Comparison of four commercial screening assays for the detection of blakpc, blandm, blaimp, blavim, and blaoxa48 in rectal secretion collected by swabs

The spread of carbapenem-resistant Enterobacteriaceae (CRE) has been enabled by the lack of control measures directed at carriers of multidrug-resistant organisms in healthcare settings. Screening patients for asymptomatic colonization on the one hand, and implementation of contact precautions on the other hand, reduces patient-to-patient transmission. Screening plates represents a relatively low-cost method for isolating CRE from rectal swabs; however, molecular assays have become widely available. This study compared the performance of four commercial molecular platforms in detecting clinically significant carbapenemase genes versus routine screening for CRE. A total of 1015 non-duplicated rectal swabs were cultured on a chromogenic carbapenem-resistant selective medium. All growing Enterobacteriaceae strains were tested for carbapenemase-related genes. The same specimens were processed using the following molecular assays: Allplex\u2122 Entero-DR, Amplidiag\uae CarbaR + MCR, AusDiagnostics MT CRE EU, and EasyScreen\u2122 ESBL/CPO. The prevalence of Klebsiella pneumoniae carbapenemase (KPC)-producing Enterobacteriaceae detected by swab culture was 2.2%, while organisms producing oxacillinase (OXA)-48 and metallo-\u3b2-lactamases were infrequent. The cost of CRE-related infection control precautions, which must be kept in place while waiting for screening results, are significant, so the molecular tests could become cost-competitive, especially when the turnaround time is decreased dramatically. Molecular assays represent a powerful diagnostic tool as they allow the rapid detection of the most clinically relevant carbapenemases

Trans-anal irrigation in patients with multiple sclerosis: Efficacy in treating disease-related bowel dysfunctions and impact on the gut microbiota: A monocentric prospective study

Background: Constipation and faecal incontinence are not so uncommon in patients with multiple sclerosis, impairing quality of life. The gut microbiota is altered in multiple sclerosis patients and likely contributes to disease pathogenesis. Trans-anal irrigation has been proven to allow treatment of neurogenic bowel dysfunction and may affect gut microbiota. Objectives: The primary outcome was trans-anal irrigation effectiveness on constipation and faecal incontinence. The secondary outcome was gut microbiota profiling compared to healthy subjects and during trans-anal irrigation adoption. Methods: We conducted a prospective cohort study on multiple sclerosis patients, screened with Patient Assessment of Constipation Quality of Life questionnaire before undergoing constipation and faecal incontinence scoring, abdomen X-ray for intestinal transit time, compilation of food and evacuation diaries and faecal sample collection for gut microbiota analysis before and after 4 weeks of trans-anal irrigation. Results and Conclusions: Eighty patients were screened of which nearly half had intestinal symptoms. The included population (n = 37) was predominantly composed of women with significantly longer disease duration, higher mean age and disability than the excluded one (p < 0.05). Twelve patients completed the trans-anal irrigation phase, which led to significant improvement of bowel dysfunction symptom-related quality of life, increase in gut microbiota diversity and reduction of the proportions of pro-inflammatory taxa (p < 0.05). Trans-anal irrigation was safe, satisfactory and could help counteract multiple sclerosis-related dysbiosis

The synergism between DHODH inhibitors and dipyridamole leads to metabolic lethality in acute myeloid leukemia

Dihydroorotate Dehydrogenase (DHODH) is a key enzyme of the de novo pyrimidine biosynthesis, whose inhibition can induce differentiation and apoptosis in acute myeloid leukemia (AML). DHODH inhibitors had shown promising in vitro and in vivo activity on solid tumors, but their effectiveness was not confirmed in clinical trials, probably because cancer cells exploited the pyrimidine salvage pathway to survive. Here, we investigated the antileukemic activity of MEDS433, the DHODH inhibitor developed by our group, against AML. Learning from previous failures, we mimicked human conditions (performing experiments in the presence of physiological uridine plasma levels) and looked for synergic combinations to boost apoptosis, including classical antileukemic drugs and dipyridamole, a blocker of the pyrimidine salvage pathway. MEDS433 induced apoptosis in multiple AML cell lines, not only as a consequence of differentiation, but also directly. Its combination with antileukemic agents further increased the apoptotic rate, but when experiments were performed in the presence of physiological uridine concentrations, results were less impressive. Conversely, the combination of MEDS433 with dipyridamole induced metabolic lethality and differentiation in all AML cell lines; this extraordinary synergism was confirmed on AML primary cells with different genetic backgrounds and was unaffected by physiological uridine concentrations, predicting in human activity

