Warfarin dosing according to the genotype-guided algorithm is most beneficial in patients with atrial fibrillation: a randomized parallel group trial.

Ther Drug Monit. 2018 Feb 27;:

Authors: Makar-Aušperger K, Krželj Cand Med K, Lovrić Benčić M, Radačić Aumiler M, Erdeljić Turk V, Božina N

Abstract
BACKGROUND: Observational studies have indicated potential benefits of CYP2C9 and VKORC1 guided dosing of warfarin but randomized clinical trials have resulted in contradictory findings. One of the reasons for contradiction may be the negligence of possible differences between warfarin indications. This study aims to determine efficacy and safety of genotype- and clinically guided dosing of warfarin in atrial fibrillation (AF), deep-vein thrombosis (DVT), and pulmonary embolism (PE) within the first five days after the introduction of therapy.
METHODS: In this single-center, single-blinded, randomized, controlled trial including patients of both sexes, ≥18 years of age, diagnosed with AF, DVT, or PE, a total of 205 consecutive patients were allocated into the group where warfarin therapy was genotype-guided (PHG), and where it was adjusted according to the clinical parameters (NPHG). Genotyping of CYP2C9*2, *3 and VKORC1 was performed using the Real-Time PCR method. The primary outcomes were the percentage of time in the therapeutic international normalized ratio (INR) (2.0-3.0) range and the percentage of patients who achieved a stable anticoagulation defined as the INR (2.0-3.0) range in at least two consecutive measurements.
RESULTS: In patients with AF, the percentage of time spent in the therapeutic range of INR was higher in the PHG group (mean=26% (SD 25.0)), than in the NPHG group (mean=14% (SD 18.6)), (Δ=12; 95% confidence interval (CI) 0-23; p=0.040). There was no significant difference in other two indications for warfarin treatment. A stable dose of warfarin was achieved in a statistically higher number of patients in the PHG group 14/30 (47%), than in the NPHG group 7/32 (22%) (OR=3.13, 95% CI 0.92-10.98; p=0.039).
CONCLUSION: CYP2C9 and VKORC1 genotype-guided dosing of warfarin may be beneficial in patients diagnosed with atrial fibrillation. There is no evidence for such conclusion in patients with DVT and PE.

PMID: 29494423 [PubMed - as supplied by publisher]

The use of pharmacogenomics, epigenomics, and transcriptomics to improve childhood asthma management: Where do we stand?

Pediatr Pulmonol. 2018 Mar 01;:

Authors: Farzan N, Vijverberg SJ, Kabesch M, Sterk PJ, Maitland-van der Zee AH

Abstract
Asthma is a complex multifactorial disease and it is the most common chronic disease in children. There is a high variability in response to asthma treatment, even in patients with good adherence to maintenance treatment, and a correct inhalation technique. Distinct underlying disease mechanisms in childhood asthma might be the reason of this heterogeneity. A deeper knowledge of the underlying molecular mechanisms of asthma has led to the recent development of advanced and mechanism-based treatments such as biologicals. However, biologicals are recommended only for patients with specific asthma phenotypes who remain uncontrolled despite high dosages of conventional asthma treatment. One of the main unmet needs in their application is lack of clinically available biomarkers to individualize pediatric asthma management and guide treatment. Pharmacogenomics, epigenomics, and transcriptomics are three omics fields that are rapidly advancing and can provide tools to identify novel asthma mechanisms and biomarkers to guide treatment. Pharmacogenomics focuses on variants in the DNA, epigenomics studies heritable changes that do not involve changes in the DNA sequence but lead to alteration of gene expression, and transcriptomics investigates gene expression by studying the complete set of mRNA transcripts in a cell or a population of cells. Advances in high-throughput technologies and statistical tools together with well-phenotyped patient inclusion and collaborations between different centers will expand our knowledge of underlying molecular mechanisms involved in disease onset and progress. Furthermore, it could help to select and stratify appropriate therapeutic strategies for subgroups of patients and hopefully bring precision medicine to daily practice.

PMID: 29493882 [PubMed - as supplied by publisher]

The mutational landscape of MYCN, Lin28b and ALKF1174L driven murine neuroblastoma mimics human disease.

