Synthesis, Characterization and Biological Evaluation of some New Thieno[2,3-d]Pyrimidine Derivatives

10-Oxo-4,6,7,8,9,10-hexahydroprazolo[1,5-a][1]benzothieno[2,3-d]pyrimidine-3-carbaldehyde (2) was prepared by Vilsmeier-Haack reaction of 3-amino-2-methyl-5,6,7,8-tetrahydro[1]benzothieno[2,3-d]pyrimidin-4(3H)-one (1). Reaction of carbaldehyde derivative 2 with malononitrile afforded arylidene malononitrile 3. Cyclization of the latter compound with thiourea yielded pyrimidinethione 4. Interaction of carbaldehyde derivative 2 in presence of thiourea with keto- compounds such as ethyl acetoacetate, or acetylacetone, or dimedone or ethyl cyanoacetate gave pyrimidine derivatives 5-8. Hydrazinolysis of carbaldehyde derivative 2 gave the hydrazone 9. Reaction of the latter with phenyl isothiocyanate afforded thiosemicarbazone 10, which underwent cyclization with oxalyl chloride to give thioxoimidazolidinedione 11. Condensation of compound 2 with thiosemicarbazide furnished thiosemicarbazone derivative 12. Reaction of compound 2 with aminopyrazolone in the presence of an acid and/or a base afforded pyrazolones 13 and 14. Treatment of carbaldehyde derivative 2 with cyanoacetohydrazide gave acrylohydrazide 15. Interaction of the latter with carbon disulfide yielded mercaptooxadiazole 16.  Condensation of compound 2 with acetylpyridazinone 17 produced chalcone 18. Reaction of  compound 18 with malononitrile in pyridine gave cyanopyran 19, while its reaction with malononitrile in presence of ammonium acetate in ethanol yielded cyanopyridine 20. Structures of the newly synthesized products have been deduced on the basis of elemental analysis and spectral data. The synthesized compounds were screened for their antimicrobial activity.Â

Investigation of the Ameliorating Effect of Copper Albumin Complex on Lysyl oxidase in monosodium iodoacetate -Induced Knee Osteoarthritis in Rats

Knee osteoarthritis (KOA) is a common type of joint degeneration which causes progressive damage of the joint structure and has less therapeutic options. It has been found that oral consumption of Copper Albumin Complex as anti-inflammatory drug has a positive effect on the treatment of joint deterioration. The present study aimed to investigate the effect of oral administration of Copper Albumin Complex (cu-albumin complex) on Lysyl oxidase (LOX) which acts as a protective factor in KOA. Fifty adult albino rats were divided into 3 groups: negative control (10 normal rats); positive control (20 rats with KOA which left without induction treatment); and treated group (20 rats with KOA which treated with administration of copper albumin complex). Treated and untreated arthritic groups were subdivided equally into mild and severe groups (10 rats for each) according to the severity of clinical signs. KOA was induced by intra-articular injection of monosodium iodoacetate (MIA). At the experimental end, the joints were examined histopathologically and immunohistochemically after cervical dislocation of rats. It was observed that the treatment with CU- was effective in reducing disease severity and in improvement of Lysyl oxidase KOA. It was concluded that Copper albumin complex has a positive effect in the improvement of LOX of Knee joint cartilages of rats affected by osteoarthritis (OA)

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 < 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

Sex difference and intra-operative tidal volume: Insights from the LAS VEGAS study

