Comparison of Host Gene Expression Profiles in Spleen Tissues of Genetically Susceptible and Resistant Mice during ECTV Infection

Ectromelia virus (ECTV), the causative agent of mousepox, has emerged as a valuable model for investigating the host-Orthopoxvirus relationship as it relates to pathogenesis and the immune response. ECTV is a mouse-specific virus and causes high mortality in susceptible mice strains, including BALB/c and C3H, whereas C57BL/6 and 129 strains are resistant to the disease. To understand the host genetic factors in different mouse strains during the ECTV infection, we carried out a microarray analysis of spleen tissues derived from BALB/c and C57BL/6 mice, respectively, at 3 and 10 days after ECTV infection. Differential Expression of Genes (DEGs) analyses revealed distinct differences in the gene profiles of susceptible and resistant mice. The susceptible BALB/c mice generated more DEGs than the resistant C57BL/6 mice. Additionally, gene ontology and KEGG pathway analysis showed the DEGs of susceptible mice were involved in innate immunity, apoptosis, metabolism, and cancer-related pathways, while the DEGs of resistant mice were largely involved in MAPK signaling and leukocyte transendothelial migration. Furthermore, the BALB/c mice showed a strong induction of interferon-induced genes, which, however, were weaker in the C57BL/6 mice. Collectively, the differential transcriptome profiles of susceptible and resistant mouse strains with ECTV infection will be crucial for further uncovering the molecular mechanisms of the host-Orthopoxvirus interaction.

http://ift.tt/2z7gQCO

3D Carbon Scaffolds for Neural Stem Cell Culture and Magnetic Resonance Imaging

Abstract

3D glassy carbon structures with percolated macropores are obtained by pyrolysis of chemically synthesized cryogels featuring tunable porosity. These batch-fabricated structures are used as scaffolds for culturing neural stem cells (NSCs) and are characterized by magnetic resonance imaging (MRI). With the aid of MRI, the successful cultivation of NSCs on a glassy carbon surface and the precise 3D locations of these cell clusters within the opaque scaffold are demonstrated. MRI also yields pore morphology and porosity analyses, pre- and post-pyrolysis. This integrated approach yields a complete 3D dataset of the NSC network, which enables the visual inspection of the morphological details of individual cell clusters without disturbing them or destroying the scaffold. Reported experimental methodology is expected to have an impact on studies designed to understand the mechanism of neurodegenerative disease (ND) development, and can serve as a protocol for the culture of various other types of cells that display compatibility with glassy carbon surfaces.

Neural stem cells cultured on 3D glassy carbon scaffolds are noninvasively characterized by high-resolution magnetic resonance imaging (MRI). Scaffolds are obtained from pyrolysis of porous cryogels, opening the potential for tailoring the scaffold morphology as dictated by the cellular microenvironment. MRI data are further processed to yield spectacular videos and reconstructed images where individual cell clusters can be identified.

http://ift.tt/2Bp5ShJ

High circulating miR-18a, miR-20a, and miR-92a expression correlates with poor prognosis in patients with non-small cell lung cancer

Abstract

The purpose of this study was to assess the predictive value of angiogenic miRNAs for disease-free survival (DFS) and overall survival (OS) of patients with non-small cell lung cancer (NSCLC). In total, 196 patients with NSCLC (tumor lymph nodes metastasis (TNM) stage I–III) were enrolled and peripheral blood samples were collected. Total RNA was extracted from blood samples, and the relative expression levels of candidate miRNAs were evaluated by real time-polymerase chain reaction (RT-PCR). The median follow-up period was 56.7 months, and the final follow-up date was in August 2016. The median DFS of all patients was 30.0 (14.0–49.0) months, whereas the median OS was 41.5 (23.0–58.0) months. Furthermore, the 5-year DFS and OS rates were 11.3% and 32.3%, respectively. Kaplan–Meier (K–M) curves showed that high plasma miR-18a (P < 0.001), miR-20a (P < 0.001), miR-92a (P < 0.001), miR-126 (P < 0.001), miR-210 (P = 0.003), and miR-19a (P = 0.027) expressions levels correlated with a worse DFS. Moreover, patients with high plasma miR-18a, miR-20a, miR-92a, miR-210, and miR-126 expression levels had a shorter OS than patients with low expression levels of these miRNAs (all P <= 0.001). Furthermore, multivariate Cox regression analyses revealed that high plasma expression levels of miR-18a, miR-20a, and miR-92a as well as lymphatic node metastasis (all P < 0.001) were independent risk factors for both DFS and OS in patients with NSCLC. Thus, the circulating miR-18a, miR-20a, and miR-92a levels may serve as novel and promising prognostic biomarkers in patients with NSCLC.

Circulating miR-18a, miR-20a, and miR-92a levels may serve as novel and promising prognostic biomarkers in patients with non-small cell lung cancer.

http://ift.tt/2kRwP2N

Intrapulmonary Pharmacokinetics of Levonadifloxacin Following Oral Administration of Alalevonadifloxacin to Healthy Adult Subjects [PublishAheadOfPrint]

Alalevonadifloxacin (WCK 2349) is a novel L-alanine ester prodrug of levonadifloxacin being developed as an oral fluoroquinolone antibiotic. The primary objective of this study was to determine and compare plasma, epithelial lining fluid (ELF), and alveolar macrophage (AM) concentrations of levonadifloxacin following oral administration of alalevonadifloxacin in healthy adult subjects. Levonadifloxacin concentrations in plasma, ELF, and AM of 30 healthy subjects were measured by LC-MS/MS following oral dosing of alalevonadifloxacin (1000 mg twice daily for 5 days). Six subjects were assigned to each bronchoalveolar lavage sampling time at 2, 4, 6, 8 or 12 hours after the ninth oral dose. Noncompartmental pharmacokinetic (PK) parameters were determined from serial total plasma concentrations collected over a 12-hour interval following the first and ninth oral doses. Penetration ratios were calculated from the AUC_0—12 for plasma, ELF, and AM using mean (and median) concentrations at each BAL sampling times. Unbound plasma concentrations (plasma protein binding ~85%) were used to determine site-to-plasma penetration ratios. Plasma PK parameter values for levonadifloxacin were similar after the first and ninth doses. The respective AUC_0-12 values based on mean ELF and AM concentrations were 172.6 and 35.3 mg·h/L, respectively. The penetration ratios for ELF and AM to unbound plasma levonadifloxacin concentrations were 7.66 and 1.58, respectively. Similar penetration ratios were observed with median concentrations. The observed plasma, ELF, and AM concentrations of levonadifloxacin support further studies of alalevonadifloxacin for treatment of lower respiratory tract bacterial infections caused by susceptible pathogens.

http://ift.tt/2kREFte

Bayesian Estimation of Tobramycin Exposure in Patients with Cystic Fibrosis -- an update [PublishAheadOfPrint]

Recently, a comparison of estimated tobramycin exposure (AUC_0-24) using Bayesian forecasting (BF) versus true exposure demonstrated accuracy in patients with cystic fibrosis. Theoretically, when using BF methods the predictive performance towards estimating an individual's exposure should improve with additional observations; however, there is limited applicable evidence against true exposure. We demonstrate that with additional data from previous dosing intervals, predicted performance to estimate exposure improves.

http://ift.tt/2kv7ufH

Reversal of azole resistance in Candida albicans by sulfa antibacterial drugs [PublishAheadOfPrint]

Invasive candidiasis presents an emerging global public health challenge due to the emergence of resistance to the frontline treatment options, such as fluconazole. Hence, the identification of other compounds capable of pairing with fluconazole and averting azole-resistance would potentially prolong the clinical utility of this important group. In an effort to repurpose drugs in the field of antifungal drug discovery, we explored sulfa antibacterial drugs for the purpose of reverting azole resistance in Candida. In this study, we assembled and investigated a library of 21 sulfa antibacterial drugs for their ability to restore fluconazole sensitivity in Candida albicans. Surprisingly, the majority of assayed sulfa drugs (15) were found to exhibit synergistic relationships with fluconazole by checkerboard assay with FIC values ranging from < 0.0312 to 0.25. Remarkably, five sulfa drugs, were able to revert azole resistance in a clinically achievable range. The structure-activity-relationships (SAR) of the amino benzene sulfonamide scaffold as antifungal agents were studied. We also identified the possible mechanism of the synergistic interaction of sulfa antibacterial drugs with azole antifungal drugs. Furthermore, the ability of sulfa antibacterial drugs to inhibit Candida biofilm by 40% in vitro was confirmed. In addition, effect of sulfa-fluconazole combination on Candida growth kinetics and efflux machinery was explored. Finally, using a Caenorhabditis elegans infection model, we demonstrated that the sulfa-fluconazole combination does possess potent antifungal activity in vivo reducing Candida in infected worms by ~50% compared to the control.

http://ift.tt/2kQzCt1

Activity of Ceftolozane-Tazobactam Tested against Pseudomonas aeruginosa and Enterobacteriaceae Isolates Collected from Respiratory Tract Specimens of Hospitalized Patients in the United States During 2013 to 2015 [PublishAheadOfPrint]

The activity of ceftolozane-tazobactam and comparator agents was evaluated against organisms deemed to be the cause of pneumonia among patients hospitalized in the United States (US) during 2013 to 2015. Isolates included 1,576 Pseudomonas aeruginosa and 2,362 Enterobacteriaceae susceptibility tested using reference broth microdilution methods. Ceftolozane-tazobactam, cefepime, ceftazidime, meropenem, and piperacillin-tazobactam inhibited 96.3%, 84.8%, 83.5%, 80.0%, and 78.6%, respectively, of the P. aeruginosa isolates. Ceftolozane-tazobactam inhibited 77.5-85.1% of isolates nonsusceptible to antipseudomonal β-lactams and 86.6% and 71.0% of the 372 (23.6% overall) multidrug- and 155 (9.8%) extensively drug-resistant isolates tested. The activity of this combination was greater than other β-lactams evaluated against all P. aeruginosa groups across all US census divisions. Ceftolozane-tazobactam was active against 90.6% of the Enterobacteriaceae, being only less active than meropenem (95.6% susceptible) among the β-lactams evaluated. Against 145 Escherichia coli and Klebsiella pneumoniae isolates carrying extended-spectrum β-lactamase (ESBLs) encoding genes without carbapenemases, ceftolozane-tazobactam inhibited 82.8% of these isolates and was more active than cefepime and piperacillin-tazobactam (15.2% and 74.3% susceptible, respectively). ESBL genes included in this analysis were mainly bla_CTX-M-15-like (89 isolates) and bla_CTX-M-14-like (22), but also bla_SHV (31) and bla_TEM (3). Ceftolozane-tazobactam also displayed activity (84.6% susceptible) against 13 isolates harboring acquired AmpC genes. All β-lactams displayed limited activity against bla_KPC-carrying isolates. Ceftolozane-tazobactam was the most active β-lactam tested against P. aeruginosa isolates from isolates that were the probable cause of pneumonia and displayed in vitro activity against Enterobacteriaceae, including isolates resistant to cephalosporins that carry ESBL genes.

http://ift.tt/2kv7qwt

Parasite-mediated degradation of synthetic ozonide antimalarials impacts in vitro antimalarial activity [PublishAheadOfPrint]

The peroxide bond of the artemisinins inspired the development of a class of fully synthetic 1,2,4-trioxolane-based antimalarials, collectively known as the ozonides. Similar to the artemisinins, heme-mediated degradation of the ozonides generates highly reactive radical species that are thought to mediate parasite killing by damaging critical parasite biomolecules. We examined the relationship between parasite dependent degradation and antimalarial activity for two ozonides, OZ277 (arterolane) and OZ439 (artefenomel), using a combination of in vitro drug stability and pulsed-exposure activity assays. Our results showed that drug degradation is parasite stage dependent and positively correlates with parasite load. Increasing trophozoite stage parasitemia leads to substantially higher rates of degradation for both OZ277 and OZ439 and this is associated with a reduction in in vitro antimalarial activity. Under conditions of very high parasitemia (~90%), OZ277 and OZ439 were rapidly degraded and completely devoid of activity in trophozoite stage parasite cultures exposed to a 3 h drug pulse. This work highlights the impact of increasing parasite load on ozonide stability and in vitro antimalarial activity and should be considered when investigating the antimalarial mode of action of the ozonide antimalarials under conditions of high parasitemia.

