Literature Watch
A commensal streptococcus hijacks a Pseudomonas aeruginosa exopolysaccharide to promote biofilm formation.
A commensal streptococcus hijacks a Pseudomonas aeruginosa exopolysaccharide to promote biofilm formation.
PLoS Pathog. 2017 Apr;13(4):e1006300
Authors: Scoffield JA, Duan D, Zhu F, Wu H
Abstract
Pseudomonas aeruginosa causes devastating chronic pulmonary infections in cystic fibrosis (CF) patients. Although the CF airway is inhabited by diverse species of microorganisms interlaced within a biofilm, many studies focus on the sole contribution of P. aeruginosa pathogenesis in CF morbidity. More recently, oral commensal streptococci have been identified as cohabitants of the CF lung, but few studies have explored the role these bacteria play within the CF biofilm. We examined the interaction between P. aeruginosa and oral commensal streptococci within a dual species biofilm. Here we report that the CF P. aeruginosa isolate, FRD1, enhances biofilm formation and colonization of Drosophila melanogaster by the oral commensal Streptococcus parasanguinis. Moreover, production of the P. aeruginosa exopolysaccharide, alginate, is required for the promotion of S. parasanguinis biofilm formation and colonization. However, P. aeruginosa is not promoted in the dual species biofilm. Furthermore, we show that the streptococcal adhesin, BapA1, mediates alginate-dependent enhancement of the S. parasanguinis biofilm in vitro, and BapA1 along with another adhesin, Fap1, are required for the in vivo colonization of S. parasanguinis in the presence of FRD1. Taken together, our study highlights a new association between streptococcal adhesins and P. aeruginosa alginate, and reveals a mechanism by which S. parasanguinis potentially colonizes the CF lung and interferes with the pathogenesis of P. aeruginosa.
PMID: 28448633 [PubMed - in process]
Little Cigars are More Toxic than Cigarettes and Uniquely Change the Airway Gene and Protein Expression.
Little Cigars are More Toxic than Cigarettes and Uniquely Change the Airway Gene and Protein Expression.
Sci Rep. 2017 Apr 27;7:46239
Authors: Ghosh A, Abdelwahab SH, Reeber SL, Reidel B, Marklew AJ, Garrison AJ, Lee S, Dang H, Herring AH, Glish GL, Kesimer M, Tarran R
Abstract
Little cigars (LCs) are regulated differently than cigarettes, allowing them to be potentially targeted at youth/young adults. We exposed human bronchial epithelial cultures (HBECs) to air or whole tobacco smoke from cigarettes vs. LCs. Chronic smoke exposure increased the number of dead cells, lactate dehydrogenase release, and interleukin-8 (IL-8) secretion and decreased apical cilia, cystic fibrosis transmembrane conductance regulator (CFTR) protein levels, and transepithelial resistance. These adverse effects were significantly greater in LC-exposed HBECs than cigarette exposed cultures. LC-exposure also elicited unique gene expression changes and altered the proteomic profiles of airway apical secretions compared to cigarette-exposed HBECs. Gas chromatography-mass spectrometry (GC-MS) analysis indicated that LCs produced more chemicals than cigarettes, suggesting that the increased chemical load of LCs may be the cause of the greater toxicity. This is the first study of the biological effects of LCs on pulmonary epithelia and our observations strongly suggest that LCs pose a more severe danger to human health than cigarettes.
PMID: 28447619 [PubMed - in process]
Proprotein Convertase Subtilisin/Kexin type 9 affects insulin but not lipid metabolism in cystic fibrosis.
Proprotein Convertase Subtilisin/Kexin type 9 affects insulin but not lipid metabolism in cystic fibrosis.
