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Background: The present study aimed to investigate the sequence-dependent anticancer effects of combined treatment with sorafenib (Sora), a Food and Drug Administration-approved multikinase inhibitor drug, and plant-derived phytochemicals (PPCs) on human colorectal cancer (CRC) cell growth, and proteins associated with the control of cell cycle and apoptosis. Methods: The cytotoxic effects of 14 PPCs on CRL1554 fibroblast cells were determined using an MTT assay. Moreover, the cytotoxicity of Sora, PPCs, and a combination of both on CRC cells were also investigated. Cell cycle analysis was performed using flow cytometry, and cell apoptosis was investigated using DNA fragmentation, Annexin V/propidium iodide double staining, and mitochondrial membrane potential analyses. The cell cycle- and apoptosis-associated protein expression levels were analysed using western blotting. Results: Based on their low levels of cytotoxicity in CRL1554 cells at ≤ 20%, curcumin, quercetin, kaempferol, and resveratrol were selected for use in subsequent experiments. The combined treatment of sora and PPCs caused levels of CRC cytotoxicity in a dose-, cell type-, and schedule-dependent manner. Moreover, the combined treatment of CRC cells arrested cell growth at the S and G2/M phases, induced apoptotic cell death, caused extensive mitochondrial membrane damage, and altered the expression of the cell cycle and apoptotic proteins. Conclusions: Results of the present study highlighted a difference in the level of sora efficacy in CRC cells when combined with PPCs. Further in vivo and clinical studies using the combined treatment of sora and PPCs are required to determine their potential as a novel therapeutic strategy for CRCs. [ABSTRACT FROM AUTHOR]

Sphingosine-1-phosphate (S1P), a bioactive lipid mediator, is generated from sphingosine by sphingosine kinases (SPHKs) 1 and 2 and is metabolized to ∆2-hexadecenal (∆2-HDE) and ethanolamine phosphate by S1P lyase (S1PL) in mammalian cells. We have recently demonstrated the activation of nuclear SPHK2 and the generation of S1P in the nucleus of lung epithelial cells exposed to Pseudomonas aeruginosa. Here, we have investigated the nuclear localization of S1PL and the role of ∆2-HDE generated from S1P in the nucleus as a modulator of histone deacetylase (HDAC) activity and histone acetylation. Electron micrographs of the nuclear fractions isolated from MLE-12 cells showed nuclei free of ER contamination, and S1PL activity was detected in nuclear fractions isolated from primary lung bronchial epithelial cells and alveolar epithelial MLE-12 cells. Pseudomonasaeruginosa-mediated nuclear ∆2-HDE generation, and H3/H4 histone acetylation was attenuated by S1PL inhibitors in MLE-12 cells and human bronchial epithelial cells. In vitro, the addition of exogenous ∆2-HDE (100–10,000 nM) to lung epithelial cell nuclear preparations inhibited HDAC1/2 activity, and increased acetylation of Histone H3 and H4, whereas similar concentrations of S1P did not show a significant change. In addition, incubation of ∆2-HDE with rHDAC1 generated five different amino acid adducts as detected by LC-MS/MS; the predominant adduct being ∆2-HDE with lysine residues of HDAC1. Together, these data show an important role for the nuclear S1PL-derived ∆2-HDE in the modification of HDAC activity, histone acetylation, and chromatin remodeling in lung epithelial cells. [ABSTRACT FROM AUTHOR]

