Sensitizing methicillin-resistant Staphylococcus aureus (MRSA) to cefuroxime: the synergic effect of bicarbonate and the wall teichoic acid inhibitor ticlopidine.

Methicillin-resistant Staphylococcus aureus (MRSA) strains are a major challenge for clinicians due, in part, to their resistance to most ß-lactams, the first-line treatment for methicillin-susceptible S. aureus. A phenotype termed "NaHCO3-responsiveness" has been identified, wherein many clinical MRSA isolates are rendered susceptible to standard-of-care ß-lactams in the presence of physiologically relevant concentrations of NaHCO3, in vitro and ex vivo; moreover, such "NaHCO3-responsive" isolates can be effectively cleared by ß-lactams from target tissues in experimental infective endocarditis (IE). One mechanistic impact of NaHCO3 exposure on NaHCO3-responsive MRSA is to repress WTA synthesis. This NaHCO3 effect mimics the phenotype of tarO-deficient MRSA, including sensitization to the PBP2-targeting ß-lactam, cefuroxime (CFX). Herein, we further investigated the impacts of NaHCO3 exposure on CFX susceptibility in the presence and absence of a WTA synthesis inhibitor, ticlopidine (TCP), in a collection of clinical MRSA isolates from skin and soft tissue infections (SSTI) and bloodstream infections (BSI). NaHCO3 and/or TCP enhanced susceptibility to CFX in vitro, by both minimum inhibitor concentration (MIC) and time-kill assays, as well as in an ex vivo simulated endocarditis vegetations (SEV) model, in NaHCO3-responsive MRSA. Furthermore, in experimental IE (presumably in the presence of endogenous NaHCO3), pre-exposure to TCP prior to infection sensitized the NaHCO3-responsive MRSA strain (but not the non-responsive strain) to enhanced clearances by CFX in target tissues. These data support the notion that NaHCO3 is acting similarly to WTA synthesis inhibitors, and that such inhibitors have potential translational applications in the treatment of certain MRSA strains in conjunction with specific ß-lactam agents.

The Purine Biosynthesis Repressor, PurR, Contributes to Vancomycin Susceptibility of Methicillin-resistant Staphylococcus aureus in Experimental Endocarditis.

BACKGROUND: Staphylococcus aureus is the most common cause of life-threatening endovascular infections, including infective endocarditis (IE). These infections, especially when caused by methicillin-resistant strains (MRSA), feature limited therapeutic options and high morbidity and mortality rates. METHODS: Herein, we investigated the role of the purine biosynthesis repressor, PurR, in virulence factor expression and vancomycin (VAN) treatment outcomes in experimental IE due to MRSA. RESULTS: The PurR-mediated repression of purine biosynthesis was confirmed by enhanced purF expression and production of an intermediate purine metabolite in purR mutant strain. In addition, enhanced expression of the transcriptional regulators, sigB and sarA, and their key downstream virulence genes (eg, fnbA, and hla) was demonstrated in the purR mutant in vitro and within infected cardiac vegetations. Furthermore, purR deficiency enhanced fnbA/fnbB transcription, translating to increased fibronectin adhesion versus the wild type and purR-complemented strains. Notably, the purR mutant was refractory to significant reduction in target tissues MRSA burden following VAN treatment in the IE model. CONCLUSIONS: These findings suggest that the purine biosynthetic pathway intersects the coordination of virulence factor expression and in vivo persistence during VAN treatment, and may represent an avenue for novel antimicrobial development targeting MRSA.

Combinations of Daptomycin plus Ceftriaxone, but Not Ascending Daptomycin Dose-Regimens, Are Effective in Experimental Endocarditis Caused by Streptococcus mitis-oralis Strains: Target Tissue Clearances and Prevention of Emergence of Daptomycin-Resistance.

