Literature Watch
The SLCO1A2 -189_-188InsA polymorphism reduces clearance of rocuronium in patients submitted to elective surgeries.
The SLCO1A2 -189_-188InsA polymorphism reduces clearance of rocuronium in patients submitted to elective surgeries.
Eur J Clin Pharmacol. 2017 Apr 14;:
Authors: Costa AC, Coelho EB, Lanchote VL, Correia BV, Abumansur JT, Lauretti GR, de Moraes NV
Abstract
PURPOSE: Rocuronium (ROC) is a neuromuscular blocker mainly eliminated by biliary excretion dependent on organic anion transporting polypeptide 1A2 (OATP1A2) hepatocellular uptake. However, the influence of SLCO1A2 (gene encoding OATP1A2) genetic polymorphism on ROC pharmacokinetics was never described before. The objective of this work was to evaluate the influence of genetic polymorphisms of SLCO1A2 on the pharmacokinetics of rocuronium (ROC).
METHODS: Patients undergoing elective surgeries under general anesthesia using rocuronium as a neuromuscular blocker were genotyped for SLCO1A2 polymorphisms in the coding region (41A>G, 382A>T, 404A>T, 502C>T, 516A>C, 559G>A, 830C>A, and 833delA) and in the promoter region (-1105G>A, -1032G>A, -715T>C, -361G>A, and -189_-188insA). Rocuronium pharmacokinetic parameters were estimated by non-compartmental analysis.
RESULTS: None of the patients had heterozygous or homozygous variant of 404A>T, 382A>T, 502C>T, 833delA, 830C>A, 41A>G, and -715T>C. A linkage disequilibrium was found between -1105G>A and -1032G>A genotypes. Patients genotyped as -A or AA (n = 17) for SLCO1A2 -189_-188InsA showed reduced total clearance of ROC compared to patients genotyped as -/- (n = 13) (151.6 vs 207.1 mL/min, p ≤ 0.05). The pharmacokinetics parameters of ROC were not significantly different between other SLCO1A2 genotypes.
CONCLUSION: SLCO1A2 -189_-188InsA polymorphism is related to the reduced clearance of rocuronium in patients submitted to elective surgeries under general anesthesia.
TRIAL REGISTRATION: NCT 02399397 ( ClinicalTrials.gov ).
PMID: 28409297 [PubMed - as supplied by publisher]
Bringing a genomic perspective to the safety of drug treatment in oncology.
Bringing a genomic perspective to the safety of drug treatment in oncology.
F1000Res. 2017;6:
Authors: Innocenti F
Abstract
This article describes the clinical relevance of toxicity of therapies administered to patients with cancer, putting the patient, rather than disease, at the center of the evaluation of safety of anti-cancer therapy. Hence, the implications of adverse events are described from the patient perspective, focusing on the impact of patient safety on quality of life and efficacy of treatment. Issues revolving around other types of safety, such as financial toxicity, are also discussed. The role played by genetics in the assessment of a patient's risk of adverse events is also discussed, both in relation to the potential of genomic research and in the context of current tools of fruition in clinical care.
PMID: 28408974 [PubMed - in process]
Identification of C21orf59 and ATG2A as novel determinants of renal function-related traits in Japanese by exome-wide association studies.
Identification of C21orf59 and ATG2A as novel determinants of renal function-related traits in Japanese by exome-wide association studies.
