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Stomach ulcers (holes in the stomach lining) and stomach cancer can be caused by an infection with the bacteria Helicobacter pylori. This infection is cured with antibiotics and an acid blocker. Some antibiotics that are used are clarithromycin (C), amoxicillin (A), metronidazole (M), and levofloxacin (L). There is limited research in Canada if these drugs work or if they do not work because the bacteria are resistant to the drugs. We found that treatment of patients who were identified for the first time was successful 88% of the time. Treatment of patients who had been treated before for this infection was successful 75% of the time. The best treatment was a combination of C, A, and M for 14 days. Bacterial resistance to drugs is common in Edmonton and increased for some drugs. Overall, treatment success was in 80% of patients when treatment was done by the guidelines. Treatments worked better in patients who were found the first time to have the infection compared to patients who had been treated before for the infection. Bacterial resistance to drugs is a common cause of treatment failure.

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Background Acute kidney injury (AKI) is common in low- and middle-income countries, and is associated with a high mortality. The high mortality rate is in large part due to the inability to perform dialysis in resource-limited settings. Due to significant cost advantages, peritoneal dialysis (PD) has been used to treat AKI in these settings. The costs, however, remain high when commercial solutions are used.Methods This is a retrospective cohort study of the outcome, and of the peritonitis rates, of patients with AKI treated with either commercially manufactured PD solutions or locally-made PD solutions. A program to treat AKI with PD was started at Mbingo Baptist Hospital in Cameroon. Between May 2013 and January 2015, solutions and connection sets were provided by the Saving Young Lives Program. From January 2015 through March 2017, solutions were locally produced and available tubing was used.Results Mortality in hospitalized AKI patients was 28% during the period when commercial solutions and tubing were utilized, and 33% when locally produced solutions and available tubing were utilized. In both groups, peritonitis occurred in 16% of treatment courses.Conclusions Locally produced PD solutions, used with locally available tubing, were used to treat AKI with PD. The mortality and peritonitis rates were similar whether locally produced or commercial supplies were used.

ABSTRACTThe species Acinetobacter baumanniiis one of the most important multidrug-resistant human pathogens. To determine its virulence and antibiotic resistance determinants, the genome of the nosocomial blaNDM-1-positive A. baumanniistrain R2090 originating from Egypt was completely sequenced. Genome analysis revealed that strain R2090 is highly related to the community-acquired Australian A. baumanniistrain D1279779. The two strains belong to sequence type 267 (ST267). Isolate R2090 harbored the chromosomally integrated transposon Tn125carrying the carbapenemase gene blaNDM-1that is not present in the D1279779 genome. To test the transferability of the metallo-β-lactamase (MBL) gene region, the clinical isolate R2090 was mated with the susceptible A. baumanniirecipient CIP 70.10, and the carbapenem-resistant derivative R2091 was obtained. Genome sequencing of the R2091 derivative revealed that it had received an approximately 66-kb region comprising the transposon Tn125embedding the blaNDM-1gene. This region had integrated into the chromosome of the recipient strain CIP 70.10. From the four known mechanisms for horizontal gene transfer (conjugation, outer membrane vesicle-mediated transfer, transformation, and transduction), conjugation could be ruled out, since strain R2090 lacks any plasmid, and a type IV secretion system is not encoded in its chromosome. However, strain R2090 possesses three putative prophages, two of which were predicted to be complete and therefore functional. Accordingly, it was supposed that the transfer of the resistance gene region from the clinical isolate R2090 to the recipient occurred by general transduction facilitated by one of the prophages present in the R2090 genome. Hence, phage-mediated transduction has to be taken into account for the dissemination of antibiotic resistance genes within the species A. baumannii.