Oncotarget. 2018 Feb 02;9(9):8334-8349

Authors: De Wilde B, Beckers A, Lindner S, Kristina A, De Preter K, Depuydt P, Mestdagh P, Sante T, Lefever S, Hertwig F, Peng Z, Shi LM, Lee S, Vandermarliere E, Martens L, Menten B, Schramm A, Fischer M, Schulte J, Vandesompele J, Speleman F

Abstract
Genetically engineered mouse models have proven to be essential tools for unraveling fundamental aspects of cancer biology and for testing novel therapeutic strategies. To optimally serve these goals, it is essential that the mouse model faithfully recapitulates the human disease. Recently, novel mouse models for neuroblastoma have been developed. Here, we report on the further genomic characterization through exome sequencing and DNA copy number analysis of four of the currently available murine neuroblastoma model systems (ALK, Th-MYCN, Dbh-MYCN and Lin28b). The murine tumors revealed a low number of genomic alterations - in keeping with human neuroblastoma - and a positive correlation of the number of genetic lesions with the time to onset of tumor formation was observed. Gene copy number alterations are the hallmark of both murine and human disease and frequently affect syntenic genomic regions. Despite low mutational load, the genes mutated in murine disease were found to be enriched for genes mutated in human disease. Taken together, our study further supports the validity of the tested mouse models for mechanistic and preclinical studies of human neuroblastoma.

PMID: 29492199 [PubMed]

Comparison of TPMT and NUDT15 polymorphisms in Chinese patients with inflammatory bowel disease.

World J Gastroenterol. 2018 Feb 28;24(8):941-948

Authors: Wang HH, He Y, Wang HX, Liao CL, Peng Y, Tao LJ, Zhang W, Yang HX

Abstract
AIM: To observe gene polymorphisms of TPMT and NUDT15, and compare their predictive value for azathioprine (AZA)-induced leukopenia in inflammatory bowel disease (IBD).
METHODS: This study enrolled 219 patients diagnosed with IBD in Xiangya Hospital, Central South University, Changsha, China from February 2016 to November 2017. Peripheral blood of all patients was collected to detect their genotypes of TPMT and NUDT15 by pyrosequencing at the Department of Clinical Pharmacology, Hunan Key Laboratory of Pharmacogenetics, Xiangya Hospital. Eighty patients were treated with AZA according to the disease condition. During the first month, patients who received AZA underwent routine blood tests and liver function tests once a week. The endpoint of the study was leukopenia induced by AZA. By analyzing patient characteristics, genotypes and leukopenia induced by drug use, we found the risk factors associated with AZA-induced leukopenia.
RESULTS: There were 219 patients with IBD (160 men and 59 women), including 39 who were confirmed with ulcerative colitis (UC), 176 with Crohn's disease (CD) and 4 with undetermined IBD (UIBD). There were 44 patients (20.1%) with mutant genotype of NUDT15 (C/T); among them, 16 received AZA, and 8 (50%) developed leukopenia. There were 175 patients (79.7%) with wild genotype of NUDT15 (C/C); among them, 64 received AZA, and 11 (17.2%) developed leukopenia. A significant difference was found between NUDT15 C/T and its wild-type C/C (P = 0.004). There were only 3 patients with TPMT mutant genotype of A/G (1.4%) who participated in the research, and 1 of them was treated with AZA and developed leukopenia. The remaining 216 patients (98.6%) were found to bear the wild genotype of TPMT (A/A); among them, 79 patients received AZA, and 18 (22.8%) developed leukopenia, and there was no significant difference from those with A/G (P = 0.071). The frequency of TPMT mutation was 1.4%, and NUDT15 mutation rate was significantly higher and reached 20.1% (P = 0.000). Therefore, NUDT15 gene polymorphism was obviously a better biomarker than TPMT gene polymorphism in the prediction of AZA-induced leukopenia.
CONCLUSION: Mutation rate of NUDT15 in Chinese IBD patients is higher than that of TPMT. NUDT15 polymorphism is a better predictor for AZA-induced leukopenia than TPMT polymorphism.

