New pyridine and chromene scaffolds as potent vasorelaxant and anticancer agents

Based on studies that have reported the association between cancer and cardiovascular diseases, new series of pyridine- (3a-o) and/or chromene- (4a-e) carbonitrile analogous were designed, synthesized and screened for their vasodilation and cytotoxic properties. The majority of the new chemical entities demonstrated significant vasodilation efficacies, compounds 3a, 3h, 3j, 3m, 3o, 4d and 4e exhibited the most promising potency with IC50 = 437.9, 481.0, 484.5, 444.8, 312.1, 427.6 and 417.2 µM, respectively, exceeding prazosin hydrochloride (IC50 = 487.3 μM). Compounds 3b-e, 3k and 3l also, revealed moderate vasodilation activity with IC50 values ranging from 489.7 to 584.5 µM. In addition, the anti-proliferative activity evaluation of the experimental compounds at 10 µM on the MCF-7 and MDA-MB 231 breast cancer cell lines illustrated the excellent anti-proliferative properties of derivatives 3d, 3g and 3i. Compound 3d was the most potent analogue with IC50 = 4.55 ± 0.88 and 9.87 ± 0.89 µM against MCF-7 and MDA-MB 231, respectively. Moreover, compound 3d stimulated apoptosis and cell cycle arrest at the S phase in MCF-7 cells in addition to its capability in accumulation of cells in pre-G1phase and activating caspase-3. Furthermore, the molecular docking of 3d was performed to discover the binding modes within the active site of caspase-3. 3d, as the only common bi-functional agent among the tested hits, demonstrated that new pyridine-3-carbonitrile derivatives bearing cycloheptyl ring systems offer potential as new therapeutic candidates with combined vasodilation and anticancer properties

Antimicrobial resistance among migrants in Europe: a systematic review and meta-analysis

BACKGROUND: Rates of antimicrobial resistance (AMR) are rising globally and there is concern that increased migration is contributing to the burden of antibiotic resistance in Europe. However, the effect of migration on the burden of AMR in Europe has not yet been comprehensively examined. Therefore, we did a systematic review and meta-analysis to identify and synthesise data for AMR carriage or infection in migrants to Europe to examine differences in patterns of AMR across migrant groups and in different settings. METHODS: For this systematic review and meta-analysis, we searched MEDLINE, Embase, PubMed, and Scopus with no language restrictions from Jan 1, 2000, to Jan 18, 2017, for primary data from observational studies reporting antibacterial resistance in common bacterial pathogens among migrants to 21 European Union-15 and European Economic Area countries. To be eligible for inclusion, studies had to report data on carriage or infection with laboratory-confirmed antibiotic-resistant organisms in migrant populations. We extracted data from eligible studies and assessed quality using piloted, standardised forms. We did not examine drug resistance in tuberculosis and excluded articles solely reporting on this parameter. We also excluded articles in which migrant status was determined by ethnicity, country of birth of participants' parents, or was not defined, and articles in which data were not disaggregated by migrant status. Outcomes were carriage of or infection with antibiotic-resistant organisms. We used random-effects models to calculate the pooled prevalence of each outcome. The study protocol is registered with PROSPERO, number CRD42016043681. FINDINGS: We identified 2274 articles, of which 23 observational studies reporting on antibiotic resistance in 2319 migrants were included. The pooled prevalence of any AMR carriage or AMR infection in migrants was 25·4% (95% CI 19·1-31·8; I2 =98%), including meticillin-resistant Staphylococcus aureus (7·8%, 4·8-10·7; I2 =92%) and antibiotic-resistant Gram-negative bacteria (27·2%, 17·6-36·8; I2 =94%). The pooled prevalence of any AMR carriage or infection was higher in refugees and asylum seekers (33·0%, 18·3-47·6; I2 =98%) than in other migrant groups (6·6%, 1·8-11·3; I2 =92%). The pooled prevalence of antibiotic-resistant organisms was slightly higher in high-migrant community settings (33·1%, 11·1-55·1; I2 =96%) than in migrants in hospitals (24·3%, 16·1-32·6; I2 =98%). We did not find evidence of high rates of transmission of AMR from migrant to host populations. INTERPRETATION: Migrants are exposed to conditions favouring the emergence of drug resistance during transit and in host countries in Europe. Increased antibiotic resistance among refugees and asylum seekers and in high-migrant community settings (such as refugee camps and detention facilities) highlights the need for improved living conditions, access to health care, and initiatives to facilitate detection of and appropriate high-quality treatment for antibiotic-resistant infections during transit and in host countries. Protocols for the prevention and control of infection and for antibiotic surveillance need to be integrated in all aspects of health care, which should be accessible for all migrant groups, and should target determinants of AMR before, during, and after migration. FUNDING: UK National Institute for Health Research Imperial Biomedical Research Centre, Imperial College Healthcare Charity, the Wellcome Trust, and UK National Institute for Health Research Health Protection Research Unit in Healthcare-associated Infections and Antimictobial Resistance at Imperial College London

