The efficacy of cefmetazole against pyelonephritis caused by extended-spectrum beta-lactamase-producing Enterobacteriaceae

SummaryObjectivesUrinary tract infections (UTIs) caused by extended-spectrum beta-lactamase (ESBL)-producing Enterobacteriaceae are on the increase. Although cefmetazole is stable in vitro against the hydrolyzing activity of ESBLs, no clinical study has ever evaluated its role in infections caused by these organisms. We therefore evaluated the efficacy of cefmetazole compared to carbapenems against pyelonephritis caused by ESBL-producing Enterobacteriaceae.MethodsA retrospective chart review was conducted at a tertiary care hospital from August 2008 to July 2010. Chart reviews were done for patients with ESBL-producing organisms in urine identified in the microbiology database. Patients who were treated with cefmetazole were compared to those treated with carbapenems. The clinical and bacteriological cure rates at 4 weeks after completion of therapy were evaluated.ResultsTwo hundred and fifty-six urine cultures growing ESBL-producing organisms were identified during the study period. Ten patients treated with cefmetazole and 12 patients treated with carbapenems were evaluated. There was no difference in clinical (9/10 vs. 12/12, p=0.46) or bacteriological cure rate (5/7 vs. 6/7, p=1.00) at 4 weeks after the completion of therapy. There was no difference in the incidence of adverse effects (2/10 vs. 2/12, p=1.00).ConclusionsCefmetazole may be a useful option for the treatment of UTIs caused by ESBL-producing organisms. Prospective and larger sized studies are needed to confirm our findings

Rebamipide suppresses TLR-TBK1 signaling pathway resulting in regulating IRF3/7 and IFN-α/β reduction

TANK-binding kinase 1 (TBK1) regulates the interferon regulatory factor (IRF) 3 and IRF7 activation pathways by double strand RNA (dsRNA) via Toll-like receptor (TLR) 3 and by lipopolysaccharide (LPS) via TLR4. Rebamipide is useful for treating inflammatory bowel disease (IBD). Although IBD is associated with nuclear factor-κB (NF-κB), any association with the TBK1-IRF pathway remains unknown. How rebamipide affects the TBK1-IRF pathway is also unclear. We analyzed the relationship between IBD (particularly ulcerative colitis; UC) and the TLR-TBK1-IRF3/7 pathway using human colon tissue, a murine model of colitis and human colonic epithelial cells. Inflamed colonic mucosa over-expressed TKB1, NAP1, IRF3, and IRF7 mRNA compared with normal mucosa. TBK1 was mainly expressed in inflammatory epithelial cells of UC patients. The expression of TBK1, IRF3, IRF7, IFN-α and IFN-β mRNA was suppressed in mice given oral dextran sulfate-sodium (DSS) and daily rectal rebamipide compared with mice given only DSS. Rebamipide reduced the expression of TBK1, IRF3 and IRF7 mRNA induced by LPS/dsRNA, but not of NF-κB mRNA in colonic epithelial cells. Rebamipide might suppress the TLR-TBK1 pathway, resulting in IRF3/7-induction of IFN-α/β and inflammatory factors. TBK1 is important in the induction of inflammation in patients with UC. If rebamipide represses the TLR-TBK1 pathway, then rectal administration should suppress inflammation of the colonic mucosa in patients with UC

Differentiated glioblastoma cells accelerate tumor progression by shaping the tumor microenvironment via CCN1-mediated macrophage infiltration

Glioblastoma (GBM) is the most lethal primary brain tumor characterized by significant cellular heterogeneity, namely tumor cells, including GBM stem-like cells (GSCs) and differentiated GBM cells (DGCs), and non-tumor cells such as endothelial cells, vascular pericytes, macrophages, and other types of immune cells. GSCs are essential to drive tumor progression, whereas the biological roles of DGCs are largely unknown. In this study, we focused on the roles of DGCs in the tumor microenvironment. To this end, we extracted DGC-specific signature genes from transcriptomic profiles of matched pairs of in vitro GSC and DGC models. By evaluating the DGC signature using single cell data, we confirmed the presence of cell subpopulations emulated by in vitro culture models within a primary tumor. The DGC signature was correlated with the mesenchymal subtype and a poor prognosis in large GBM cohorts such as The Cancer Genome Atlas and Ivy Glioblastoma Atlas Project. In silico signaling pathway analysis suggested a role of DGCs in macrophage infiltration. Consistent with in silico findings, in vitro DGC models promoted macrophage migration. In vivo, coimplantation of DGCs and GSCs reduced the survival of tumor xenograft-bearing mice and increased macrophage infiltration into tumor tissue compared with transplantation of GSCs alone. DGCs exhibited a significant increase in YAP/TAZ/TEAD activity compared with GSCs. CCN1, a transcriptional target of YAP/TAZ, was selected from the DGC signature as a candidate secreted protein involved in macrophage recruitment. In fact, CCN1 was secreted abundantly from DGCs, but not GSCs. DGCs promoted macrophage migration in vitro and macrophage infiltration into tumor tissue in vivo through secretion of CCN1. Collectively, these results demonstrate that DGCs contribute to GSC-dependent tumor progression by shaping a mesenchymal microenvironment via CCN1-mediated macrophage infiltration. This study provides new insight into the complex GBM microenvironment consisting of heterogeneous cells