PMID: 29491687 [PubMed - in process]

COX2/PTGS2 Expression Is Predictive of Response to Neoadjuvant Celecoxib in HER2-negative Breast Cancer Patients.

Anticancer Res. 2018 Mar;38(3):1485-1490

Authors: DE Cremoux P, Hamy AS, Lehmann-Che J, Scott V, Sigal B, Mathieu MC, Bertheau P, Guinebretière JM, Pierga JY, Giacchetti S, Brain E, Marty M, Asselain B, Spyratos F, Bièche I

Abstract
BACKGROUND: The prognostic and predictive role of cyclo-oxygenase-2 (COX2) in breast cancer is still debated, and in particular, its role as a target of COX2 inhibitor (celecoxib) in neoadjuvant setting.
MATERIALS AND METHODS: We analyzed a series of 156 breast cancer samples from patients of the COX2 inhibitor-treated arm included in the REMAGUS-02 randomized phase II trial. COX2 gene expression was assessed by reverse transcription and quantitative polymerase chain reaction using ribonucleic acid from frozen biopsies. Pathological complete response (pCR) was the surrogate end-point.
RESULTS: Significantly higher rates of grade 3, and estrogen and progesterone receptor negativity were observed in tumors with the highest expression of COX2. pCR rates were significantly higher in COX2-overexpressing tumors in patients receiving celecoxib. The test for interaction between COX2 gene expression and the celecoxib effect was statistically significant (p<0.01), but was not retained in the multivariate analysis.
CONCLUSION: COX2 overexpression is predictive of pCR in patients with celecoxib-treated tumors. The efficacy of celecoxib in breast cancer might be improved by quantification of COX2 gene expression.

PMID: 29491076 [PubMed - in process]

Cardiovascular disease and diabetes in patients with African or Asian background.

Tidsskr Nor Laegeforen. 2017 11 28;137(22):

Authors: Aambø A, Klemsdal TO

Abstract
BACKGROUND: Population groups of different ancestry appear to have varying prevalence of diabetes, different risks of developing cardiovascular disease and different responses to certain drugs that are used for these conditions. We wished to review the literature in this field.
MATERIAL AND METHOD: We have performed searches in several databases for systematic review articles published from the year 2000 onwards, and supplemented these with articles from reference lists, our own literature archives and a pyramid search in the Norwegian Electronic Health Library database. Altogether 37 articles were included.
RESULTS: With regard to diagnosed diabetes, the prevalence of coronary heart disease and stroke varies among groups of South Asian, East Asian, African and European ancestry. In patients of South Asian ancestry, the risk of coronary heart disease appears to be twice that of Europeans, and the disease occurs 5–10 years earlier. The prevalence of stroke is especially high in persons of African ancestry. Risk factors such as dyslipidemia and hypertension are distributed differently among these groups. The therapeutic response to drugs such as beta blockers, ACE inhibitors and various statins differs; for example, statin doses in Asians may often be halved in relation to those used for Caucasians, and ACE inhibitors are not recommended as monotherapy for hypertension in persons of African ancestry. These differences are partly attributable to variations in genetic disposition.
INTERPRETATION: The findings are clinically significant – better insight in this field enables optimal tailoring of treatment for each patient, with more rapid achievement of goals and reduced risk of adverse effects. The recommendations given in this article are consistent with and complement the Directorate of Health’s revised guidelines for the treatment of diabetes.

PMID: 29181932 [PubMed - indexed for MEDLINE]

Anthracene Bisureas as Powerful and Accessible Anion Carriers.

Chemistry. 2018 Mar 01;:

Authors: Davis AP, Dias C, Valkenier H

Abstract
Synthetic anion carriers (anionophores) have potential as biomedical research tools and as treatments for conditions arising from defective natural transport systems (notably cystic fibrosis). Highly active anionophores which are readily accessible and easily deliverable are especially valuable. Previous work has resulted in steroid and trans-decalin based anionophores with exceptional activity for chloride/nitrate exchange in vesicles, but poor accessibility and deliverability. Here we show that anthracene 1,8-bisureas can fulfil all three criteria. In particular, a bis-nitrophenyl derivative is prepared in two steps from commercial starting materials, yet shows comparable transport activity to the best currently known. Moreover, unlike earlier highly active systems, it does not need to be preincorporated in test vesicles but can be introduced subsequent to vesicle formation. This transporter also shows the ability to transfer between vesicles, and is therefore uniquely effective for anion transport at low transporter loadings. The results suggest that anthracene bisureas are promising candidates for application in biological research and medicine.