BACKGROUND: One key element of lung-protective ventilation is the use of a low tidal volume (VT). A sex difference in use of low tidal volume ventilation (LTVV) has been described in critically ill ICU patients.OBJECTIVES: The aim of this study was to determine whether a sex difference in use of LTVV also exists in operating room patients, and if present what factors drive this difference.DESIGN, PATIENTS AND SETTING: This is a posthoc analysis of LAS VEGAS, a 1-week worldwide observational study in adults requiring intra-operative ventilation during general anaesthesia for surgery in 146 hospitals in 29 countries.MAIN OUTCOME MEASURES: Women and men were compared with respect to use of LTVV, defined as VT of 8 ml kg-1 or less predicted bodyweight (PBW). A VT was deemed 'default' if the set VT was a round number. A mediation analysis assessed which factors may explain the sex difference in use of LTVV during intra-operative ventilation.RESULTS: This analysis includes 9864 patients, of whom 5425 (55%) were women. A default VT was often set, both in women and men; mode VT was 500 ml. Median [IQR] VT was higher in women than in men (8.6 [7.7 to 9.6] vs. 7.6 [6.8 to 8.4] ml kg-1 PBW, P < 0.001). Compared with men, women were twice as likely not to receive LTVV [68.8 vs. 36.0%; relative risk ratio 2.1 (95% CI 1.9 to 2.1), P < 0.001]. In the mediation analysis, patients' height and actual body weight (ABW) explained 81 and 18% of the sex difference in use of LTVV, respectively; it was not explained by the use of a default VT.CONCLUSION: In this worldwide cohort of patients receiving intra-operative ventilation during general anaesthesia for surgery, women received a higher VT than men during intra-operative ventilation. The risk for a female not to receive LTVV during surgery was double that of males. Height and ABW were the two mediators of the sex difference in use of LTVV.TRIAL REGISTRATION: The study was registered at Clinicaltrials.gov, NCT01601223

In vitro assessment of the antimicrobial activity of silver and zinc oxide nanoparticles against fish pathogens

Abstract Background Antibiotic resistance is a global issue that threatens public health. The excessive use of antibiotics contributes to this problem as the genes of antibiotic resistance can be transferred between the bacteria in humans, animals and aquatic organisms. Metallic nanoparticles could serve as future substitutes for some conventional antibiotics because of their antimicrobial activity. The aim of this study was to evaluate the antimicrobial effects of silver and zinc oxide nanoparticles against major fish pathogens and assess their safety in vitro. Silver nanoparticles were synthesized by chemical reduction and characterized with UV–Vis spectroscopy, transmission electron microscopy and zeta sizer. The concentrations of silver and zinc oxide nanoparticles were measured using inductively coupled plasma-mass spectrometry. Subsequently, silver and zinc oxide nanoparticles were tested for their antimicrobial activity against Aeromonas hydrophila, Aeromonas salmonicida subsp. salmonicida, Edwardsiella ictaluri, Edwardsiella tarda, Francisella noatunensis subsp. orientalis, Yersinia ruckeri and Aphanomyces invadans and the minimum inhibitory concentrations were determined. MTT assay was performed on eel kidney cell line (EK-1) to determine the cell viability after incubation with nanoparticles. The interaction between silver nanoparticles and A. salmonicida was investigated by transmission electron microscopy. Results The tested nanoparticles exhibited marked antimicrobial activity. Silver nanoparticles inhibited the growth of both A. salmonicida and A. invadans at a concentration of 17 µg/mL. Zinc oxide nanoparticles inhibited the growth of A. salmonicida, Y. ruckeri and A. invadans at concentrations of 15.75, 31.5 and 3.15 µg/mL respectively. Silver nanoparticles showed higher cell viability when compared to zinc oxide nanoparticles in the MTT assay. Transmission electron microscopy showed the attachment of silver nanoparticles to the bacterial membrane and disruption of its integrity. Conclusions This is the first study on inhibitory effects of silver and zinc oxide nanoparticles towards A. salmonicida and A. invadans. Moreover, zinc oxide nanoparticles inhibited the growth of Y. ruckeri. In low concentrations, silver nanoparticles were less cytotoxic than zinc oxide nanoparticles and represent an alternative antimicrobial compound against A. hydrophila, A. salmonicida and A. invadans

MiR-29a promotes lipid droplet and triglyceride formation in HCV infection by inducing expression of SREBP-1c and CAV1