http://ift.tt/2kRDYzT

Effect of genetic variation of NAT2 on isoniazid, SLCO1B1, and CES2 on rifampin pharmacokinetics in Ghanaian children with tuberculosis [PublishAheadOfPrint]

Isoniazid and rifampin are essential components of first-line antituberculosis (anti-TB) therapy. Understanding the relationship between genetic factors and the pharmacokinetics of these drugs could be useful in optimizing treatment outcomes, but this is understudied in children. We investigated the relationship between N-acetyltransferase type 2 (NAT2) genotypes and isoniazid pharmacokinetics, as well as that between the solute carrier organic anion transporter family member 1B1 (encoded by SLCO1B1) and carboxylesterase 2 (CES2) single nucleotide polymorphisms (SNPs) and rifampin pharmacokinetics in Ghanaian children. Blood samples were collected at times 0, 1, 2, 4, and 8 hours post-dose in children with tuberculosis (TB) on standard first-line therapy for at least 4 weeks. Isoniazid and rifampin concentrations were determined by validated LC/MS/MS method and pharmacokinetic parameters calculated using noncompartmental analysis. Genotyping of NAT2, SLCO1B1 and CES2 SNPs were performed using validated TaqMan® genotyping assays. Kruskal—Wallis test was used to compare pharmacokinetic parameters among the three genotypic groups followed by Wilcoxon Rank Sum test for pairwise group comparisons. Genotype status inferred by the NAT2 4-SNP and 7-SNP genotyping panel identified children with slow acetylator phenotype but not the rapid. For rifampin, only the rare SLCO1B1*1b homozygous variant was associated with rifampin pharmacokinetics. Our findings suggest that NAT2 and SCLCO1B1*1b genotyping may have minimal clinical utility in dosing decisions at the population level in Ghanaian children, but it could be useful at the individual level or in populations that have high frequency of implicated genotypes. Further studies in other populations are warranted.

http://ift.tt/2kRDdae

Pharmacokinetic/pharmacodynamic (PK/PD) Determinants of Vancomycin Efficacy in Enterococcal Bacteremia [PublishAheadOfPrint]

Background. While pharmacokinetic-pharmacodynamic targets for vancomycin therapy are recognized for invasive methicillin-resistant Staphylococcus aureus (MRSA) infections, scant data are available to guide therapy for other gram positive infections.

Methods. A retrospective single-centre cohort of patients with Enterococcus spp. bacteremia hospitalized between 1^st January 2009 and 31^st May 2015 were studied. Average vancomycin AUC_0-24hrs was computed using a Bayesian approach. MIC was determined by gradient diffusion (E-test, bioMerieux) and the average AUC_0-24hrs/MIC over the initial 72 hours of therapy was calculated. We assessed 30-day all-cause mortality as the primary outcome. Classification and regression tree analysis (CART) was used to identify vancomycin AUC_0-24hrs/MIC associated with 30-day mortality.

Results. Fifty-seven patients with enterococcal bacteremia (32 E. faecium, 21 E. faecalis, 4 other Enteroccocus spp.) were studied. The median vancomycin MIC was 0.75 mg/L (range 0.38-3 mg/L). All-cause 30-day mortality occurred in 10 out of 57 patients (17.5%). A CART-derived vancomycin AUC/MIC_Etest of ≥389 was associated with reduced mortality (P= 0.017); failure to achieve this independently predicted 30-day mortality [OR 5.65 (95% CI 1.18-27.03), P= 0.03].

Conclusion. We found that a vancomycin AUC/MIC_Etest (≥389), achieved within 72 hours, was associated with reduced mortality. Larger, prospective studies are warranted to verify the vancomycin pharmacodynamic targets associated with maximal clinical outcomes and acceptable safety.

http://ift.tt/2kuFcSb

Antimicrobial Activity of Dalbavancin Tested against Staphylococcus aureus with Decreased Susceptibility to Glycopeptides, Daptomycin, and/or Linezolid from United States Medical Centers [PublishAheadOfPrint]

Dalbavancin activity was assessed against a large collection of Staphylococcus aureus (n=59,903), including isolates with decreased susceptibility to vancomycin (MIC ≥2 mg/L; n=1,141), daptomycin (MIC ≥2 mg/L; n=48), telavancin (MIC ≥0.12 mg/L; n=52), teicoplanin (MIC ≥4 mg/L; n=143), and/or linezolid (MIC ≥8 mg/L; n=25). Dalbavancin displayed susceptibility rates ranging from 90.4% (isolates with telavancin MIC ≥0.12 mg/L) to 100.0% (linezolid-resistant isolates), and lower MIC values than the comparators against these resistant subsets.

http://ift.tt/2ktTiUb

Pyrazinamide resistance among multidrug-resistant Mycobacterium tuberculosis clinical isolates in Myanmar [PublishAheadOfPrint]

The emergence and spread of multidrug-resistant tuberculosis (MDR-TB) have been a serious threat to control TB....

http://ift.tt/2kRcHxy

Aminoarabinosylation of lipid A is critical for the development of colistin resistance in Pseudomonas aeruginosa [PublishAheadOfPrint]

Lipid A aminoarabinosylation is invariably associated with colistin resistance in Pseudomonas aeruginosa; however, the existence of alternative, aminoarabinosylation-independent colistin resistance mechanisms in this bacterium remained elusive. By combining reverse genetics with experimental evolution assays we demonstrate that a functional lipid A aminoarabinosylation pathway is critical for acquisition of colistin resistance in reference and clinical P. aeruginosa isolates. This highlights lipid A aminoarabinosylation as a promising target for the design of colistin adjuvants against P. aeruginosa.

http://ift.tt/2ktTbrJ

Impact of Real-Time Therapeutic Drug Monitoring on the Prescription of Antibiotics in Burn Patients Requiring Admission to the Intensive Care Unit [PublishAheadOfPrint]

Background: As pharmacokinetics after burn trauma are difficult to predict, we conducted a 3-year prospective, monocentric, randomized controlled trial to determine the extent of under and overdosing of antibiotics and further evaluate the impact of systematic therapeutic drug monitoring (TDM) with same day real-time dose adaptation to reach and maintain antibiotic concentrations within therapeutic range.

Methods: Forty-five consecutive burn patients treated with antibiotics were prospectively screened. Forty fulfilled inclusion criteria; after one refusal and one withdraw consent, 19 were randomly assigned to an intervention group (real-time antibiotic concentration determination and subsequent adaptations), and 19 to a standard-of-care group (antibiotic administration at physician's discretion without real-time TDM).

Results: Seventy-three infectious episodes were analyzed. Before intervention, only 46/82 (56%) initial trough concentrations fell within the range. There was no difference between groups in initial trough concentrations (adjusted HR=1.39 [95%CI: 0.81-2.39], p=0.227) or time to reach the target. However, thanks to real-time dose adjustments, trough concentrations of the intervention group remained more within the predefined range (57/77 [74.0%] vs. 48/85 [56.5%], adjusted OR=2.34 [95%CI: 1.17-4.81], p=0.018); more days were spent within the target range (193 days/297 days on antibiotics [65.0%] vs. 171/311 [55.0%], adjusted OR=1.64 [95%CI: 1.16-2.32], p=0.005); and fewer results were below target trough concentrations (25/118 [21.2%] vs. 44/126 [34.9%], adjusted OR=0.47 [95%CI: 0.26-0.87], p=0.015). No difference in infection outcomes was observed between study groups.

Conclusions: Systematic TDM with same day real-time dose adaptation was effective in reaching and maintaining therapeutic antibiotic concentrations in infected burn patients, which prevented both over- and under-dosing. A larger multicentric study is needed to further evaluate the impact of this strategy on infection outcomes and the emergence of antibiotic resistance during long-term burn treatment.

This study was registered with the ClinicalTrials.gov platform on September 27^th 2013.

Trial Registration: NCT01965340.

http://ift.tt/2kRVgNu

Effects of Renal Impairment and Hemodialysis on the Pharmacokinetics and Safety of the Glecaprevir and Pibrentasvir Combination in HCV-Negative Subjects [PublishAheadOfPrint]

Hepatitis C virus (HCV) infection is an independent risk factor for developing chronic renal impairment and end-stage renal disease. Limited treatment options are available for HCV genotypes 2, 3, 5, and 6 infection in patients with eGFR <30 mL/min. Glecaprevir and pibrentasvir are active against all six major HCV genotypes, primarily excreted in the bile, and have minimal renal elimination. Therefore, combined treatment with these direct-acting antivirals may be useful for patients with HCV infection and chronic kidney disease. A Phase 1, multicenter, open-label study evaluated the effects of renal impairment on the pharmacokinetics and safety of glecaprevir/pibrentasvir. In sub-study 1, 38 subjects with chronic kidney disease Stages 2 to 5 not on dialysis or with normal renal function received single doses of the glecaprevir 300 mg and pibrentasvir 120 mg combination. In sub-study 2, 8 subjects requiring hemodialysis received single doses of the glecaprevir 300 mg and pibrentasvir 120 mg combination under dialysis and non-dialysis conditions. Regression analyses demonstrated increased glecaprevir and pibrentasvir plasma exposure, as determined by area under the curve, with decreasing renal function up to 56% and 46%, respectively, in subjects with eGFR <15 mL/min/1.73 m². In dialysis-dependent subjects, glecaprevir and pibrentasvir exposures were similar (≤ 18% difference) when study drugs were administered before hemodialysis or on a non-dialysis day. Adverse events were mostly mild, the most common being self-limited fatigue (3 subjects). The study findings support clinical evaluation of glecaprevir/pibrentasvir without dose adjustment in HCV-infected subjects with renal impairment.