The Streptococcus mitis-oralis subgroup of the viridans group streptococci (VGS) are the most common cause of infective endocarditis (IE) in many parts of the world. These organisms are frequently resistant in vitro to standard ß-lactams (e.g., penicillin; ceftriaxone [CRO]), and have the notable capacity for rapidly developing high-level and durable daptomycin resistance (DAP-R) during exposures in vitro, ex vivo, and in vivo. In this study, we used 2 prototypic DAP-susceptible (DAP-S) S. mitis-oralis strains (351; and SF100), which both evolved stable, high-level DAP-R in vitro within 1 to 3 days of DAP passage (5 to 20 µg/mL DAP). Of note, the combination of DAP + CRO prevented this rapid emergence of DAP-R in both strains during in vitro passage. The experimental rabbit IE model was then employed to quantify both the clearance of these strains from multiple target tissues, as well as the emergence of DAP-R in vivo under the following treatment conditions: (i) ascending DAP-alone dose-strategies encompassing human standard-dose and high-dose-regimens; and (ii) combinations of DAP + CRO on these same metrics. Ascending DAP-alone dose-regimens (4 to 18 mg/kg/d) were relatively ineffective at either reducing target organ bioburdens or preventing emergence of DAP-R in vivo. In contrast, the combination of DAP (4 or 8 mg/kg/d) + CRO was effective at clearing both strains from multiple target tissues (often with sterilization of bio-burdens in such organs), as well as preventing the emergence of DAP-R. In patients with serious S. mitis-oralis infections such as IE, especially caused by strains exhibiting intrinsic ß-lactam resistance, initial therapy with combinations of DAP + CRO may be warranted.

The role of error risk taking and perceived organizational innovation climate in the relationship between perceived psychological safety and innovative work behavior: A moderated mediation model.

To better understand how to motivate innovative work behavior (IWB) at the individual level in organizations, we investigate the link between perceived psychological safety and IWB and the role of error risk taking and perceived organizational innovation climate in this study. In particular, we hypothesize a moderated mediation model in which (a) perceived psychological safety is positively related to IWB, (b) error risk taking mediates the positive relationship between perceived psychological safety and IWB, and (c) perceived organizational innovation climate strengthens the positive link between error risk taking and IWB and the mediated link between perceived psychological safety and IWB via error risk taking. We tested the hypothesized model using data collected from 315 full-time employees working at six information and communication technology companies in a high-technology business district of Egypt. The findings largely support our hypotheses. We conclude by discussing the theoretical and practical implications.

Bayesian Evaluation of Three Serological Tests for Diagnosis of Brucella infections in Dromedary Camels Using Latent Class Models.

Brucellosis is a zoonotic disease with significant economic and public health impacts. The disease has been found in ruminants, including camels, but clinical diagnosis of camel brucellosis is difficult due to the lack of clinical signs. Thus, this study aimed to estimate the sensitivity (Se) and specificity (Sp) of the Buffered Plate Antigen Test (BPAT), Rose Bengal Test (RBT), and indirect ELISA (i-ELISA) for the diagnosis of Brucella infection in dromedary camels imported from Sudan to Egypt. The secondary objective of the study was to calculate the animal-level true prevalence of Brucella infection in imported camels. A cross-sectional study was carried out on 921 apparently healthy camels randomly selected from those imported from Sudan and kept in the quarantine stations in the Shalateen area of the Red Sea Governorate, Egypt, between June 2018 and January 2019. Serum samples were collected and analyzed using BPAT, RBT, and i-ELISA. The posterior estimates [medians and 95% Bayesian probability intervals (95% BPI)] for Se and Sp of the three serological tests were obtained using Bayesian latent class models (BLCMs). The BLCM was fitted with the assumption that the BPAT and RBT tests were conditionally dependent on the true brucellosis status of camels. All tests had comparable and high Se (>86%) and Sp (>98%). The animal-level true prevalence of Brucella infection in imported camels was 8.6% (95% BPI: 6.8 - 10.7). Based on these findings, the three assays could be used for the initial screening of Brucella infection in camels. However, the BPAT and RBT are more suitable for use in camel brucellosis control and eradication program in Egypt because of their low unit cost and fast turnaround time compared to the i-ELISA. In addition, BPAT and RBT could be performed in the field where in-vivo tests are rarely used due to logistic and management constraints.