Establishment of an Endogenous Clostridium difficile Rat Infection Model and Evaluation of the Effects of Clostridium butyricum MIYAIRI 588 Probiotic Strain

Clostridium difficile is well known as an agent responsible for pseudomembranous colitis and antibiotic-associated diarrhea. The hamster model utilizing an oral route for infection of C. difficile has been considered to be the standard model for analysis of C. difficile infection (CDI) but this model exhibits differences to human CDI, most notably as most hamsters die without exhibiting diarrhea. Therefore, we attempted to develop a new non-lethal and diarrheal rat CDI model caused by endogenous C. difficile using metronidazole (MNZ) and egg white. In addition, the effects of probiotic strain Clostridium butyricum MIYAIRI 588 (CBM) on CDI were examined using this model. Syrian Golden hamsters received clindamycin phosphate orally at 30 mg/kg on 5 days before challenge with either C. difficile VPI10463 (hypertoxigenic strain) or KY34 (low toxigenic clinical isolate). Mortality and the presence of diarrhea were observed twice a day for the duration of the experiment. Wistar rats received 10% egg white dissolved in drinking water for 1 week ad libitum following intramuscular administration of 200 mg/kg MNZ twice a day for 3 days. Diarrhea score was determined for each day and fecal water content, biotin concentration, and cytotoxin titer in feces were examined. More than 70% of hamsters orally infected with C. difficile died without exhibiting diarrhea regardless of toxigenicity of strain. The rats receiving egg white after MNZ administration developed diarrhea due to overgrowth of endogenous C. difficile. This CDI model is non-lethal and diarrheal, and some rats in this model were spontaneously cured. The incidence of diarrhea was significantly decreased in C. butyricum treated rats. These results indicate that the CDI model using egg white and MNZ has potentially better similarity to human CDI, and implies that treatment with C. butyricum may reduce the risk of CDI

Utility of Regular Management of Physical Activity and Physical Function in Hemodialysis Patients

Background/Aims: Several clinical practice guidelines recommend regular assessment of physical activity and physical function as part of routine care in hemodialysis patients. However, there is no clear evidence to support these recommendations. We investigated whether the proportion of attendance at a regular program for management of physical activity and physical function can predict all-cause mortality and cardiovascular events in hemodialysis patients. Methods: This retrospective cohort study consisted of 266 hemodialysis patients participating in the management program at least once. Participants were tracked for 3 years after their first attendance at the management program to determine their attendance proportion. The main study outcomes included all-cause mortality and a composite of fatal and nonfatal cardiovascular events. Results: Median patient age was 64.5 (interquartile range, 56.8 – 72.0) years, 45% were women, and the median time on hemodialysis was 35.5 (interquartile range, 12.0 – 114.3) months at baseline. Sixty-five patients died over a median follow-up of 79 months. The incidence of cardiovascular events was 60 over a median follow-up of 68 months. Even after adjusting for any of the prognostic models, participants who attended ≤ 75% of sessions (n = 140) had higher risks of mortality (hazard ratio (HR), 1.79; 95% confidence interval (CI): 1.00 – 3.36; P = 0.049) and cardiovascular events (HR, 1.84; 95% CI: 1.07 – 3.48; P = 0.03) than those attending > 75% of sessions (n = 126). Conclusion: Hemodialysis patients in whom physical activity and physical function could be assessed more regularly had better prognosis than those with only intermittent assessment

Repeated freeze–thaw cycles reduce the survival rate of osteocytes in bone-tendon constructs without affecting the mechanical properties of tendons