Patients undergoing carotid endarterectomy (CEA) may experiment neurologic deficits during the carotid cross-clamping due to secondary cerebral hypoperfusion. An associated risk of postoperative stroke incidence is also well established. This work aimed to assess the postoperative adverse events related to neurologic deficits in the awake test after clamping and to determine its predictive factors. Methods. From January 2012 to January 2018, 79 patients from a referral hospital that underwent CEA with regional anesthesia for carotid stenosis and manifested neurologic deficits were gathered. Consecutively selected controls (n = 85) were submitted to the same procedure without developing neurological changes. Postoperative complications such as stroke, myocardial infarction, all-cause death, and Clavien–Dindo classification were assessed 30 days after the procedure. Univariate and binary logistic regressions were performed for data assessment. Results. Patients with clamping associated neurologic deficits were significantly more obese than the control group (aOR = 9.30; 95% CI: 2.57–33.69; p =.01). Lower degree of ipsilateral stenosis and higher degree of contralateral stenosis were independently related to clamping intolerance (aOR = 0.70; 95% CI: 0.49–0.99; p =.047 and aOR = 1.30; 95% CI: 1.06–1.50; p =.009, respectively). Neurologic deficits were a main 30-day stroke predictor (aOR = 4.30; 95% CI: 1.10–16.71; p =.035). Conclusions. Neurologic deficits during carotid clamping are a predictor of perioperative stroke. Body mass index > 30 kg/m2, a lower degree of ipsilateral stenosis, and a higher degree of contralateral stenosis are independent predictors of neurologic deficits and, therefore, might play a role in the prevention of procedure-related stroke. [ABSTRACT FROM AUTHOR]

Background: Acute treatment of cerebral edema and elevated intracranial pressure is a common issue in patients with neurological injury. Practical recommendations regarding selection and monitoring of therapies for initial management of cerebral edema for optimal efficacy and safety are generally lacking. This guideline evaluates the role of hyperosmolar agents (mannitol, HTS), corticosteroids, and selected non-pharmacologic therapies in the acute treatment of cerebral edema. Clinicians must be able to select appropriate therapies for initial cerebral edema management based on available evidence while balancing efficacy and safety.Methods: The Neurocritical Care Society recruited experts in neurocritical care, nursing, and pharmacy to create a panel in 2017. The group generated 16 clinical questions related to initial management of cerebral edema in various neurological insults using the PICO format. A research librarian executed a comprehensive literature search through July 2018. The panel screened the identified articles for inclusion related to each specific PICO question and abstracted necessary information for pertinent publications. The panel used GRADE methodology to categorize the quality of evidence as high, moderate, low, or very low based on their confidence that the findings of each publication approximate the true effect of the therapy.Results: The panel generated recommendations regarding initial management of cerebral edema in neurocritical care patients with subarachnoid hemorrhage, traumatic brain injury, acute ischemic stroke, intracerebral hemorrhage, bacterial meningitis, and hepatic encephalopathy.Conclusion: The available evidence suggests hyperosmolar therapy may be helpful in reducing ICP elevations or cerebral edema in patients with SAH, TBI, AIS, ICH, and HE, although neurological outcomes do not appear to be affected. Corticosteroids appear to be helpful in reducing cerebral edema in patients with bacterial meningitis, but not ICH. Differences in therapeutic response and safety may exist between HTS and mannitol. The use of these agents in these critical clinical situations merits close monitoring for adverse effects. There is a dire need for high-quality research to better inform clinicians of the best options for individualized care of patients with cerebral edema. [ABSTRACT FROM AUTHOR]

INTRODUCTION: Carbon monoxide (CO) is a toxic gas with potential for detriment to spaceflight operations. An analytical model was developed to investigate if a maximum CO contamination of 1 ppm in the oxygen (02) supply reached dangerous levels during extravehicular activity (EVA). Occupational monitoring pre- and postsuited exposures provided supplementary data for review. METHODS: The analytical model estimated 02 and CO concentrations in the extravehicular mobility unit (EMU) based on 02 and CO flow rates into and out of the system. The model was based on 3 h of prebreathe at 15.2 psia, 8 h of EVA at 4.3 psia, and 1 h at 15.2 psia for suit doffing. The Coburn-Forster-Kane equation was used to calculate crewmember carboxyhemoglobin saturation (COHb%) as a function of time. Monitoring of hemoglobin CO saturation (Spco) with a CO-oximeter was conducted pre- and post-EVA during operations on the International Space Station and in ground-based analog environments. RESULTS: The model predicted a maximum PCO in the EMU of 0.061 mmHg and a maximum crewmember COHb% of 2.1 %. Operational Spco measurements in mean ± SD during ground-based analog testing were 0.7% ± 1.8% pretest and 0.5% ± 1.5% posttest. Spco values on the ISS were 1.5% ± 0.7% pre-EVA and 1.1 % ± 0.3% post-EVA. DISCUSSION: The model predicted that astronauts are not exposed to toxic levels of CO during EVA and operational measurements did not show significant differences between Spco levels between pre- and post-EVA. [ABSTRACT FROM AUTHOR]

