was a decrease in pulmonary exacerbations in trials of six months or longer. Voice alteration and rash appear to be the only adverse events reported with increased frequency in randomised controlled trials. There is not enough evidence to firmly conclude if dornase alfa is superior to hyperosmolar agents in improving lung function.
Topics: Adolescent; Child; Child, Preschool; Cystic Fibrosis; Deoxyribonuclease I; Expectorants; Humans; Infant; Mannitol; Randomized Controlled Trials as Topic; Recombinant Proteins; Saline Solution, Hypertonic
PubMed: 27043279
DOI: 10.1002/14651858.CD001127.pub3 -
Pediatric Pulmonology Feb 2016The metabolism of sodium, potassium, and chloride and the acid-base balance are sometimes altered in cystic fibrosis. Textbooks and reviews only marginally address the... (Review)
Review
BACKGROUND
The metabolism of sodium, potassium, and chloride and the acid-base balance are sometimes altered in cystic fibrosis. Textbooks and reviews only marginally address the homeostasis of magnesium in cystic fibrosis.
METHODS
We performed a search of the Medical Subject Headings terms (cystic fibrosis OR mucoviscidosis) AND (magnesium OR hypomagnes[a]emia) in the US National Library of Medicine and Excerpta Medica databases.
RESULTS
We identified 25 reports dealing with magnesium and cystic fibrosis. The results of the review may be summarized as follows. First, hypomagnesemia affects more than half of the cystic fibrosis patients with advanced disease; second, magnesemia, which is normally age-independent, relevantly decreases with age in cystic fibrosis; third, aminoglycoside antimicrobials frequently induce both acute and chronic renal magnesium-wasting; fourth, sweat magnesium concentration was normal in cystic fibrosis patients; fifth, limited data suggest the existence of an impaired intestinal magnesium balance. Finally, stimulating observations suggest that magnesium supplements might achieve an improvement in respiratory muscle strength and mucolytic activity of both recombinant and endogenous deoxyribonuclease.
CONCLUSIONS
The first comprehensive review of the literature confirms that, despite being one of the most prevalent minerals in the body, the importance of magnesium in cystic fibrosis is largely overlooked. In these patients, hypomagnesemia should be sought once a year. Furthermore, the potential of supplementation with this cation deserves more attention.
Topics: Aminoglycosides; Cystic Fibrosis; Deoxyribonucleases; Dietary Supplements; Enzyme Replacement Therapy; Expectorants; Homeostasis; Humans; Intestinal Mucosa; Kidney; Magnesium; Muscle Strength; Respiratory Muscles; Water-Electrolyte Imbalance
PubMed: 26663706
DOI: 10.1002/ppul.23356