This study is registered at ClinicalTrials.gov: NCT 02442258.

http://ift.tt/2kvoMsX

Depot subcutaneous injection with chalcone CH8-loaded PLGA microspheres aiming at a single-dose treatment of cutaneous leishmaniasis [PublishAheadOfPrint]

Conventional chemotherapy of cutaneous leishmaniasis (CL) is based on multiple parenteral or intralesional injections with systemically toxic drugs. Aiming at a single-dose localized therapy, biodegradable PLGA (poly-(lactide-co-glycolide) microparticles loaded with 7.8% of an antileishmanial nitrochalcone named CH8 (CH8/PLGA) were constructed to promote sustained subcutaneous release. In vitro, murine macrophages avidly phagocytosed CH8/PLGA smaller than 6μm without triggering oxidative mechanisms. Upon 48-hour incubation, both CH8 and CH8/PLGA were 40 times more toxic to intracellular Leishmania amazonensis than to macrophages. In vivo, BALB/c were given one or three subcutaneous injections in the infected ear with 1.2mg/kg of CH8 in free or CH8/PLGA forms, while controls received three CH8-equivalent doses of naked PLGA microparticles or Glucantime. While a single injection with CH8/PLGA reduced the parasite loads by 91%, triple injections with free CH8 or CH8/PLGA caused 80% and 97% reduction, respectively, in relation to saline controls. Glucantime treatment was the least effective (only 36% reduction) and the most toxic as seen by elevated alanine aminotransferase serum levels. Together, those findings show that CH8/PLGA microparticles can be effectively and safely used for single-dose treatment of CL.

http://ift.tt/2kRq8NY

Successive emergence of ceftazidime-avibactam resistance through distinct genomic adaptations in blaKPC-2-harboring Klebsiella pneumoniae ST307 [PublishAheadOfPrint]

Ceftazidime-avibactam (CAZ/AVI) is a promising novel treatment for carbapenem-resistant Enterobacteriaceae (CRE). Despite improved treatment outcomes compared to aminoglycoside- and colistin-based regimens, rapid evolution of CAZ/AVI resistance during treatment has previously been reported in Klebsiella pneumoniae ST258 bla_KPC-3 harboring isolates. Here, we report the step-wise evolution and isolation of two phenotypically distinct CAZ/AVI resistant Klebsiella pneumoniae phenotypes from a patient with pancreatitis. All susceptible (n=3) and resistant (n=5) isolates were of the ST307 clonal background, a rapidly emerging clone. Taking advantage of short-read Illumina and long-read Oxford Nanopore sequencing and full-length assembly of the core chromosome and plasmids, we demonstrate that CAZ/AVI resistance first occurred through a 532G->T bla_KPC-2 point mutation in bla_KPC-2 (D179Y protein substitution) following only 12 days of CAZ/AVI exposure. While subsequent isolates exhibited substantially decreased meropenem (MEM) MICs (≤ 2 μg/mL), later cultures demonstrated a second CAZ/AVI resistance phenotype with a lower CAZ/AVI MIC (12 μg/ml) but also MEM resistance (MIC > 128 μg/ml). These CAZ/AVI and MEM-resistant isolates showed evidence of multiple genomic adaptations, mainly through insertions and deletions. This included amplification and transposition of wild-type bla_KPC-2 into a novel plasmid, IS1 insertion upstream of ompK36 and disruption of the rfb gene locus in these isolates. Our findings illustrate the potential of CAZ/AVI resistance to emerge in non-K. pneumoniae ST258 clonal backgrounds and alternative bla_KPC variants. These results raise concerns about strong selective pressures incurred by novel carbapenemase inhibitors such as avibactam on isolates previously considered invulnerable to CAZ/AVI resistance. There is an urgent need to further characterize non-KPC mediated modes of carbapenem resistance and the intrinsic bacterial factors that facilitate rapid emergence of resistance during treatment.

Importance Few treatment options are available for carbapenem-resistant Enterobacteriaceae infections, leading to high morbidity and mortality. Novel beta-lactam/beta-lactamase inhibitor combinations such as ceftazidime/avibactam (CAZ/AVI) promise better clinical outcomes. In K. pneumoniae ST258 CAZ/AVI resistance due to bla_KPC-3 mutations following in vivo exposure has been reported. Our report demonstrates that diverse mechanisms of CAZ/AVI resistance can develop in K. pneumoniae ST307, an emerging multi-drug resistant clone. We studied sequential K. pneumoniae ST307 isolates that rapidly developed CAZ/AVI resistance during treatment. We initially noted a 532G->T point mutation in bla_KPC-2 leading to a D179Y protein substitution, associated with decreased carbapenem MIC. After cessation of CAZ/AVI a novel phenotype emerged, characterized by both CAZ/AVI and high-level meropenem resistance. Using short- and long-read sequencing, we detected a transposed copy of bla_KPC-2 and additional transposon insertions into the bacterial chromosome. Our findings highlight the vulnerability of novel carbapenemase inhibitors to resistance and demonstrate that numerous resistance mechanisms may evolve during antibiotic exposure.

http://ift.tt/2kvcjW5

Characterization of KPC-encoding plasmids from Enterobacteriaceae isolated in a Czech hospital [PublishAheadOfPrint]

Ten Enterobacteriaceae, collected in a Czech hospital, carried bla_KPC-positive plasmids of different sizes (~30, ~45, and ~80 kb). Sequencing revealed three types of plasmids (A to C) with Tn4401a. Type A plasmids comprised an IncR backbone and a KPC-2-encoding multidrug resistant (MDR) region. Type B were derivatives of type A plasmids carrying an IncN3-like segment, while type C were IncP6 plasmids sharing the same KPC-2-encoding MDR region with type A and B plasmids.

http://ift.tt/2kUW3xg

Prediction of fluoroquinolone susceptibility directly from whole genome sequence data using liquid chromatography-tandem mass spectrometry to identify mutant genotypes. [PublishAheadOfPrint]

Fluoroquinolone resistance in Gram-negative bacteria is multifactorial, involving target site mutations, reductions in fluoroquinolone entry due to reduced porin production, increased fluoroquinolone efflux, enzymes that modify fluoroquinolones, and Qnr, a DNA mimic that protects the drug target from fluoroquinolone binding. Here we report a comprehensive analysis using transformation and in vitro mutant selection, of the relative importance of each of these mechanisms in fluoroquinolone non-susceptibility, using Klebsiella pneumoniae as a model system. Our improved biological understanding was then used to generate 47 rules that can predict fluoroquinolone susceptibility in K. pneumoniae clinical isolates. Key to the success of this predictive process was the use of liquid chromatography tandem mass spectrometry to measure the abundance of proteins in extracts of cultured bacteria, identifying which sequence variants seen in the whole genome sequence data were functionally important in the context of fluoroquinolone susceptibility.

http://ift.tt/2kvcbG5

Nitric oxide-mediated induction of dispersal in Pseudomonas aeruginosa biofilms is inhibited by flavohemoglobin production and is enhanced by imidazole [PublishAheadOfPrint]

The biological signal molecule nitric oxide (NO) was found to induce biofilm dispersal across a range of bacterial species, which led to its consideration for therapeutic strategies to treat biofilms and biofilm-related infections. However, biofilms are often not completely dispersed after exposure to NO. To better understand this phenomenon, we investigated the response of Pseudomonas aeruginosa biofilm cells to successive NO treatments. When biofilms were first pre-treated with a low, non-effective dose of NO, a second dose of the signal molecule, at a concentration usually capable of inducing dispersal, did not have any effect. Amperometric analysis revealed that pre-treated P. aeruginosa cells had enhanced NO scavenging activity and this effect was associated with the production of the flavohemoglobin Fhp. Further, qRT-PCR analysis showed that fhp expression increased by over 100-fold in NO pre-treated biofilms compared to untreated biofilms. Biofilms of mutant strains harboring deletions in fhp or fhpR, encoding a NO-responsive regulator of fhp, were not affected in their dispersal response after the initial pre-treatment with NO. Overall, these results suggest that FhpR can sense NO to trigger production of the flavohemoglobin Fhp and inhibit subsequent dispersal responses to NO. Finally, the addition of imidazole, which can inhibit the NO dioxygenase activity of flavohemoglobin, attenuated the prevention of dispersal after NO pre-treatment, and improved the dispersal response in older, starved biofilms. This study clarifies the underlying mechanisms of impaired dispersal induced by repeated NO treatments and offers new perspective for improving the use of NO in biofilm control strategies.

http://ift.tt/2kRDaey

ADGRV1 is implicated in myoclonic epilepsy

Summary

Objective

To investigate the significance of variation in ADGRV1 (also known as GPR98, MASS1, and VLGR1), MEF2C, and other genes at the 5q14.3 chromosomal locus in myoclonic epilepsy.

Methods

We studied the epilepsy phenotypes of 4 individuals with 5q14.3 deletion and found that all had myoclonic seizures. We then screened 6 contiguous genes at 5q14.3, MEF2C, CETN3, MBLAC2, POLR3G, LYSMD3, and ADGRV1, in a 95-patient cohort with epilepsy and myoclonic seizures. Of these genes, point mutations in MEF2C cause a phenotype involving seizures and intellectual disability. A role for ADGRV1 in epilepsy has been proposed previously, based on a recessive mutation in the Frings mouse model of audiogenic seizures, as well as a shared homologous region with another epilepsy gene, LGI1.

Results

Six patients from the myoclonic epilepsy cohort had likely pathogenic ultra-rare ADGRV1 variants, and statistical analysis showed that ultra-rare variants were significantly overrepresented when compared to healthy population data from the Genome Aggregation Database. Of the remaining genes, no definite pathogenic variants were identified.

Significance

Our data suggest that the ADGRV1 variation contributes to epilepsy with myoclonic seizures, although the inheritance pattern may be complex in many cases. In patients with 5q14.3 deletion and epilepsy, ADGRV1 haploinsufficiency likely contributes to seizure development. The latter is a shift from current thinking, as MEF2C haploinsufficiency has been considered the main cause of epilepsy in 5q14.3 deletion syndrome. In cases of 5q14.3 deletion and epilepsy, seizures likely occur due to haploinsufficiency of one or both of ADGRV1 and MEF2C.

http://ift.tt/2CPxRna

CTLA-4 polymorphisms are associated with treatment outcomes of patients with multiple myeloma receiving bortezomib-based regimens

Abstract

Single-nucleotide polymorphisms (SNPs) of cytotoxic T lymphocyte antigen-4 (CTLA-4) are important risk factors associated with autoimmune diseases and malignancies. This study explored the association of CTLA-4SNPs with the development of myeloma and evaluated the outcome of patients receiving bortezomib-based regimens in relation to CTLA-4SNPs. Peripheral blood samples from 86 patients with multiple myeloma (MM) and 154 healthy controls were obtained to investigate CTLA4 polymorphisms. Five SNP genotypes of CTLA-4, namely, −1772 (rs733618), −1661 (rs4553808), −318 (rs5742909), CT60 (rs3087243), and +49 (rs231775), were evaluated through TaqMan SNP genotyping assays (Applied Biosystems). Some of the CTLA-4 polymorphisms displayed frequencies that vary among ethnic groups. Kaplan–Meier analysis revealed that patients with rs733618 GG showed a significantly lower disease-free survival (0 vs. 57.4%, P = 0.020) and overall survival (46.3 vs. 83.3%, P = 0.026) than those with GA+AA following bortezomib-based therapy. Multivariate analyses showed that rs733618 GG was a risk factor for OS (HR = 0.012; 95% CI = 0.001–0.199; P = 0.002). The incidence of nonhematologic grade 3/4 adverse events significantly increased in the rs4553808 GG+GA group compared with that in the AA group (P = 0.036). CTLA-4 rs733618 GG reduced the progression-free survival and the overall survival of patients with MM who received bortezomib-based therapy. Information regarding CTLA-4 polymorphisms and haplotypes may be used to improve MM therapy. Future studies must determine the precise effect of CTLA-4 polymorphisms and haplotypes on MM therapy outcomes by using different cohorts with a large number of subjects.

http://ift.tt/2DhZSow

The influence of developmental timing on B cell diversity

Trine A Kristiansen | Stijn Vanhee | Joan Yuan

http://ift.tt/2Bq3s2J

Trial of Contralateral Seventh Cervical Nerve Transfer for Spastic Arm Paralysis

Spastic limb paralysis due to injury to a cerebral hemisphere from stroke, traumatic brain injury, or cerebral palsy is a cause of long-term disability. It is estimated that 30 to 60% of stroke survivors are unable to use their paralyzed hand. The spastic arm posture impairs activities of daily…

http://ift.tt/2BeKnvS

Rewiring to Regain Function in Patients with Spastic Hemiplegia

Spastic hemiplegia results from several relatively common disorders, including stroke, traumatic brain injury, and cerebral palsy. Frequently, upper-limb function is impaired. In this issue of the Journal, Zheng et al. report a new approach to the treatment of this condition: the use of a…

http://ift.tt/2BU5KpY

MUC1-C Induces PD-L1 and Immune Evasion in Triple-Negative Breast Cancer

The immune checkpoint ligand PD-L1 and the transmembrane mucin MUC1 are upregulated in triple-negative breast cancer (TNBC), where they contribute to its aggressive pathogenesis. Here, we report that genetic or pharmacological targeting of the oncogenic MUC1 subunit MUC1-C is sufficient to suppress PD-L1 expression in TNBC cells. Mechanistic investigations showed that MUC1-C acted to elevate PD-L1 transcription by recruitment of MYC and NF-κB p65 to the PD-L1 promoter. In an immunocompetent model of TNBC in which Eo771/MUC1-C cells were engrafted into MUC1 transgenic mice, we showed that targeting MUC1-C associated with PD-L1 suppression, increases in tumor-infiltrating CD8+ T cells and tumor cell killing. MUC1 expression in TNBCs also correlated inversely with CD8, CD69, and GZMB, and downregulation of these markers associated with decreased survival. Taken together, our findings show how MUC1 contributes to immune escape in TNBC, and they offer a rationale to target MUC1-C as a novel immunotherapeutic approach for TNBC treatment.Significance: These findings show how upregulation of the transmembrane mucin MUC1 contributes to immune escape in an aggressive form of breast cancer, with potential implications for a novel immunotherapeutic approach. Cancer Res; 78(1); 1–11. ©2017 AACR.