Background: Stroke is common in tuberculous meningitis (TBM), and aspirin has been shown to reduce mortality. A combination of aspirin and corticosteroid may be more useful in this condition.Aim: To evaluate the effect of aspirin and corticosteroid adjunctive therapy alone or in combination in determining the outcome of TBM.Materials and Methods: One hundred and fifty-three patients with TBM were evaluated from a prospectively maintained registry. The diagnosis of TBM was based on the clinical, magnetic resonance imaging (MRI)/computed tomography (CT), and cerebrospinal fluid criteria. The baseline clinical, laboratory, and radiological findings were noted. All patients received the standard 4-drug antituberculous (rifampicin, isoniazid, pyrazinamide, and ethambutol) treatment. Group I patients received in addition, aspirin, in the dose of 150 mg daily; group II patients received aspirin 150 mg plus prednisolone 40 mg daily; and, group III patients received none of these adjunctive therapies. The outcome at 3 months was defined in terms of death or functional disability.Results: Group I had 44, group II had 50, and group III had 41 patients. The baseline characteristics of all these patients were similar, except in group II, where patients had more severe meningitis and focal deficits compared to the patients in group I and III. At 3 months, 32 (23%) patients died; 8 (18.2%) in group I, 9 (18%) in group II, and 14 (34.1%) in group III. There was insignificant survival benefit in group II (hazard ratio [HR], 1.55; 95% confidence interval (CI), 0.96-26.49; P = 0.07). The three-month functional outcome and side effects were not significantly different in the three groups.Conclusion: Aspirin with corticosteroid adjunctive treatment seems to be beneficial in reducing mortality in TBM. [ABSTRACT FROM AUTHOR]

The present study aimed to investigate the effects of dietary supplementation with powdered peanut skin (PS) as natural antioxidant and growth promoter on growth performance, carcass characteristics, serum metabolites and meat quality of Cobb broiler chickens. A total of 240 unsexed Cobb 500 1-week-old broiler chicks were randomly assigned to four treatment groups with six replicates. The dietary treatments consisted of the basal diet as control and PS groups (1.0, 2.0, and 3.0 PS g/kg). Results showed that the highest values (P < 0.01) of live bodyweight and bodyweight gain were observed in the control group at 3 weeks of age and during the period of 1-3 weeks of age, respectively compared with all levels of PS. During 1-3 weeks of age, feed intake per day chicks fed the diet containing PS levels decreased numerically (P> 0.01) with increased levels of PS compared with the control. Supplementing 1.0 or 3.0 g/kg of PS insignificantly enhanced feed conversion ratio at 1-6 weeks of age. Dietary treatments significantly depressed giblets (P = 0.002), thigh (P = 0.0.027) and abdominal fat percentages (P>0.0.1), however, increased (P=0.004) breast percentage of broiler chicks at 6 weeks of age. The lowest value of serum creatinine and urea achieved by chicks fed diet contained 3.0 PS g/kg diet. Also, high density lipoprotein cholesterol in addition to triglycerides were significantly (P < 0.05 and P < 0.01) decreased with increasing level of PS supplementation. It can be concluded that PS as a phytogenic additive could be used as a supplementation to broiler diets to lower abdominal fat in carcass and cholesterol, creatinin and urea in blood. Sensory characteristics were not affected except that appearance was improved. Water-holding capacity was also improved. [ABSTRACT FROM AUTHOR]

