Total Synthesis of Eleuthoside A; Application of Rh-Catalyzed Intramolecular Cyclization of Diazonaphthoquinone

The first total synthesis of (±)-eleutherol and eleuthoside A, the natural cytotoxic substances extracted from medicinal Indonesian plant, is described. First, the synthesis of (±)-eleutherol has been ­accomplished in nine steps starting from bromo methoxy aldehyde with the aid of diazo-transfer chemistry approach. Second, a metal-­catalyzed intramolecular cyclization reaction of the corresponding ­diazonaphthoquinone led to the desired eleuotherol, which served as a precursor to eleuthoside A. Then, several glycosidation routes, using different glucosyl donors, were experimented to reach effective O-glycosidation of eleutherol. The only successful strategy involved Koenigs–Knorr glycosidation using peracetyl glycosyl bromide in the presence of Ag2O and quinoline. This strategy furnished our desired acetylated glycoside of β-configuration, regioselectively. Finally, deacetylation and successive separation of diastereomers were conducted to give eleuthoside A

Allelic Discrimination of Vitamin D Receptor Polymorphisms and Risk of Type 2 Diabetes Mellitus: A Case-Controlled Study

(1) Background: Type 2 diabetes mellitus (T2DM) is one of the rapidly growing healthcare problems, and several vitamin D receptor (VDR) polymorphisms seem to modulate the risk of T2DM. Our research was designed to investigate the allelic discrimination of VDR polymorphisms and T2DM occurrence risk. (2) Methods: This case-control research included 156 patients with T2DM and 145 healthy control subjects. Most of the study population were males 56.6% vs. 62.8% in the case and control groups, respectively. Genotyping for VDR single nucleotide polymorphisms (SNPs), rs228570 (Fok1), rs7975232 (Apa1), and rs1544410 (Bsm1) was compared between both groups. (3) Results: There was a negative link between vitamin D levels and insulin sensitivity. A significant difference was noted in the allelic discrimination of VDR polymorphism rs228570 and rs1544410 between the study groups (p \u3c 0.001). No difference was observed in the allelic discrimination of VDR polymorphism rs7975232 between the groups (p = 0.063). Moreover, T2DM patients had significantly higher levels of fasting blood sugar (FBS), glycated hemoglobin HbA1c, 2-h post-prandial blood sugar (PP), serum glutamic oxaloacetic transaminase (SGOT), serum glutamic-pyruvic transaminase (SGPT), total cholesterol, and triglycerides (p \u3c 0.001), while High-Density Lipoprotein (HDL) Cholesterol (HDL-C) was significantly decreased (p = 0.006). (4) Conclusions: VDR polymorphisms had a positive association with T2DM risk among the Egyptian population. Further large-scale research using deep sequencing of samples is strongly urged to investigate different vitamin D gene variants and interactions, as well as the influence of vitamin D on T2DM

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

Bioethanol a Microbial Biofuel Metabolite; New Insights of Yeasts Metabolic Engineering

Scarcity of the non-renewable energy sources, global warming, environmental pollution, and raising the cost of petroleum are the motive for the development of renewable, eco-friendly fuels production with low costs. Bioethanol production is one of the promising materials that can subrogate the petroleum oil, and it is considered recently as a clean liquid fuel or a neutral carbon. Diverse microorganisms such as yeasts and bacteria are able to produce bioethanol on a large scale, which can satisfy our daily needs with cheap and applicable methods. Saccharomyces cerevisiae and Pichia stipitis are two of the pioneer yeasts in ethanol production due to their abilities to produce a high amount of ethanol. The recent focus is directed towards lignocellulosic biomass that contains 30–50% cellulose and 20–40% hemicellulose, and can be transformed into glucose and fundamentally xylose after enzymatic hydrolysis. For this purpose, a number of various approaches have been used to engineer different pathways for improving the bioethanol production with simultaneous fermentation of pentose and hexoses sugars in the yeasts. These approaches include metabolic and flux analysis, modeling and expression analysis, followed by targeted deletions or the overexpression of key genes. In this review, we highlight and discuss the current status of yeasts genetic engineering for enhancing bioethanol production, and the conditions that influence bioethanol production

The Impact of SKP2 Gene Expression in Chronic Myeloid Leukemia

Introduction: The prognosis of chronic myeloid leukemia (CML) patients has been dramatically improved with the introduction of imatinib (IM), the first tyrosine kinase inhibitor (TKI). TKI resistance is a serious problem in IM-based therapy. The human S-phase kinase-associated protein 2 (SKP2) gene may play an essential role in the genesis and progression of CML. Aim of the study: We try to explore the diagnostic/prognostic impact of SKP2 gene expression to predict treatment response in first-line IM-treated CML patients at an early response stage. Patients and methods: The gene expression and protein levels of SKP2 were determined using quantitative RT-PCR and ELISA in 100 newly diagnosed CML patients and 100 healthy subjects. Results: SKP2 gene expression and SKP2 protein levels were significantly upregulated in CML patients compared to the control group. The receiver operating characteristic (ROC) analysis for the SKP2 gene expression level, which that differentiated the CML patients from the healthy subjects, yielded a sensitivity of 86.0% and a specificity of 82.0%, with an area under the curve (AUC) of 0.958 (p &lt; 0.001). The ROC analysis for the SKP2 gene expression level, which differentiated optimally from the warning/failure responses, yielded a sensitivity of 70.59% and a specificity of 71.21%, with an AUC of 0.815 (p &lt; 0.001). Conclusion: The SKP2 gene could be an additional diagnostic and an independent prognostic marker for predicting treatment responses in first-line IM-treated CML patients at an early time point (3 months)

