A contemporary analysis of clinical and demographic factors of chronic rhinosinusitis patients and their association with disease severity.

Ir J Med Sci. 2017 May 30;:

Authors: Hoehle LP, Phillips KM, Caradonna DS, Gray ST, Sedaghat AR

Abstract
BACKGROUND: Chronic rhinosinusitis (CRS) is highly prevalent, significantly decreases quality of life and leads to tremendous health care costs every year. No recent study has characterised the prevalence of potentially CRS-modifying patient characteristics and simultaneously shown their impact on CRS severity.
AIMS: We sought to determine the prevalence of potential clinical and demographic CRS-modifying characteristics and their associations with CRS symptom severity in a large contemporary cohort of CRS patients.
METHODS: Retrospective review of CRS patients who visited our rhinology clinics between February 2016 and February 2017 was conducted. CRS symptom severity was measured using the 22-item Sinonasal Outcomes Test (SNOT-22) questionnaire, which all patients received. Association was sought between SNOT-22 score (as dependent variable) and patients' clinical and demographic characteristics using linear regression.
RESULTS: Of the 572 included patients, the mean age was 51.1 years (SD = 15.8) and the mean SNOT-22 score was 34.3 (SD = 22.6). Prevalence of granulomatous diseases, immunodeficiency and cystic fibrosis were each approximately 5%. Prevalence of aeroallergen hypersensitivity was 42.3% and prevalence of asthma was 27.8%. More severe CRS symptomatology was associated with smoking tobacco (adjusted β = 5.47, p = 0.034) and comorbid asthma (adjusted β = 12.02, p < 0.001), whilst less severe symptomatology was associated with older age (adjusted β = -0.23, p = 0.002) and diagnosis of cystic fibrosis (adjusted β = -11.87, p = 0.009).
CONCLUSIONS: In a contemporary cohort of CRS patients, prevalence of disease-modifying comorbidities ranged from approximately 5 to over 40%. Smoking tobacco and asthma were associated with more severe CRS symptomatology, whilst older age and diagnosis of cystic fibrosis were associated with less severe CRS symptomatology.

PMID: 28560517 [PubMed - as supplied by publisher]

Cystic fibrosis: Thymosin α1 rescues CFTR activity.

Nat Rev Drug Discov. 2017 May 31;16(6):386

Authors: Crunkhorn S

PMID: 28559563 [PubMed - in process]

Molecular typing of Mycobacterium Abscessus isolated from cystic fibrosis patients.

Int J Mycobacteriol. 2017 Apr-Jun;6(2):138-141

Authors: Trovato A, Baldan R, Costa D, Simonetti TM, Cirillo DM, Tortoli E

Abstract
BACKGROUND: The possibility of inter-human transmission of Mycobacterium abscessus in cystic fibrosis centres has been recently hypothesized suggesting the need for the molecular characterization of strains isolated from such patients.
MATERIALS AND METHODS: One hundred and forty one isolates of M. abscessus grown from sputum samples of 29 patients with cystic fibrosis were genotyped resorting to variable number of tandem repeats (VNTR) determination and whole genome sequencing (WGS).
RESULTS: Out of 29 VNTR profiles, 15 were unique to the same number of patients while seven were shared by multiple patients. WGS showed that only two of the patients sharing common VNTR patterns were indeed infected by the same strain. The shared VNTR patterns were mostly present among the isolates of M. abscessus subsp. abscessus.
CONCLUSION: As expected WGS showed a clearly higher discriminatory power in comparison with VNTR and appeared the only molecular epidemiology tool suitable to effectively discriminate the isolates of M. abscessus subsp. abscessus.

PMID: 28559514 [PubMed - in process]

Inhaled Drug Therapy 2016: The Year in Review.

Respir Care. 2017 May 30;:

Authors: Dhand R

Abstract
Some recent salient publications related to inhaled drug therapy are discussed. Unexpectedly, a 2.5-μg once-daily dose of tiotropium (Respimat) had greater efficacy than the 5.0-μg daily dose. Occurrence of a reverse dose response serves to caution us that administering more drug is not always beneficial. Small-airway inflammation contributes to pathogenesis of asthma, especially severe asthma. However, there is no conclusive evidence that the use of small-particle aerosols to target small airways improves clinical outcomes in controlled clinical trials. Clinical outcomes of patients with symptomatic asthma have been better in "real-life" studies when fine-particle aerosols were compared with conventional (large-particle) aerosols. In subjects with COPD, the FLAME study indicates that a long-acting antimuscarinic agent/long-acting β-agonist combination was superior to an inhaled corticosteroid/long-acting β-agonist combination in preventing exacerbations. Another study in children with asthma and adults with asthma or COPD showed that peak inhalation flow must be considered in the context of the dry powder inhaler resistance. Investigators from the United Kingdom have shown modest success in replacing the defective cystic fibrosis transmembrane regulator gene in subjects with cystic fibrosis with a plasmid encoding the normal cystic fibrosis transmembrane regulator gene packaged within a non-viral vector. Also, inhaled antibiotics in patients with non-cystic fibrosis bronchiectasis and inhaled interferon-|gg in patients with idiopathic pulmonary fibrosis have shown encouraging results but are investigational at this time. Compared to combustion cigarettes, use of e-cigarettes reduces exposure to carcinogens and volatile organic compounds. However, high levels of benzaldehyde in the vapor from cherry-flavored cigarettes raise concerns about the safety of some food flavorings in e-cigarettes.

PMID: 28559466 [PubMed - as supplied by publisher]

Efficacy of Rhesus Theta (θ)-Defensin-1 in Experimental Models of Pseudomonas aeruginosa Lung Infection and Inflammation.

Antimicrob Agents Chemother. 2017 May 30;:

Authors: Bensman TJ, Jayne JG, Sun M, Kimura E, Meinert J, Wang JC, Schaal JB, Tran D, Rao AP, Akbari O, Selsted ME, Beringer PM

Abstract
Rationale: Chronic airway infection and inflammation contribute to the progressive loss of lung function and shortened survival of patients with cystic fibrosis (CF). Rhesus theta (θ) defensin-1 (RTD-1) is a macrocyclic host defense peptide with antimicrobial and immunomodulatory activities. Combined with favorable preclinical safety and peptide stability data, RTD-1 warrants investigation to determine its therapeutic potential for treatment of CF lung disease.Objectives: We sought to evaluate the therapeutic potential of RTD-1 for CF airway infection and inflammation using in vitro, ex vivo, and in vivo models.Methods: We evaluated RTD-1's effects on basal and P. aeruginosa induced inflammation in CF sputum leukocytes and CF bronchial epithelial cells. Peptide stability was evaluated by incubation with CF sputum. Airway pharmacokinetics, safety and tolerance studies were performed in naïve mice. Aerosolized RTD-1 treatment effects were assessed by analyzing lung bacterial burden and airway inflammation using an established model of chronic P. aeruginosa endobronchial infection in CF (ΔF508) mice.Measurements and Main Results: RTD-1 directly reduces metalloprotease activity, as well as inflammatory cytokine secretion from CF airway leukocyte and bronchial epithelial cells. Intrapulmonary safety, tolerability and stability data support the aerosol administration route. RTD-1 reduced bacterial lung burden, airway neutrophils, and inflammatory cytokines in CF mice with chronic P. aeruginosa lung infection.Conclusions: Collectively, these studies support further development of RTD-1 for treatment of CF airway disease.

PMID: 28559270 [PubMed - as supplied by publisher]

Aerosolized Polymyxin B for Treatment of Respiratory Tract Infections: Determination of Pharmacokinetic/Pharmacodynamic Indices for Aerosolized Polymyxin B against Pseudomonas aeruginosa in a Mouse Lung Infection Model.

Antimicrob Agents Chemother. 2017 May 30;:

Authors: Lin YW, Zhou QT, Onufrak NJ, Wirth V, Chen K, Wang J, Forrest A, Chan HK, Li J

Abstract
Pulmonary administration of polymyxins is increasingly used for the treatment of respiratory tract infections caused by multidrug-resistant Gram-negative bacteria, such as those in patients with cystic fibrosis. However, there is a lack of pharmacokinetics (PK), pharmacodynamics (PD) and toxicity data of aerosolized polymyxin B to inform rational dosage selection. The PK and PD of polymyxin B following pulmonary and intravenous dosing were conducted in neutropenic infected mice and the data were analyzed by a population PK model. Dose-fractionation study was performed for total daily doses between 2.06 and 24.8 mg base/kg against Pseudomonas aeruginosa ATCC 27853, PAO1, and FADDI-PA022 (MIC = 1 mg/L for all three strains). Histopathological examination of lung was undertaken at 24 h post treatment in both healthy and neutropenic infected mice. A two-compartment PK model was required for both epithelial lining fluid (ELF) and plasma drug exposure. The model consisted of central and peripheral compartments and was described by bidirectional first-order distribution clearance. AUC/MIC was the most predictive PK/PD index to describe the antimicrobial efficacy of aerosolized polymyxin B in treating lung infections in mice (R(2)=0.70-0.88 for ELF and R(2)=0.70-0.87 for plasma). The AUC/MIC targets associated with bacteriostasis against the three P. aeruginosa strains were 1326-1506 in ELF and 3.14-4.03 in plasma. Histopathological results showed that polymyxin B aerosols significantly reduced lung inflammation and preserved lung epithelial integrity. This study highlights the advantageous PK/PD characteristics of pulmonary delivery of polymyxin B over intravenous administration in achieving high drug exposure in ELF.