Clin Invest Med. 2017 Apr 26;40(2):E59-E65
Authors: Coriati A, Arslanian E, Bouvet GF, Prat A, Seidah NG, Rabasa-Lhoret R, Berthiaume Y
Abstract
PURPOSE: Cystic Fibrosis (CF) is the most common genetic disorder and, with improved survival, glucose abnormalities have emerged as a major comorbidity. Proprotein convertase subtilisin/kexin type 9 (PCSK9), a regulator of plasma LDL-cholesterol homeostasis, is associated with lipid and glucose metabolism in healthy individuals. Here we report on the link between PCSK9 and markers of metabolism in CF.
METHODS: Cross-sectional analysis was performed on CF patients (≥ 18 years, N=94) from the Montreal Cohort, without known diabetes, and on healthy individuals (N=19). The levels of PCSK9 and lipid markers were quantified and all subjects underwent a 2 h oral glucose tolerance test.
RESULTS: No significant differences in PCSK9 levels were found between healthy individuals and patients with CF, or between the groups with different degrees of glucose tolerance. No association was found between PCSK9 and markers of lipid metabolism; however, a positive correlation was found between PCSK9 and total insulin secretion and a negative one with insulin sensitivity in CF patients who had normal glucose tolerance.
CONCLUSION: Circulating levels of PCSK9 in the CF population are comparable to those in the healthy population. There are no associations between PCSK9 levels and either glucose or lipid homeostasis parameters. Nevertheless, a statistically significant link was observed between PCSK9 and markers of insulin homeostasis, solely in CF patients who presented normal glucose tolerance. Further exploration of the relationship between PCSK9 and insulin homeostasis in CF patients with normal glucose tolerance is warranted.
PMID: 28447578 [PubMed - in process]
Ecology of the Human Opportunistic Black Yeast Exophiala dermatitidis Indicates Preference for Human-Made Habitats.
Ecology of the Human Opportunistic Black Yeast Exophiala dermatitidis Indicates Preference for Human-Made Habitats.
Mycopathologia. 2017 Apr 26;:
Authors: Babič MN, Zupančič J, Gunde-Cimerman N, de Hoog S, Zalar P
Abstract
Exophiala dermatitidis is an ascomycetous black yeast from the order Chaetothyriales. Its growth characteristics include the polymorphic life cycle, ability to grow at high and low temperatures, at a wide pH range, survival at high concentrations of NaCl, and survival at high UV and radioactive radiation. Exophiala dermatitidis causes deep or localized phaeohyphomycosis in immuno-compromised people worldwide and is regularly encountered in the lungs of cystic fibrosis patients. Regardless of numerous ecological studies worldwide, little is known about its natural habitat or the possible infection routes. The present review summarizes the published data on its frequency of occurrence in nature and in man-made habitats. We additionally confirmed its presence with culture-depending methods from a variety of habitats, such as glacial meltwater, mineral water, mineral-rich salt-pan mud, dishwashers, kitchens and different environments polluted with aromatic hydrocarbons. In conclusion, the frequency of its recovery was the highest in man-made indoor habitats, connected to water sources, and exposed to occasional high temperatures and oxidative stress.
PMID: 28447292 [PubMed - as supplied by publisher]
Population dynamics of Staphylococcus aureus in Cystic Fibrosis patients to determine transmission events utilizing WGS.
Population dynamics of Staphylococcus aureus in Cystic Fibrosis patients to determine transmission events utilizing WGS.
J Clin Microbiol. 2017 Apr 26;:
Authors: Ankrum A, Hall BG
Abstract
Strict infection control practices have been implemented for healthcare visits by Cystic Fibrosis patients in an attempt to prevent transmission of important pathogens. This study used whole genome sequencing (WGS) to determine strain relatedness and assess population dynamics of Staphylococcus aureus isolates from a cohort of CF patients as assessed by strain relatedness. 311 S. aureus isolates were collected from respiratory cultures of 115 CF patients during a 22 month study period. Whole genome sequencing was performed and using SNP analysis, phylogenetic trees were assembled to determine relatedness between isolates. MRSA phenotypes were predicted using PPFS2 and compared to the observed phenotype. The accumulation of SNPs in multiple isolates obtained over time from the same patient was examined to determine if a genomic molecular clock could be calculated.Pairs of isolates with ≤ 71 SNP differences were considered to be the "same" strain. All of the "same" strain isolates were either from the same patient or siblings pairs. There were 47 examples of patients being superinfected with an unrelated strain. Predicted MRSA phenotype was accurate in all but three isolates. Mutation rates were unable to be determined because the branching order in the phylogenetic tree was inconsistent with the order of isolation.The observation that transmissions were identified between sibling patients shows that WGS is an effective tool for determining transmission between patients. The observation that transmission only occurred between siblings suggests that Staphylococcus aureus acquisition in our CF population occurred outside the hospital environment and indicates that current infection prevention efforts appear effective.