Surgical site infection after gastrointestinal surgery in high-income, middle-income, and low-income countries: a prospective, international, multicentre cohort study

Background: Surgical site infection (SSI) is one of the most common infections associated with health care, but its importance as a global health priority is not fully understood. We quantified the burden of SSI after gastrointestinal surgery in countries in all parts of the world. Methods: This international, prospective, multicentre cohort study included consecutive patients undergoing elective or emergency gastrointestinal resection within 2-week time periods at any health-care facility in any country. Countries with participating centres were stratified into high-income, middle-income, and low-income groups according to the UN's Human Development Index (HDI). Data variables from the GlobalSurg 1 study and other studies that have been found to affect the likelihood of SSI were entered into risk adjustment models. The primary outcome measure was the 30-day SSI incidence (defined by US Centers for Disease Control and Prevention criteria for superficial and deep incisional SSI). Relationships with explanatory variables were examined using Bayesian multilevel logistic regression models. This trial is registered with ClinicalTrials.gov, number NCT02662231. Findings: Between Jan 4, 2016, and July 31, 2016, 13 265 records were submitted for analysis. 12 539 patients from 343 hospitals in 66 countries were included. 7339 (58·5%) patient were from high-HDI countries (193 hospitals in 30 countries), 3918 (31·2%) patients were from middle-HDI countries (82 hospitals in 18 countries), and 1282 (10·2%) patients were from low-HDI countries (68 hospitals in 18 countries). In total, 1538 (12·3%) patients had SSI within 30 days of surgery. The incidence of SSI varied between countries with high (691 [9·4%] of 7339 patients), middle (549 [14·0%] of 3918 patients), and low (298 [23·2%] of 1282) HDI (p < 0·001). The highest SSI incidence in each HDI group was after dirty surgery (102 [17·8%] of 574 patients in high-HDI countries; 74 [31·4%] of 236 patients in middle-HDI countries; 72 [39·8%] of 181 patients in low-HDI countries). Following risk factor adjustment, patients in low-HDI countries were at greatest risk of SSI (adjusted odds ratio 1·60, 95% credible interval 1·05–2·37; p=0·030). 132 (21·6%) of 610 patients with an SSI and a microbiology culture result had an infection that was resistant to the prophylactic antibiotic used. Resistant infections were detected in 49 (16·6%) of 295 patients in high-HDI countries, in 37 (19·8%) of 187 patients in middle-HDI countries, and in 46 (35·9%) of 128 patients in low-HDI countries (p < 0·001). Interpretation: Countries with a low HDI carry a disproportionately greater burden of SSI than countries with a middle or high HDI and might have higher rates of antibiotic resistance. In view of WHO recommendations on SSI prevention that highlight the absence of high-quality interventional research, urgent, pragmatic, randomised trials based in LMICs are needed to assess measures aiming to reduce this preventable complication

Impact of opioid-free analgesia on pain severity and patient satisfaction after discharge from surgery: multispecialty, prospective cohort study in 25 countries