Oncotarget. 2017 Mar 30;:
Authors: Yamada Y, Sakuma J, Takeuchi I, Yasukochi Y, Kato K, Oguri M, Fujimaki T, Horibe H, Muramatsu M, Sawabe M, Fujiwara Y, Taniguchi Y, Obuchi S, Kawai H, Shinkai S, Mori S, Arai T, Tanaka M
Abstract
We have performed exome-wide association studies to identify genetic variants that influence renal function-related traits or confer susceptibility to chronic kidney disease or hyperuricemia in Japanese. Exome-wide association studies for estimated glomerular filtration rate and the serum concentration of creatinine were performed with 12,565 individuals, that for the serum concentration of uric acid with 9934 individuals, and those for chronic kidney disease or hyperuricemia with 5161 individuals (3270 cases, 1891 controls) or 11,686 individuals (2045 cases, 9641 controls), respectively. The relation of genotypes of single nucleotide polymorphisms to estimated glomerular filtration rate or the serum concentrations of creatinine or uric acid was examined by linear regression analysis, and that of allele frequencies of single nucleotide polymorphisms to chronic kidney disease or hyperuricemia was examined with Fisher's exact test. The exome-wide association studies revealed that 25, seven, and six single nucleotide polymorphisms were significantly (P <1.21 × 10-6) associated with estimated glomerular filtration rate or the serum concentrations of creatinine or uric acid, respectively, and that 49 and 35 polymorphisms were significantly associated with chronic kidney disease or hyperuricemia, respectively. Subsequent multivariable logistic regression analysis with adjustment for covariates revealed that four and three single nucleotide polymorphisms were related (P < 0.05) to chronic kidney disease or hyperuricemia, respectively. Among polymorphisms identified in the present study, rs76974938 [C/T (D67N)] of C21orf59 and rs188780113 [G/A (R478C)] of ATG2A may be novel determinants of estimated glomerular filtration rate and chronic kidney disease or of the serum concentration of uric acid, respectively.
PMID: 28410202 [PubMed - as supplied by publisher]
Genetic Effects on the Correlation Structure of CVD Risk Factors: Exome-Wide Data From a Ghanaian Population.
Genetic Effects on the Correlation Structure of CVD Risk Factors: Exome-Wide Data From a Ghanaian Population.
Glob Heart. 2017 Apr 10;:
Authors: Kodaman N, Sobota RS, Asselbergs FW, Oetjens MT, Moore JH, Brown NJ, Aldrich MC, Williams SM
Abstract
Plasma concentration of plasminogen activator inhibitor-1 (PAI-1) is highly correlated with several cardiovascular disease (CVD) risk factors. It also plays a direct role in CVD, including myocardial infarction and stroke, by impeding the dissolution of thrombi in the blood. Insofar as PAI-1 links CVD's risk factors to its endpoints, genetic variants modulating the relationship between PAI-1 and risk factors may be of particular clinical and biological interest. The high heritability of PAI-1, which has not been explained by genetic association studies, may also, in large part, be due to this relationship with CVD risk factors. Using exome-wide data from 1,032 Ghanaian study participants, we tested for heterogeneity of correlation by genotype between PAI-1 and 4 CVD risk factors (body mass index, triglycerides, mean arterial pressure, and fasting glucose) under the hypothesis that loci involved in the relationship between PAI-1 and other risk factors will also modify their correlational structure. We found more significant heterogeneities of correlation by genotype than we found marginal effects, with no evidence of type I inflation. The most significant result among all univariate and multivariate tests performed in this study was the heterogeneity of correlation between PAI-1 and mean arterial pressure at rs10738554, near SLC24A2, a gene previously associated with high blood pressure in African Americans.
PMID: 28408189 [PubMed - as supplied by publisher]
Genomics: Tool to predict and prevent male infertility.
Genomics: Tool to predict and prevent male infertility.
Front Biosci (Schol Ed). 2017 Jun 01;9:448-508
Authors: Halder A, Kumar P, Jain M, Kalsi AK
Abstract
A large number of human diseases arise as a result of genetic abnormalities. With the advent of improved molecular biology techniques, the genetic etiology of male infertility is increasing. The common genetic factors responsible for male infertility are chromosomal abnormalities, Yq microdeletion and cystic fibrosis. These are responsible for approximately 30 percent cases of male infertility. About 40 percent cases of male infertility are categorized as idiopathic. These cases may be associated with genetic and genomic abnormalities. During last few years more and more genes are implicated in male infertility leading to decline in prevalence of idiopathic etiology. In this review we will summarize up to date published works on genetic etiologies of male infertility including our own works. We also briefly describe reproductive technologies used to overcome male infertility, dangers of transmitting genetic disorders to offspring and ways to prevent transmission of genetic disorders during assisted reproduction. At the end we will provide our points on how genomic information can be utilized for prediction and prevention of male infertility in coming years.
