Sinteza, protuupalno, analgetsko i antikonvulzivno djelovanje 1,8-dihidro-1-aril-8-alkil pirazolo(3,4-b)indola

A series of 1,8-dihydro-1-aryl-8-alkyl pyrazolo(3,4-b)indoles 4a-j, 5a-j and 6a-j has been synthesized and tested for their anti-inflammatory and anticonvulsant activities. Formation of the pyrazoloindole derivatives was achieved by treating arylhydrazones of N-alkyl indole-3-carboxaldehydes 1a-j, 2a-j and 3a-j with ten times their mass of polyphosphoric acid as a condensing agent. The newly synthesized compounds were evaluated for their anti-inflammatory, analgesic and anticonvulsant activities compared to indomethacin, flufenamic acid and diazepam as positive controls. Detailed synthesis, spectroscopic and toxicity data are reported.Serija 1,8-dihidro-1-aril-8-alkil pirazolo(3,4-b)indola 4a-j, 5a-j i 6a-j sintetizirana je i testirana na protuupalno i antikonvulzivno djelovanje. Pirazolindol derivati pripravljeni su reakcijom arilhidrazona N-alkil indol-3-karboksaldehida 1a-j, 2a-j i 3a-j s deset puta većom masom polifosforne kiseline kao sredstva za kondenzaciju. Novosintetizirani spojevi testirani su na protuupalno, analgetsko i antikonvulzivno djelovanje i uspoređeni s djelovanjem indometacina, flufenaminske kiseline i diazepama. U radu su dati detaljni sintetski, spektroskopski i toksikološki podaci

Sinteza i biološko djelovanje novih 1-benzil i 1-benzoil 3-heterocikličkih derivata indola

Starting from 1-benzyl- (2a) and 1-benzoyl-3-bromoacetyl indoles (2b) new heterocyclic, 2-thioxoimidazolidine (4a,b), imidazolidine-2,4-dione (5a,b), pyrano(2,3-d)imidazole (8a,b and 9a,b), 2-substituted quinoxaline (11a,b–17a,b) and triazolo(4,3-a)quinoxaline derivatives (18a,b and 19a,b) were synthesized and evaluated for their antimicrobial and anticancer activities. Antimicrobial activity screening performed with concentrations of 0.88, 0.44 and 0.22 g mm2 showed that 3-(1-substituted indol-3-yl)quinoxalin-2(1H)ones (11a,b) and 2-(4-methyl piperazin-1-yl)-3-(1-substituted indol-3-yl) quinoxalines (15a,b) were the most active of all the tested compounds towards P. aeruginosa, B. cereus and S. aureus compared to the reference drugs cefotaxime and piperacillin, while 2-chloro-3-(1-substituted indol-3-yl)quinoxalines (12a,b) were the most active against C. albicans compared to the reference drug nystatin. On the other hand, 2-chloro-3-(1-benzyl indol-3-yl) quinoxaline (12a) display potent efficacy against ovarian cancer xenografts in nude mice with tumor growth suppression of 100 0.3 %.U radu je opisana sinteza, antimikrobno i antitumorsko djelovanje heterocikličkih derivata indola. Polazeći iz 1-benzil- i 1-benzoil-3-bromacetil indola (2a i 2b) sintetizirani su novi heterociklički spojevi 2-tioksoimidazolidini (4a,b), imidazolidin-2,4-dioni (5a,b), pirano(2,3-d)imidazoli (8a,b i 9a,b), 2-supstituirani kinoksalini (11a,b–17a,b) i triazolo(4,3-a)kinoksalini (18a,b i 19a,b). Sintetizirani spojevi testirani su na antimikrobno i antitumorsko djelovanje. Ispitivanje antimikrobnog djelovanja provedeno je s koncentracijama otopina 0,88, 0,44 i 0,22 g mm2 i uspoređeno s referentnim lijekovima cefotaksimom i piperacilinom. Rezultati pokazuju da su 3-(1-supstituirani indol-3-il)kinoksalin-2(1H)oni (11a,b) i 2-(4-metil piperazin-1-il)-3-(1-supstituirani indol-3-il) kinoksalini (15a,b) najaktivniji spojevi na sojeve P. aeruginosa, B. cereus i S. aureus, dok su 2-klor-3-(1-supstituirani indol-3-il)kinoksalini (12a,b) najaktivniji na C. albicans (usporedba s nistatinom). Osim toga, 2-klor-3-(1-benzil indol-3-il) kinoksalin (12a) pokazuje veliku učinkovitost na tumore ovarija miševa (supresija rasta tumora 100 0,3 %)

Cyanobacteria—From the Oceans to the Potential Biotechnological and Biomedical Applications