Rheumatoid arthritis (RA) is a systemic autoimmune disease whose major characteristics persistent joint inflammation that results in joint destruction and failure of the function. Collagen-induced arthritis (CIA) rat is an autoimmune disease model and in many ways shares features with RA. The CIA is associated with systemic manifestations, including alterations in the metabolism. Nuclear magnetic resonance (NMR) spectroscopy-based metabolomics has been successfully applied to the perchloric acid extract of the joint tissue of CIA rat and control rat for the analysis of aqueous metabolites. GPC (Glycerophosphocholine), carnitine, acetate, and creatinine were important discriminators of CIA rats as compared to control rats. Level of lactate (significance; p = 0.004), alanine (p = 0.025), BCA (Branched-chain amino acids) (p = 0.006) and creatinine (p = 0.023) was significantly higher in CIA rats as compared to control rats. Choline (p = 0.038) and GPC (p = 0.009) were significantly reduced in CIA rats as compared to control rats. Choline to GPC correlation was good and negative (Pearson correlation = -0.63) for CIA rats as well as for control rats (Pearson correlation = -0.79). All these analyses collectively considered as metabolic fingerprinting of the joint tissue of CIA rat as compared to control rat. The metabolic fingerprinting of joint tissue of CIA rats was different as compared to control rats. The metabolic fingerprinting reflects inflammatory disease activity in CIA rats with synovitis, demonstrating that underlying inflammatory process drives significant changes in metabolism that can be measured in the joint tissue. Therefore, the outcome of this study may be helpful for understanding the mechanism of metabolic processes in RA. This may be also helpful for the development of advanced diagnostic methods and therapy for RA. [ABSTRACT FROM AUTHOR]

Background: Arterial shunting during carotid endarterectomy (CEA) is essential in some patients because of insufficient cerebral perfusion during cross-clamping. However, the optimal diagnostic modality identifying these patients is still debated. None of the currently used modalities has been proved superior to another. The aim of this study was to assess the cost-effectiveness of two modalities, stump pressure measurement (SPM) versus electroencephalography (EEG) combined with transcranial Doppler (TCD) during CEA. Methods: Two retrospective cohorts of consecutive patients undergoing CEA with different intraoperative neuromonitoring strategies (SPM vs. EEG/TCD) were analyzed. Clinical data were collected from patient hospital records. Primary clinical outcome was in-hospital stroke or death. Total admission costs were calculated based on volumes of healthcare resources. Analyses of effects and costs were adjusted for clinical differences between patients by means of a propensity score, and cost-effectiveness was estimated. Results: A total of 503 (239 SPM; 264 EEG/TCD) patients were included, of whom 19 sustained a stroke or died during admission (3.3 vs. 4.2%, respectively, adjusted risk difference 1.3% (95% CI −2.3-4.8%)). Median total costs were €4946 (IQR 4424-6173) in the SPM group versus €7447 (IQR 6890-8675) in the EEG/TCD group. Costs for neurophysiologic assessments were the main determinant for the difference. Conclusions: Given the evidence provided by this small retrospective study, SPM would be the favored strategy for intraoperative neuromonitoring if cost-effectiveness was taken into account when deciding which strategy to adopt. [ABSTRACT FROM AUTHOR]

Aberrant promoter methylation of multiple genes is associated with various diseases, including Alzheimer's disease (AD). The goal of the present study was to determine whether dopamine receptor D4 (DRD4) promoter methylation is associated with AD. In the current study, the methylation levels of the DRD4 promoter were measured in 46 AD patients and 61 controls using bisulfite pyrosequencing technology. The results of the present study demonstrated that DRD4 promoter methylation was significantly higher in AD patients than in controls. A further breakdown analysis by gender revealed that there was a significant association of DRD4 promoter methylation with AD in males (23 patients and 45 controls). In conclusion, the results of the present study demonstrated that elevated DRD4 promoter methylation was associated with AD risk in males. [ABSTRACT FROM AUTHOR]

The study was conducted to evaluate the suitability of using immature jackfruit and chevon meat in emulsion-based products preparation and to assess their quality during refrigerated storage. Chevon meat patties (treatments T2, T3 and T4) were prepared in which chevon meat was substituted with 10%, 20% and 30% immature jackfruit and compared with patties from chevon meat (control T1). The addition of jackfruit in chevon meat patties overall significantly (P< 0.05) influenced proximate analysis, physico-chemical characteristics, textural profile, microbiological profile and sensory scores of the products. Results also showed significant (P< 0.05) effect of jackfruits on storage qualities of the chevon meat patties under refrigerated storage (4°C ± 1°C) for about nine days. The patties remained stable with minor changes in physico-chemical, microbiological and sensory quality during refrigerated storage for nine days. Hence chevon meat and immature jackfruit effectively be utilized in developing patties. [ABSTRACT FROM PUBLISHER]