The prognostic roles of PYCR2 and ZBTB18 expression in tissues of colorectal carcinoma and non-neoplastic tissues: an immunohistochemical study

Background: It is important to detect novel biomarkers responsible for the progression and spread of colorectal cancer (CRC) to better evaluate the prognosis of the patients, provide better management, and foster the development of therapeutic targets. In humans, pyrroline-5-carboxylate reductase 2 (PYCR2) is encoded on chromosome 1q42.12, and its metabolic activity has been linked to oncogenesis in many cancers. Zinc finger and broad-complex, tramtrack, and bric-à-brac (BTB) domain-containing protein 18 (ZBTB18), a zinc finger transcriptional repressor, has been found to have a tumor-suppressor role and to be methylated in CRCs. To date, the prognostic roles of PYCR2 and ZBTB18 in CRC patients have not been thoroughly studied. Objective: To evaluate the tissue protein expression of PYCR2 and ZBTB18 in CRC and adjacent non-neoplastic intestinal tissues, to detect their roles in CRC carcinogenesis, progression and metastases. Patients and methods: After applying the inclusion criteria, 60 CRC patients were included in the study. Tissue samples from the tumor and the adjacent non-neoplastic tissues were stained with PYCR2 and ZBTB18. The patients were followed up for about 30 months (range: 10 to 36 months). We performed a correlation regarding the expression of the markers, and clinicopathological and prognostic parameters. Results Upregulation of PYCR2 and downregulation of ZBTB18 were found to be higher in CRC tissue than in the adjacent non-neoplastic colonic mucosa (p = 0.026 and p < 0.001 respectively). High expression of PYCR2 and low expression of ZBTB18 were positively correlated with large tumor size, higher tumor grade, advanced tumor stage, presence of spread to lymph nodes, and presence of distant metastases (p < 0.001). High PYCR2 and low ZBTB18 expressions were significantly associated with poor response to therapy (p = 0.008 and 0.0.17 respectively), as well as high incidence of progression and recurrence (p = 0.005), and unfavorable overall survival (OS) rates (p = 0.001). Conclusion: High expression of PYCR2 and low expression of ZBTB18 were independent predictors of CRC, progression, poor prognosis and unfavorable patient OS and progression-free survival (PFS) rates. (AU)

Lateralized readiness potentials can identify hemisphere of recovery in stroke patients.

BACKGROUND: Event related cortical potentials related to motor action are referred to as movement related cortical potentials. The late component of which is the readiness potential (RP) and its polarity is more negative in the hemisphere responsible for planning of motor action. This lateralized nature of RP during unilateral hand movement is studied as lateralized readiness potential (LRP) by calculating the contralateral-minus-ipsilateral difference wave for each hand. OBJECTIVE: The aim was to identify the hemisphere contributing to motor recovery in acute and chronic stroke patients through recording LRPs. METHODS: Twenty-nine cases with cerebrovascular stroke (15 acute and 14 chronic) were included in the study. EEG was recorded in response to self-cued button presses by the paretic side to obtain the averaged LRP amplitude. The hemisphere with greater negativity was considered the side of recovery. Functional recovery was assessed by Fugl Meyer test. RESULTS: In acute cases, recovery was more related to LRP activity in the contralesional hemisphere (73%), whereas lateralization was equal in chronic cases; 50% in either group. LRP amplitude was higher in the contralesional hemisphere (p = 0.02). Functional recovery assessed by the Fugl Meyer test (FM) was similar whether recovery was ipsi- or contralesional. CONCLUSIONS: Early after stroke, motor recovery is more likely to involve compensatory activity in the contralesional hemisphere, while in the chronic phase, the ipsilesional hemisphere may recover its function and become more active. Further research is needed to verify if the technique mentioned in our study could be used to guide customized NIBS protocols tailoring the optimal site and parameters for each patient.