Background: Balancing opioid stewardship and the need for adequate analgesia following discharge after surgery is challenging. This study aimed to compare the outcomes for patients discharged with opioid versus opioid-free analgesia after common surgical procedures.Methods: This international, multicentre, prospective cohort study collected data from patients undergoing common acute and elective general surgical, urological, gynaecological, and orthopaedic procedures. The primary outcomes were patient-reported time in severe pain measured on a numerical analogue scale from 0 to 100% and patient-reported satisfaction with pain relief during the first week following discharge. Data were collected by in-hospital chart review and patient telephone interview 1 week after discharge.Results: The study recruited 4273 patients from 144 centres in 25 countries; 1311 patients (30.7%) were prescribed opioid analgesia at discharge. Patients reported being in severe pain for 10 (i.q.r. 1-30)% of the first week after discharge and rated satisfaction with analgesia as 90 (i.q.r. 80-100) of 100. After adjustment for confounders, opioid analgesia on discharge was independently associated with increased pain severity (risk ratio 1.52, 95% c.i. 1.31 to 1.76; P &lt; 0.001) and re-presentation to healthcare providers owing to side-effects of medication (OR 2.38, 95% c.i. 1.36 to 4.17; P = 0.004), but not with satisfaction with analgesia (beta coefficient 0.92, 95% c.i. -1.52 to 3.36; P = 0.468) compared with opioid-free analgesia. Although opioid prescribing varied greatly between high-income and low- and middle-income countries, patient-reported outcomes did not.Conclusion: Opioid analgesia prescription on surgical discharge is associated with a higher risk of re-presentation owing to side-effects of medication and increased patient-reported pain, but not with changes in patient-reported satisfaction. Opioid-free discharge analgesia should be adopted routinely

New Thiophenyl-pyrazolyl-thiazole Hybrids as DHFR Inhibitors: Design, Synthesis, Antimicrobial Evaluation, Molecular Modeling, and Biodistribution Studies

The antibiotic resistance problems constitute a considerable threat to human health worldwide; thus, the discovery of new antimicrobial candidates to conquer this issue is an imperative requirement. From this view, new thiophenyl-pyrazolyl-thiazole hybrids 3–10 were synthesized and screened for their antibacterial efficiency versus Gram – and Gram + bacterial strains compared to the reference drug amoxicillin. It was noticed that the new hybrids displayed significant antibacterial efficacy versus Gram – bacteria, especially against Pseudomonas aeruginosa. Also, all the screened candidates demonstrated a noticeable antifungal effect against Candida albicans (MICs = 3.9–125 μg/mL) relative to fluconazole (MIC = 250 μg/mL). Moreover, the new hybrids were investigated for their antituberculosis potency against Mycobacterium tuberculosis (RCMB 010126). Derivatives 4c, 6b, 8b, 9b, and 10b demonstrated prominent antituberculosis efficiency (MICs = 0.12–1.95 μg/mL) compared with the reference drug isoniazid (MIC = 0.12 μg/mL). The latter derivatives were further assessed for their inhibitory potency versus M. tuberculosis DHFR enzyme. The compounds 4c, 6b and 10b presented a remarkable suppression effect with IC50 values of 4.21, 5.70, and 10.59 μM, respectively, compared to that of trimethoprim (IC50 = 6.23 μM). Furthermore, biodistribution profile using radiolabeling way revealed a perceived uptake of 131I-compound 6b into infection induced models. The docking study for the new hybrids 4c, 6b, 8b, 9b and 10b was performed to illustrate the various binding modes with Mtb DHFR enzyme. In silico ADMET studies for the most potent inhibitors 4c, 6b and 10b were also accomplished to predict their pharmacokinetic and physicochemical features

Suppression of type 2 diabetes mellitus-induced aortic ultrastructural alterations in rats by insulin:an association of vascular injury biomarkers