http://ift.tt/2z6ZHZE

KRAS Oncogenic Signaling Extends beyond Cancer Cells to Orchestrate the Microenvironment

KRAS is one of the most frequently mutated oncogenes in cancer, being a potent initiator of tumorigenesis, a strong inductor of malignancy, and a predictive biomarker of response to therapy. Despite the large investment to understand the effects of KRAS activation in cancer cells, pharmacologic targeting of KRAS or its downstream effectors has not yet been successful at the clinical level. Recent studies are now describing new mechanisms of KRAS-induced tumorigenesis by analyzing its effects on the components of the tumor microenvironment. These studies revealed that the activation of KRAS on cancer cells extends to the surrounding microenvironment, affecting the properties and functions of its constituents. Herein, we discuss the most emergent perspectives on the relationship between KRAS-mutant cancer cells and their microenvironment components. Cancer Res; 78(1); 1–8. ©2017 AACR.

http://ift.tt/2BqfKYM

Epigenetic Reprogramming Strategies to Reverse Global Loss of 5-Hydroxymethylcytosine, a Prognostic Factor for Poor Survival in High-grade Serous Ovarian Cancer

PURPOSE: A major challenge in platinum-based cancer therapy is the clinical management of chemoresistant tumors, which have a largely unknown pathogenesis at the level of epigenetic regulation. EXPERIMENTAL DESIGN: We evaluated the potential of using global loss of 5-hydroxymethylcytosine (5-hmC) levels as a novel diagnostic and prognostic epigenetic marker to better assess platinum-based chemotherapy response and clinical outcome in high-grade serous tumors (HGSOC), the most common and deadliest subtype of ovarian cancer. Furthermore, we identified a targetable pathway to reverse these epigenetic changes, both genetically and pharmacologically. RESULTS: This study shows that decreased 5-hmC levels are an epigenetic hallmark for malignancy and tumor progression in HGSOC. In addition, global 5-hmC loss is associated with a decreased response to platinum-based chemotherapy, shorter time to relapse, and poor overall survival in newly diagnosed HGSOC patients. Interestingly, the rescue of 5-hmC loss restores sensitivity to platinum chemotherapy in vitro and in vivo, decreases the percentage of tumor cells with cancer stem cell markers, and increases overall survival in an aggressive animal model of platinum resistant disease. CONCLUSIONS: Consequently, a global analysis of patient 5-hmC levels should be included in future clinical trials, which use pretreatment with epigenetic adjuvants to elevate 5-hmC levels and improve the efficacy of current chemotherapies. Identifying prognostic epigenetic markers and altering chemotherapeutic regimens to incorporate DNMTi pretreatment in tumors with low 5-hmC levels could have important clinical implications for newly diagnosed HGSOC disease.

http://ift.tt/2BbpCRS

Loss-of-function mutations in Calcitonin receptor (CALCR) identify highly aggressive glioblastoma with poor outcome

Purpose Despite significant advances in the understanding of the biology, the prognosis of glioblastoma (GBM) remains dismal. The objective was to carry out whole exome sequencing (WES) of Indian glioma and integrate with that of TCGA to find clinically relevant mutated pathways. Experimental Design WES of different astrocytoma samples (n=42; Indian cohort) was carried out and compared to that of TCGA cohort. An integrated analysis of mutated genes from Indian and TCGA cohorts was carried out to identify survival association of pathways with genetic alterations. Patient-derived glioma stem-like cells, glioma cell lines and mouse xenograft models were used for functional characterization of Calcitonin Receptor (CALCR) and establish it as a therapeutic target. Results A similar mutation spectrum between Indian cohort and TCGA cohort was demonstrated. An integrated analysis identified GBMs with defective "Neuroactive ligand-receptor interaction" pathway (n=23; 9.54%) have significantly poor prognosis (p0.0001). Further, GBMs with mutated Calcitonin receptor (CALCR) or reduced transcripts levels predicted poor prognosis. Exogenously added Calcitonin (CT) inhibited various properties of glioma cells and pro-oncogenic signaling pathways in a CALCR-dependent manner. Patient-derived mutations in CALCR abolished these functions with the degree of loss-of-function negatively correlating with patient survival. WT CALCR, but not the mutant versions, inhibited Ras-mediated transformation of immortalized astrocytes in vitro. Further, CT inhibited patient derived neurospheres growth and in vivo glioma tumor growth in a mouse model. Conclusions We demonstrate CT-CALCR signaling axis is an important tumor suppressor pathway in glioma and establish CALCR as a novel therapeutic target for GBM.

http://ift.tt/2BUmBc8

BET Proteins as Targets for Anticancer Treatment [Review]

Bromodomain and extraterminal domain (BET) proteins are epigenetic readers that regulate gene expression and are involved in cancer pathogenesis. Over the last years, several BET inhibitors have been developed and clinically tested. Results from the first clinical trials show limited single-agent activity in a small subset of patients with hematologic malignancies and in NUT carcinoma. Adverse events have been observed and may limit treatment compliance. Here, we review the preclinical rationale for targeting BET proteins in cancer and the preliminary results from clinical trials, and outline future directions for the use of BET inhibitors as antitumor agents.

Significance: BET inhibitors represent a new class of anticancer agents. Results from the first clinical trials confirm the antitumor potential of BET inhibitors, but their efficacy as single agents seems to be limited. Based on preclinical data, combination therapies with other anticancer agents and the development of a new generation of compounds may open new possibilities for targeting BET proteins as effective anticancer strategies. Cancer Discov; 8(1); 1–13. ©2017 AACR.

http://ift.tt/2CNF6vW

Motor learning and metaplasticity in striatal neurons: relevance for Parkinson’s disease

Abstract

Nigro-striatal dopamine transmission is central to a wide range of neuronal functions, including skill learning, which is disrupted in several pathologies such as Parkinson's disease. The synaptic plasticity mechanisms, by which initial motor learning is stored for long time periods in striatal neurons, to then be gradually optimized upon subsequent training, remain unexplored. Addressing this issue is crucial to identify the synaptic and molecular mechanisms involved in striatal-dependent learning impairment in Parkinson's disease. In this study, we took advantage of interindividual differences between outbred rodents in reaching plateau performance in the rotarod incremental motor learning protocol, to study striatal synaptic plasticity ex vivo. We then assessed how this process is modulated by dopamine receptors and the dopamine active transporter, and whether it is impaired by overexpression of human α-synuclein in the mesencephalon; the latter is a progressive animal model of Parkinson's disease. We found that the initial acquisition of motor learning induced a dopamine active transporter and D1 receptors mediated long-term potentiation, under a protocol of long-term depression in striatal medium spiny neurons. This effect disappeared in animals reaching performance plateau. Overexpression of human α-synuclein reduced striatal dopamine active transporter levels, impaired motor learning, and prevented the learning-induced long-term potentiation, before the appearance of dopamine neuronal loss. Our findings provide evidence of a reorganization of cellular plasticity within the dorsolateral striatum that is mediated by dopamine receptors and dopamine active transporter during the acquisition of a skill. This newly identified mechanism of cellular memory is a form of metaplasticity that is disrupted in the early stage of synucleinopathies, such as Parkinson's disease, and that might be relevant for other striatal pathologies, such as drug abuse.

http://ift.tt/2kSooEj

Plague in Madagascar — A Tragic Opportunity for Improving Public Health

When plague first arrived in Madagascar in November 1898, its appearance mirrored events in port cities around the world. Alexandria, Bombay, Buenos Aires, San Francisco, Saigon, and Sydney were all affected as part of the "third pandemic," a global event that began in China but spread widely with…

http://ift.tt/2Bp3U0Q

Long-Acting Beta agonists (LABAs) and Inhaled Corticosteroids (ICS): Drug Safety Communication - Boxed Warning About Asthma-Related Death Removed

Audience: Pharmacy, Pulmonology, Internal Medicine, Family Practice [Posted 12/20/2017] ISSUE: FDA's most prominent warning, the Boxed Warning, about asthma-related death has been removed from the drug labels of medicines that contain both an ICS...

http://ift.tt/2BbZlmC

Safety and efficacy of parenteral iron in children with inflammatory bowel disease

Abstract

Objectives

Iron deficiency anaemia (IDA) frequently complicates inflammatory bowel disease (IBD) in children and adults. Oral iron may exacerbate gastrointestinal symptoms and absorption may be insufficient in intestinal inflammation. Even where oral iron is successful, repletion of iron stores can be unacceptably slow. Intravenous (IV) iron compounds were in the past associated with serious adverse reactions and historically were considered a last resort in children. New generation preparations have a safer profile in adults although reluctance to use them in children may persist, where safety data is lacking. We investigate the safety and efficacy of ferric carboxymaltose (FCM) and iron sucrose (IS) in children.

Methods

We retrospectively identified all children with IBD who received parenteral iron over a 38 month period in a single regional referral centre. Safety, tolerability and adverse events were established by case note review. Efficacy was assessed by change in haematinic indices pre- and post-treatment.

Results

41 children (18 male; median age 14yrs, range 3-17) received a total of 104 iron infusions. 44% (18) had Crohn's disease (CD); 56% (23) ulcerative colitis (UC). 35 received FC, seven IS and one both. Three children developed mild rash post infusion which resolved quickly with chlorphenamine. Mean increase in haemoglobin (Hb) was 2.5g/dl (0.3-5.8). Iron levels increased by a mean of 8.4 g/dl (1-25), transferrin saturation by 16.2% (2-47). Transferrin decreased by 0.84 g/dl (0.3-3.4).