A Randomized Controlled Trial for Prevention of Postspinal Anesthesia Shivering in Gynecological Surgeries: Mirtazapine vs. Dexamethasone.

Background: The frequency of shivering regarding regional anesthesia is 55%. Newer effective and tolerable options for postspinal anesthesia shivering (PSAS) prophylaxis are necessary to improve patients' quality of care. This research assessed the impact of preemptive mirtazapine versus preemptive dexamethasone to decrease frequency and severity of PSAS in gynecological procedures. Methods: 300 patients booked for gynecological procedures under spinal anesthesia (SA) were randomly apportioned into three groups (100 each) to get one preemptive dose of 30 mg mirtazapine tablet (M group), 8 mg dexamethasone diluted in 100 ml of saline infusion (D group) or placebo (C group) two hours before surgery. Incidence of clinically significant PSAS was the primary outcome. Core temperature, shivering score, hemodynamics changes, adverse events, and patient satisfaction score were documented as secondary outcomes. Results: Compared with C group, mirtazapine and dexamethasone decreased incidence of clinically significant shivering (74% vs. 16% and 31%, respectively; P < 0.001). M and D groups had less hypotensive episodes during 5-25 min after intrathecal injection (P < 0.001). 90 min after SA, tympanic temperatures were lower than baseline values in the three groups (P < 0.001). Pruritus, nausea, and vomiting were more often in C group (P < 0.001), whereas sedation was more frequent in M group (P < 0.001). C group had the lowest satisfaction scores (P < 0.001). Conclusion: Prophylactic administration of mirtazapine or dexamethasone attenuated shivering with minimal hazards in patients scheduled for gynecological surgeries under spinal anesthesia with priority to mirtazapine. The trial is registered with NCT03675555.

A comparison between different management surgical approaches in the treatment of splenic flexure colon cancer

Background: There are many surgical approaches which described extent of resection of the colon for adequate surgicalmanagement of splenic flexure cancer, but up till now there is no established surgical procedure, this is because the presence of double lymphatic drainage of themesenteric vessels. Segmental resection of the colon for the management of splenic flexure cancer was a recently accepted surgical procedure. Objective: In the present study, we aimed to compare three surgical management techniques to clarify the best management approach of Egyptian patients with splenic flexure cancer regarding operative, clinical, and oncological outcomes: segmental resection, and extended left or right hemicolectomy,. Materials and Methods In the present study, we included 90 patients with splenic flexure cancer. Cases were divided into 3 groups. Each group included 30 patients in order to compare three surgical techniques: segmental resection, extended left hemicolectomy, and extended right hemicolectomy. Results: We have found no statistically significant differences between the three included groups regarding operative findings, postoperative complications, local recurrence, distant recurrence, disease progression, recurrence-free survival rate, progression-free survival rate, and overall survival rate. The operative time was longer, and the number of lymph nodes was higher in the extended right hemicolectomy group (p<0.001). Conclusion: We have shown that segmental resection of the splenic flexure is surgically and clinically suitable for the adequate management of operable cases of carcinoma of the splenic flexure. (AU)

Synthesis and Toxicological Effect of Some New Pyrrole Derivatives as Prospective Insecticidal Agents against the Cotton Leafworm, Spodoptera littoralis (Boisduval).

Herein, a series of biologically active pyrrole derivatives, namely 2-[(3-cyano-5-aryl-1H-pyrrol-2-yl)thio]acetic acids 2a-c, 2-[(2-hydroxyethyl)-thio]-5-aryl-1H-pyrrole-3-carbonitriles 3a-c, and 2-[(2-amino-ethyl)thio]-5-aryl-1H-pyrrole-3-carbonitriles 4a-c, 2,2'-disulfanediylbis(5-aryl-1H-pyrrole-3-carbonitriles) 5a-c, 2-((3-cyano-5-aryl-1H-pyrrol-2-yl)thio)acetates 6a-c, 2-[(3-cyano-5-phenyl-1H-pyrrol-2-yl)thio]acetohydrazides 7a-c, and 2-{2-[(3-cyano-5-aryl-1H-pyrrol-2-yl)thio]acetyl}-N-phenyl-hydrazinecarbothioamides 8a-c, as insecticidal agents, were synthesized via adaptable, smoothly accessible 2-(2-oxo-2-arylylethyl)malononitriles 1a-c. The structures were proved using infrared (IR), nuclear magnetic resonance (NMR), and mass spectrum (MS) techniques. Under laboratory conditions, the toxicological characteristics were tested towards Spodoptera littoralis, cotton leafworm insect type. In respect to the LC50 values, compounds 6a, 7a, 8c, and 3c possess the highest insecticidal bioefficacy, with values of 0.5707, 0.1306, 0.9442, and 5.883 ppm, respectively. The study paves the way towards discovering new materials for potential use as insecticidal active agents.