PMID: 28559256 [PubMed - as supplied by publisher]

Electronic applications for the CFQ-R scoring.

Respir Res. 2017 May 30;18(1):108

Authors: Ronit A, Gelpi M, Argentiero J, Mathiesen I, Nielsen SD, Pressler T, Quittner AL

Abstract
Patient reported outcomes (PROs) have become widely accepted outcome measures in cystic fibrosis (CF) and other respiratory diseases. The Cystic Fibrosis-Questionnaire-Revised (CFQ-R) is the best validated and most widely used PRO for CF. Data collection can be time-intensive, and electronic platforms would greatly facilitate the feasibility, utility and accuracy of administration of the CFQ-R. Given that the CFQ-R is utilized in virtually all clinical trials worldwide and is increasingly integrated into clinical practice, we developed a software application that will help users to administer, score and save CFQ-R data for all versions. All codes are open access, which will enable other PRO users to design similar applications for other respiratory diseases, such as primary ciliary dyskinesia and non-CF bronchiectasis.

PMID: 28558706 [PubMed - in process]

Single nucleotide variant in Nucleoporin 107 may be predictive of sensitivity to chemotherapy in patients with ovarian cancer.

Pharmacogenet Genomics. 2017 May 30;:

Authors: Alanee S, Delfino K, Wilber A, Robinson K, Brard L, Semaan A

Abstract
BACKGROUND: Alterations in nuclear pore complex (NPC) genes have been previously associated with response to chemotherapy. Using agnostic exome sequencing, we envisioned that new alleles in NPC genes, predictive of sensitivity to platinum treatment, could be discovered.
METHODS: Twenty-two platinum-sensitive and six platinum-resistant ovarian cancer patients were tested. Platinum sensitivity was defined as disease-free survival greater than 6 months. Next-generation sequencing of exomes was used to compare platinum-sensitive and platinum-resistant patients. Single nucleotide variants (SNVs) associated with platinum sensitivity in NPC genes (n=30 genes) were identified.
RESULTS: SNVs in three NPC genes were associated with response to platinum on univariate analysis. SNV rs79419059 (10T>C) in Nucleoporin 107 (Nup107) was associated with platinum resistance (P=0.0061), whereas rs2302811 (3662-4A>G) in Nucleoporin 188 (Nup188) and rs77246077 (3420-67T>A) in Nucleoporin 214 (Nup214) were associated with platinum sensitivity (P=0.0483 and 0.0091, respectively). Controlling for other confounders, multivariate age-adjusted Cox proportional hazard analysis showed rs79419059 to be significantly associated with platinum resistance (odds ratio: 4.519, 95% confidence interval: 1.317-15.501, P=0.0457).
CONCLUSION: We identified a variant in the 3'-UTR region Nup107 unique to sensitivity to platinum in ovarian cancer. With validation of this variant, it is possible that a new marker predictive of patient response may be identified.

PMID: 28562428 [PubMed - as supplied by publisher]

Clinically Focused Molecular Investigation of 1000 Consecutive Families with Inherited Retinal Disease.