Aims: To examine the regulation of SREBP-1c and CAV1 by microRNA-29a (miR-29a) in cells infected with hepatitis C virus (HCV) in an attempt to control HCV-induced non-alcoholic fatty liver disease. Methods: In order to examine the manipulation of SREBP-1c and CAV1 by miR-29a, oleic acid (OA)-treated JFH-I-infected Huh-7 cells were used. OA was added 24 h post-transfection and gene expression was investigated by qRT-PCR at 48 h post treatment. The functional impact of the observed alteration in SREBP-1c and CAV1 expression was analyzed by examining lipid droplet (LD) and triglyceride (TG) content at 72 h post-OA treatment using light microscopy and spectrophotometry, respectively. Viral load was quantified by qRT-PCR at 72 h post-transfection. Results: OA treatment induced the expression of miR-29a and SREBP-1c, as compared to untreated cells. Forced miR-29a expression led to a significant up-regulation of SREBP-1c as well as CAV1 compared to mock untransfected cells. Ectopic expression of miR-29a resulted in a marked increase in LDs and their respective TGs, while miR-29a antagomirs decreased both the LD and TG content compared to mock untransfected cells. Moreover, forcing the expression of miR-29a in JFH-1 HCV-infected Huh-7 cells resulted in 53% reduction in viral titers compared to mock untransfected Huh-7 cells. Conclusion: Inducing miR-29a expression significantly induces SREBP-1c and CAV1 expression, thereby increasing LDs as well as their respective TGs. Nonetheless, forcing the expression of miR-29a resulted in reduction of HCV RNA levels in Huh-7 cells

In vitro assessment of the antimicrobial activity of silver and zinc oxide nanoparticles against fish pathogens

Background: Antibiotic resistance is a global issue that threatens public health. The excessive use of antibiotics contributes to this problem as the genes of antibiotic resistance can be transferred between the bacteria in humans, animals and aquatic organisms. Metallic nanoparticles could serve as future substitutes for some conventional antibiotics because of their antimicrobial activity. The aim of this study was to evaluate the antimicrobial effects of silver and zinc oxide nanoparticles against major fish pathogens and assess their safety in vitro. Silver nanoparticles were synthesized by chemical reduction and characterized with UV–Vis spectroscopy, transmission electron microscopy and zeta sizer. The concentrations of silver and zinc oxide nanoparticles were measured using inductively coupled plasma-mass spectrometry. Subsequently, silver and zinc oxide nanoparticles were tested for their antimicrobial activity against Aeromonas hydrophila, Aeromonas salmonicida subsp. salmonicida, Edwardsiella ictaluri, Edwardsiella tarda, Francisella noatunensis subsp. orientalis, Yersinia ruckeri and Aphanomyces invadans and the minimum inhibitory concentrations were determined. MTT assay was performed on eel kidney cell line (EK-1) to determine the cell viability after incubation with nanoparticles. The interaction between silver nanoparticles and A. salmonicida was investigated by transmission electron microscopy. Results: The tested nanoparticles exhibited marked antimicrobial activity. Silver nanoparticles inhibited the growth of both A. salmonicida and A. invadans at a concentration of 17 µg/mL. Zinc oxide nanoparticles inhibited the growth of A. salmonicida, Y. ruckeri and A. invadans at concentrations of 15.75, 31.5 and 3.15 µg/mL respectively. Silver nanoparticles showed higher cell viability when compared to zinc oxide nanoparticles in the MTT assay. Transmission electron microscopy showed the attachment of silver nanoparticles to the bacterial membrane and disruption of its integrity. Conclusions: This is the first study on inhibitory effects of silver and zinc oxide nanoparticles towards A. salmonicida and A. invadans. Moreover, zinc oxide nanoparticles inhibited the growth of Y. ruckeri. In low concentrations, silver nanoparticles were less cytotoxic than zinc oxide nanoparticles and represent an alternative antimicrobial compound against A. hydrophila, A. salmonicida and A. invadans.© The Author(s) 201