PMID: 28446577 [PubMed - as supplied by publisher]
Prevalence and Outcomes of Achromobacter species Infections in Adults with Cystic Fibrosis: A North American Cohort Study.
Prevalence and Outcomes of Achromobacter species Infections in Adults with Cystic Fibrosis: A North American Cohort Study.
J Clin Microbiol. 2017 Apr 26;:
Authors: Edwards BD, Greysson-Wong J, Somayaji R, Waddell B, Whelan FJ, Storey DG, Rabin HR, Surette MG, Parkins MD
Abstract
Introduction:Achromobacter species are now increasingly recognized in CF, with unclear epidemiology and impact.Methods: We studied a cohort of patients attending a Canadian adult CF clinic who had positive sputum cultures for Achromobacter species from 1984-2013. Infection was categorized as transient or persistent (≥50% positive cultures in one year). Those with persistent infection were matched 2:1 with age, sex, and time-matched controls without history of Achromobacter infection and mixed effects models used to assess pulmonary exacerbation(PEx) frequency and lung function decline. Isolates were retrospectively assessed from a biobank, speciated by nrdA sequencing, and genotyped using PFGE.Results: Thirty-four patients (11% of clinic), median age 24 years (IQR 20.3-29.8) developed Achromobacter infection. Ten patients (29%) developed persistent infection. Persistence did not denote permanence, as most patients ultimately cleared infection, often after years. Patients were more likely to experience PEx at incident isolation compared with prior or subsequent visits (OR 2.7[95% CI 1.2--6.7];p=0.03). Following persistent infection, there was no difference in annual lung function decline (-1.08% [95% CI -2.73-0.57] vs. -2.74% [95% CI -4.02-1.46]; p=0.12) or odds of PEx (OR 1.21 [95% CI 0.45--3.28]; p=0.70). Differential virulence amongst Achromobacter species was not observed and no cases of transmission occurred.Conclusion: We demonstrated that incident Achromobacter infection was associated with greater risk of PEx, however, neither transient nor chronic infection associated with worsened long-term prognosis. Large, multicenter studies are needed to clarify the clinical impact, natural history and transmissibility of Achromobacter.
PMID: 28446570 [PubMed - as supplied by publisher]
Lung lymphoid neogenesis in cystic fibrosis: a model of adaptive responses to bacteria?
Lung lymphoid neogenesis in cystic fibrosis: a model of adaptive responses to bacteria?
Eur Respir J. 2017 Apr;49(4):
Authors: Gohy ST, Ladjemi MZ, Pilette C
PMID: 28446564 [PubMed - in process]
Pseudomonas aeruginosa adaptation and diversification in the non-cystic fibrosis bronchiectasis lung.
Pseudomonas aeruginosa adaptation and diversification in the non-cystic fibrosis bronchiectasis lung.