Ophthalmology. 2017 May 27;:

Authors: Stone EM, Andorf JL, Whitmore SS, DeLuca AP, Giacalone JC, Streb LM, Braun TA, Mullins RF, Scheetz TE, Sheffield VC, Tucker BA

Abstract
PURPOSE: To devise a comprehensive multiplatform genetic testing strategy for inherited retinal disease and to describe its performance in 1000 consecutive families seen by a single clinician.
DESIGN: Retrospective series.
PARTICIPANTS: One thousand consecutive families seen by a single clinician.
METHODS: The clinical records of all patients seen by a single retina specialist between January 2010 and June 2016 were reviewed, and all patients who met the clinical criteria for a diagnosis of inherited retinal disease were included in the study. Each patient was assigned to 1 of 62 diagnostic categories, and this clinical diagnosis was used to define the scope and order of the molecular investigations that were performed. The number of nucleotides evaluated in a given subject ranged from 2 to nearly 900 000.
MAIN OUTCOME MEASURES: Sensitivity and false genotype rate.
RESULTS: Disease-causing genotypes were identified in 760 families (76%). These genotypes were distributed across 104 different genes. More than 75% of these 104 genes have coding sequences small enough to be packaged efficiently into an adeno-associated virus. Mutations in ABCA4 were the most common cause of disease in this cohort (173 families), whereas mutations in 80 genes caused disease in 5 or fewer families (i.e., 0.5% or less). Disease-causing genotypes were identified in 576 of the families without next-generation sequencing (NGS). This included 23 families with mutations in the repetitive region of RPGR exon 15 that would have been missed by NGS. Whole-exome sequencing of the remaining 424 families revealed mutations in an additional 182 families, and whole-genome sequencing of 4 of the remaining 242 families revealed 2 additional genotypes that were invisible by the other methods. Performing the testing in a clinically focused tiered fashion would be 6.1% more sensitive and 17.7% less expensive and would have a significantly lower average false genotype rate than using whole-exome sequencing to assess more than 300 genes in all patients (7.1% vs. 128%; P < 0.001).
CONCLUSIONS: Genetic testing for inherited retinal disease is now more than 75% sensitive. A clinically directed tiered testing strategy can increase sensitivity and improve statistical significance without increasing cost.

PMID: 28559085 [PubMed - as supplied by publisher]

Sphingomyelin Phosphodiesterase 3 Enhances Cytodifferentiation of Periodontal Ligament Cells.

J Dent Res. 2017 Mar;96(3):339-346

Authors: Miyauchi S, Kitagaki J, Masumoto R, Imai A, Kobayashi K, Nakaya A, Kawai S, Fujihara C, Asano Y, Yamashita M, Yanagita M, Yamada S, Kitamura M, Murakami S

Abstract
Sphingomyelin phosphodiesterase 3 ( Smpd3), which encodes neutral sphingomyelinase 2 (nSMase2), is a key molecule for skeletal development as well as for the cytodifferentiation of odontoblasts and alveolar bone. However, the effects of nSMase2 on the cytodifferentiation of periodontal ligament (PDL) cells are still unclear. In this study, the authors analyzed the effects of Smpd3 on the cytodifferentiation of human PDL (HPDL) cells. The authors found that Smpd3 increases the mRNA expression of calcification-related genes, such as alkaline phosphatase (ALPase), type I collagen, osteopontin, Osterix (Osx), and runt-related transcription factor (Runx)-2 in HPDL cells. In contrast, GW4869, an inhibitor of nSMase2, clearly decreased the mRNA expression of ALPase, type I collagen, and osteocalcin in HPDL cells, suggesting that Smpd3 enhances HPDL cytodifferentiation. Next, the authors used exome sequencing to evaluate the genetic variants of Smpd3 in a Japanese population with aggressive periodontitis (AgP). Among 44 unrelated subjects, the authors identified a single nucleotide polymorphism (SNP), rs145616324, in Smpd3 as a putative genetic variant for AgP among Japanese people. Moreover, Smpd3 harboring this SNP did not increase the sphingomyelinase activity or mRNA expression of ALPase, type I collagen, osteopontin, Osx, or Runx2, suggesting that this SNP inhibits Smpd3 such that it has no effect on the cytodifferentiation of HPDL cells. These data suggest that Smpd3 plays a crucial role in maintaining the homeostasis of PDL tissue.

PMID: 28221099 [PubMed - indexed for MEDLINE]

SOS2 and ACP1 Loci Identified through Large-Scale Exome Chip Analysis Regulate Kidney Development and Function.