Management of Severe Traumatic Brain Injury: A Single Institution Experience in a Middle-Income Country.

Introduction: Severe traumatic brain injury (TBI) is a major public health problem usually resulting in mortality or severe disabling morbidities of the victims. Intracranial pressure (ICP) monitoring is recently recognized as an imperative modality in the management of severe TBI, whereas growing evidence, based on randomized controlled trials (RCTs), suggests that ICP monitoring does not affect the outcome when compared with clinical and radiological data-based management. Also, ICP monitoring carries a considerable risk of intracranial infection that cannot be overlooked. The aim of this study is to assess the different aspects of our current local institutional management of severe TBI using non-invasive ICP monitoring for a potential need to change our management strategy. Methods: We retrospectively reviewed our data of TBI from June 2019 through January 2020. Patients with severe TBI were identified. Their demographics, Glasgow coma score (GCS) at presentation, treatments received, and imaging data were extracted from the charts. Glasgow outcome scale extended (GOS-E) at 6 months was also assessed for the patients. Results: Twenty patients with severe TBI were identified on chart review. Ten patients received only medical treatment measures to lower the ICP, whereas the other 10 patients had additional surgical interventions. In one patient, a ventriculostomy tube was inserted to monitor ICP and to drain cerebrospinal fluid (CSF). This was complicated by ventriculostomy-associated infection (VAI) and the tube was removed. In our cohort, the total mortality rate was 40%. The average GOS-E for the survivor patients managed without ICP monitoring based on the clinical and radiological data was 6.2 at 6 months follow-up. The 6-month overall good outcome, based on GOS-E, was 33.3%. Conclusion: Although recent guidelines advocate for the use of ICP monitoring in the management of severe TBI, they remain underutilized in our practice due to many factors. External ventricular drains were mainly used to drain CSF; however, the higher rates of VAIs in our institution compared with the literature-reported rates are not in favor of the use of ICP monitoring. We recommend doing a comparative study between our current practice using clinical-and radiological-based management and subdural or intraparenchymal bolts. More structured RCTs are needed to validate these findings in our setting.

Green Synthesis of Zinc Oxide Nanoparticles (ZnO-NPs) by Pseudomonas aeruginosa and Their Activity against Pathogenic Microbes and Common House Mosquito, Culex pipiens.

The synthesis of nanoparticles by green approaches is gaining unique importance due to its low cost, biocompatibility, high productivity, and purity, and being environmentally friendly. Herein, biomass filtrate of Pseudomonas aeruginosa isolated from mangrove rhizosphere sediment was used for the biosynthesis of zinc oxide nanoparticles (ZnO-NPs). The bacterial isolate was identified based on morphological, physiological, and 16S rRNA. The bio-fabricated ZnO-NPs were characterized using color change, UV-visible spectroscopy, FT-IR, TEM, and XRD analyses. In the current study, spherical and crystalline nature ZnO-NPs were successfully formed at a maximum SPR (surface plasmon resonance) of 380 nm. The bioactivities of fabricated ZnO-NPs including antibacterial, anti-candida, and larvicidal efficacy were investigated. Data analysis showed that these bioactivities were concentration-dependent. The green-synthesized ZnO-NPs exhibited high efficacy against pathogenic Gram-positive bacteria (Staphylococcus aureus and Bacillus subtilis), Gram-negative bacteria (Escherichia coli and Pseudomonas aeruginosa), and unicellular fungi (Candida albicans) with inhibition zones of (12.33 ± 0.9 and 29.3 ± 0.3 mm), (19.3 ± 0.3 and 11.7 ± 0.3 mm), and (22.3 ± 0.3 mm), respectively, at 200 ppm. The MIC value was detected as 50 ppm for E. coli, B. subtilis, and C. albicans, and 200 ppm for S. aureus and P. aeruginosa with zones of inhibition ranging between 11.7 ± 0.3-14.6 ± 0.6 mm. Moreover, the biosynthesized ZnO-NPs showed high mortality for Culex pipiens with percentages of 100 ± 0.0% at 200 ppm after 24 h as compared with zinc acetate (44.3 ± 3.3%) at the same concentration and the same time.