Concentration–response curves (CRCs) of adenosine receptor (AR) agonists, NECA (nonspecific), CCPA (A1specific), CGS-216870 (A2Aspecific), BAY 60-6583 (A2Bspecific), and Cl-IB-MECA (A3specific) for mesenteric arteries (MAs) from 4 AR knockout (KO) mice (A1, A2A, A2B, and A3) and their wild type (WT) were constructed. The messenger RNA expression of MAs from KO mice and WT were also studied. Adenosine (10−5to 10−4M) and NECA (10−6to 10−5M) induced relaxation in all mice except A2BKO mice, which only showed constriction by adenosine at 10−6to 10−4and NECA at 10−8to 10−5M. The CCPA induced a significant constriction at 10−8and 10−7M in all mice, except A1KO. BAY 60-6583 induced relaxation (10−7to 10−5M) in WT and no response in A2BKO except at 10−5M. The CRCs for BAY 60-6583 in A1, A2A, and A3KO mice shifted to the left when compared with WT mice, suggesting an upregulation of A2BAR. No responses were noted to CGS-21680 in all mice. Cl-IB-MECA only induced relaxation at concentration greater than 10−7M, and no differences were found between different KO mice. The CRC for Bay 60-6583 was not significantly changed in the presence of 10−5M of L-NAME, 10−6M of indomethacin, or both. Our data suggest that A2BAR is the predominant AR subtype and the effect may be endothelial independent, whereas A1AR plays a significant modulatory role in mouse MAs.

Context: Circulating tumor DNA (ctDNA) is a promising biomarker in cancer.Materials and methods: We generated xenograft models of cancer and detected ctDNA in plasma by qRCR targeting human AluJ sequences.Results: Our assay reached single cell sensitivity in vitroand a correlation between ctDNA amount and tumor size was observed in vivo. Treatment with a mitogen activated protein kinase kinase (MEK)-inhibitor (BAY 869766) reduced ctDNA levels. Using this assay, we also confirmed that high levels of cell-free DNA are found in cancer patients compared to healthy individuals.Discussion and conclusion: We show that ctDNA may be useful biomarker for monitoring tumor growth and treatment response.

ABSTRACTScreening of a transposon insertion mutant library of Pseudomonas aeruginosafor increased susceptibility to paromomycin identified a number of genes whose disruption enhanced susceptibility of this organism to multiple aminoglycosides, including tobramycin, amikacin, and gentamicin. These included genes associated with lipid biosynthesis or metabolism (lptA, faoA), phosphate uptake (pstB), and two-component regulators (amgRS, PA2797-PA2798) and a gene of unknown function (PA0392). Deletion mutants lacking these showed enhanced panaminoglycoside susceptibility that was reversed by the cloned genes, confirming their contribution to intrinsic panaminoglycoside resistance. None of these mutants showed increased aminoglycoside permeation of the cell envelope, indicating that increased susceptibility was not related to enhanced aminoglycoside uptake owing to a reduced envelope barrier function. Several mutants (pstB, faoA, PA0392, amgR) did, however, show increased cytoplasmic membrane depolarization relative to wild type following gentamicin exposure, consistent with the membranes of these mutants being more prone to perturbation, likely by gentamicin-generated mistranslated polypeptides. Mutants lacking any two of these resistance genes in various combinations invariably showed increased aminoglycoside susceptibility relative to single-deletion mutants, confirming their independent contribution to resistance and highlighting the complexity of the intrinsic aminoglycoside resistome in P. aeruginosa. Deletion of these genes also compromised the high-level panaminoglycoside resistance of clinical isolates, emphasizing their important contribution to acquired resistance.

Context: The receptor tyrosine kinase MET contributes to a wide range of biological activities, including survival, proliferation, and metastasis, which play an important role in cancer progression. MET is frequently overexpressed or amplified in a range of malignancies. Therefore, MET is an attractive therapeutic target for treatment of cancer. BAY-853474 is a novel specific MET inhibitor highly effective in preclinical tumor models.Objective: For response monitoring in clinical studies, soluble plasma biomarkers are the most convenient and least invasive choice. Therefore, we sought to identify such biomarkers in xenograft models.Results: We show that BAY-853474 reduces the tumor burden in U87MG glioblastoma, NCI-H1993 nonsmall cell lung cancer, and HS746T gastric cancer xenograft models. We demonstrate that the dose dependence is reflected by inhibition of MET phosphorylation and that the soluble plasma biomarkers hepatocyte growth factor, vascular endothelial growth factor, and interleukin-8 as well as the MET-ectodomain can be used to monitor the tumor size and response to treatment. Clinical samples, however, show only moderately elevated levels of these biomarker candidates in cancer patients even with MET amplification. We, therefore, established an immunohistochemistry (IHC) protocol to detect MET phosphorylation that is suitable to monitor the effect of BAY-853474 in tumor biopsies.Conclusion: IHC-based analysis of target phosphorylation in tumor biopsies is recommended in addition to testing plasma biomarkers for response monitoring.