PMID: 28410128 [PubMed - in process]
Magnesium for treating sickle cell disease.
Magnesium for treating sickle cell disease.
Cochrane Database Syst Rev. 2017 Apr 14;4:CD011358
Authors: Than NN, Soe HH, Palaniappan SK, Abas AB, De Franceschi L
Abstract
BACKGROUND: Sickle cell disease is an autosomal recessive inherited haemoglobinopathy which causes painful vaso-occlusive crises due to sickle red blood cell dehydration. Vaso-occlusive crises are common painful events responsible for a variety of clinical complications; overall mortality is increased and life expectancy decreased compared to the general population. Experimental studies suggest that intravenous magnesium has proven to be well-tolerated in individuals hospitalised for the immediate relief of acute (sudden onset) painful crisis and has the potential to decrease the length of hospital stay. Some in vitro studies and open studies of long-term oral magnesium showed promising effect on pain relief but failed to show its efficacy. The studies show that oral magnesium therapy may prevent sickle red blood cell dehydration and prevent recurrent painful episodes. There is a need to access evidence for the impact of oral and intravenous magnesium effect on frequency of pain, length of hospital stay and quality of life.
OBJECTIVES: To evaluate the effects of short-term intravenous magnesium on the length of hospital stay and quality of life in children and adults with sickle cell disease. To determine the effects of long-term oral magnesium therapy on the frequency of painful crises and the quality of life in children and adults with sickle cell disease.
SEARCH METHODS: We searched the Cochrane Haemoglobinopathies Trials Register, compiled from electronic database searches and handsearching of journals and conference abstract books.Date of last search of the Cochrane Cystic Fibrosis and Genetic Disorders Group's Haemoglobinopathies Trials Register: 01 December 2016.Date of last search of other resources (clinical trials registries): 29 March 2017.
SELECTION CRITERIA: We searched for published and unpublished randomized controlled studies of oral or intravenous magnesium compared to placebo or no magnesium.
DATA COLLECTION AND ANALYSIS: Authors independently assessed the study quality and extracted the data using standard Cochrane methodologies.
MAIN RESULTS: We included five randomized placebo-controlled studies with a total of 386 participants (aged three to 53 years). Two shorter parallel studies (n = 306) compared intravenous magnesium sulphate to placebo (normal saline) for admission to hospital due to a vaso-occlusive crisis, for which we were able to analyse data. The quality of evidence was moderate for studies presenting this comparison mainly due to limitations due to risk of bias and imprecision. Two of the three longer-term studies comparing oral magnesium pidolate to placebo had a cross-over design. The third was a parallel factorial study which compared hydroxyurea and oral magnesium to each other and to placebo over a longer period of time; we only present the comparison of oral magnesium to placebo from this study. The quality of evidence was very low with uncertainty of the estimation.The eight-hourly dose levels in the two studies of intravenous magnesium were different; one used 100 mg/kg while the second used 40 mg/kg. Only one of these studies (n = 104) reported the mean daily pain score while hospitalised (a non-significant difference between groups, moderate quality evidence). The second study (n = 202) reported a number of child- and parent-reported quality of life scores. None of the scores showed any difference between treatment groups (low quality evidence). Data from one study (n = 106) showed no difference in length of stay in hospital between groups (low quality evidence). Both studies reported on adverse events, but not defined by severity as we had planned. One study showed significantly more participants receiving intravenous magnesium experienced warmth at infusion site compared to placebo; there were no differences between groups for other adverse events (low quality evidence).Three studies (n = 80) compared oral magnesium pidolate to placebo. None of them reported data which we were able to analyse. One study (n = 24) reported on the number of painful days and stated there was no difference between two groups (low quality evidence). None of the studies reported on quality of life or length of hospital stay. Two studies (n = 68) reported there were no differences in levels of magnesium in either plasma or red blood cells (moderate quality evidence). Two studies (n = 56) reported adverse events. One reported episodes of mild diarrhoea and headache, all of which resolved without stopping treatment. The second study reported adverse events as gastrointestinal disorders, headache or migraine, upper respiratory infections and rash; which were all evenly distributed across treatment groups (moderate quality evidence).