DOK2 inhibits EGFR-mutated lung adenocarcinoma

Somatic mutations in the EGFR proto-oncogene occur in ~15% of human lung adenocarcinomas and the importance of EGFR mutations for the initiation and maintenance of lung cancer is well established from mouse models and cancer therapy trials in human lung cancer patients. Recently, we identified DOK2 as a lung adenocarcinoma tumor suppressor gene. Here we show that genomic loss of DOK2 is associated with EGFR mutations in human lung adenocarcinoma, and we hypothesized that loss of DOK2 might therefore cooperate with EGFR mutations to promote lung tumorigenesis. We tested this hypothesis using genetically engineered mouse models and find that loss of Dok2 in the mouse accelerates lung tumorigenesis initiated by oncogenic EGFR, but not that initiated by mutated Kras. Moreover, we find that DOK2 participates in a negative feedback loop that opposes mutated EGFR; EGFR mutation leads to recruitment of DOK2 to EGFR and DOK2-mediated inhibition of downstream activation of RAS. These data identify DOK2 as a tumor suppressor in EGFR-mutant lung adenocarcinoma

Strengths-Based Analysis of Student Success in Online Courses

Online courses today give a broad, diverse population access to higher education. Despite postsecondary institutions embracing this opportunity, scholarly literature reveals persistent concern over low retention rates in online courses. In response to this concern, an explanatory sequential, mixed methods study was conducted in three phases at a public research university to simultaneously explore personal, circumstantial, and course variables associated with student success from a strengths-based perspective. Existing data on student enrollments across four years were analyzed. A subset of Phase One students from a single semester were invited in the second phase to complete an assessment of non-cognitive attributes and personal perceptions, followed in the third phase by interviews among a stratified sample of successful students from the previous phase to elaborate on factors impacting their success. Quantitative analyses identified seven individual variables with statistical and practical significance for online student success. Interestingly, the combination of factors classified as predictive of success changed with student academic standing. The impact of differential success factors across academic experience may explain mixed results in previous studies. The themes that emerged from the interviews with students were congruent with quantitative findings. A unique perspective was shared when students discussed “teaching themselves,” providing additional insight into perceptions of teaching presence not formerly understood. The combination of a more contextual research approach, a strengths-based perspective, and insights from student perceptions yielded implications for educational practice

Biotrickling filtration of isopropanol under intermittent loading conditions

This paper investigates the removal of isopropanol by gas phase biotrickling filtration. Two plastic packing materials, one structured and one random, have been evaluated in terms of oxygen mass transfer and isopropanol removal efficiency (RE). Oxygen mass transfer experiments were performed at gas velocities of 104 and 312 m h-1 and liquid velocities between 3 and 33 m h-1. Both materials showed similar mass transfer coefficients up to liquid velocities of 15 m h-1. At greater liquid velocities, the structured packing exhibited greater oxygen mass transfer coefficients. Biotrickling filtration experiments were carried out at inlet loads (IL) from 20 to 65 g C m-3 h -1 and empty bed residence times (EBRT) from 15 14 to 160 s. To simulate typical industrial emissions, intermittent isopropanol loading (16 h/day, 5 16 day/week) and intermittent spraying frequency (15 min/1.5 hours) were applied. Maximum elimination capacity (EC) of 51 g C m-3 h -1 has been obtained for the random packing (IL of 65 g C m-3 h -1 17 , EBRT of 18 50 s). The decrease in irrigation frequency to 15 min every 3 hours caused a decrease in the outlet emissions from 86 to 59 mg C Nm-3 (inlet of 500 mg C Nm-3). The expansion of spraying to night and weekend periods promoted the degradation of the isopropanol accumulated in the water tank during the day, reaching effluent concentrations as low as 44 mg C Nm-3. After a 7 week starvation period, theperformance was recovered in less than 10 days, proving the robustness of the proces

Distinct Mechanisms for Induction and Tolerance Regulate the Immediate Early Genes Encoding Interleukin 1β and Tumor Necrosis Factor α