Conclusions

New generation parenteral iron preparations are safe, well tolerated and efficacious in children with IDA and IBD.

http://ift.tt/2BQxrjI

The Regulatory Accountability Act of 2017 — Implications for FDA Regulation and Public Health

In the past year, federal health policy has been characterized by pervasive uncertainty, but a consistent theme from the Trump administration and some prominent legislators has been opposition to regulation. Last spring, Congress took a substantial step toward making regulation by federal agencies…

http://ift.tt/2z7l9xU

Plague in Madagascar — A Tragic Opportunity for Improving Public Health

When plague first arrived in Madagascar in November 1898, its appearance mirrored events in port cities around the world. Alexandria, Bombay, Buenos Aires, San Francisco, Saigon, and Sydney were all affected as part of the "third pandemic," a global event that began in China but spread widely with…

http://ift.tt/2Bp3U0Q

Trial of Contralateral Seventh Cervical Nerve Transfer for Spastic Arm Paralysis

Spastic limb paralysis due to injury to a cerebral hemisphere from stroke, traumatic brain injury, or cerebral palsy is a cause of long-term disability. It is estimated that 30 to 60% of stroke survivors are unable to use their paralyzed hand. The spastic arm posture impairs activities of daily…

http://ift.tt/2BeKnvS

Rewiring to Regain Function in Patients with Spastic Hemiplegia

Spastic hemiplegia results from several relatively common disorders, including stroke, traumatic brain injury, and cerebral palsy. Frequently, upper-limb function is impaired. In this issue of the Journal, Zheng et al. report a new approach to the treatment of this condition: the use of a…

http://ift.tt/2BU5KpY

Aging in HIV-Infected Subjects: A New Scenario and a New View

The prevalence of HIV-infected people aged 50 years or older is increasing rapidly; the proportion will increase from 28% to 73% in 2030. In addition, HIV-infected individuals may be more vulnerable to age-related condition. There is growing evidence that the prevalence of comorbidities and other age-related conditions (geriatric syndromes, functional or neurocognitive/mental problems, polypharmacy, and social difficulties) is higher in the HIV-infected population than in their uninfected counterparts. However, despite the potential impact of this situation on health care, little information exists about the optimal clinical management of older HIV-infected people. Here we examine the age-related conditions in older HIV-infected persons and address clinical management according to author expertise and published literature. Our aim is to advance the debate about the most appropriate management of this population, including less well-studied aspects, such as frequency of screening for psychological/mental and social and functional capabilities.

http://ift.tt/2DhCDuz

Vestibulo-cochlear function in inflammatory neuropathies

Inflammatory neuropathies are a heterogeneous group of peripheral nerve disorders linked by their immune-related pathogenesis. They are caused by auto-immune inflammation within the peripheral nerves associated with destruction of myelin and/or axons (Lunn et al., 2009). Inflammatory neuropathies may be acute (e.g., Guillain-Barré Syndrome, GBS) or chronic (e.g., Chronic Inflammatory Demyelinating Neuropathy, CIDP; Multifocal Motor Neuropathy, MMN) and are closely related to neuropathies associated with paraproteinemia (Lunn et al., 2009).

http://ift.tt/2BSJz3z

Spectral and temporal electroencephalography measures reveal distinct neural networks for the acquisition, consolidation, and interlimb transfer of motor skills in healthy young adults

Motor practice results in skill acquisition, an asymptotic process leading to quicker and more accurate movements (Willingham, 1998). Synapses that form de novo and strengthen in the offline period after motor practice make the newly acquired motor skill stable and less susceptible to interference because the skill becomes consolidated into motor memory (Brashers-Krug et al., 1996; Shadmehr and Holcomb, 1997; Dayan and Cohen, 2011). Curiously, unilateral motor practice also improves skill performance in the contralateral non-practiced limb, most likely through synaptic adaptations in the hemisphere ipsilateral to the practiced limb (Hortobagyi et al., 2011; Veldman et al., 2015; Nojima et al., 2012; Lee and Carroll, 2007).

http://ift.tt/2BbuBSu

Cortical sources of resting state electroencephalographic rhythms probe brain function in naïve HIV individuals

Human immunodeficiency virus (HIV) causes neurological, cognitive, and behavioral symptoms during the progression of the infection (Reger et al., 2002; Anthony and Bell 2008; Antinori et al., 2007). From an epidemiological point of view, subclinical neuropathy was reported in 10-40% of asymptomatic subjects with HIV and 53-100% in those with the AIDS (Chavanet et al., 1988; Gastaut et al., 1989). Also, 50-70% of subjects with HIV suffer from neurologic and the so-called HIV-associated neurocognitive disorders (HANDs) including deficits of episodic memory, attention, cognitive-motor, and executive functions such as planning and problem solving (Selnes, 2005).

http://ift.tt/2BR7WhV

Caecal volvulus incarcerated in the epiploic foramen

http://ift.tt/2BpmVjZ

Adult intussusception involving colonic lipoma: a case study

http://ift.tt/2z6ogpS

How to do a structured rectal mobilization in complex pelvic endometriosis

http://ift.tt/2BpmiXo

Improved perioperative outcomes of laparoscopic distal pancreatosplenectomy: modified lasso technique

Background

Simultaneous division of the splenic artery, splenic vein and pancreatic parenchyma during laparoscopic distal pancreatosplenectomy (LDPS) is known as the lasso technique, which is considered to be simple to perform. However, the original lasso technique carries a risk of post-operative bleeding from the splenic artery. We modified the original lasso technique to improve its technical safety and compared the perioperative outcomes of LDPS performed with the modified lasso technique (ml-LDPS) with those of conventional LDPS (c-LDPS).

Methods

From August 2006 to July 2016, 30 patients underwent c-LDPS and 31 patients underwent ml-LDPS for distal pancreatectomy involving <50% of the pancreas. The perioperative outcomes of the two groups were compared.

Results

The ml-LDPS technique resulted in a shorter operation time (201 min versus 162 min, P < 0.01), less intraoperative blood loss (20 mL versus 200 mL, P < 0.01), a shorter post-operative hospital stay (8.0 days versus 12.5 days, P < 0.01), and a lower incidence of clinically relevant post-operative pancreatic fistulas (6.5% versus 26.7%, P = 0.04) compared with c-LDPS. The surgical approach (c-LDPS or ml-LDPS) was identified as an independent predictor of the development of clinically relevant post-operative pancreatic fistulas via multivariate analysis.

Conclusion

The ml-LDPS method had beneficial effects on the operation time, intraoperative bleeding, the post-operative morbidity rate and the length of the post-operative hospital stay. The ml-LDPS procedure is a simple, safe and effective way of performing planned LDPS.

http://ift.tt/2z5pSA2

Quick eating caused plastic bread bag clip ingestion and severe gastrointestinal bleed in young adult: a case report

http://ift.tt/2BpmQNd

Jejunal diverticulitis secondary to enterolith: a case report

http://ift.tt/2z73ma9

The Antagonistic Effect of Selenium on Lead-Induced Immune Dysfunction via Recovery of Cytokine and Heat Shock Protein Expression in Chicken Neutrophils

Abstract

Lead (Pb) is a ubiquitous and toxic heavy metal and it can damage the immune system in humans and animals. Many researchers have reported that Selenium (Se) could possess various pharmacological effects in mammals. However, few studies have been carried out to investigate the protective role of Se in birds, especially in chickens. In this study, we investigated the protective effects of Se against Pb-induced inflammatory responses and the expression of heat shock proteins (HSPs) in peripheral blood neutrophils. One hundred eighty Hy-Line brown chickens were randomly divided into the control group (Con group), Se supplementation group (+Se group), Pb supplementation group (+Pb group), and the Se and Pb compound group (Se+Pb group). On the 90th day of the experiment, the peripheral blood was collected to extract neutrophils, and then, the levels of HSPs and cytokines were examined. The results showed that, after Pb treatment, the levels of IL-(1β, 1R, 4, 8, 10, and 12β), TGF-β4, and HSP (27, 40, 60, 70, and 90) mRNA were significantly increased and levels of IL-2 and IFN-γ mRNA were decreased compared with those in the control group. Compared with the control group, the protein levels of HSP60 and HSP70 were also increased in the Pb treatment group. Co-administration of Se (1 mg/kg/day) and Pb resulted in a reversal of the Pb-induced cytokine changes in neutrophils accompanied by a significant decrease in HSPs. Our study demonstrated that Pb could decrease the immune function via changing the expression of cytokines and HSPs in chicken neutrophils, but Se could relieve the toxic effect induced by Pb.

http://ift.tt/2oXMvXy

The PRKD1 E710D hotspot mutation is highly specific in separating polymorphous adenocarcinoma of the palate from adenoid cystic carcinoma and pleomorphic adenoma on FNA

BACKGROUND

Polymorphous adenocarcinoma (PAC) of the palatal minor salivary glands, previously known as polymorphous low-grade adenocarcinoma, is the second most common intraoral malignant salivary gland carcinoma after adenoid cystic carcinoma (ACC) and carries an excellent prognosis. Unfortunately, PAC demonstrates cytological overlap with 2 other salivary gland tumors frequently encountered in the same location, namely ACC and pleomorphic adenoma (PA). Recently, the protein kinase D1 (PRKD1) hotspot mutation E710D was demonstrated to be specific for PAC and to be present in the majority of cases. The objective of the current study was to investigate the value of PRKD1 hotspot sequencing in identifying PAC in paired fine-needle aspiration (FNA) and surgical specimens from cases of PAC, ACC, and PA.

METHODS

Paired May-Grunwald-Giemsa-stained FNA and corresponding surgical specimens were collected from 18 PAC cases, 25 ACC cases, and 21 PA cases. Both sets of specimens were subjected to dideoxynucleotide sequencing of PRKD1 exon 15, including the PRKD1 E710D hotspot.

RESULTS

Of the PAC cases, approximately 50% demonstrated identical PRKD1 E710D hotspot mutations on the FNA specimen and corresponding surgical specimen. Two ACC specimens had point mutations within the sequenced region in the FNA specimen as well as the surgical specimen, but none were located in the hotspot region. None of the PA cases demonstrated PRKD1 mutations. The specificity of the PRKD1 hotspot mutation for identifying PAC among ACC and PA cases was 100% whereas the sensitivity was 50%.

CONCLUSIONS

The PRKD1 E710D hotspot mutation is highly specific for identifying PAC on FNA among cases of ACC and PA, whereas the sensitivity is only modest. Alternative PRKD1 mutations exclude PAC, and are more suggestive of ACC. Cancer Cytopathol 2017. © 2017 American Cancer Society.

http://ift.tt/2oZzJHZ

Caring for Migrants and Refugees With End-Stage Kidney Disease in Europe

With the number of migrants and refugees increasing globally, the nephrology community is increasingly confronted with issues relating to the management of end-stage kidney disease in this population, including medical, logistical, financial, and moral-ethical questions. Beginning with data for the state of affairs regarding refugees in Europe and grounded in moral reasoning theory, this Policy Forum Perspective contends that to improve care for this specific population, there is a need for: (1) clear demarcations of responsibilities across the societal (macro), local (meso), and individual (micro) levels, such that individual providers are aware of available resources and able to provide essential medical care while societies and local communities determine the general approach to dialysis care for refugees; (2) additional data and evidence to facilitate decision making based on facts rather than emotions; and (3) better information and education in a broad sense (cultural sensitivity, legal rights and obligations, and medical knowledge) to address specific needs in this population.

http://ift.tt/2BEZ0K1

Use of Lung Ultrasound for the Assessment of Volume Status in CKD

Adequate assessment of fluid status is an imperative objective in the management of all types of patients in cardiology, intensive care, and especially nephrology. Fluid overload is one of the most common modifiable risk factors directly associated with hypertension, heart failure, left ventricular hypertrophy, and eventually, higher morbidity and mortality risk in these categories of patients. Different methods are commonly used to determine fluid status (eg, clinical assessment, natriuretic peptide concentrations, echocardiography, inferior vena cava measurements, or bioimpedance analysis).

http://ift.tt/2CLEPJG

Plague in Madagascar — A Tragic Opportunity for Improving Public Health

New England Journal of Medicine, Ahead of Print.


http://ift.tt/2B9h9P3

Echocardiography Grading for Pulmonary Arteriovenous Malformation Screening in Children with Hereditary Hemorrhagic Telangiectasia

Transthoracic contrast echocardiography (TTCE) has high sensitivity but low specificity in screening for pulmonary arteriovenous malformations (pAVMs) in children with hereditary hemorrhagic telangiectasia (HHT). Here we describe characteristics of TTCE that might be used to reduce the need for confirmatory computed tomography scans in children with HHT.

http://ift.tt/2BoeQfo

Variability in State-Based Recommendations for Management of Alpha Thalassemia Trait and Silent Carrier Detected on the Newborn Screen

We conducted an inventory of state-based recommendations for follow-up of alpha thalassemia silent carrier and trait identified on newborn screen. We found wide variability in the nature and timing of these recommendations. We recommend a standardized recommendation to guide pediatricians in evidenced-based care for this population.

http://ift.tt/2z5uOVt

Spontaneous Regression of a Recalcitrant Wart after Bivalent Papillomavirus Vaccination