Diabetes represents a major public health problem and an estimated 70% of people with diabetes die of cardiovascular complications. The protective effect of insulin treatment against ultrastructural damage to the tunica intima and tunica media of the aorta induced by type 2 diabetes mellitus (T2DM) has not been investigated before using transmission electron microscopy (TEM). Therefore, we induced T2DM in rats using high fat diet and streptozotocin (50 mg/kg) and administered insulin daily by i.v injection for 8 weeks to the treatment group. Whereas, the T2DM control group were left untreated for the duration of the experiment. A comparison was also made between the effect of insulin on aortic tissue and the blood level of biomarkers of vascular injury, inflammation, and oxidative stress. T2DM induced profound ultrastructural damage to the aortic endothelium and vascular smooth muscle cells, which were substantially protected with insulin. Furthermore, insulin returned blood sugar to a control level and significantly (p &lt; .05) inhibited diabetic up-regulation of endothelial and leukocyte intercellular adhesion molecule-1 (ICAM-1), vascular cell adhesion protein 1 (VCAM-1), endothelial cell adhesion molecules, P-selectin and E-selectin, tumor necrosis factor-alpha (TNF-α), C-reactive protein (CRP), and malondialdehyde (MDA). Furthermore, insulin augmented the blood level of the anti-oxidant enzyme superoxide dismutase (SOD). We conclude that in a rat model of T2DM, insulin treatment substantially reduces aortic injury secondary to T2DM for a period of 8 weeks, possibly due to the inhibition of hyperglycemia, vascular activation, inflammation, and oxidative stress.</p

Suppression of type 2 diabetes mellitus-induced aortic ultrastructural alterations in rats by insulin:an association of vascular injury biomarkers

Diabetes represents a major public health problem and an estimated 70% of people with diabetes die of cardiovascular complications. The protective effect of insulin treatment against ultrastructural damage to the tunica intima and tunica media of the aorta induced by type 2 diabetes mellitus (T2DM) has not been investigated before using transmission electron microscopy (TEM). Therefore, we induced T2DM in rats using high fat diet and streptozotocin (50 mg/kg) and administered insulin daily by i.v injection for 8 weeks to the treatment group. Whereas, the T2DM control group were left untreated for the duration of the experiment. A comparison was also made between the effect of insulin on aortic tissue and the blood level of biomarkers of vascular injury, inflammation, and oxidative stress. T2DM induced profound ultrastructural damage to the aortic endothelium and vascular smooth muscle cells, which were substantially protected with insulin. Furthermore, insulin returned blood sugar to a control level and significantly (p &lt; .05) inhibited diabetic up-regulation of endothelial and leukocyte intercellular adhesion molecule-1 (ICAM-1), vascular cell adhesion protein 1 (VCAM-1), endothelial cell adhesion molecules, P-selectin and E-selectin, tumor necrosis factor-alpha (TNF-α), C-reactive protein (CRP), and malondialdehyde (MDA). Furthermore, insulin augmented the blood level of the anti-oxidant enzyme superoxide dismutase (SOD). We conclude that in a rat model of T2DM, insulin treatment substantially reduces aortic injury secondary to T2DM for a period of 8 weeks, possibly due to the inhibition of hyperglycemia, vascular activation, inflammation, and oxidative stress.</p

Metformin Protects against Diabetic Cardiomyopathy: An Association between Desmin–Sarcomere Injury and the iNOS/mTOR/TIMP-1 Fibrosis Axis

The intermediate filament protein desmin is essential for maintaining the structural integrity of sarcomeres, the fundamental unit of cardiac muscle. Diabetes mellitus (DM) can cause desmin to become dysregulated, following episodes of nitrosative stress, through the activation of the iNOS/mTOR/TIMP-1 pathway, thereby stimulating collagen deposition in the myocardium. In this study, type 2 diabetes mellitus (T2DM) was induced in rats. One group of animals was pre-treated with metformin (200 mg/kg) prior to diabetes induction and subsequently kept on metformin until sacrifice at week 12. Cardiac injuries developed in the diabetic rats as demonstrated by a significant (p p < 0.0001) correlation between desmin tissue levels/sarcomere damage and glycated hemoglobin, heart rate, iNOS, mTOR, and fibrosis was observed. These findings demonstrate an association between damage of the cardiac contractile unit—desmin and sarcomere—and the iNOS/mTOR/TIMP-1/collagen axis of fibrosis in T2DM-induced cardiomyopathy, with metformin exhibiting beneficial cardiovascular pleiotropic effects