AUTHORS' CONCLUSIONS: Moderate to low quality evidence showed neither intravenous magnesium and oral magnesium therapy has an effect on reducing painful crisis, length of hospital stay and changing quality of life in treating sickle cell disease. Therefore, no definitive conclusions can be made regarding its clinical benefit. Further randomized controlled studies, perhaps multicentre, are necessary to establish whether intravenous and oral magnesium therapies have any effect on improving the health of people with sickle cell disease.
PMID: 28409830 [PubMed - as supplied by publisher]
Hypoxia and the hypoxia-regulated transcription factor HIF-1α suppress the host defence of airway epithelial cells.
Hypoxia and the hypoxia-regulated transcription factor HIF-1α suppress the host defence of airway epithelial cells.
Innate Immun. 2017 May;23(4):373-380
Authors: Polke M, Seiler F, Lepper PM, Kamyschnikow A, Langer F, Monz D, Herr C, Bals R, Beisswenger C
Abstract
Chronic diseases of the respiratory tract, such as cystic fibrosis, are associated with mucosal and systemic hypoxia. Innate immune functions of airway epithelial cells are required to prevent and control infections of the lung parenchyma. The transcription factor hypoxia-inducible factor 1α (HIF-1α) regulates cellular adaptation to low oxygen conditions. Here, we show that hypoxia and HIF-1α regulate innate immune mechanisms of cultured human bronchial epithelial cells (HBECs). Exposure of primary HBECs to hypoxia or the prolyl hydroxylase inhibitor dimethyloxaloylglycine (DMOG) resulted in a significantly decreased expression of inflammatory mediators (IL-6, IFN-γ-induced protein 10) in response to ligands for TLRs (flagellin, polyI:C) and Pseudomonas aeruginosa, whereas the expression of inflammatory mediators was not affected by hypoxia or DMOG in the absence of microbial factors. Small interfering RNA-mediated knockdown of HIF-1α in HBECs and in the bronchial epithelial cell line Calu-3 resulted in increased expression of inflammatory mediators. The inflammatory response was decreased in lungs of mice stimulated with inactivated P. aeruginosa under hypoxia. These data suggest that hypoxia suppresses the innate immune response of airway epithelial cells via HIF-1α.
PMID: 28409544 [PubMed - in process]
Body composition and lung function in children with cystic fibrosis and meconium ileus.
Body composition and lung function in children with cystic fibrosis and meconium ileus.
Eur J Pediatr. 2017 Apr 13;:
Authors: Doulgeraki A, Petrocheilou A, Petrocheilou G, Chrousos G, Doudounakis SE, Kaditis AG
Abstract
The aim of this study was to explore whether history of meconium ileus (MI) at birth in children and adolescents with cystic fibrosis (CF) adversely affects body composition and lung function in later life. Data of children and adolescents with CF who underwent spirometry and DXA as part of their routine care were analyzed. Associations between MI (explanatory variable) and areal bone mineral density (total body less head-TBLH aBMD), lean tissue mass (LTM), and fat mass (FM) (outcomes) were assessed using general linear models. Potential relationships of TBLH aBMD, LTM, and FM with FEV1 (additional outcome) were also explored. One hundred and one subjects with CF (mean age 14 ± 3 years) were included, 19 (18.8%) of whom had history of MI. Negative associations were demonstrated between history of MI and FEV1 (P = 0.04), TBLH aBMD (P = 0.03), and FM (P < 0.01) but not between history of MI and LTM (P = 0.07) after adjustment for other variables. Lung function was positively associated with TBLH aBMD (P < 0.01) and LTM (P = 0.02) but not with FM (P = 0.20).