PMID: 29493830 [PubMed - as supplied by publisher]

Understanding the Role of Staphylococcus aureus in Non-Cystic Fibrosis Bronchiectasis: Where Are We Now?

Ann Am Thorac Soc. 2018 Mar;15(3):310-311

Authors: Somayaji R, Ramos KJ, Hoffman LR

PMID: 29493339 [PubMed - in process]

Preschool Multiple-Breath Washout Testing. An Official American Thoracic Society Technical Statement.

Am J Respir Crit Care Med. 2018 Mar 01;197(5):e1-e19

Authors: Robinson PD, Latzin P, Ramsey KA, Stanojevic S, Aurora P, Davis SD, Gappa M, Hall GL, Horsley A, Jensen R, Lum S, Milla C, Nielsen KG, Pittman JE, Rosenfeld M, Singer F, Subbarao P, Gustafsson PM, Ratjen F, ATS Assembly on Pediatrics

Abstract
BACKGROUND: Obstructive airway disease is nonuniformly distributed throughout the bronchial tree, although the extent to which this occurs can vary among conditions. The multiple-breath washout (MBW) test offers important insights into pediatric lung disease, not available through spirometry or resistance measurements. The European Respiratory Society/American Thoracic Society inert gas washout consensus statement led to the emergence of validated commercial equipment for the age group 6 years and above; specific recommendations for preschool children were beyond the scope of the document. Subsequently, the focus has shifted to MBW applications within preschool subjects (aged 2-6 yr), where a "window of opportunity" exists for early diagnosis of obstructive lung disease and intervention.
METHODS: This preschool-specific technical standards document was developed by an international group of experts, with expertise in both custom-built and commercial MBW equipment. A comprehensive review of published evidence was performed.
RESULTS: Recommendations were devised across areas that place specific age-related demands on MBW systems. Citing evidence where available in the literature, recommendations are made regarding procedures that should be used to achieve robust MBW results in the preschool age range. The present work also highlights the important unanswered questions that need to be addressed in future work.
CONCLUSIONS: Consensus recommendations are outlined to direct interested groups of manufacturers, researchers, and clinicians in preschool device design, test performance, and data analysis for the MBW technique.

PMID: 29493315 [PubMed - in process]

Seeing Cilia: Imaging Modalities for Ciliary Motion and Clinical Connections.

Am J Physiol Lung Cell Mol Physiol. 2018 Mar 01;:

Authors: Peabody JE, Shei RJ, Bermingham BM, Phillips SE, Turner B, Rowe SM, Solomon GM

Abstract
The respiratory tract is lined with multi-ciliated epithelial cells that function to move mucus and trapped particles via the mucociliary transport apparatus. Genetic and acquired ciliopathies result in diminished mucociliary clearance, contributing to disease pathogenesis. Recent innovations in imaging technology has advanced our understanding of ciliary motion in health and disease states. Application of imaging modalities including transmission electron microscopy (TEM), high-speed video microscopy (HSVM), and micron-optical coherence tomography (μOCT) could improve diagnostics and be applied for precision medicine. In this review, we provide an overview of ciliary motion, imaging modalities, and ciliopathic diseases of the respiratory system including Primary Ciliary Dyskinesia (PCD), cystic fibrosis (CF), Chronic Obstructive Pulmonary Disease (COPD), and Idiopathic Pulmonary Fibrosis (IPF).

PMID: 29493257 [PubMed - as supplied by publisher]

A hypomorphic inherited pathogenic variant in DDX3X causes male intellectual disability with additional neurodevelopmental and neurodegenerative features.