Interleukin-1β and Tumor Necrosis Factor α play related, but distinct, roles in immunity and disease. Our study revealed major mechanistic distinctions in the Toll-like receptor (TLR) signaling-dependent induction for the rapidly expressed genes (IL1B and TNF) coding for these two cytokines. Prior to induction, TNF exhibited pre-bound TATA Binding Protein (TBP) and paused RNA Polymerase II (Pol II), hallmarks of poised immediate-early (IE) genes. In contrast, unstimulated IL1B displayed very low levels of both TBP and paused Pol II, requiring the lineage-specific Spi-1/PU.1 (Spi1) transcription factor as an anchor for induction-dependent interaction with two TLR-activated transcription factors, C/EBPβ and NF-κB. Activation and DNA binding of these two pre-expressed factors resulted in de novo recruitment of TBP and Pol II to IL1B in concert with a permissive state for elongation mediated by the recruitment of elongation factor P-TEFb. This Spi1-dependent mechanism for IL1B transcription, which is unique for a rapidly-induced/poised IE gene, was more dependent upon P-TEFb than was the case for the TNF gene. Furthermore, the dependence on phosphoinositide 3-kinase for P-TEFb recruitment to IL1B paralleled a greater sensitivity to the metabolic state of the cell and a lower sensitivity to the phenomenon of endotoxin tolerance than was evident for TNF. Such differences in induction mechanisms argue against the prevailing paradigm that all IE genes possess paused Pol II and may further delineate the specific roles played by each of these rapidly expressed immune modulators. © 2013 Adamik et al

po 450 interplay between coding and non coding genome in human parathyroid tumours

Introduction Parathyroid tumours are the second most common endocrine neoplasia in women, after thyroid cancer. Mutations in the oncosuppressor CDC73 are the key event in most carcinomas whereas alterations in the tumour suppressor MEN1 (located at 11q13.1) occur in up to a third of sporadic adenomas. Although lncRNAs play a regulatory role in endocrine cancer pathogenesis, a lncRNAs profiling in human parathyroid tumours is still missing. Here, we identified a 'molecular signature' able to distinguish among parathyroid histotypes and a new potential epigenetic role of MEN1 in lncRNAs regulation. Material and methods Ninety lncRNAs were investigated in 4 parathyroid carcinomas (PCas), 12 adenomas (PAds) and 2 normal glands (PaNs). Hierarchical clustering (HCL) and Significance Analysis of Microarray (SAM) were performed to identify differences in lncRNAs expression. Significant lncRNAs were validated in additional 7 PCas, 26 PAds, 6 atypical PAds (aPAds) and 4 PaNs. CDC73 and MEN1 genes mutations were detected by Sanger sequencing. PAds genomic characterisation was obtained by array Comparative Genomic Hybridization (aCGH). HEK293 cells were transiently silenced for MEN1 expression to analyse MEN1-lncRNAs correlation. Results and discussions Nine lncRNAs were identified as differentially expressed in parathyroid tissues. Specifically, KCNQ1OT1 and SNHG6 were enriched in PaNs, reduced HAR1B, MEG3, HOXA3as and NEAT1 expression characterised PAds, whereas BC200, HOXA6as and WT1-AS were upregulated in PCas. HCL identified 3 clusters in which PaNs and PCas were distinctly separated, while aPAds were closer to PCas. Moreover, PAds clustered in a highly heterogeneous way. Notably, PCas and aPAds harbouring CDC73-mutations overexpressed the majority of the lncRNAs, compared to CDC73 wild-type samples. Interestingly, BACE1-AS, KCNQ1OT1, NEAT1 and SNHG6 levels in PAds were positively correlated with MEN1 levels. aCGH analysis revealed that Chr11 loss of heterozygosity (LOH) was the main chromosomal aberration in PAds. Of note, Chr11 LOH was associated with significant HAR1B upregulation and these data were confirmed in HEK293 cells knocked-down for MEN1. Conclusion Parathyroid histotypes are characterised by different lncRNAs signatures, suggesting a correlation with tumour aggressiveness and pathogenetic mechanisms. Further, our data highlight that lncRNAs profiles are related to CDC73 gene mutation status, chromosome 11 derangements and MEN1 inactivation