Cyanobacteria are photosynthetic prokaryotic organisms which represent a significantsource of novel, bioactive, secondary metabolites, and they are also considered an abundant source ofbioactive compounds/drugs, such as dolastatin, cryptophycin 1, curacin toyocamycin, phytoalexin,cyanovirin-N and phycocyanin. Some of these compounds have displayed promising results insuccessful Phase I, II, III and IV clinical trials. Additionally, the cyanobacterial compounds applied tomedical research have demonstrated an exciting future with great potential to be developed into newmedicines. Most of these compounds have exhibited strong pharmacological activities, includingneurotoxicity, cytotoxicity and antiviral activity against HCMV, HSV-1, HHV-6 and HIV-1, so thesemetabolites could be promising candidates for COVID-19 treatment. Therefore, the effective large-scale production of natural marine products through synthesis is important for resolving the existingissues associated with chemical isolation, including small yields, and may be necessary to betterinvestigate their biological activities. Herein, we highlight the total synthesized and stereochemicaldeterminations of the cyanobacterial bioactive compounds. Furthermore, this review primarilyfocuses on the biotechnological applications of cyanobacteria, including applications as cosmetics,food supplements, and the nanobiotechnological applications of cyanobacterial bioactive compoundsin potential medicinal applications for various human diseases are discussed.Stockholm UniversityPeer Reviewe

HER2/neu expression status of post BCG recurrent non-muscle-invasive bladder urothelial carcinomas in relation to their primary ones

Background: Transurethral resection (TUR) followed by adjuvant therapy is still the treatment of choice of Non-Muscle-Invasive Bladder Urothelial Carcinoma (NMIBUC). However, recurrence is one of the most troublesome features of these lesions. Early second resection and adjuvant BCG therapy has been shown to improve the outcome. Objective: To evaluate the prognostic value of C-erbB-2 (HER2/neu) expression status in Non-Muscle-Invasive Bladder Urothelial Carcinoma cases, before and after intravesical Bacillus Calmette Guerin (BCG immunotherapy). Materials and methods: HER2/neu expression was studied in 120 (Ta-T1) Non-Muscle-Invasive Urothelial Carcinoma cases. The expression was evaluated and compared to the expression after Bacillus Calmette Guerin (BCG) immunotherapy. Results: HER2/neu expression in low and high grade of the Non- Muscle-Invasive Urothelial Carcinoma was (38%) and (83%) respectively. The difference of the expression rates by tumor grade was statistically significant. In recurring lesions post BCG therapy, C-erbB-2 expression was markedly decreased (31.6%) when compared to its expression before therapy (65%). Conclusions: The HER2/neu expression increased as the tumor grade rose. The reduction in expression following BCG treatment in Non-Invasive transitional cell carcinoma cases could reflect a reduction of the potential malignancy of the tumor

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

Effects of hospital facilities on patient outcomes after cancer surgery: an international, prospective, observational study

Background Early death after cancer surgery is higher in low-income and middle-income countries (LMICs) compared with in high-income countries, yet the impact of facility characteristics on early postoperative outcomes is unknown. The aim of this study was to examine the association between hospital infrastructure, resource availability, and processes on early outcomes after cancer surgery worldwide.Methods A multimethods analysis was performed as part of the GlobalSurg 3 study-a multicentre, international, prospective cohort study of patients who had surgery for breast, colorectal, or gastric cancer. The primary outcomes were 30-day mortality and 30-day major complication rates. Potentially beneficial hospital facilities were identified by variable selection to select those associated with 30-day mortality. Adjusted outcomes were determined using generalised estimating equations to account for patient characteristics and country-income group, with population stratification by hospital.Findings Between April 1, 2018, and April 23, 2019, facility-level data were collected for 9685 patients across 238 hospitals in 66 countries (91 hospitals in 20 high-income countries; 57 hospitals in 19 upper-middle-income countries; and 90 hospitals in 27 low-income to lower-middle-income countries). The availability of five hospital facilities was inversely associated with mortality: ultrasound, CT scanner, critical care unit, opioid analgesia, and oncologist. After adjustment for case-mix and country income group, hospitals with three or fewer of these facilities (62 hospitals, 1294 patients) had higher mortality compared with those with four or five (adjusted odds ratio [OR] 3.85 [95% CI 2.58-5.75]; p<0.0001), with excess mortality predominantly explained by a limited capacity to rescue following the development of major complications (63.0% vs 82.7%; OR 0.35 [0.23-0.53]; p<0.0001). Across LMICs, improvements in hospital facilities would prevent one to three deaths for every 100 patients undergoing surgery for cancer.Interpretation Hospitals with higher levels of infrastructure and resources have better outcomes after cancer surgery, independent of country income. Without urgent strengthening of hospital infrastructure and resources, the reductions in cancer-associated mortality associated with improved access will not be realised

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