CONCLUSION: Among children and adolescents with CF, those with history of MI have lower bone mineral density, FM, and lung function. What is Known: • Among children and adolescents with cystic fibrosis, those with history of meconium ileus in the neonatal period are at risk of having lower body mass index percentile and FEV 1 percent predicted. What is New: • Children and adolescents with cystic fibrosis and history of meconium ileus have decreased bone mineral density and fat mass compared to patients without such history. • Lower lung function in children with MI coexists with suboptimal bone mineral density.
PMID: 28409283 [PubMed - as supplied by publisher]
CFTR Gene Mutations in the Egyptian Population: Current and Future Insights for Genetic Screening Strategy.
CFTR Gene Mutations in the Egyptian Population: Current and Future Insights for Genetic Screening Strategy.
Front Genet. 2017;8:37
Authors: El-Seedy AS, Shafiek H, Kitzis A, Ladevèze V
PMID: 28408918 [PubMed - in process]
Patient knowledge and pulmonary medication adherence in adult patients with cystic fibrosis.
Patient knowledge and pulmonary medication adherence in adult patients with cystic fibrosis.
Patient Prefer Adherence. 2017;11:691-698
Authors: Lin AH, Kendrick JG, Wilcox PG, Quon BS
Abstract
BACKGROUND AND OBJECTIVES: Patient knowledge of lung function (ie, forced expiratory volume in 1 s [FEV1]% predicted) and the intended benefits of their prescribed pulmonary medications might play an important role in medication adherence, but this relationship has not been examined previously in patients with cystic fibrosis (CF).
METHODS: All patients diagnosed with CF and without prior lung transplantation were invited to complete knowledge and self-reported medication adherence questionnaires during routine outpatient visits to the Adult CF Clinic, St Paul's Hospital, Vancouver, Canada from June 2013 to August 2014.
RESULTS: A total of 142 out of 167 (85%) consecutive adults attending CF clinic completed patient knowledge and medication adherence survey questionnaires. Sixty-four percent of the patients recalled their last FEV1% predicted value within 5%, and 70% knew the intended benefits of all their prescribed medications. Self-reported adherence rates were highest for inhaled antibiotics (81%), azithromycin (87%), and dornase alpha (76%) and lowest for hypertonic saline (47%). Individuals who knew their FEV1% predicted value within 5% were more likely to self-report adherence to dornase alpha (84% vs 62%, P=0.06) and inhaled antibiotics (88% vs 64%, P=0.06) compared to those who did not, but these associations were not statistically significant. There were no significant associations observed between patient knowledge of intended medication benefits and self-reported medication adherence.
CONCLUSION: Contrary to our hypothesis, disease- and treatment-related knowledge was not associated with self-reported medication adherence. This suggests other barriers to medication adherence should be targeted in future studies aiming to improve medication adherence in adults with CF.
PMID: 28408806 [PubMed - in process]
Airway Clearance Techniques for Primary Ciliary Dyskinesia; is the Cystic Fibrosis literature portable?
Airway Clearance Techniques for Primary Ciliary Dyskinesia; is the Cystic Fibrosis literature portable?
Paediatr Respir Rev. 2017 Mar 16;:
Authors: Schofield LM, Duff A, Brennan C
Abstract
Primary Ciliary Dyskinesia (PCD) is a rare inherited disease with impaired mucociliary clearance. Airway clearance techniques (ACTs) are commonly recommended for patients with PCD to facilitate mucus clearance, despite a lack of evidence in this group. Current physiotherapy practice in PCD is based on evidence extrapolated from the field of Cystic Fibrosis (CF). This paper focuses on the available evidence and outlines challenges in extrapolating evidence between the conditions for best clinical practice.