J Am Soc Nephrol. 2017 Mar;28(3):981-994

Authors: Li M, Li Y, Weeks O, Mijatovic V, Teumer A, Huffman JE, Tromp G, Fuchsberger C, Gorski M, Lyytikäinen LP, Nutile T, Sedaghat S, Sorice R, Tin A, Yang Q, Ahluwalia TS, Arking DE, Bihlmeyer NA, Böger CA, Carroll RJ, Chasman DI, Cornelis MC, Dehghan A, Faul JD, Feitosa MF, Gambaro G, Gasparini P, Giulianini F, Heid I, Huang J, Imboden M, Jackson AU, Jeff J, Jhun MA, Katz R, Kifley A, Kilpeläinen TO, Kumar A, Laakso M, Li-Gao R, Lohman K, Lu Y, Mägi R, Malerba G, Mihailov E, Mohlke KL, Mook-Kanamori DO, Robino A, Ruderfer D, Salvi E, Schick UM, Schulz CA, Smith AV, Smith JA, Traglia M, Yerges-Armstrong LM, Zhao W, Goodarzi MO, Kraja AT, Liu C, Wessel J, CHARGE Glycemic-T2D Working Group,, CHARGE Blood Pressure Working Group,, Boerwinkle E, Borecki IB, Bork-Jensen J, Bottinger EP, Braga D, Brandslund I, Brody JA, Campbell A, Carey DJ, Christensen C, Coresh J, Crook E, Curhan GC, Cusi D, de Boer IH, de Vries AP, Denny JC, Devuyst O, Dreisbach AW, Endlich K, Esko T, Franco OH, Fulop T, Gerhard GS, Glümer C, Gottesman O, Grarup N, Gudnason V, Hansen T, Harris TB, Hayward C, Hocking L, Hofman A, Hu FB, Husemoen LL, Jackson RD, Jørgensen T, Jørgensen ME, Kähönen M, Kardia SL, König W, Kooperberg C, Kriebel J, Launer LJ, Lauritzen T, Lehtimäki T, Levy D, Linksted P, Linneberg A, Liu Y, Loos RJ, Lupo A, Meisinger C, Melander O, Metspalu A, Mitchell P, Nauck M, Nürnberg P, Orho-Melander M, Parsa A, Pedersen O, Peters A, Peters U, Polasek O, Porteous D, Probst-Hensch NM, Psaty BM, Qi L, Raitakari OT, Reiner AP, Rettig R, Ridker PM, Rivadeneira F, Rossouw JE, Schmidt F, Siscovick D, Soranzo N, Strauch K, Toniolo D, Turner ST, Uitterlinden AG, Ulivi S, Velayutham D, Völker U, Völzke H, Waldenberger M, Wang JJ, Weir DR, Witte D, Kuivaniemi H, Fox CS, Franceschini N, Goessling W, Köttgen A, Chu AY

Abstract
Genome-wide association studies have identified >50 common variants associated with kidney function, but these variants do not fully explain the variation in eGFR. We performed a two-stage meta-analysis of associations between genotypes from the Illumina exome array and eGFR on the basis of serum creatinine (eGFRcrea) among participants of European ancestry from the CKDGen Consortium (nStage1: 111,666; nStage2: 48,343). In single-variant analyses, we identified single nucleotide polymorphisms at seven new loci associated with eGFRcrea (PPM1J, EDEM3, ACP1, SPEG, EYA4, CYP1A1, and ATXN2L; PStage1<3.7×10(-7)), of which most were common and annotated as nonsynonymous variants. Gene-based analysis identified associations of functional rare variants in three genes with eGFRcrea, including a novel association with the SOS Ras/Rho guanine nucleotide exchange factor 2 gene, SOS2 (P=5.4×10(-8) by sequence kernel association test). Experimental follow-up in zebrafish embryos revealed changes in glomerular gene expression and renal tubule morphology in the embryonic kidney of acp1- and sos2-knockdowns. These developmental abnormalities associated with altered blood clearance rate and heightened prevalence of edema. This study expands the number of loci associated with kidney function and identifies novel genes with potential roles in kidney formation.

PMID: 27920155 [PubMed - indexed for MEDLINE]

Molecular complexity of the megakaryocyte-platelet system in health and disease.

Hamostaseologie. 2016 Aug 03;36(3):159-60

Authors: Scharf RE

PMID: 27485023 [PubMed - indexed for MEDLINE]

A whole genome approach to platelet and bleeding disorders.