Eur Respir J. 2017 Apr;49(4):
Authors: Hilliam Y, Moore MP, Lamont IL, Bilton D, Haworth CS, Foweraker J, Walshaw MJ, Williams D, Fothergill JL, De Soyza A, Winstanley C
Abstract
To characterise Pseudomonas aeruginosa populations during chronic lung infections of non-cystic fibrosis bronchiectasis patients, we used whole-genome sequencing to 1) assess the diversity of P. aeruginosa and the prevalence of multilineage infections; 2) seek evidence for cross-infection or common source acquisition; and 3) characterise P. aeruginosa adaptations.189 isolates, obtained from the sputa of 91 patients attending 16 adult bronchiectasis centres in the UK, were whole-genome sequenced.Bronchiectasis isolates were representative of the wider P. aeruginosa population. Of 24 patients from whom multiple isolates were examined, there were seven examples of multilineage infections, probably arising from multiple infection events. The number of nucleotide variants between genomes of isolates from different patients was in some cases similar to the variations observed between isolates from individual patients, implying the possible occurrence of cross-infection or common source acquisition.Our data indicate that during infections of bronchiectasis patients, P. aeruginosa populations adapt by accumulating loss-of-function mutations, leading to changes in phenotypes including different modes of iron acquisition and variations in biofilm-associated polysaccharides. The within-population diversification suggests that larger scale longitudinal surveillance studies will be required to capture cross-infection or common source acquisition events at an early stage.
PMID: 28446558 [PubMed - in process]
Bacteria-driven peribronchial lymphoid neogenesis in bronchiectasis and cystic fibrosis.
Bacteria-driven peribronchial lymphoid neogenesis in bronchiectasis and cystic fibrosis.
Eur Respir J. 2017 Apr;49(4):
Authors: Frija-Masson J, Martin C, Regard L, Lothe MN, Touqui L, Durand A, Lucas B, Damotte D, Alifano M, Fajac I, Burgel PR
Abstract
We aimed to characterise lymphoid neogenesis in bronchiectasis and cystic fibrosis (CF) lungs and to examine the role of bacterial infection.Lymphoid aggregates were examined using immunohistochemical staining and morphometric analysis in surgical lung sections obtained from nonsmokers and patients with bronchiectasis or CF. Sterile, Pseudomonas aeruginosa- or Staphylococcus aureus-coated agarose beads were instilled intratracheally in mice. Kinetics of lymphoid neogenesis and chemokine expression were examined over 14 days.Lymphoid aggregates were scarce in human lungs of nonsmokers, but numerous peribronchial lymphoid aggregates containing B-lymphocytes, T-lymphocytes, germinal centres and high endothelial venules were found in bronchiectasis and CF. Mouse lungs contained no lymphoid aggregate at baseline. During persistent P. aeruginosa or S. aureus airway infection peribronchial lymphoid neogenesis occurred. At day 14 after instillation, lymphoid aggregates expressed markers of tertiary lymphoid organs and the chemokines CXCL12 and CXCL13. The airway epithelium was an important site of CXCL12, CXCL13 and interleukin-17A expression, which began at day 1 after instillation.Peribronchial tertiary lymphoid organs are present in bronchiectasis and in CF, and persistent bacterial infection triggered peribronchial lymphoid neogenesis in mice. Peribronchial localisation of tertiary lymphoid organs and epithelial expression of chemokines suggest roles for airway epithelium in lymphoid neogenesis.
PMID: 28446556 [PubMed - in process]
Risk factors for persistent methicillin-resistant Staphylococcus aureus infection in cystic fibrosis.
Risk factors for persistent methicillin-resistant Staphylococcus aureus infection in cystic fibrosis.
J Cyst Fibros. 2017 Apr 23;:
Authors: Jennings MT, Dasenbrook EC, Lechtzin N, Boyle MP, Merlo CA
Abstract
BACKGROUND: Methicillin-resistant Staphylococcus aureus (MRSA) has emerged as an important pathogen in cystic fibrosis (CF). Over 25% of individuals in the United States with CF are found to have MRSA in respiratory culture specimens, and persistent MRSA infection has been associated with more rapid decline in lung function and increased mortality. The objective of this study was to investigate clinical and demographic characteristics that are associated with the development of persistent MRSA infection in a CF population.
METHODS: This was a retrospective cohort study of individuals followed from 2002 to 2012 in the Cystic Fibrosis Foundation Patient Registry. A time-to-event analysis for the development of persistent MRSA infection was performed, and multivariable Cox proportional hazards models were constructed to identify risk factors for infection.