A 10-year-old girl presented with a wart located on the right finger of her hand that had appeared 9 months before (Figure, A). It had been refractory to multiple topical treatments used, including cryotherapy (6 sessions), salicylic acid, and cantharidin. Ten days after receiving the first dose of the human papillomavirus (HPV) bivalent vaccine, total remission of the wart was noted (Figure, B).

http://ift.tt/2z5sqhN

Cardiovascular Monitoring During Video Urodynamic Studies in Persons With Spinal Cord Injury

Objective The aims of the study were to observe cardiovascular responses during video urodynamic studies and to identify correlations between autonomic dysreflexia events and video urodynamic study findings in spinal cord injuries. Design Thirty-four persons with spinal cord injury were enrolled and investigated using continuous cardiovascular monitoring during video urodynamic studies. Associations between cardiovascular responses and video study variables were analyzed. Results Bladder type–specific cardiovascular responses occurred during the study. The incidence of overactive detrusor during urodynamic study and bladder trabeculation on voiding cystourethrogram was significantly higher in autonomic dysreflexia persons with spinal cord injury (P

http://ift.tt/2kRpSi3

Effects of Transcranial Direct Current Stimulation Plus Physical Therapy on Gait in Patients With Parkinson Disease: A Randomized Controlled Trial

Objective The aim of the study was to study the combined effects of transcranial direct current stimulation (tDCS) and physical therapy on the walking ability of patients with Parkinson disease (PD). Study Design The study used an experimental, double-blinded, randomized controlled trial. Results After intervention, group 1 (only tDCS) demonstrated a significant increase in gait speed by 0.13 to 0.14 m/sec (17.8%–19.2%) and an increase in step length by 5.9 to 6.1 cm (14.0%–14.5%), whereas group 2 (tDCS and physical therapy) revealed a significant increase in gait speed by 0.10 to 0.13 m/sec (14.9%–19.4%) and step length by 4.5 to 5.4 cm (10.6%–12.8%) and group 3 (sham tDCS and physical therapy) showed a significant increase in gait speed by 0.09 to 0.14 m/sec (13.0%–20.3%) and step length by 3.0 to 5.4 cm (6.8%–12.3%). All these results lasted for at least 8 wks after intervention. Upon comparing the parameters of gait among the three groups at every follow-up visit, no significant difference was observed. Conclusions Anodal tDCS or physical therapy could be used alone or together as a combination treatment to improve the walking speed of patients with Parkinson disease. The effects lasted for approximately 8 wks. The combination treatment was not superior to the use of tDCS or physical therapy alone.

http://ift.tt/2COK0bX

Effects of Light-Emitting Diode Therapy on Muscle Hypertrophy, Gene Expression, Performance, Damage, and Delayed-Onset Muscle Soreness: A Case–Control Study With a Pair of Identical Twins

No abstract available

http://ift.tt/2CL3dvi

Effects of Myofascial Release on Pressure Pain Thresholds in Patients With Neck Pain: A Single-Blind Randomized Controlled Trial

Objective This study aimed to investigate the efficacy of myofascial release therapy (MRT) for improving pressure pain thresholds (PPTs) and pain in patients with mechanical neck pain. Design Forty-one participants with neck pain were randomly allocated to either a MRT group (five sessions) or a physical therapy (PT) group (ten sessions) for 2 wks. The multimodal PT program included ultrasound therapy (US), transcutaneous electric nerve stimulation, and massage. Visual analog scale (VAS) and PPTs in suboccipital and upper trapezius muscles were measured at baseline, at the end of treatment, and at 1 month follow-up. Results At the end of treatment, significant mean differences in VAS (−0.99, 95% confidence interval [CI] = −1.82 to −0.16), in both left (0.28, 95% CI = 0.06 to 0.50) and right (0.40, 95% CI = 0.16 to 0.63) suboccipital PPTs and in the right trapezius PPT (0.38, 95% CI = 0.07 to 0.69) were observed. At 1-month follow-up, significant mean differences were found for VAS (−1.85, 95% CI = −2.76 to −0.94) and both left (0.46, 95% CI = 0.12 to 0.80) and right (0.38, 95% CI = 0.06 to 0.69) suboccipital PPTs. Conclusions This study provides evidence that MRT could be better than a multimodal PT program for short-term improvement of pain and PPTs in patients with neck pain.

http://ift.tt/2CMeewc

Cochrane Rehabilitation: Organization and Functioning

No abstract available

http://ift.tt/2CMecEA

Pre-therapy Neural State of Bilateral Motor and Premotor Cortices Predicts Therapy Gain After Subcortical Stroke: A Pilot Study

Objective The aim of the study was to examine whether neural state of spared motor and premotor cortices captured before a therapy predicts therapy-related motor gains in chronic subcortical stroke. Design Ten survivors, presenting chronic moderate upper limb impairment, underwent proton magnetic resonance spectroscopy, magnetic resonance imaging, clinical, and kinematics assessments before a 4-wk impairment-oriented training. Clinical/kinematics assessments were repeated after therapy, and motor gain was defined as positive values of clinical upper limb/elbow motion changes and negative values of trunk motion changes. Candidate predictors were N-acetylaspartate-neuronal marker, glutamate-glutamine-indicator of glutamatergic neurotransmission, and myo-inositol-glial marker, measured bilaterally within the upper limb territory in motor and premotor (premotor cortex, supplementary motor area) cortices. Traditional predictors (age, stroke length, pre-therapy upper limb clinical impairment, infarct volume) were also investigated. Results Poor motor gain was associated with lower glutamate-glutamine levels in ipsilesional primary motor cortex and premotor cortex (r = 0.77, P = 0.01 and r = 0.78, P = 0.008, respectively), lower N-acetylaspartate in ipsilesional premotor cortex (r = 0.69, P = 0.02), higher glutamate-glutamine in contralesional primary motor cortex (r = −0.68, P = 0.03), and lower glutamate-glutamine in contralesional supplementary motor area (r = 0.64, P = 0.04). These predictors outperformed myo-inositol metrics and traditional predictors (P ≈ 0.05–1.0). Conclusions Glutamatergic state of bilateral motor and premotor cortices and neuronal state of ipsilesional premotor cortex may be important for predicting motor outcome in the context of a restorative therapy.

http://ift.tt/2kQkzPW

Interventional Spine Considerations for Dural Ectasia in a Patient With Marfan Syndrome

For patients with Marfan syndrome who present with radicular low back pain, interventional spine providers should be familiar with dural ectasia with variable diffuse thinning of the posterior wall of the lumbar spine and sacrum. Providers should carefully weigh the risks and benefits of offering elective procedures because altered anatomy may put these patients at higher risk of dural puncture. Patient selection is essential because hydrostatic pressures and/or neural tension should also be considered as potential pain generators that may not be relieved by steroid injections. Careful evaluation of recent magnetic resonance images and vigilant procedural technique is highly recommended.

http://ift.tt/2kQW9G4

Women Physicians Are Underrepresented in Recognition Awards From the Association of Academic Physiatrists

Objective Determine representation by gender for individual recognition awards presented to physicians by the Association of Academic Physiatrists (AAP). Design Cross-sectional survey was used. Lists of individual recognition award recipients for the 27-yr history of the AAP awards (1990–2016) were analyzed. The primary outcome measures were the total numbers of men versus women physician award recipients overall and for the past decade (2007–2016). Results No awards were given to women physicians for the past 4 yrs (2013–2016) or in half of the award categories for the past decade (2007–2016). No woman received the outstanding resident/fellow award since its inception (2010–2016). There was a decrease in the proportion of awards given to women in the past decade (2007–2016, 7 of 39 awards, 17.9%) as compared with the first 17 yrs (1990–2006, 10 of 46 awards, 21.7%). Furthermore, compared with their proportional membership within the specialty, women physicians were underrepresented for the entire 27-yr history of the AAP awards (1990–2016, 17 of 85 awards, 20%). According to the Association of American Medical Colleges, the proportion of full-time female physical medicine and rehabilitation faculty members was 38% in 1992 and 41% in 2013. Conclusions Women physicians have been underrepresented by the AAP in recognition awards. Although the reasons are not clear, these findings should be further investigated.

http://ift.tt/2kTWdoC

Increased Reliability of Quantitative Ultrasound Measures of the Supraspinatus Tendon Using Multiple Image Analysts and Analysis Runs

Quantitative ultrasound (QUS) is an inexpensive and promising tool for sensitive measurement of tendon pathology. However, few studies have reported the psychometric properties of measurements obtained using this technique for assessments of the supraspinatus tendon. The present study was undertaken to determine the variance contributed by several sources of error (participant, ultrasound operator, image analyst, analysis session) to QUS measures of the supraspinatus tendon. Transverse images of the supraspinatus tendon were captured from eleven subjects (22 shoulders) by two ultrasonographers, and each image was analyzed by two image analysts who each completed two analysis runs. Generalizability theory and intraclass correlations were used to assess the reliability of seven QUS metrics. Measures of tendon/cartilage thickness demonstrated the greatest degree of overall dependability (ϕ = 0.84), followed by echogenicity (ϕ = 0.56), variance (ϕ = 0.55), and entropy (ϕ = 0.47), suggesting that these measures of the supraspinatus tendon may be promising metrics for assessing differences in tendon health. Interrater reliability between ultrasound operators ranged from low to moderate for different QUS metrics, but using more than one image analyst and performing repeated measurement analysis runs on each image help increase reliability of QUS measures for the supraspinatus tendon.

http://ift.tt/2kTnPKz

Mobility Functional Outcomes of Neurofibromatosis Patients: A Preliminary Report

Objective The aim of the study was to describe the mobility outcomes of neurofibromatosis (NF) patients who received acute inpatient rehabilitation. Design This is a retrospective study of 62 consecutive neurofibromatosis patients of any age who received physical medicine and rehabilitation consultations at a comprehensive cancer center. Postoperative, inpatient rehabilitation admission and discharge functional independence measures (FIM scores) of transfers and gait and length of hospital stay were obtained from 37 patients who were transferred to inpatient rehabilitation (acute rehabilitation) and 25 who had an alternative disposition (consultation only). Results Mean age was 34 yrs. Both groups had similar postoperative FIM transfer and gait scores; however, at approximately postoperative day 10, the consultation only group was discharged with median FIM of 5 (supervision level) as compared with the acute rehabilitation group FIM of 4 (P = 0.000). The acute rehabilitation group had improved mobility FIM scores from postoperative to rehabilitation admission and again from rehabilitation admission to discharge (P

http://ift.tt/2kUaPE6

Potential Harms With Long-Term Glucocorticoid Use

No abstract available

http://ift.tt/2kTnEin

Cytotoxicity of Local Anesthetics in Mesenchymal Stem Cells

Cell therapy based on the trophic, mitogenic, and immunomodulatory capacity of mesenchymal stem cells is a promising treatment modality for degenerative musculoskeletal conditions. Local anesthetics have been commonly used in interventional procedures for alleviating pain, but local anesthetics may have negative impact on MSC dosing because of cytotoxicity or other biological effects. Because previous studies have not reached consensus yet on the potential complications of local anesthetics in cell therapy, we reviewed 11 studies that involve in vitro experimentation with MSCs using aminoamide-type anesthetics including lidocaine, ropivacaine, mepivacaine, bupivacaine, articaine, and prilocaine. Three studies that compare the effects of different types of local anesthetic agents showed that ropivacaine has the least detrimental effects on mesenchymal stem cell populations, whereas lidocaine seems to have the most significant effects on stem cell viability. Concentration- and time-dependent effects on cell viability were reported with bupivacaine, ropivacaine, lidocaine, and mepivacaine. We conclude that local anesthetic agents have time- and concentration-dependent detrimental effects on MSCs. However, in vivo studies will be required to understand the interactions of these agents with MSCs, because in vitro studies cannot replicate the pharmacokinetics of anesthetics in vivo or the recovery of MSCs in a more physiological environment.