Hum Genomics. 2018 Mar 01;12(1):11

Authors: Kellaris G, Khan K, Baig SM, Tsai IC, Zamora FM, Ruggieri P, Natowicz MR, Katsanis N

Abstract
BACKGROUND: Intellectual disability (ID) is a common condition with a population prevalence frequency of 1-3% and an enrichment for males, driven in part by the contribution of mutant alleles on the X-chromosome. Among the more than 500 genes associated with ID, DDX3X represents an outlier in sex specificity. Nearly all reported pathogenic variants of DDX3X are de novo, affect mostly females, and appear to be loss of function variants, consistent with the hypothesis that haploinsufficiency at this locus on the X-chromosome is likely to be lethal in males.
RESULTS: We evaluated two male siblings with syndromic features characterized by mild-to-moderate ID and progressive spasticity. Quad-based whole-exome sequencing revealed a maternally inherited missense variant encoding p.R79K in DDX3X in both siblings and no other apparent pathogenic variants. We assessed its possible relevance to their phenotype using an established functional assay for DDX3X activity in zebrafish embryos and found that this allele causes a partial loss of DDX3X function and thus represents a hypomorphic variant.
CONCLUSIONS: Our genetic and functional data suggest that partial loss of function of DDX3X can cause syndromic ID. The p.R79K allele affects a region of the protein outside the critical RNA helicase domain, offering a credible explanation for the observed retention of partial function, viability in hemizygous males, and lack of pathology in females. These findings expand the gender spectrum of pathology of this locus and suggest that analysis for DDX3X variants should be considered relevant for both males and females.

PMID: 29490693 [PubMed - in process]

A novel single variant in the MEFV gene causing Mediterranean fever and Behçet's disease: a case report.

J Med Case Rep. 2018 Mar 01;12(1):53

Authors: Zerkaoui M, Laarabi FZ, Ajhoun Y, Chkirate B, Sefiani A

Abstract
BACKGROUND: Familial Mediterranean fever is an autoinflammatory disease of unknown etiology, characterized clinically by recurrent attacks of sudden-onset fever with arthralgia and/or thoracoabdominal pain and pathogenetically by autosomal recessive inheritance due to a mutation in the MEFV gene. Behçet's disease is an inflammatory disease characterized by recurrent oral and genital aphthous ulcerations, uveitis, and skin lesions. Preliminarily, our literature review suggested that patients with familial Mediterranean fever who also have Behçet's disease have only a single mutated familial Mediterranean fever gene. The MEFV gene mutation responsible for familial Mediterranean fever is probably a susceptibility factor for Behçet's disease, particularly for patients with vascular involvement, and both disorders can occur concurrently in a patient, as in the present case.
CASE PRESENTATION: A 10-year-old girl of Moroccan origin presented to our institution for genetic consultation for genetic testing of the MEFV gene. She had fever associated with abdominal and diffuse joint pain in addition to headache. These symptoms have oriented pediatricians to familial Mediterranean fever. The evolution was marked by Behçet's syndrome symptoms. Sanger sequencing followed by complete exome sequencing analysis of the MEFV gene for the proband mutation revealed a novel variant. We conclude that the novel single variant c.2078 T > A (p.Met693Lys) could be responsible for the association of familial Mediterranean fever and Behçet's disease.
CONCLUSION: To the best of our knowledge, this is the first report of a new variant in exon 10 of the MEFV gene in a Moroccan family. This novel variant should be listed in the MEFV sequence variant databases.

PMID: 29490685 [PubMed - in process]

[Advances in genetic research of cerebral palsy].

Zhongguo Dang Dai Er Ke Za Zhi. 2017 Sep;19(9):1022-1026

Authors: Wang FF, Luo R, Qu Y, Mu DZ

Abstract
Cerebral palsy is a group of syndromes caused by non-progressive brain injury in the fetus or infant and can cause disabilities in childhood. Etiology of cerebral palsy has always been a hot topic for clinical scientists. More and more studies have shown that genetic factors are closely associated with the development of cerebral palsy. With the development and application of various molecular and biological techniques such as chromosome microarray analysis, genome-wide association study, and whole exome sequencing, new achievements have been made in the genetic research of cerebral palsy. Chromosome abnormalities, copy number variations, susceptibility genes, and single gene mutation associated with the development of cerebral palsy have been identified, which provides new opportunities for the research on the pathogenesis of cerebral palsy. This article reviews the advances in the genetic research on cerebral palsy in recent years.