PMID: 28408202 [PubMed - as supplied by publisher]
Current and Emerging Therapies in Multiple Sclerosis: Implications for the Radiologist, Part 1-Mechanisms, Efficacy, and Safety.
Current and Emerging Therapies in Multiple Sclerosis: Implications for the Radiologist, Part 1-Mechanisms, Efficacy, and Safety.
AJNR Am J Neuroradiol. 2017 Apr 13;:
Authors: McNamara C, Sugrue G, Murray B, MacMahon PJ
Abstract
Imaging for the diagnosis and follow-up of patients with suspected or confirmed multiple sclerosis is a common scenario for many general radiologists and subspecialty neuroradiologists. The field of MS therapeutics has rapidly evolved with multiple new agents now being used in routine clinical practice. To provide an informed opinion in discussions concerning newer MS agents, radiologists must have a working understanding of the strengths and limitations of the various novel therapies. The role of imaging in MS has advanced beyond monitoring and surveillance of disease activity to include treatment complications. An understanding of the new generation of MS drugs in conjunction with the key role that MR imaging plays in the detection of disease progression, opportunistic infections, and drug-related adverse events is of vital importance to the radiologist and clinical physician alike. Radiologists are in a unique position to detect many of the described complications well in advance of clinical symptoms. Part 1 of this review outlines recent developments in the treatment of MS and discusses the published clinical data on the efficacy and safety of the currently approved and emerging therapies in this condition as they apply to the radiologist. Part 2 will cover pharmacovigilance and the role the neuroradiologist plays in monitoring patients for signs of opportunistic infection and/or disease progression.
PMID: 28408630 [PubMed - as supplied by publisher]
New drugs, new toxicities: severe side effects of modern targeted and immunotherapy of cancer and their management.
New drugs, new toxicities: severe side effects of modern targeted and immunotherapy of cancer and their management.
Crit Care. 2017 Apr 14;21(1):89
Authors: Kroschinsky F, Stölzel F, von Bonin S, Beutel G, Kochanek M, Kiehl M, Schellongowski P, Intensive Care in Hematological and Oncological Patients (iCHOP) Collaborative Group
Abstract
Pharmacological and cellular treatment of cancer is changing dramatically with benefits for patient outcome and comfort, but also with new toxicity profiles. The majority of adverse events can be classified as mild or moderate, but severe and life-threatening complications requiring ICU admission also occur. This review will focus on pathophysiology, symptoms, and management of these events based on the available literature.While standard antineoplastic therapy is associated with immunosuppression and infections, some of the recent approaches induce overwhelming inflammation and autoimmunity. Cytokine-release syndrome (CRS) describes a complex of symptoms including fever, hypotension, and skin reactions as well as lab abnormalities. CRS may occur after the infusion of monoclonal or bispecific antibodies (MABs, BABs) targeting immune effectors and tumor cells and is a major concern in recipients of chimeric antigen receptor (CAR) modified T lymphocytes as well. BAB and CAR T-cell treatment may also be compromised by central nervous system (CNS) toxicities such as encephalopathy, cerebellar alteration, disturbed consciousness, or seizures. While CRS is known to be induced by exceedingly high levels of inflammatory cytokines, the pathophysiology of CNS events is still unclear. Treatment with antibodies against inhibiting immune checkpoints can lead to immune-related adverse events (IRAEs); colitis, diarrhea, and endocrine disorders are often the cause for ICU admissions.Respiratory distress is the main reason for ICU treatment in cancer patients and is attributable to infectious agents in most cases. In addition, some of the new drugs are reported to cause non-infectious lung complications. While drug-induced interstitial pneumonitis was observed in a substantial number of patients treated with phosphoinositol-3-kinase inhibitors, IRAEs may also affect the lungs.Inhibitors of angiogenetic pathways have increased the antineoplastic portfolio. However, vessel formation is also essential for regeneration and tissue repair. Therefore, severe vascular side effects, including thromboembolic events, gastrointestinal bleeding or perforation, hypertension, and congestive heart failure, compromise antitumor efficacy.The limited knowledge of the pathophysiology and management of life-threatening complications relating to new cancer drugs presents a need to provide ICU staff, oncologists, and organ specialists with evidence-based algorithms.