http://ift.tt/2kTnzv5

Reply to the Letter to the Editor on “Effects of Light-Emitting Diode Therapy on Muscle Hypertrophy, Gene Expression, Performance, Damage, and Delayed-Onset Muscle Soreness: Case-Control Study With a Pair of Identical Twins”

No abstract available

http://ift.tt/2BQnLWe

Point-of-Care Ultrasonography Findings and Care Use Among Patients Undergoing Ultrasound-Guided Shoulder Injections

Objective The aims of the study were to assess the overall reduction of pain in patients undergoing ultrasound-guided shoulder injections and to characterize the preinjection point-of-care ultrasound findings and use of clinical services postinjection including the use of magnetic resonance imaging and surgeries. Design Data of 172 patients who underwent ultrasound-guided subacromial subdeltoid injection or glenohumeral joint injection were reviewed for preinjection point-of-care ultrasound findings, change in pain intensity at 2 mos from baseline, and use of care at 6 mos' postinjection. Pain intensity was measured by the numeric rating scale and a dichotomous report of global impression of significant improvement in pain. Responders were defined as those with 50% or more reduction in numeric rating scale or those with global impression of 50% or more improvement. Results There were 141 responders among the 172 patients analyzed. Full-thickness rotator cuff tears were higher in the ultrasound-guided subacromial subdeltoid injection group when compared with the glenohumeral joint injection group (P = 0.038) and abnormal bicipital tendon findings higher in the glenohumeral joint injection group (P = 0.016). There were no significant differences in specific abnormal U findings between responders versus nonresponders. Twelve patients had a shoulder magnetic resonance imaging and four patients underwent operative interventions after the injection. Conclusions Overall pain reduction after ultrasound-guided shoulder injections was favorable in the short term. There was no specific preinjection point-of-care ultrasound findings associated with clinical pain reduction after injection. Additional imaging and operative intervention after ultrasound-guided shoulder injections seemed to be relatively low.

http://ift.tt/2BTjCki

Presumed Acute Leukemia Presenting as Acute Spinal Cord Injury

No abstract available

http://ift.tt/2BRqlv7

The Ingestion of Fluorescent, Magnetic Nanoparticles for Determining Fluid-uptake Abilities in Insects

Fluid-feeding insects have the ability to acquire minute quantities of liquids from porous surfaces. This protocol describes a method to directly determine the ability for insects to ingest liquids from porous surfaces using feeding solutions with fluorescent, magnetic nanoparticles.

http://ift.tt/2Bn3W9r

Prediction for sustained deep molecular response of BCR-ABL1 levels in patients with chronic myeloid leukemia in chronic phase

BACKGROUND

The achievement of a sustained deep molecular response is a goal of increasing relevance because it opens the possibility of treatment discontinuation. The objective of this analysis was to develop a prediction model for a sustained molecular response with BCR-ABL1 level <0.0032% on the international scale (MR^4.5) for at least 2 years according to BCR-ABL1 levels achieved within the first 12 months of therapy.

METHODS

Data for 603 patients with newly diagnosed chronic myeloid leukemia in chronic phase in consecutive prospective clinical trials were analyzed. The best fit average molecular response was defined by robust linear regression models, with which the average molecular levels were defined. The minimum acceptable molecular response was defined by quantile regression for the 95th percentile, with which the worst 5% BCR-ABL1 levels were identified.

RESULTS

In 603 patients with a median follow-up of 103 months, 2002 BCR-ABL1–level data points within 1 year of tyrosine kinase inhibitors were identified. The regression equation for the best fit average levels for a sustained MR^4.5 was Log₁₀(PCR) = −0.1424 × (Months) – 0.8668, and the regression equation for minimum acceptable levels was Log₁₀(PCR) = −0.1403 × (Months) + 0.6142 (where PCR indicates polymerase chain reaction). To achieve a sustained MR^4.5, the best fit average levels were 0.051%, 0.019%, 0.007%, and 0.003% at 3, 6, 9, and 12 months, respectively; the minimum acceptable levels were 1.561%, 0.592%, 0.225%, and 0.085% at 3, 6, 9, and 12 months, respectively.

CONCLUSIONS

This model proposes optimal values that predict the highest probability of reaching such a goal. These values can be used to guide therapy when a sustained MR^4.5 is the objective. Cancer 2017. © 2017 American Cancer Society.

http://ift.tt/2kSdDln

Low testosterone at first prostate-specific antigen failure and assessment of risk of death in men with unfavorable-risk prostate cancer treated on prospective clinical trials

BACKGROUND

Low testosterone at the time of diagnosis of prostate cancer has been associated with a worse prognosis. Whether this is true and how to define the best treatment approach at the time of first prostate-specific antigen (PSA) failure to the authors' knowledge has not been elucidated to date and was studied herein.

METHODS

Between 1995 and 2001, a total of 58 men with unfavorable-risk PC who were treated on clinical trials with radiotherapy and androgen deprivation therapy (ADT) had available testosterone levels at the time of PSA failure. Cox and Fine and Gray regressions were performed to ascertain whether low versus normal testosterone was associated with the risk of PC-specific mortality, other-cause mortality, and all-cause mortality adjusting for age, salvage ADT, and known PC prognostic factors.

RESULTS

After a median follow-up of 6.68 years after PSA failure, 31 men (53.4%) had died; 10 of PC (32.3%), of which 8 of 11 (72.7%) versus 2 of 47 (4.3%) deaths occurred in men with low versus normal testosterone at the time of PSA failure, respectively. A significant increase in the risk of all-cause mortality (adjusted hazard ratio [AHR], 2.54; 95% confidence interval [95% CI], 1.04-6.21 [P = .04]) and PC-specific mortality (AHR, 13.71; 95% CI, 2.4-78.16 [P = .003]), with a reciprocal trend toward a decreased risk of other-cause mortality (AHR, 0.18; 95% CI, 0.02-1.55 [P = .12]) was observed in men with low versus normal testosterone.

CONCLUSIONS

Low, but not necessarily castrate, testosterone levels at the time of PSA failure confer a very poor prognosis. These observations provide evidence to support testosterone testing at the time of PSA failure. Given prolonged survival when abiraterone or docetaxel is added to ADT in men with castrate-sensitive metastatic PC and possibly localized high-risk PC provides a rationale supporting their use with ADT in men with low testosterone in the setting of a phase 2 trial. Cancer 2017. © 2017 American Cancer Society.

http://ift.tt/2ktQyWF

Bovine leukemia virus linked to breast cancer but not coinfection with human papillomavirus: Case-control study of women in Texas

BACKGROUND

Bovine leukemia virus (BLV) and human papillomavirus (HPV) were previously identified in human breast tissue and have been associated with breast cancer in independent studies. The objective of the current study was to test for the presence of BLV and HPV in the same breast tissue specimens to determine whether the viruses were associated with breast cancer either singly or together.

METHODS

Archival formalin-fixed paraffin-embedded breast tissue sections from 216 women were received from The University of Texas MD Anderson Cancer Center along with patient diagnosis. In situ polymerase chain reaction and/or DNA hybridization methods were used to detect targeted DNA segments of BLV and HPV. Standard statistical methods were used to calculate age-adjusted odds ratios, attributable risk, and P values for the trend related to the association between presence of a virus and a diagnosis of breast disease.

RESULTS

Women diagnosed with breast cancer were significantly more likely to have BLV DNA in their breast tissue compared with women with benign diagnoses and no history of breast cancer. Women with breast pathology classified as premalignant and no history of breast cancer also were found to have an elevated risk of harboring BLV DNA in their breast tissue. HPV status was not associated with malignancy, premalignant breast disease, or the presence of BLV in the breast tissues.

CONCLUSIONS

The data from the current study supported previous findings of a significant association between BLV DNA in breast tissue and a diagnosis of breast cancer, but did not demonstrate oncogenic strains of HPV associated with breast cancer or the presence of BLV DNA in breast tissue. The authors believe the findings of the current study contribute to overall knowledge regarding a possible causal role for viruses in human breast cancer. Cancer 2017. © 2017 American Cancer Society.

http://ift.tt/2kRg73i

Pooled analysis of stereotactic ablative radiotherapy for primary renal cell carcinoma: A report from the International Radiosurgery Oncology Consortium for Kidney (IROCK)

BACKGROUND

Stereotactic ablative radiotherapy (SABR) is an emerging therapy for primary renal cell carcinoma. The authors assessed safety, efficacy, and survival in a multi-institutional setting. Outcomes between single-fraction and multifraction SABR were compared.

METHODS

Individual patient data sets from 9 International Radiosurgery Oncology Consortium for Kidney institutions across Germany, Australia, the United States, Canada, and Japan were pooled. Toxicities were recorded using Common Terminology Criteria for Adverse Events, version 4.0. Patient, tumor, and treatment characteristics were stratified according to the number of radiotherapy fractions (single vs multiple). Survival outcomes were examined using Kaplan-Meier estimates and Cox proportional-hazards regression.

RESULTS

Of 223 patients, 118 received single-fraction SABR, and 105 received multifraction SABR. The mean patient age was 72 years, and 69.5% of patients were men. There were 83 patients with grade 1 and 2 toxicity (35.6%) and 3 with grade 3 and 4 toxicities (1.3%). The rates of local control, cancer-specific survival, and progression-free survival were 97.8%, 95.7%, and 77.4%, respectively, at 2 years; and they were 97.8%, 91.9%, and 65.4%, respectively, at 4 years. On multivariable analysis, tumors with a larger maximum dimension and the receipt of multifraction SABR were associated with poorer progression-free survival (hazard ratio, 1.16 [P < .01] and 1.13 [P = .02], respectively) and poorer cancer-specific survival (hazard ratio, 1.28 [P < .01] and 1.33 [P = .01], respectively). There were no differences in local failure between the single-fraction cohort (n = 1) and the multifraction cohort (n = 2; P = .60). The mean ( ± standard deviation) estimated glomerular filtration rate at baseline was 59.9 ± 21.9 mL per minute, and it decreased by 5.5 ± 13.3 mL per minute (P < .01).

CONCLUSIONS

SABR is well tolerated and locally effective for treating patients who have primary renal cell carcinoma and has an acceptable impact on renal function. An interesting observation is that patients who receive single-fraction SABR appear to be less likely to progress distantly or to die of cancer. Cancer 2017. © 2017 American Cancer Society.

http://ift.tt/2ktQoyx

Personal history of proliferative breast disease with atypia and risk of multifocal breast cancer

BACKGROUND

A history of proliferative breast disease with atypia (PBDA) may be indicative of an increased risk not just of breast cancer but also of a more aggressive form of breast cancer.

METHODS

Multifocal breast cancer (MFBC), defined as 2 or more tumors in the same breast upon a diagnosis of cancer, is associated with a poorer prognosis than unifocal (single-tumor) breast cancer. PBDA, including atypical ductal hyperplasia and atypical lobular hyperplasia, is a known risk factor for breast cancer. Using New Hampshire Mammography Network data collected for 3567 women diagnosed with incident breast cancer from 2004 to 2014, this study assessed the risk of MFBC associated with a previous diagnosis of PBDA.

RESULTS

Women with a history of PBDA were found to be twice as likely to be subsequently diagnosed with MFBC as women with no history of benign breast disease (BBD; odds ratio [OR], 2.23; 95% confidence interval [CI], 1.08-4.61). Ductal carcinoma in situ on initial biopsy was associated with a 2-fold increased risk of MFBC in comparison with invasive cancer (OR, 2.13; 95% CI, 1.58-2.88). BBD and proliferative BBD without atypia were not associated with MFBC.