Frozen bone-patellar tendon bone allografts are useful in anterior cruciate ligament reconstruction as the freezing procedure kills tissue cells, thereby reducing immunogenicity of the grafts. However, a small portion of cells in human femoral heads treated by standard bone-bank freezing procedures survive, thus limiting the effectiveness of allografts. Here, we characterized the survival rates and mechanisms of cells isolated from rat bones and tendons that were subjected to freeze–thaw treatments, and evaluated the influence of these treatments on the mechanical properties of tendons. After a single freeze–thaw cycle, most cells isolated from frozen bone appeared morphologically as osteocytes and expressed both osteoblast- and osteocyte-related genes. Transmission electron microscopic observation of frozen cells using freeze-substitution revealed that a small number of osteocytes maintained large nuclei with intact double membranes, indicating that these osteocytes in bone matrix were resistant to ice crystal formation. We found that tendon cells were completely killed by a single freeze–thaw cycle, whereas bone cells exhibited a relatively high survival rate, although survival was significantly reduced after three freeze–thaw cycles. In patella tendons, the ultimate stress, Young’s modulus, and strain at failure showed no significant differences between untreated tendons and those subjected to five freeze–thaw cycles. In conclusion, we identified that cells surviving after freeze–thaw treatment of rat bones were predominantly osteocytes. We propose that repeated freeze–thaw cycles could be applied for processing bone-tendon constructs prior to grafting as the treatment did not affect the mechanical property of tendons and drastically reduced surviving osteocytes, thereby potentially decreasing allograft immunogenecity

Sitagliptin and Carotid Atherosclerosis in Type 2 Diabetes

Background Experimental studies have suggested that dipeptidyl peptidase-4 (DPP-4) inhibitors provide cardiovascular protective effects. We performed a randomized study to evaluate the effects of sitagliptin added on to the conventional therapy compared with conventional therapy alone (diet, exercise, and/or drugs, except for incretin-related agents) on the intima-media thickness (IMT) of the carotid artery, a surrogate marker for the evaluation of atherosclerotic cardiovascular disease, in people with type 2 diabetes mellitus (T2DM). Methods and Findings We used a multicenter PROBE (prospective, randomized, open label, blinded endpoint) design. Individuals aged ≥30 y with T2DM (6.2% ≤ HbA1c < 9.4%) were randomly allocated to receive either sitagliptin (25 to 100 mg/d) or conventional therapy. Carotid ultrasound was performed at participating medical centers, and all parameters were measured in a core laboratory. Of the 463 enrolled participants with T2DM, 442 were included in the primary analysis (sitagliptin group, 222; conventional therapy group, 220). Estimated mean (± standard error) common carotid artery IMT at 24 mo of follow-up in the sitagliptin and conventional therapy groups was 0.827 ± 0.007 mm and 0.837 ± 0.007 mm, respectively, with a mean difference of −0.009 mm (97.2% CI −0.028 to 0.011, p = 0.309). HbA1c level at 24 mo was significantly lower with sitagliptin than with conventional therapy (6.56% ± 0.05% versus 6.72%± 0.05%, p = 0.008; group mean difference −0.159, 95% CI −0.278 to −0.041). Episodes of serious hypoglycemia were recorded only in the conventional therapy group, and the rate of other adverse events was not different between the two groups. As it was not a placebo-controlled trial and carotid IMT was measured as a surrogate marker of atherosclerosis, there were some limitations of interpretation. Conclusions In the PROLOGUE study, there was no evidence that treatment with sitagliptin had an additional effect on the progression of carotid IMT in participants with T2DM beyond that achieved with conventional treatment

Circulating T follicular helper 2 cells, T follicular regulatory cells and regulatory B cells are effective biomarkers for predicting the response to house dust mite sublingual immunotherapy in patients with allergic respiratory diseases

The relationships between T follicular helper (Tfh) cells and antigen-specific immunoglobulins (sIgs) in patients with allergic respiratory diseases who are receiving antigen immunotherapy (AIT) have not been fully clarified. Therefore, we started to perform house dust mite sublingual immunotherapy (HDM-SLIT) for 20 patients with atopic asthma comorbid with allergic rhinitis (AA+AR) who were already receiving ordinary treatments including inhaled corticosteroid (ICS). We examined percentages of circulating T follicular helper (cTfh) and regulatory (cTfr) cells and percentages of circulating regulatory T (cTreg) and B (cBreg) cells by FACS and we examined levels of Der-p/f sIgs by ELISA. Based on the symptom score (asthma control questionnaire: ACQ) and medication score ((global initiative for asthma: GINA) treatment step score) in patients with AA, the patients were divided into responders and non-responders. The percentage of cTfh2 cells significantly decreased and the percentage of cTfh1 cells significantly increased within the first year. Der-p/f sIgEs decreased after a transient elevation at 3 months in both groups. Notably, the percentage of cTfh2 cells and the ratio of cTfh2/cBreg cells and Der-p/f sIgEs greatly decreased in responders from 6 months to 12 months. The percentages of cTfr and cTreg cells showed significant negative correlations with the percentage of cTfh2 cells. The percentage of IL-4+ cTfh cells were significantly decreased and the percentage of IFN-γ+ cTfh cells were increased before treatment to 24 months in 6 patients examined (4 responders and 2 non-responders). We performed multi plelogistic regression analysis based on these results, the ratios of cTfh2/cTfr cells and cTfh2/cBreg cells at the start of therapy were statistically effective biomarkers for predicting the response to HDM-SLIT in patients with AA+AR