PMID: 28407743 [PubMed - in process]
Efficacy and safety of a four-drug fixed-dose combination regimen versus separate drugs for treatment of pulmonary tuberculosis: a systematic review and meta-analysis.
Efficacy and safety of a four-drug fixed-dose combination regimen versus separate drugs for treatment of pulmonary tuberculosis: a systematic review and meta-analysis.
Braz J Microbiol. 2017 Apr - Jun;48(2):198-207
Authors: Lima GC, Silva EV, Magalhães PO, Naves JS
Abstract
INTRODUCTION: Tuberculosis, particularly multi-drug-resistant tuberculosis, is a major cause of morbidity and mortality worldwide. To the best of our knowledge, however, no study to date has assessed the combined use of the four available drugs for tuberculosis treatment, which is an issue of great clinical relevance.
OBJECTIVE: To determine whether the four-drug fixed-dose combination is safer or more effective than separate drugs for treatment of pulmonary tuberculosis.
METHODS: A systematic review of the literature was performed in accordance with Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines.
RESULTS: In pooled results from five randomized controlled trials with 3502 patients across Africa, Asia, and Latin America, four-drug fixed-dose combination therapy was no better than separate drugs therapy in terms of culture conversion after 2 and 6 months of treatment. There were no significant differences between the groups in overall incidence of adverse effects. However, the meta-analytic measure (log odds ratio) revealed that separate drugs treatment had a 1.65 [exp (0.5)=1.65] increased chance of gastrointestinal adverse effects compared to four-drug fixed-dose combination treatment.
CONCLUSIONS: The reviewed studies showed that four-drug fixed-dose combination therapy provides greater patient comfort by reducing the number of pills and the incidence of gastrointestinal adverse effects, as well as simplifying pharmaceutical management at all levels.
PMID: 28063922 [PubMed - indexed for MEDLINE]
Unique Inflammatory Mediators and Specific IgE Levels Distinguish Local from Systemic Reactions after Anthrax Vaccine Adsorbed Vaccination.
Unique Inflammatory Mediators and Specific IgE Levels Distinguish Local from Systemic Reactions after Anthrax Vaccine Adsorbed Vaccination.
Clin Vaccine Immunol. 2016 08;23(8):664-71
Authors: Garman L, Smith K, Muns EE, Velte CA, Spooner CE, Munroe ME, Farris AD, Nelson MR, Engler RJ, James JA
Abstract
Although the U.S. National Academy of Sciences concluded that anthrax vaccine adsorbed (AVA) has an adverse event (AE) profile similar to those of other adult vaccines, 30 to 70% of queried AVA vaccinees report AEs. AEs appear to be correlated with certain demographic factors, but the underlying immunologic pathways are poorly understood. We evaluated a cohort of 2,421 AVA vaccinees and found 153 (6.3%) reported an AE. Females were more likely to experience AEs (odds ratio [OR] = 6.0 [95% confidence interval {CI} = 4.2 to 8.7]; P < 0.0001). Individuals 18 to 29 years of age were less likely to report an AE than individuals aged 30 years or older (OR = 0.31 [95% CI = 0.22 to 0.43]; P < 0.0001). No significant effects were observed for African, European, Hispanic, American Indian, or Asian ancestry after correcting for age and sex. Additionally, 103 AEs were large local reactions (LLRs), whereas 53 AEs were systemic reactions (SRs). In a subset of our cohort vaccinated 2 to 12 months prior to plasma sample collection (n = 75), individuals with LLRs (n = 33) had higher protective-antigen (PA)-specific IgE levels than matched, unaffected vaccinated individuals (n = 50; P < 0.01). Anti-PA IgE was not associated with total plasma IgE, hepatitis B-specific IgE, or anti-PA IgG in individuals who reported an AE or in matched, unaffected AVA-vaccinated individuals. IP-10 was also elevated in sera of individuals who developed LLRs (P < 0.05). Individuals reporting SRs had higher levels of systemic inflammation as measured from C-reactive protein (P < 0.01). Thus, LLRs and SRs are mediated by distinct pathways. LLRs are associated with a vaccine-specific IgE response and IP-10, whereas SRs demonstrate increased systemic inflammation without a skewed cytokine profile.