ObjectiveLeft ventricular diastolic dysfunction (LVDD) is considered a precursor of diabetic cardiomyopathy, while the metabolic syndrome (MetS) is associated with an increased risk of cardiovascular morbidity and mortality. This study aimed to evaluate the association between LVDD, MetS and glucose metabolism disturbances classifi ed by oral glucose tolerance testing (oGTT).Methods and resultsThe presence of LVDD was evaluated in 166 subjects with normal ejection fraction, 43 (26%) of whom had type 2 diabetes at inclusion. In subjects without diabetes, an oGTT was performed. The MetS was diagnosed as indentifi ed by the NCEPIII-criteria, while LVDD was verifi ed and graded according to the current guidelines.MetS was diagnosed in 97 (59%) patients, 44% of whom had known diabetes. The prevalence of LVDD was 68% in subjects with MetS vs. 19% in patients without MetS, respectively (P< 0.001). A severe form of LVDD was observed in 34% and 15% of patients with and without MetS, respectively (P= 0.001), whereupon the prevalence of mild and severe diastolic dysfunction increased with the number of MetS criteria (P= 0.001). In the MetS group, early diastolic tissue relaxation velocity (E´) was signifi cantly reduced (6.9 ± 1.8 cm/s vs. 7.7 ± 2.1 cm/s; P= 0.009) and the E/E´ ratio was signifi cantly higher (10.5 ± 3.9 vs. 9.1 ± 3.0 cm/s, P= 0.015) as compared to the group without MetS (n = 69).ConclusionMetS was associated with a higher prevalence and severity of LVDD, whereupon coexisting diabetes aggravates these fi nding. Patients displaying MetS with concomitant LVDD might represent a target population in which appropriate medical care for early heart failure prevention should be initiated

Objective: Besides persisting high pulmonary arterial pressure and increased pulmonary vascular resistance, remodelling of pulmonary tissues and subsequently the right heart are the key pathomechanisms of pulmonary hypertension (PH). Extracellular matrix maintenance in this context plays a central role.Methods: We tested the hypothesis that plasma concentration of matrix metalloproteinase (MMP)-2, tissue inhibitor of matrix metalloproteinases (TIMP)-4 and tenascin C (TNC) might be useful as biomarkers for assessing the severity of PH. Therefore, the concentrations of MMP-2, TIMP-4, TNC and N-terminal b-type natriuretic peptide (NT-proBNP) of 36 PH patients were compared with those of 44 age- and gender-matched healthy volunteers. Additionally, lung function, 6-min walk distance and right heart function were assessed.Results: In PH patients, significantly elevated plasma levels of MMP-2, TIMP-4, TNC and NT-proBNP were detected. In particular, TIMP-4 was significantly increased in patients with higher NYHA classification, and in patients with severe right ventricular hypertrophy.Conclusion: Monitoring of plasma TIMP-4 and to a lesser extent of MMP-2 and TNC levels in PH patients might help to assess the beneficial effects of PH pharmacotherapy on tissue remodelling.