RESULTS: The study cohort included 19,434 individuals, of which 5844 would develop persistent MRSA infection. In the adjusted model, pancreatic insufficiency (HR: 1.49; 95% CI: 1.29-1.72), CF related diabetes (HR: 1.13; 95% CI: 1.05-1.20), co-infection with P. aeruginosa (HR: 1.21; 95% CI: 1.13-1.28), and number of hospitalizations/year (HR: 1.09; 95% CI: 1.06-1.12) were all associated with increased risk, whereas higher socio-economic status (HR: 0.87; 95% CI: 0.82-0.93) was associated with a lower risk. Receiving care at a CF center with increased MRSA prevalence was associated with increased risk of MRSA infection: highest quartile (HR: 2.33; 95% CI: 2.13-2.56).
CONCLUSIONS: No easily modifiable risk factors for persistent MRSA were identified in this study. However, several risk factors for patients at higher risk for persistent MRSA infection were identified, for example centers with a high baseline MRSA prevalence, and may be useful in designing center-specific MRSA infection prevention and control strategies and/or eradication protocols. Additional studies are needed in order to evaluate if attention to these risk factors can improve clinical outcomes.
PMID: 28446387 [PubMed - as supplied by publisher]
High CFTR expression in Philadelphia chromosome-positive acute leukemia protects and maintains continuous activation of BCR-ABL and related signaling pathways in combination with PP2A.
High CFTR expression in Philadelphia chromosome-positive acute leukemia protects and maintains continuous activation of BCR-ABL and related signaling pathways in combination with PP2A.
Oncotarget. 2017 Apr 11;8(15):24437-24448
Authors: Yang X, Yan T, Gong Y, Liu X, Sun H, Xu W, Wang C, Naren D, Zheng Y
Abstract
Cystic fibrosis transmembrane conductance regulator (CFTR) is classified as an anion channel transporter of Cl- and HCO3-. Through interactions with its PDZ domain, CFTR is capable of regulating other proteins, such as protein phosphatase 2A (PP2A). The aberrant expression and mutation of CFTR have been observed in several tumor, but not in philadelphia chromosome-positive(Ph+) acute leukemia, including Ph+ B cell acute lymphoblastic leukemia(Ph+ B-ALL) and chronic myelogenous leukemia blast crisis phases (CML-BC). In this study, we demonstrated the mean expression level of CFTR in Ph+ acute leukemia cells was markedly higher than that in Ph- B-ALL and CML-chronic phase cells. CFTRinh-172, a classic CFTR inhibitor, down-regulated the expression of CFTR, p-BCR-ABL and classical Wnt/β-catenin signaling in Ph+ acute leukemia cells, while imatinib had no effect on CFTR. Importantly, reduced efficacy of CFTRinh-172 was closely associated with elevated PP2A phosphatase activity. Furthermore, we confirmed an interaction between CFTR and the PP2AA subunit in K562 cells. In addition, we demonstrated CFTR and PP2AA interact in the cytosol, resulting in PP2A complex inactivation and increased degradation of PP2A substrates via the lysosomal/proteasome pathway. In conclusion, our results showed CFTR was highly expressed in Ph+ acute leukemia, which protected and maintained the continuous activation of BCR-ABL and the canonical Wnt/β-catenin signaling pathway by decreasing PP2A phosphatase activity. According to this working model of the CFTR-PP2A-BCR-ABL axis, targeting the CFTR protein will activate PP2A and may offer a new treatment strategy for Ph+ acute leukemia, especially for patients exhibiting high levels of CFTR expression.
PMID: 28445932 [PubMed - in process]
Novel missense mutation in DLL4 in a Japanese sporadic case of Adams-Oliver syndrome.
Novel missense mutation in DLL4 in a Japanese sporadic case of Adams-Oliver syndrome.