PMID: 28899476 [PubMed - indexed for MEDLINE]

An update on the safety of current therapies for Alzheimer's disease: focus on rivastigmine.

Ther Adv Drug Saf. 2018 Mar;9(3):171-178

Authors: Khoury R, Rajamanickam J, Grossberg GT

Abstract
Alzheimer's disease (AD) is the most common cause of major neurocognitive disorders worldwide. Despite all research efforts, therapeutic options for AD are still limited to two drug classes: cholinesterase inhibitors (ChEIs) and the NMDA-receptor antagonist memantine. Donepezil, rivastigmine and galantamine are the three ChEIs FDA-approved as first-line treatment for AD. Although they share the same mode of action, they differ in terms of their pharmacologic characteristics and route of administration, which can impact their safety and tolerability profile. Rivastigmine, available in both oral and transdermal patch formulations, is a slowly reversible dual inhibitor of acetyl and butyryl cholinesterase, selective for the G1 isoform of acetylcholinesterase, without hepatic metabolism by the CYP-450 system. Despite its unique features, it has been associated with a higher incidence of adverse events in comparison to other ChEIs. The oral form, approved for the treatment of mild to moderate AD, is associated with a higher incidence of gastrointestinal side effects. The transdermal patch formulation approved for use across all stages of AD has been shown to have a better tolerability profile in comparison to both the oral form and even other ChEIs. One important tolerability concern is adverse dermatologic reactions, which are mostly benign, and can be either preventable or manageable. One important safety concern is the risk of treatment overdose by administering multiple patches at the same time, potentially leading to fatal outcomes. This can be prevented by educating patients and caregivers about the proper use of the patch. The goal for the future would be to optimize the patch formulation to increase both efficacy and safety.

PMID: 29492246 [PubMed]

Voriconazole: Poor Oral Bioavailability and Possible Renal Toxicity in an Infant With Invasive Aspergillosis.

J Pediatr Pharmacol Ther. 2018 Jan-Feb;23(1):54-58

Authors: Walldorf JA, Kishk OA, Campbell JD, Lardieri AB

Abstract
Voriconazole is the recommended agent of choice for treatment of invasive aspergillosis; however, achieving therapeutic serum concentrations while avoiding toxicity, both with intravenous and oral formulations, is challenging in infants. We report the case of an infant with confirmed invasive aspergillosis who developed renal toxicity possibly associated with IV voriconazole. Renal function improved upon withdrawal of the IV agent and switch to the oral formulation. The infant subsequently required large oral weight-based dosing to achieve therapeutic voriconazole serum concentrations. This case illustrates a rare side effect associated with voriconazole as well as the issues surrounding the pharmacokinetic profile of voriconazole in a pediatric patient.

PMID: 29491753 [PubMed]

Anticholinergic medication for antipsychotic-induced tardive dyskinesia.