CCL2 rs1024611Gene Polymorphism in Philadelphia-Negative Myeloproliferative Neoplasms

Introduction: The onset of the Philadelphia chromosome-negative myeloproliferative neoplasms (MPNs) is caused by acquired somatic mutations in target myeloid genes “driver mutations”. The CCL2 gene is overexpressed by non-Hodgkin lymphomas and multiple solid tumors. Aim of the study: to evaluate the possible association of CCL2 rs1024611 SNP and its expression level and the risk of developing Philadelphia-negative MPNs. Patients and methods: A total of 128 newly diagnosed Philadelphia-negative MPN patient and 141 healthy subjects were evaluated for the genotype distribution of CCL2 rs1024611 and CCL2 expression levels. Results: The CCL2 rs1024611 G/G genotype was more frequent and significantly frequent among PMF and Post-PV/ET-MF patients and the mean CCL2 expression levels were significantly higher in PMF and Post-PV/ET-MF compared to the healthy subjects. The CCL2 rs1024611 SNP was significantly correlated to the CCL2 gene expression level and fibrosis grade. ROC analysis for the CCL2 gene expression level that discriminates MF patients from PV + ET patients revealed a sensitivity of 80.43% and a specificity of 73.17% with an AUC of 0.919 (p < 0.001). Conclusion: The CCL2 rs1024611 polymorphism could be an independent risk factor for developing MF (PMF and Post-PV/ET-MF). Moreover, CCL2 gene expression could be potential genetic biomarker of fibrotic progression

Prophylactic and Ameliorative Effects of PPAR-&gamma; Agonist Pioglitazone in Improving Oxidative Stress, Germ Cell Apoptosis and Inflammation in Gentamycin-Induced Testicular Damage in Adult Male Albino Rats

Peroxisome proliferator-activated receptor gamma (PPAR-&gamma;) is ubiquitously expressed in testicular tissue and plays a crucial role in regulating various physiological processes. Pioglitazone (PIO) is one of the PPAR-&gamma; agonists, having anti-oxidant and anti-inflammatory effects. Patients on gentamycin treatment may undergo serious side effects such as testicular damage. To the best of our knowledge, this was the first study to investigate the possible protective anti-inflammatory and anti-apoptotic effects of PIO on gentamycin-induced testicular damage. Fifty adult male Wistar albino rats included in the study as the control group (CTL) received normal saline; a gentamycin-induced testicular damage group (GM) received gentamycin (100 mg/kg); PIO5, PIO10, PIO20 groups received PIO at a dose of 5, 10, and 20 mg/ kg, respectively, for 21 days, and gentamycin was started at day 15 of the experiment for 6 days. The parameters of spermatozoa and histopathological alterations in the testes were significantly improved in the PIO20 group. Moreover, MDA levels, inflammatory mediators, and apoptotic Bax expression were decreased. The activity of glutathione peroxidase, catalase, total antioxidant capacity, and anti-apoptotic Bcl-2 genes expression were increased. It was concluded that PIO20 could protect against gentamycin-induced testicular damage in Wistar rats through its anti-oxidant, anti-inflammatory, and antiapoptotic effects

Urinary Tumor Necrosis Factor-Like Weak Inducer of Apoptosis (uTWEAK) as a biomarker for lupus nephritis activity and its correlation with histolopathological findings of renal biopsy

Background: Lupus nephritis (LN) remains the strongest predictor of overall patient morbidity and mortality in systemic lupus erythematosus (SLE). Aim of the work: To evaluate urinary Tumor Necrosis Factor-Like Weak Inducer of Apoptosis (uTWEAK) as a biomarker for LN activity and its correlation with histological findings of renal biopsy. Patients and methods: 42 SLE patients were recruited and 20 control. SLE disease activity index (SLEDAI) and rSLEDAI were calculated. uTWEAK was estimated by ELISA. Patients were divided into those with (n = 22) and without (n = 20) active renal disease. Renal biopsy was perfromed to those with active LN. The activity index (AI) and Chronicity Index (CI) were scored. Results: The 42 patients were 35 (83.3%) females and 7 (16.7%) males (F:M 5:1) with a mean age of 31.3 ± 11.1 years (18–50 years). There was a significant difference in the uTWEAK levels between patients with active LN, inactive LN and control (7 ± 4.5, 2.5 ± 1.4 and 0.3 ± 0.4 ng/mg Cr respectively) (p < 0.0001). uTWEAK significantly correlated with rSLEDAI (r = 0.47, p = 0.02), and with AI (r = 0.47, p = 0.03), hypercellularity (r = 0.47, p = 0.03), fibrinoid necrosis (r = 0.46, p = 0.03), cellular crescent (r = 58, p = 0.004) and tubular atrophy (r = 48, p = 0.02) in renal biopsy of active LN patients. uTWEAK was a significant independent predictor of LN (p = 0.003) with a sensitivity of 77.3% and specificity of 90%. Conclusion: uTWEAK might clearly be a candidate marker for LN activity and may replace invasive renal biopsy, potentially serving as a helpful biomarker in the clinical follow-up. It could represent an interesting biological tool if the diagnosis of a flare is in doubt. Keywords: SLE, Lupus nephritis, rSLEDAI, Renal biopsy, uTWEA