J Hum Genet. 2017 Apr 27;:
Authors: Nagasaka M, Taniguchi-Ikeda M, Inagaki H, Ouchi Y, Kurokawa D, Yamana K, Harada R, Nozu K, Sakai Y, Mishra SK, Yamaguchi Y, Morikoka I, Toda T, Kurahashi H, Iijima K
Abstract
Adams-Oliver syndrome (AOS, OMIM; 100300) is a rare genetic disease characterized by aplasia cutis congenita, terminal transverse limb defects and cutis marmorata with vascular anomalies such as congenital heart defects. The etiology of this syndrome has remained largely unknown but defective Notch signaling during vascular formation has been suggested. Here we describe a sporadic Japanese newborn case with clinically diagnosed AOS. Trio whole-exome sequencing identified a de novo, novel, heterozygous missense mutation in the Delta-like 4 ligand gene (DLL4 c.572G>A, p.Arg191His) in the patient. DLL4 functions as a requisite ligand for NOTCH1 receptor, which is essential for vascular formation. Amino acid substitution of Arg191 to His was predicted by molecular models to interfere with direct binding between DLL4 and NOTCH1. DLL4 has recently been identified as a causative gene of an autosomal dominant type of AOS with milder symptoms. The case described here showed gradual recovery from skull defects after birth and no psychomotor developmental delay has been observed. This is the second report of an AOS case with DLL4 mutation, and the phenotypic characteristics between the two cases are compared and discussed.Journal of Human Genetics advance online publication, 27 April 2017; doi:10.1038/jhg.2017.48.
PMID: 28446798 [PubMed - as supplied by publisher]
Safety, Pharmacokinetics and Pharmacologic Effects of the Selective Androgen Receptor Modulator, GSK2881078, in Healthy Men and Postmenopausal Women.
Safety, Pharmacokinetics and Pharmacologic Effects of the Selective Androgen Receptor Modulator, GSK2881078, in Healthy Men and Postmenopausal Women.
Br J Clin Pharmacol. 2017 Apr 27;:
Authors: Clark RV, Walker AC, Andrews S, Turnbull P, Wald JA, Magee MH
Abstract
AIM: Selective androgen receptor modulators (SARMs) induce anabolic effects on muscle without the adverse effects of androgenic steroids. In this first-in-human study, we report safety, tolerability, pharmacokinetics (PK), and pharmacodynamics of the SARM GSK2881078.
METHODS: In Part A, healthy young men (n = 10) received a single dose of study drug (0 mg, 0.05 mg, 0.1 mg, 0.2 mg GSK2881078 or matching-placebo). In Part B, repeat-dose cohorts in men (n = 65) were 0.05 mg, 0.2 mg then 0.08 mg, 0.24 mg, 0.48 mg, 0.75 mg, or placebo; in women (n = 24), 0.24 mg, 0.35 mg, or placebo (7 days for 0.5 mg, 14 days for other doses).
RESULTS: PK analysis showed dose-proportional increases in exposure and a long >100-h half-life. No significant effects on vital signs, electrocardiograms, cardiac telemetry, or standard clinical lab studies were observed. A dose-response effect was observed on lowering both high-density lipoprotein and sex-hormone-binding globulin. In females at 0.35 mg, differences from placebo were -0.518 mmol/L (95% CI: -0.703, -0.334) and -39.1 nmol/L (-48.5, -29.7), respectively. Women showed greater sensitivity to these parameters at lower doses than men. Drug-related adverse events (AEs) were mild. One woman developed a drug rash and was withdrawn. Two men had elevated creatine phosphokinase after physical exertion during follow-up. A serious AE occurred in a subject on placebo.
CONCLUSIONS: These data demonstrate pharmacodynamic effects with acceptable tolerability and support further clinical evaluation of this SARM.
PMID: 28449232 [PubMed - as supplied by publisher]
Swallowing Disorders in Schizophrenia.
Swallowing Disorders in Schizophrenia.