Cochrane Database Syst Rev. 2018 01 17;1:CD000204

Authors: Bergman H, Soares-Weiser K

Abstract
BACKGROUND: Antipsychotic (neuroleptic) medication is used extensively to treat people with serious mental illnesses. However, it is associated with a wide range of adverse effects, including movement disorders. Because of this, many people treated with antipsychotic medication also receive anticholinergic drugs in order to reduce some of the associated movement side-effects. However, there is also a suggestion from animal experiments that the chronic administration of anticholinergics could cause tardive dyskinesia.
OBJECTIVES: To determine whether the use or the withdrawal of anticholinergic drugs (benzhexol, benztropine, biperiden, orphenadrine, procyclidine, scopolamine, or trihexylphenidyl) are clinically effective for the treatment of people with both antipsychotic-induced tardive dyskinesia and schizophrenia or other chronic mental illnesses.
SEARCH METHODS: We retrieved 712 references from searching the Cochrane Schizophrenia Group's Study-Based Register of Trials including the registries of clinical trials (16 July 2015 and 26 April 2017). We also inspected references of all identified studies for further trials and contacted authors of trials for additional information.
SELECTION CRITERIA: We included reports identified in the search if they were controlled trials dealing with people with antipsychotic-induced tardive dyskinesia and schizophrenia or other chronic mental illness who had been randomly allocated to (a) anticholinergic medication versus placebo (or no intervention), (b) anticholinergic medication versus any other intervention for the treatment of tardive dyskinesia, or (c) withdrawal of anticholinergic medication versus continuation of anticholinergic medication.
DATA COLLECTION AND ANALYSIS: We independently extracted data from included trials and we estimated risk ratios (RR) with 95% confidence intervals (CIs). We assumed that people who left early had no improvement. We assessed risk of bias and created a 'Summary of findings' table using GRADE.
MAIN RESULTS: The previous version of this review included no trials. We identified two trials that could be included from the 2015 and 2017 searches. They randomised 30 in- and outpatients with schizophrenia in the USA and Germany. Overall, the risk of bias was unclear, mainly due to poor reporting: allocation concealment was not described; generation of the sequence was not explicit; studies were not clearly blinded; and outcome data were not fully reported.Findings were sparse. One study reported on the primary outcomes and found that significantly more participants allocated to procyclidine (anticholinergic) had not improved to a clinically important extent compared with those allocated to isocarboxazid (MAO-inhibitor) after 40 weeks' treatment (1 RCT, n = 20; RR 4.20, 95% CI 1.40 to 12.58; very low quality evidence); that there was no evidence of a difference in the incidence of any adverse effects (1 RCT, n = 20; RR 0.33, 95% CI 0.02 to 7.32; very low quality evidence); or acceptability of treatment (measured by participants leaving the study early) (1 RCT, n = 20; RR 0.33, 95% CI 0.02 to 7.32; very low quality evidence). The other trial compared anticholinergic withdrawal with anticholinergic continuation and found no evidence of a difference in the incidence of acceptability of treatment (measured by participants leaving the study early) (1 RCT, n = 10; RR 2.14, 95% CI 0.11 to 42.52; very low quality evidence).No trials reported on social confidence, social inclusion, social networks, or personalised quality of life - outcomes designated important to patients. No studies comparing either i. anticholinergics with placebo or no treatment, or ii. studies of anticholinergic withdrawal, were found that reported on the primary outcome 'no clinically important improvement in TD symptoms and adverse events'.
AUTHORS' CONCLUSIONS: Based on currently available evidence, no confident statement can be made about the effectiveness of anticholinergics to treat people with antipsychotic-induced tardive dyskinesia. The same applies for the withdrawal of such medications. Whether the withdrawal of anticholinergics may benefit people with antipsychotic-induced TD should be evaluated in a parallel-group, placebo-controlled randomised trial, with adequate sample size and at least 6 weeks of follow-up.

PMID: 29341071 [PubMed - indexed for MEDLINE]

SUVmax of 18F-FDG PET/CT correlates to expression of major chemotherapy-related tumor markers and serum tumor markers in gastric adenocarcinoma patients.

Oncol Rep. 2017 Jun;37(6):3433-3440

Authors: Bai L, Guo CH, Zhao Y, Gao JG, Li M, Shen C, Guo YM, Duan XY

Abstract
The expression of P53 was previously found by us significantly correlated with maximal standardized uptake value (SUVmax) in non-small cell lung cancer (NSCLC) patients. Hence, the aim of this study was to clarify the relationship between SUVmax and the status of the chemotherapy-related tumor marker expression or serum tumor markers in gastric adenocarcinoma patients. Sixty-four gastric adenocarcinoma patients who underwent 18F-FDG PET/CT prior to treatment were enrolled in this study. Immunohistochemistry was performed to detect changes of Her-2, P53 and Survivin in lesions, and electrochemiluminescence (ECL) method was used to quantify expression of serum CA72-4, CA19-9 and CEA of these patients. Then, the relationships between these parameters above were assessed by Spearman correlation analysis. Also, receiver-operating characteristic (ROC) curve was performed to determine the best cut-off value of SUVmax for suggesting chemotherapy resistant tumor markers. Besides, we identified a linear correlation to estimate the equations between SUVmax and the serum tumor markers. Our results showed that higher SUVmax was detected in patients with positive expression of Her-2 and P53, compared with negative groups. The Spearman correlation analysis showed that SUVmax was associated with Her-2 or P53 with the moderate relevant Pearson correlation coefficient. ROC curve analysis showed that the sensitivity and specificity of SUVmax for suggesting Her-2 or P53-positive, when the cut-off value of SUVmax was set at 3.25 or 5.45, respectively. Moreover, the relationship between SUVmax and serum tumor markers were analyzed by linear correlation analysis, and serum CA72-4 and CA19-9 could be used as independent parameters to establish an equation for SUVmax by the linear regression models. These results suggested that SUVmax of 18F-FDG PET/CT could be used to predict and evaluate Her-2 or P53 related chemotherapy resistance of gastric adenocarcinoma patients. However, before PET/CT scanning, serum tumor markers could be used to calculate the SUVmax approximately.