Hamostaseologie. 2016 Aug 03;36(3):161-6

Authors: Laffan M, BRIDGE Bleeding and Platelet Disorders Consortium

Abstract
The sequencing of hundreds of thousands of human exomes and hundreds of thousands of whole genomes is providing a progressively accurate and complete catalogue of human genetic variation. The initial studies to use genome wide data to help understand platelet disorders performed genome wide association studies to identify loci linked to variations in blood cell parameters. These studies used normal variation to find corresponding genetic variation. We next wished to investigate the genetic basis of bleeding disorders which may also provide a key to novel genes regulating platelet and haemostatic functions. The BRIDGE consortium (www.bridgestudy.org) is funded by the NIHR and brings together 13 rare disease gene discovery projects. The aim of these projects is to investigate as yet undiagnosed rare inherited diseases and identify the underlying mutational basis. We have used a cluster analysis based on the Human Phenotype Ontology in combination with next generation sequencing techniques to help identify patients with similar phenotypes which we hypothesise will arise from defects in the same gene. Preliminary results validate the clustering approach and have also resulted in a number of novel genes important for normal and pathogenic platelet physiology.

PMID: 26781766 [PubMed - indexed for MEDLINE]

Dopamine D2 receptors and the circadian clock reciprocally mediate antipsychotic drug-induced metabolic disturbances.

NPJ Schizophr. 2017;3:17

Authors: Freyberg Z, McCarthy MJ

Abstract
Antipsychotic drugs are widely prescribed medications, used for numerous psychiatric illnesses. However, antipsychotic drugs cause serious metabolic side effects that can lead to substantial weight gain and increased risk for type 2 diabetes. While individual drugs differ, all antipsychotic drugs may cause these important side effects to varying degrees. Given that the single unifying property shared by these medications is blockade of dopamine D2 and D3 receptors, these receptors likely play a role in antipsychotic drug-induced metabolic side effects. Dopamine D2 and dopamine D3 receptors are expressed in brain regions critical for metabolic regulation and appetite. Surprisingly, these receptors are also expressed peripherally in insulin-secreting pancreatic beta cells. By inhibiting glucose-stimulated insulin secretion, dopamine D2 and dopamine D3 receptors are important mediators of pancreatic insulin release. Crucially, antipsychotic drugs disrupt this peripheral metabolic regulatory mechanism. At the same time, disruptions to circadian timing have been increasingly recognized as a risk factor for metabolic disturbance. Reciprocal dopamine and circadian signaling is important for the timing of appetitive/feeding behaviors and insulin release, thereby coordinating cell metabolism with caloric intake. In particular, circadian regulation of dopamine D2 receptor/dopamine D3 receptor signaling may play a critical role in metabolism. Therefore, we propose that antipsychotic drugs' blockade of dopamine D2 receptor and dopamine D3 receptors in pancreatic beta cells, hypothalamus, and striatum disrupts the cellular timing mechanisms that regulate metabolism. Ultimately, understanding the relationships between the dopamine system and circadian clocks may yield critical new biological insights into mechanisms of antipsychotic drug action, which can then be applied into clinical practice.

PMID: 28560263 [PubMed - in process]

Ceftazidime-induced thrombocytopenia.

Rev Esp Anestesiol Reanim. 2017 May 27;:

Authors: Domingo-Chiva E, Díaz-Rangel M, Monsalve-Naharro JÁ, Cuesta-Montero P, Catalá-Ripoll JV, García-Martínez EM

Abstract
Ceftazidime is an antibiotic belonging to the group of third generation cephalosporins, frequently used in clinical practice for its broad antibacterial spectrum. A case report is presented on a 78-year-old man who entered the intensive care unit due to respiratory failure secondary to nosocomial pneumonia in the postoperative period of a laparoscopic hepatic bisegmentectomy for a hepatocarcinoma. It required invasive mechanical ventilation and was treated with ceftazidime, developing a progressive decrease in platelet count after the onset of this drug and after re-exposure to it, not coinciding with the introduction of other drugs. The adverse reaction was reported to the Spanish pharmacosurveillance system and according to the Naranjo algorithm the causal relationship was probable. Since no case of ceftazidime-induced thrombocytopenia was found in the literature, we consider knowledge of it relevant as an adverse effect to be taken into account given its potential severity, especially when it cannot be explained by other causes.

PMID: 28559046 [PubMed - as supplied by publisher]

Is gender still a predisposing factor in contrast-media associated adverse drug reactions? A systematic review and meta-analysis of randomized trials and observational studies.