Dysphagia. 2017 Apr 26;:
Authors: Kulkarni DP, Kamath VD, Stewart JT
Abstract
Disorders of swallowing are poorly characterized but quite common in schizophrenia. They are a source of considerable morbidity and mortality in this population, generally as a result of either acute asphyxia from airway obstruction or more insidious aspiration and pneumonia. The death rate from acute asphyxia may be as high as one hundred times that of the general population. Most swallowing disorders in schizophrenia seem to fall into one of two categories, changes in eating and swallowing due to the illness itself and changes related to psychotropic medications. Behavioral changes related to the illness are poorly understood and often involve eating too quickly or taking inappropriately large boluses of food. Iatrogenic problems are mostly related to drug-induced extrapyramidal side effects, including drug-induced parkinsonism, dystonia, and tardive dyskinesia, but may also include xerostomia, sialorrhea, and changes related to sedation. This paper will provide an overview of common swallowing problems encountered in patients with schizophrenia, their pathophysiology, and management. While there is a scarcity of quality evidence in the literature, a thorough history and examination will generally elucidate the predominant problem or problems, often leading to effective management strategies.
PMID: 28447217 [PubMed - as supplied by publisher]
Serious Adverse Effects of Testosterone Abuse.
Serious Adverse Effects of Testosterone Abuse.
Am J Nurs. 2017 Feb;117(2):20-21
Authors: Aschenbrenner DS
PMID: 28125486 [PubMed - indexed for MEDLINE]
Nephrotoxic Medication Exposure in U.S. Adults with Predialysis Chronic Kidney Disease: Health Services Utilization and Cost Outcomes.
Nephrotoxic Medication Exposure in U.S. Adults with Predialysis Chronic Kidney Disease: Health Services Utilization and Cost Outcomes.
J Manag Care Spec Pharm. 2016 Aug;22(8):959-68
Authors: Davis-Ajami ML, Fink JC, Wu J
Abstract
BACKGROUND: Nephrotoxic medication exposure increases risks for acute kidney injury, permanent renal function loss, and costly preventable adverse drug events. Exposure to medications associated with inducing acute tubular nephritis or tubular toxicity versus nonexposure among those with predialysis renal disease-a population vulnerable to increased risk of kidney injury-may affect health services utilization and cost outcomes. Few studies quantify nephrotoxic medication exposure in chronic kidney disease (CKD) and associated costs.
OBJECTIVE: To examine exposure to medications associated with inducing acute tubular nephritis or tubular toxicity versus nonexposure and the effect on health services utilization and cost outcomes in a nationally representative sample of adults with predialysis CKD.
METHODS: This retrospective study used Medical Expenditure Panel Survey (MEPS) household component longitudinal files (years 2006-2012; panels 11-16). Participants included 809 MEPS respondents aged > 18 years with predialysis CKD, after excluding those participants with cancer, kidney stone, renal dialysis, or transplant procedures (approximately 14.7 million U.S. noninstitutionalized individuals). Two groups were created to evaluate the main measures: (1) participants prescribed 1 or more medications associated with risk of acute tubular nephritis and/or tubular toxicity (termed "nephrotoxic exposure") and (2) participants with nonexposure. Medications cited in published literature as associated with tubular kidney damage were used. Multivariable regression models assessed the pattern of nephrotoxic medication exposure and its effect on health services utilization and expenses.