PMID: 27280620 [PubMed - indexed for MEDLINE]
Collaborative R01s for Clinical Studies of Mental Illness Not Involving Clinical Trials (Collaborative R01)
Limited Competition: National Swine Resource and Research Center (U42)
"systems biology"; +29 new citations
29 new pubmed citations were retrieved for your search. Click on the search hyperlink below to display the complete search results:
These pubmed results were generated on 2017/04/14
PubMed comprises more than millions of citations for biomedical literature from MEDLINE, life science journals, and online books. Citations may include links to full-text content from PubMed Central and publisher web sites.
Biotagging of Specific Cell Populations in Zebrafish Reveals Gene Regulatory Logic Encoded in the Nuclear Transcriptome.
Biotagging of Specific Cell Populations in Zebrafish Reveals Gene Regulatory Logic Encoded in the Nuclear Transcriptome.
Cell Rep. 2017 Apr 11;19(2):425-440
Authors: Trinh LA, Chong-Morrison V, Gavriouchkina D, Hochgreb-Hägele T, Senanayake U, Fraser SE, Sauka-Spengler T
Abstract
Interrogation of gene regulatory circuits in complex organisms requires precise tools for the selection of individual cell types and robust methods for biochemical profiling of target proteins. We have developed a versatile, tissue-specific binary in vivo biotinylation system in zebrafish termed biotagging that uses genetically encoded components to biotinylate target proteins, enabling in-depth genome-wide analyses of their molecular interactions. Using tissue-specific drivers and cell-compartment-specific effector lines, we demonstrate the specificity of the biotagging toolkit at the biochemical, cellular, and transcriptional levels. We use biotagging to characterize the in vivo transcriptional landscape of migratory neural crest and myocardial cells in different cellular compartments (ribosomes and nucleus). These analyses reveal a comprehensive network of coding and non-coding RNAs and cis-regulatory modules, demonstrating that tissue-specific identity is embedded in the nuclear transcriptomes. By eliminating background inherent to complex embryonic environments, biotagging allows analyses of molecular interactions at high resolution.
PMID: 28402863 [PubMed - in process]
Sequential Response to Multiple Developmental Network Circuits Encoded in an Intronic cis-Regulatory Module of Sea Urchin hox11/13b.
Sequential Response to Multiple Developmental Network Circuits Encoded in an Intronic cis-Regulatory Module of Sea Urchin hox11/13b.
Cell Rep. 2017 Apr 11;19(2):364-374
Authors: Cui M, Vielmas E, Davidson EH, Peter IS
Abstract
Gene expression in different spatial domains is often controlled by separate cis-regulatory modules (CRMs), but regulatory states determining CRM activity are not only distinct in space, they also change continuously during developmental time. Here, we systematically analyzed the regulatory sequences controlling hox11/13b expression and identified a single CRM required throughout embryonic gut development. We show that within this CRM, distinct sets of binding sites recognizing Ets, Tcf, and homeodomain transcription factors control the dynamic spatial expression of hox11/13b in each developmental phase. Several binding sites execute multiple, sometimes contradictory, regulatory functions, depending on the temporal and spatial regulatory context. In addition, we identified a nearby second CRM operating in inter-modular AND logic with the first CRM to control hox11/13b expression in hindgut endoderm. Our results suggest a mechanism for continuous gene expression in response to changing developmental network functions that depends on sequential combinatorial regulation of individual CRMs.
PMID: 28402858 [PubMed - in process]
Pages