CONCLUSIONS

Women with a history of previous PBDA may be at increased risk for MFBC. Women with a history of PBDA may benefit from additional presurgical clinical workup. Cancer 2017. © 2017 American Cancer Society.

http://ift.tt/2kRfOpa

In Vitro Enzyme Measurement to Test Pharmacological Chaperone Responsiveness in Fabry and Pompe Disease

There is a demand to make pre-clinical testing for a novel class of "orphan" drugs called pharmacological chaperones reproducible, fast, and efficient. We developed a simple, highly standardized, and versatile cell culture-based assay to screen for eligible patients as well as novel pharmacological chaperone drugs.

http://ift.tt/2BHuCPn

Pantoprazole Sodium for Injection 40 Mg Per Vial: Recall - Presence of Glass Particles

Audience: Pharmacy, Gastroenterology [Posted 12/20/2017] ISSUE: AuroMedics Pharma LLC is voluntarily recalling one lot of Pantoprazole Sodium for Injection 40 mg per vial, to the hospital level. The product was found to contain glass particles in...

http://ift.tt/2krYpEn

Pantoprazole Sodium for Injection 40 Mg Per Vial: Recall - Presence of Glass Particles

Audience: Pharmacy, Gastroenterology [Posted 12/20/2017] ISSUE: AuroMedics Pharma LLC is voluntarily recalling one lot of Pantoprazole Sodium for Injection 40 mg per vial, to the hospital level. The product was found to contain glass particles in...

http://ift.tt/2krYpEn

Biotinylated Cell-penetrating Peptides to Study Intracellular Protein-protein Interactions

This is a protocol to study intracellular protein-protein interactions based on the biotin-avidin pull-down system with the novelty of combining cell-penetrating sequences. The main advantage is that the target sequence is incubated with living cells instead of cell lysates and therefore the interactions will occur within the cellular context.

http://ift.tt/2BGbH7u

Hydrogen-rich water increases postharvest quality by enhancing antioxidant capacity in Hypsizygus marmoreus

In the present study, we aimed to assess the effect of hydrogen-rich water (HRW) on the physicochemical characteristics and antioxidant capacity of Hypsizygus marmoreus during 12 days of postharvest storage at 4 ...

http://ift.tt/2CMRigx

De novo transcriptome assembly: a new laccase multigene family from the marine-derived basidiomycete Peniophora sp. CBMAI 1063

Laccases are multicopper oxidases that are able to catalyze reactions involving a range of substrates, including phenols and amines, and this ability is related to the existence of different laccases. Basidiom...

http://ift.tt/2BPxc8j

Pathological and Radiological Splenic Vein Involvement are Predictors of Poor Prognosis and Early Liver Metastasis After Surgery in Patients with Pancreatic Adenocarcinoma of the Body and Tail

Abstract

Background

The prognostic impact of pancreatic ductal adenocarcinoma (PDAC) invasion to the splenic vessel is controversial.

Objective

The aim of this study was to assess the clinical value of pathological and radiological splenic vessel invasion in PDACs of the body and tail.

Methods

Medical records of patients with resectable PDAC of the body and tail who underwent distal pancreatectomy between 2003 and 2016 at the Kobe University Hospital were retrospectively analyzed.

Results

Overall, 68 patients (29 female and 39 male patients) were enrolled. Pathologically determined splenic vein invasion (p-SV) and splenic artery invasion (p-SA) were identified in 21 (30.9%) and 5 (7.4%) patients, respectively. The p-SV (but not p-SA) was an independent prognostic factor in multivariate analysis (p = 0.009). On analysis of recurrence patterns, patients with PDAC positive for p-SV were at a higher risk for liver metastasis (p = 0.022); however, the associations were not significant for other recurrence patterns. Liver metastasis occurred earlier in patients who were positive for p-SV (p = 0.015). Preoperative computed tomography effectively diagnosed pathological vessel invasion (SV: sensitivity, 95.2%, specificity, 72.3%; SA: sensitivity, 100%, specificity, 84.1%). Radiological SV invasion remained significant in multivariate analysis regarding postoperative survival (p = 0.007), and was also associated with early liver metastases (p = 0.008).

Conclusions

Pathological/radiological SV invasion were independent adverse prognostic factors associated with early liver metastasis in patients with PDAC of the body/tail. Assessment of these findings may be useful in determining optimal therapeutic options in these patients.

http://ift.tt/2krT3c6

Isolation in small populations of Wayampi Amerindians promotes endemicity and homogenization of their faecal virome, but its distribution is not entirely random

Abstract

The isolated community of the Wayampi Amerindians has been extensively studied for the presence of beta lactamase-producing enterobacteria and their gut microbiota. However, no information about their virome was available. This study tries to establish potential associations between the virome and diverse epidemiological data, through the metagenomic study of the faecal prophages and DNA viruses from 31 samples collected in 2010. Taxonomic assignments, composition, abundance and diversity analyses were obtained to characterize the virome and were compared between groups according to several demographic, environmental and medical data. Prophages outnumbered viruses. Composition and abundance of virome indicated relatively low variability. Diversity within samples showed no significant differences, regardless of the group comparison. Significant differences were observed in the beta diversity among samples according to hospitalisation and gender, but not by extended spectrum β-lactamase carriage, antibiotic intake or possession of pets, although some viruses differed in some cases (e.g. immunodeficiency-associated stool virus associated to antibiotic intake). The faecal virome of adult Wayampi is more homogeneous than that from Western populations. Not a single factor analysed can explain alone the observed distribution of the virome, but differences by gender (fewer variability in females than males), may reflect differences in life habits and work.

http://ift.tt/2BFjQJi

Distinct effects of the nephridial symbionts Verminephrobacter and Ca. Nephrothrix on reproduction and maturation of its earthworm host Eisenia andrei

Abstract

Verminephrobacter, the most common specific symbionts in the nephridia (excretory organs) of lumbricid earthworms, have been shown to improve reproduction of the garden earthworm Aporrectodea tuberculata under nutrient limitation. It is unknown, how general this beneficial trait is in the Verminephrobacter-earthworm symbiosis, whether other nephridial symbionts also affect host fitness, and what the mechanism of the fitness increase is. Here we report beneficial effects of Verminephrobacter and Candidatus Nephrothrix on life history traits of the compost worm Eisenia andrei, which in addition to these two symbionts also hosts Agromyces-like bacteria in its mixed nephridial community: while growth was identical between control, Verminephrobacter-free, and aposymbiotic worms, control worms produced significantly more cocoons and offspring than both Verminephrobacter-free and aposymbiotic worms, confirming the reproductive benefit of Verminephrobacter in a second host with different ecology and feeding behavior. Furthermore, worms with Verminephrobacter and Ca. Nephrothrix, or with only Ca. Nephrothrix present, reached sexual maturity significantly earlier than aposymbiotic worms; this is the first evidence for a beneficial role of Ca. Nephrothrix in earthworms. Riboflavin content in cocoons and whole earthworms was unaffected by the presence or absence of nephridial symbionts, suggesting that nutritional supplementation with this vitamin does not play a major role in this symbiosis.

http://ift.tt/2COAVzI

Transcriptional and Environmental Control of Bacterial Denitrification and N2O Emissions

Abstract

In oxygen-limited environments, denitrifying bacteria can switch from oxygen-dependent respiration to nitrate (NO₃⁻) respiration in which the NO₃⁻ is sequentially reduced via nitrite (NO₂⁻), nitric oxide (NO) and nitrous oxide (N₂O) to dinitrogen (N₂). However, atmospheric N₂O continues to rise, a significant proportion of which is microbial in origin. This implies that the enzyme responsible for N₂O reduction, nitrous oxide reductase (NosZ), does not always carry out the final step of denitrification either efficiently, or in synchrony with the rest of the pathway. Despite a solid understanding of the biochemistry underpinning denitrification, there is a relatively poor understanding of how environmental signals and respective transcriptional regulators control expression of the denitrification apparatus. This mini-review will describe the current picture for transcriptional regulation of denitrification in the model bacterium, Paracoccus denitrificans, highlighting differences in other denitrifying bacteria where appropriate, as well as gaps in our understanding. Alongside this, the emerging role of small regulatory RNAs (sRNAs) in regulation of denitrification will be discussed. We will conclude by speculating how this information, aside from providing a better understanding of the denitrification process, can be translated into development of novel greenhouse gas mitigation strategies.

http://ift.tt/2kQqQv2

Vibrioferrin production by the food spoilage bacterium Pseudomonas fragi

Abstract

Pseudomonas fragi is a meat and milk spoilage bacterium with high iron requirements, however mechanisms of iron acquisition remain largely unknown. The aim of this work was to investigate siderophore production as an iron acquisition system for P. fragi. A vibrioferrin siderophore gene cluster was identified in 13 P. fragi and experiments were conducted with a representative strain of this group (F1801). Chromeazurol S assays showed P. fragi F1801 produced siderophores under iron starvation at optimum growth and refrigeration temperature. Conversely, supplementation of low iron media with 50 μM FeCl₃ repressed transcription of the vibrioferrin genes and siderophore production. Disruption of the siderophore receptor (pvuA) caused polar effects on downstream vibrioferrin genes, resulting in impaired siderophore production of the ΔpvuA mutant. Growth of this mutant was compared to growth of a control strain (Δlip) with wild-type vibrioferrin genes in low iron media supplemented with iron chelators 2,2'-bipyridyl or apo-transferrin. While 25 μM 2,2'-bipyridyl caused impaired growth of ΔpvuA, growth of the mutant was completely inhibited by 2.5 μM apo-transferrin, but could be restored by FeCl_3-addition. In summary, this work identifies a vibrioferrin-mediated iron acquisition system of P. fragi, which is required for growth of this bacterium under iron-starvation.

http://ift.tt/2kttKX3

Comparison of three DNA extraction methods for the detection and quantification of GMO in Ecuadorian manufactured food

In Ecuador, food products need to be labeled if exceeded 0.9% of transgenic content in whole products. For the detection of genetically modified organisms (GMOs), three DNA extraction methods were tested in 35...

http://ift.tt/2ksX8fY

Effects of a naturally occurring amino acid substitution in bovine PrP: a model for inherited prion disease in a natural host species

The most common hereditary prion disease is human Creutzfeldt-Jakob disease (CJD), associated with a mutation in the prion gene resulting in a glutamic acid to lysine substitution at position 200 (E200K) in th...

http://ift.tt/2kRRzY5

Spectrum and antibiogram of bacteria isolated from patients presenting with infected wounds in a Tertiary Hospital, northern Tanzania

This study aimed to determine the spectrum and antibiogram of the isolated bacteria from patients presenting with infected wounds at Kilimanjaro Christian Medical Centre in northern Tanzania.

http://ift.tt/2ksOcrf

Health-related quality of life for First Nations and Caucasian women in the First Nations Bone Health Study

Studies about the health of Indigenous (i.e., original inhabitants) populations often focus on chronic diseases and risk behaviors, emphasizing physical aspects of health. Our objective was to test for differe...

http://ift.tt/2kQV7cW

A multiplex marker set for microsatellite typing and sexing of sooty terns Onychoprion fuscatus

Seabirds have suffered dramatic population declines in recent decades with one such species being the sooty tern Onychoprion fuscatus. An urgent call to re-assess their conservation status has been made given tha...

http://ift.tt/2ktcSji

Overlapping Peptide Library to Map Qa-1 Epitopes in a Protein

Qa-1 (HLA-E in human) belongs to a group of non-classical major histocompatibility complex 1b molecules. Immunization with Qa-1-binding epitopes has been shown to augment tissue-specific immune regulation and ameliorate several autoimmune diseases. Herein we describe an overlapping peptide library strategy for the identification of Qa-1 epitopes in a protein.

http://ift.tt/2oVlqnH

47th Annual Meeting of the German Society for Immunology, 12–15 September, 2017, Erlangen, Germany

http://ift.tt/2kPBbHy