RESULTS: Nephrotoxic medication exposure occurred in 72% of adult MEPS respondents. Of those, 47.2% and 52.8% were prescribed 1 and at least 2 nephrotoxic medications, respectively. Coexistent chronic conditions included hypertension (72.3%), diabetes (49.5%), coronary heart disease (33%), arthritis (23.6%), and chronic obstructive pulmonary disease (17.6%). Eligible MEPS respondents aged ≥ 65 years, from the U.S. South region, and with Charlson Comorbidity Index (CCI) score > 0 were 75% (vs. aged 18-45 years), 83% (vs. Northeast), and 72%-96% (vs. CCI = 0) more likely to be exposed to nephrotoxic medications. Uninsured participants showed 55% less likelihood of nephrotoxic exposure, compared with privately insured participants. Higher utilization was shown in the nephrotoxic medication exposure group (vs. nonexposure): prescription fills (52.8 vs. 26.8, P < 0.001), emergency department visits (56.2 vs. 29.3 per 1,000 patient months, P < 0.001), and hospitalization (51.8 vs. 23.4 per 1,000 patient months, P < 0.001). Unadjusted all-cause expenses were greater for the following categories: medical ($119,935 vs. $11,462, P < 0.001), prescription drug ($4,828 vs. $2,816, P < 0.001), and total health expenses ($24,663 vs. $14,277, P < 0.001). Adjusted all-cause expenses were greater for total (29.7% greater, P = 0.003), prescription medications (56.6% greater, P < 0.001), and medical (23.4% greater, P = 0.036), but there were no differences in predialysis CKD-related utilization and expenses.
CONCLUSIONS: Increased vigilance is needed when prescribing nephrotoxic medications in predialysis CKD, particularly in patients with comorbid conditions and the elderly. Nephrotoxic medication exposure in predialysis CKD has the potential for increased health services utilization and cost outcomes.
DISCLOSURES: There was no grant or intramural funding for this research. The authors have no conflicts of interest, financial or otherwise, to disclose. Study concept and design were primarily contributed by Davis-Ajami, along with Fink and Wu. Davis-Ajami took the lead in data collection, along with Wu, and data interpretation was performed by David-Ajami, Wu, and Fink. All authors participated in manuscript preparation and revision.
PMID: 27459659 [PubMed - indexed for MEDLINE]
Scrotal Cooling to Protect Against Cisplatin-induced Spermatogenesis Toxicity: Preliminary Outcome of an Experimental Controlled Trial.
Scrotal Cooling to Protect Against Cisplatin-induced Spermatogenesis Toxicity: Preliminary Outcome of an Experimental Controlled Trial.
Urology. 2016 05;91:90-8
Authors: Aminsharifi A, Hekmati P, Noorafshan A, Karbalay-Doost S, Nadimi E, Aryafar A, Hosseinabadi OK, Naseri MM, ZarePoor M
Abstract
OBJECTIVE: To investigate the protective effects of scrotal cooling on cisplatin-induced gonadal toxicity in an animal model.
METHODS: Twenty-one male BALB/c mice were divided into 3 groups. The cisplatin group received 2 cycles of cisplatin (2.5 mg/kg/day for 5 days with 16 days of recovery) intraperitoneally, and the cisplatin + cooling group received the same regimen of cisplatin with a cooling protocol: cooling induction for 30 minutes before injection and cooling for 60 minutes after injection. Mice in control group were given an injection of 2 mL normal saline intraperitoneally. After 35 days of recovery (1 cycle of spermatogenesis), the volume of the testes (Cavalieri method), volume density of the tubules and epithelium (point-counting method), and number of cells (optical dissector method) were estimated.
RESULTS: The volume of the testes, tubules, and epithelium was reduced between 61% and 66%, and the number of the spermatogonia, spermatocytes, round spermatids, and long spermatids was reduced between 70% and 93% in cisplatin group compared with that of control mice. Cisplatin affected spermatids to a greater extent, and Sertoli cells to a lesser extent than the other cells. The volume and number of the cells were reduced in the cisplatin + cooling group but to a lesser extent compared with those of mice in the cisplatin group. Sertoli cells were more intact in the cisplatin + cooling group compared with those of the control group.
CONCLUSION: Scrotal cooling during cisplatin administration seems to have beneficial effects on spermatogenesis. Scrotal cooling may hold promise as a way to protect fertility.
PMID: 26845053 [PubMed - indexed for MEDLINE]
Revision Applications for Regenerative Medicine Innovation Projects (RMIP) (U01)
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Revision Applications for Regenerative Medicine Innovation Projects (RMIP) (R01)
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