A mathematical model of ascending Henle limb (AHL) epithelium has been fashioned using kinetic representations of Na+-K+-2Cl−cotransporter (NKCC2), KCC4, and type 3 Na+/H+exchanger (NHE3), with transporter densities selected to yield the reabsorptive Na+flux expected for rat tubules in vivo. Of necessity, this model predicts fluxes that are higher than those measured in vitro. The kinetics of the NKCC and KCC are such that Na+reabsorption by the model tubule is responsive to variation in luminal NaCl concentration over the range of 30 to 130 mM, with only minor changes in cell volume. Peritubular KCC accounts for about half the reabsorptive Cl−flux, with the remainder via peritubular Cl−channels. Transcellular Na+flux is turned off by increasing peritubular KCl, which produces increased cytosolic Cl−and thus inhibits NKCC2 transport. In the presence of physiological concentrations of ammonia, there is a large acid challenge to the cell, due primarily to NH4+entry via NKCC2, with diffusive NH3exit to both lumen and peritubular solutions. When NHE3 density is adjusted to compensate this acid challenge, the model predicts luminal membrane proton secretion that is greater than the HCO3−-reabsorptive fluxes measured in vitro. The model also predicts luminal membrane ammonia cycling, with uptake via NKCC2 or K+channel, and secretion either as NH4+by NHE3 or as diffusive NH3flux in parallel with a secreted proton. If such luminal ammonia cycling occurs in vivo, it could act in concert with luminal K+cycling to facilitate AHL Na+reabsorption via NKCC2. With physiological ammonia, peritubular KCl also blunts NHE3 activity by inhibiting NH4+uptake on the Na-K-ATPase, and alkalinizing the cell.

The diagnosis and management of hyponatremia can be intimidating, for both trainees and clinicians alike. We present five clinical scenarios of patients with hyponatremia. These discussions reinforce concepts reviewed elsewhere in this issue of Seminars in Nephrology and/or emphasize specific causes and management issues.

The matrix metalloproteinases (MMPs) and their endogenous inhibitors, the tissue inhibitors of metalloproteinases (TIMPs) play a key role in extracellular matrix maintenance and are altered in the failing heart, both in experimental models and in chronic end-stage heart failure in humans. As the common diagnostic markers of heart failure, atrial natriuretic peptide (ANP) and B-type natriuretic peptide (BNP) primarily reflect increased pressure loading, determination of soluble, heart-derived MMPs and TIMPs in plasma, as well as the determination of the emerging fibrosis marker osteopontin (OPN) might be valuable tools for detecting heart fibrosis. In this study the effect of spironolactone treatment on plasma MMP-2, TIMP-1 and OPN levels was assessed in a heart failure animal model. Unilaterally nephrectomized Sprague Dawley rats received subcutaneous injection of 100 mg deoxycorticosterone acetate (DOCA) once a week and 1% (w/v) NaCl in drinking water. Blood pressure was monitored weekly and blood samples were collected after 1, 2 and 4 weeks. After 6 weeks, left ventricular contractility (LVC) and heart weight-to-body weight ratio (HW/BW) were assessed. DOCA treatment increased plasma MMP-2, TIMP-1 and OPN concentrations. Alterations of plasma marker levels were correlated with changes of HW/BW and paralleled impaired LVC. Furthermore, beneficial effects of spironolactone treatment were observed. In DOCA-salt hypertensive rats, plasma concentrations of MMP-2, TIMP-1 and OPN reflected heart failure associated with haemodynamic, functional and morphological changes. Based on these findings, it appears reasonable to use plasma markers of fibrosis to monitor the development of heart failure.

Abstract: Chloride/formate exchange, in parallel with Na+/H+ exchange and nonionic diffusion of H2CO2, has been proposed as a mechanism of electroneutral transcellular Cl− reabsorption by the proximal tubule. However, the measured brush border H2CO2 permeability of the rat proximal tubule is at least an order of magnitude too low to support sufficient H2CO2 recycling. To investigate the possibility that an unstirred layer within the brush border might depress the measured H2CO2 permeability, we constructed a mathematical model of a villous membrane. Axial fluxes along villous and intervillous spaces were specified by Nernst-Planck diffusion equations. Model parameters were set to achieve agreement with ion and water fluxes measured in the rat proximal tubule. The equations were solved numerically to generate steady-state concentration profiles in the villous and intervillous spaces. An apparent brush border H2CO2 permeability was determined by perturbing luminal [H2CO2] and calculating the change in H2CO2 flux. Overall, the ratio of apparent brush border H2CO2 permeability to cell membrane H2CO2 permeability was greater than 90%. Contributing to the small decrease in apparent permeability are finite diffusion coefficients, folding of the membrane, and acidification of the luminal solution. An approximate analysis of this system shows the critical parameters of brush border formate transport to be the actual membrane H2CO2 permeability, and the diffusion coefficients of HCO 3− and HCO 3− . Nevertheless, decreasing the diffusion coefficients by one order of magnitude failed to depress apparent brush border H2CO2 permeability by more than an additional 25%. We conclude that although permeability is systematically underestimated across a villous membrane, unstirred layer effects in the brush border are still too small to resolve the discrepancy between the measured value of H2CO2 permeability and the value needed to allow recycling.