PMID: 28498457 [PubMed - indexed for MEDLINE]

Cariogenic Potential of the commonly Prescribed Pediatric Liquid Medicaments in Kingdom of Saudi Arabia: An in vitro Study.

J Contemp Dent Pract. 2017 Apr 01;18(4):307-311

Authors: Gupta M, Panda S

Abstract
AIM: The aim of this study was to assess the cariogenic potential of the commonly prescribed pediatric liquid medicaments (PLMs) for dental disease in Jazan region, Kingdom of Saudi Arabia.
MATERIALS AND METHODS: Seven most commonly prescribed PLMs were selected by prior questioning the pediatric dentists as well as general dentists in Jazan region. The endogenous pH and sucrose concentrations of the liquid medicaments were assessed. The endogenous pH was assessed by Hanna pH meter instrument. The sucrose concentration was assessed by anthrone reagent method.
RESULTS: All the PLM were acidic. The pH of the PLM ranged from 4.22 to 6.10. All the PLM contained sucrose and its concentration ranged from 5.38 to 11.41 gm% in the samples.
CONCLUSION: In this study, all the PLM were acidic and contained sucrose. Hence, they have cariogenic potential.
CLINICAL SIGNIFICANCE: Parents and dentists are unaware of the hidden sugars and cariogenicity of these medications. Strict oral hygiene instructions are mandatory for the children taking these medications. The use of PLM should also be minimized and parents should seek early dental treatment to restore child's oral health.

PMID: 28349909 [PubMed - indexed for MEDLINE]

Nor-Binaltorphimine Blocks the Adverse Effects of Morphine after Spinal Cord Injury.

J Neurotrauma. 2017 Mar 15;34(6):1164-1174

Authors: Aceves M, Bancroft EA, Aceves AR, Hook MA

Abstract
Opioids are frequently used for the treatment of pain following spinal cord injury (SCI). Unfortunately, we have shown that morphine administered in the acute phase of SCI results in significant, adverse secondary consequences including compromised locomotor and sensory recovery. Similarly, we showed that selective activation of the κ-opioid receptor (KOR), even at a dose 32-fold lower than morphine, is sufficient to attenuate recovery of locomotor function. In the current study, we tested whether activation of the KOR is necessary to produce morphine's adverse effects using nor-Binaltorphimine (norBNI), a selective KOR antagonist. Rats received a moderate spinal contusion (T12) and 24 h later, baseline locomotor function and nociceptive reactivity were assessed. Rats were then administered norBNI (0, 0.02, 0.08, or 0.32 μmol) followed by morphine (0 or 0.32 μmol). Nociception was reassessed 30 min after drug treatment, and recovery was evaluated for 21 days. The effects of norBNI on morphine-induced attenuation of recovery were dose dependent. At higher doses, norBNI blocked the adverse effects of morphine on locomotor recovery, but analgesia was also significantly decreased. Conversely, at low doses, analgesia was maintained, but the adverse effects on recovery persisted. A moderate dose of norBNI, however, adequately protected against morphine's adverse effects without eliminating its analgesic efficacy. This suggests that activation of the KOR system plays a significant role in the morphine-induced attenuation of recovery. Our research suggests that morphine, and other opioid analgesics, may be contraindicated for the SCI population. Blocking KOR activity may be a viable strategy for improving the safety of clinical opioid use.

PMID: 27736318 [PubMed - indexed for MEDLINE]

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