Evaluating the value of Amphiregulin, Phosphatase and Tensin Homologue (PTEN) and P21 Expression for Anti-EGFR Treatment in Metastatic Colorectal Carcinoma.

BACKGROUND: Despite the significant progress in target therapy for the treatment of metastatic colorectal carcinoma (mCRC), the overall survival isn't satisfactory. METHODS: We assessed the expression of Amphiregulin, PTEN, and P21 in sections from 23 paraffin blocks prepared from 23 patients with left-sided mCRC using immunohistochemistry (IHC). The relationship between their level of expressions, clinicopathological parameters, response to anti-EGFR, and prognosis were analyzed. RESULTS: High Amphiregulin, PTEN and low P21 expression levels were associated with low tumor grade (p= 0.038 and 0.025 respectively), better response to anti-EGFR treatment (p <0.001), and favorable outcome {progression-free survival (PFS) and overall survival (OS)} (p <0.05). There was a direct relation between Amphiregulin and PTEN expressions (phi coefficient=+0.840), while there was an inverse relation between P21expression and both Amphiregulin (phi coefficient= -0.840) and PTEN expressions (phi coefficient = -1.000), which was statistically significant (P <0.001). CONCLUSION: High Amphiregulin and PTEN expression levels and low P21 expression levels were associated with better response to anti-EGFR therapy and improved survival outcome. They might be considered predictive markers of response to anti-EGFR therapy in mCRC.

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Prognostic Significances of NEDD-9 and FOXL-1 Expression in Intestinal Type Gastric Carcinoma: an Immunohistochemical Study.

BACKGROUND: Gastric cancer (GC) is mostly diagnosed at advanced stage, so prognosis is poor. Therefore, it is necessary to understand the molecular mechanism of GC development to design new targeted treatment to improve the prognosis of gastric cancer patients. AIM OF THE WORK: To assess the prognostic value of NEDD-9 and FOXL-1 expression in intestinal type gastric cancer patients, as well as their relationship to clinicopathologic features of the disease and patients outcome. PATIENTS AND METHODS: This is a retrospective study; we included 50 sections from formalin-fixed, paraffin-embedded tissue samples which included intestinal type GC and adjacent non-neoplastic gastric mucosa in the same block that were subjected to immunohistochemistry with anti-NEDD-9 and anti-FOXL-1 antibody. Patients were retrospectively followed up for about 5 years for assessment of tumor progression and survival in relation to marker expression. RESULTS: High NEDD-9 and low FOXL-1 expression were found in intestinal type GC more than adjacent non-neoplastic mucosa (p < 0.001). NEDD-9 high expression and FOXL-1 low expression were associated with presence of helicobacter pylori gastritis (p = 0.010, 0.049), high grade (p = 0.007, 0.004), high stage (p < 0.001), presence of distant metastases (p = 0.029, 0.021), poor DFS (p = 0.003), and OS rates (< 0.001). CONCLUSION: NEDD-9 overexpression and FOXL-1 deficiency in intestinal type GC can help in prediction of tumor prognosis and it can guide the selection of patients for future therapies in gastric carcinoma.