Compared with heart failure (HF) care 20 to 30 years ago, there has been tremendous advancement in therapy for ambulatory HF with reduced ejection fraction with the use of agents that block maladaptive neurohormonal pathways. However, during the past decade, with few notable exceptions, the frequency of successful drug development programs has fallen as most novel therapies have failed to offer incremental benefit or raised safety concerns (ie, hypotension). Moreover, no therapy has been approved specifically for HF with preserved ejection fraction or for worsening chronic HF (including acutely decompensated HF). Across the spectrum of HF, preliminary results from many phase II trials have been promising but are frequently followed by unsuccessful phase III studies, highlighting a disconnect in the translational process between basic science discovery, early drug development, and definitive clinical testing in pivotal trials. A major unmet need in HF drug development is the ability to identify homogeneous subsets of patients whose underlying disease is driven by a specific mechanism that can be targeted using a new therapeutic agent. Drug development strategies should increasingly consider therapies that facilitate reverse remodeling by directly targeting the heart itself rather than strictly focusing on agents that unload the heart or target systemic neurohormones. Advancements in cardiac imaging may allow for more focused and direct assessment of drug effects on the heart early in the drug development process. To better understand and address the array of challenges facing current HF drug development, so that future efforts may have a better chance for success, the Food and Drug Administration facilitated a meeting on February 17, 2015, which was attended by clinicians, researchers, regulators, and industry representatives. The following discussion summarizes the key takeaway dialogue from this meeting.

BACKGROUND: Seasonal outbreaks of winter respiratory viruses are responsible for increases in morbidity and mortality in the community. Previous studies have used hospitalizations, intensive care unit and emergency department (ED) visits as indicators of seasonal influenza incidence.OBJECTIVES: To evaluate whether ED visits can be used as a proxy to detect respiratory viral disease outbreaks, as measured by laboratory confirmation.METHODS: An Emergency Department Syndromic Surveillance system was used to collect ED chief complaints in Eastern Ontario from 2006 to 2010. Comparable laboratory-confirmed cases of respiratory viral infections were collected from the Public Health Ontario Laboratory in Kingston, Ontario. Correlations between ED visits and laboratory-confirmed cases were calculated.RESULTS: Laboratory-confirmed cases of selected respiratory viruses were significantly correlated with ED visits for respiratory and fever/influenza-like illness. In particular, respiratory syncytial virus (Spearman’s rho = 0.593), rhinovirus (Spearman’s rho = 0.280), influenza A (Spearman’s rho = 0.528), influenza B (Spearman’s rho = 0.426) and pH1N1 (Spearman’s rho = 0.470) increased laboratory test levels were correlated with increased volume of ED visits across a number of age demographics. For the entire study population and all studied viruses, the Spearman’s rho was 0.702, suggesting a strong correlation with ED visits. Laboratory-confirmed cases lagged in reporting by between one and two weeks for influenza A and pH1N1 compared with ED visit volume.CONCLUSION: These findings support the use of an Emergency Department Syndromic Surveillance system to track the incidence of respiratory viral disease in the community. These methods are efficient and can be performed using automated electronic data entry versus the inherent delays in the primary care sentinel surveillance system, and can aid the timely implementation of preventive and preparatory health interventions.