Intraoperative ventilator settings and their association with postoperative pulmonary complications in neurosurgical patients: post-hoc analysis of LAS VEGAS study

Background: Limited information is available regarding intraoperative ventilator settings and the incidence of postoperative pulmonary complications (PPCs) in patients undergoing neurosurgical procedures. The aim of this post-hoc analysis of the 'Multicentre Local ASsessment of VEntilatory management during General Anaesthesia for Surgery' (LAS VEGAS) study was to examine the ventilator settings of patients undergoing neurosurgical procedures, and to explore the association between perioperative variables and the development of PPCs in neurosurgical patients. Methods: Post-hoc analysis of LAS VEGAS study, restricted to patients undergoing neurosurgery. Patients were stratified into groups based on the type of surgery (brain and spine), the occurrence of PPCs and the assess respiratory risk in surgical patients in Catalonia (ARISCAT) score risk for PPCs. Results: Seven hundred eighty-four patients were included in the analysis; 408 patients (52%) underwent spine surgery and 376 patients (48%) brain surgery. Median tidal volume (VT) was 8 ml [Interquartile Range, IQR = 7.3-9] per predicted body weight; median positive end-expiratory pressure (PEEP) was 5 [3 to 5] cmH20. Planned recruitment manoeuvres were used in the 6.9% of patients. No differences in ventilator settings were found among the sub-groups. PPCs occurred in 81 patients (10.3%). Duration of anaesthesia (odds ratio, 1.295 [95% confidence interval 1.067 to 1.572]; p = 0.009) and higher age for the brain group (odds ratio, 0.000 [0.000 to 0.189]; p = 0.031), but not intraoperative ventilator settings were independently associated with development of PPCs. Conclusions: Neurosurgical patients are ventilated with low VT and low PEEP, while recruitment manoeuvres are seldom applied. Intraoperative ventilator settings are not associated with PPCs

Association between night-time surgery and occurrence of intraoperative adverse events and postoperative pulmonary complications

Background: The aim of this post hoc analysis of a large cohort study was to evaluate the association between night-time surgery and the occurrence of intraoperative adverse events (AEs) and postoperative pulmonary complications (PPCs). Methods: LAS VEGAS (Local Assessment of Ventilatory Management During General Anesthesia for Surgery) was a prospective international 1-week study that enrolled adult patients undergoing surgical procedures with general anaesthesia and mechanical ventilation in 146 hospitals across 29 countries. Surgeries were defined as occurring during 'daytime' when induction of anaesthesia was between 8: 00 AM and 7: 59 PM, and as 'night-time' when induction was between 8: 00 PM and 7: 59 AM. Results: Of 9861 included patients, 555 (5.6%) underwent surgery during night-time. The proportion of patients who developed intraoperative AEs was higher during night-time surgery in unmatched (43.6% vs 34.1%; P<0.001) and propensity-matched analyses (43.7% vs 36.8%; P = 0.029). PPCs also occurred more often in patients who underwent night-time surgery (14% vs 10%; P = 0.004) in an unmatched cohort analysis, although not in a propensity-matched analysis (13.8% vs 11.8%; P = 0.39). In a multivariable regression model, including patient characteristics and types of surgery and anaesthesia, night-time surgery was independently associated with a higher incidence of intraoperative AEs (odds ratio: 1.44; 95% confidence interval: 1.09-1.90; P = 0.01), but not with a higher incidence of PPCs (odds ratio: 1.32; 95% confidence interval: 0.89-1.90; P = 0.15). Conclusions: Intraoperative adverse events and postoperative pulmonary complications occurred more often in patients undergoing night-time surgery. Imbalances in patients' clinical characteristics, types of surgery, and intraoperative management at night-time partially explained the higher incidence of postoperative pulmonary complications, but not the higher incidence of adverse events