Eur J Radiol. 2017 Apr;89:81-89

Authors: Lee H, Song S, Oh YK, Kang W, Kim E

Abstract
OBJECTIVE: To evaluate the role of gender as a risk factor for developing contrast media-associated adverse drug reactions (CM-ADRs) by comparing the incidence of CM-ADR between male and female patients according to study design, ADR type, and computed tomography (CT) examination.
MATERIAL AND METHODS: We systematically searched three electronic databases for eligible studies. In the studies included (n=18), we assessed effect estimates of the relative incidence of CM-ADR, analysed by experimental design, ADR type and CT examination. This was calculated by using a random effects model if clinical conditions showed heterogeneity; otherwise, a fixed effects model was used.
RESULTS: We identified 10,776 patients administered CM. According to the designs, studies were classified into randomised controlled trials (RCTs) and observational studies. Results were as follows: risk ratio (RR)=1.07 (95% confidence interval (CI): 0.79-1.46, P=0.66) for RCTs, and RR=0.77 (95% CI: 0.58-1.04, P=0.09) for observational studies. The results of analysis according to ADR type and for undergoing CT demonstrated that the incidence of CM-ADR did not differ between males and females.
CONCLUSIONS: We found no significant difference in the incidence of CM-ADRs between male and female patients according to study design, ADR type, or CT examination. Future studies to determine why gender has shown different roles as a risk factor between CM-ADRs and non-CM ADRs are needed.

PMID: 28267554 [PubMed - indexed for MEDLINE]

Review of Childhood Obesity: From Epidemiology, Etiology, and Comorbidities to Clinical Assessment and Treatment.

Mayo Clin Proc. 2017 Feb;92(2):251-265

Authors: Kumar S, Kelly AS

Abstract
Childhood obesity has emerged as an important public health problem in the United States and other countries in the world. Currently 1 in 3 children in the United States is afflicted with overweight or obesity. The increasing prevalence of childhood obesity is associated with emergence of comorbidities previously considered to be "adult" diseases including type 2 diabetes mellitus, hypertension, nonalcoholic fatty liver disease, obstructive sleep apnea, and dyslipidemia. The most common cause of obesity in children is a positive energy balance due to caloric intake in excess of caloric expenditure combined with a genetic predisposition for weight gain. Most obese children do not have an underlying endocrine or single genetic cause for their weight gain. Evaluation of children with obesity is aimed at determining the cause of weight gain and assessing for comorbidities resulting from excess weight. Family-based lifestyle interventions, including dietary modifications and increased physical activity, are the cornerstone of weight management in children. A staged approach to pediatric weight management is recommended with consideration of the age of the child, severity of obesity, and presence of obesity-related comorbidities in determining the initial stage of treatment. Lifestyle interventions have shown only modest effect on weight loss, particularly in children with severe obesity. There is limited information on the efficacy and safety of medications for weight loss in children. Bariatric surgery has been found to be effective in decreasing excess weight and improving comorbidities in adolescents with severe obesity. However, there are limited data on the long-term efficacy and safety of bariatric surgery in adolescents. For this comprehensive review, the literature was scanned from 1994 to 2016 using PubMed using the following search terms: childhood obesity, pediatric obesity, childhood overweight, bariatric surgery, and adolescents.

PMID: 28065514 [PubMed - indexed for MEDLINE]

Ceftriaxone-induced hemolytic anemia in a child successfully managed with intravenous immunoglobulin.

Turk J Pediatr. 2016;58(2):216-219

Authors: Vehapoğlu A, Göknar N, Tuna R, Çakır FB

Abstract
Drug-induced hemolytic anemia is an immune-mediated phenomenon that leads to the destruction of red blood cells. Here, we present a case of life-threatening ceftriaxone-induced hemolytic anemia (CIHA) in a previously healthy 3-year-old girl. We also reviewed the literature to summarize the clinical features and treatment of hemolytic anemia. Acute hemolysis is a rare side effect of ceftriaxone therapy associated with high mortality. Our patient had a sudden loss of consciousness with macroscopic hematuria and her hemoglobin dropped from 10.2 to 2.2 g/dl over 4 hours, indicating that the patient had life-threatening hemolysis after an intravascular dose of ceftriaxone who had previously been treated with ceftriaxone in intramuscular form for six days. CIHA is associated with a positive direct antiglobulin test, revealing the presence of IgG in all cases and C3d in most cases. Our patient's direct antiglobulin test was positive for IgG (3+) and for C3d (4+). The case was managed successfully with supportive measures and intravenous immunoglobulin therapy. Ceftriaxone is used very frequently in children; an early diagnosis and proper treatment of hemolytic anemia are essential to improve the patient outcome. The pathophysiological mechanism is the same as for non-drug autoimmune hemolytic anemia. However, there is still no consensus treatment for CIHA. Intravenous immunoglobulin can be used in clinical emergencies, such as our case, or in refractory cases.

PMID: 27976566 [PubMed - indexed for MEDLINE]

A computational model predicts adjunctive pharmacotherapy for cardiac safety via selective inhibition of the late cardiac Na current.

J Mol Cell Cardiol. 2016 Oct;99:151-161

Authors: Yang PC, El-Bizri N, Romero L, Giles WR, Rajamani S, Belardinelli L, Clancy CE

Abstract
BACKGROUND: The QT interval is a phase of the cardiac cycle that corresponds to action potential duration (APD) including cellular repolarization (T-wave). In both clinical and experimental settings, prolongation of the QT interval of the electrocardiogram (ECG) and related proarrhythmia have been so strongly associated that a prolonged QT interval is largely accepted as surrogate marker for proarrhythmia. Accordingly, drugs that prolong the QT interval are not considered for further preclinical development resulting in removal of many promising drugs from development. While reduction of drug interactions with hERG is an important goal, there are promising means to mitigate hERG block. Here, we examine one possibility and test the hypothesis that selective inhibition of the cardiac late Na current (INaL) by the novel compound GS-458967 can suppress proarrhythmic markers.
METHODS AND RESULTS: New experimental data has been used to calibrate INaL in the Soltis-Saucerman computationally based model of the rabbit ventricular action potential to study effects of GS-458967 on INaL during the rabbit ventricular AP. We have also carried out systematic in silico tests to determine if targeted block of INaL would suppress proarrhythmia markers in ventricular myocytes described by TRIaD: Triangulation, Reverse use dependence, beat-to-beat Instability of action potential duration, and temporal and spatial action potential duration Dispersion.
CONCLUSIONS: Our computer modeling approach based on experimental data, yields results that suggest that selective inhibition of INaL modifies all TRIaD related parameters arising from acquired Long-QT Syndrome, and thereby reduced arrhythmia risk. This study reveals the potential for adjunctive pharmacotherapy via targeted block of INaL to mitigate proarrhythmia risk for drugs with significant but unintended off-target hERG blocking effects.

PMID: 27545042 [PubMed - indexed for MEDLINE]

In Vivo Monitoring of Sevoflurane-induced Adverse Effects in Neonatal Nonhuman Primates Using Small-animal Positron Emission Tomography.

Anesthesiology. 2016 Jul;125(1):133-46

Authors: Zhang X, Liu S, Newport GD, Paule MG, Callicott R, Thompson J, Liu F, Patterson TA, Berridge MS, Apana SM, Brown CC, Maisha MP, Hanig JP, Slikker W, Wang C

Abstract
BACKGROUND: Animals exposed to sevoflurane during development sustain neuronal cell death in their developing brains. In vivo micro-positron emission tomography (PET)/computed tomography imaging has been utilized as a minimally invasive method to detect anesthetic-induced neuronal adverse effects in animal studies.
METHODS: Neonatal rhesus monkeys (postnatal day 5 or 6, 3 to 6 per group) were exposed for 8 h to 2.5% sevoflurane with or without acetyl-L-carnitine (ALC). Control monkeys were exposed to room air with or without ALC. Physiologic status was monitored throughout exposures. Depth of anesthesia was monitored using quantitative electroencephalography. After the exposure, microPET/computed tomography scans using F-labeled fluoroethoxybenzyl-N-(4-phenoxypyridin-3-yl) acetamide (FEPPA) were performed repeatedly on day 1, 1 and 3 weeks, and 2 and 6 months after exposure.
RESULTS: Critical physiologic metrics in neonatal monkeys remained within the normal range during anesthetic exposures. The uptake of [F]-FEPPA in the frontal and temporal lobes was increased significantly 1 day or 1 week after exposure, respectively. Analyses of microPET images recorded 1 day after exposure showed that sevoflurane exposure increased [F]-FEPPA uptake in the frontal lobe from 0.927 ± 0.04 to 1.146 ± 0.04, and in the temporal lobe from 0.859 ± 0.05 to 1.046 ± 0.04 (mean ± SE, P < 0.05). Coadministration of ALC effectively blocked the increase in FEPPA uptake. Sevoflurane-induced adverse effects were confirmed by histopathologic evidence as well.
CONCLUSIONS: Sevoflurane-induced general anesthesia during development increases glial activation, which may serve as a surrogate for neurotoxicity in the nonhuman primate brain. ALC is a potential protective agent against some of the adverse effects associated with such exposures.

PMID: 27183169 [PubMed - indexed for MEDLINE]