DESIGN AND SYNTHESIS OF NOVEL SCAFFOLDS AND BUILDING BLOCKS

Medicinal chemistry focuses on the aspect related to the structural design, synthesis and identification of therapeutically interesting compounds, i.e. pharmaceuticals, as well as the molecular reasons of their mechanism of action, including the understanding of the factors involved in the structure-activity relationships, absorption, distribution, metabolism, elimination and toxicity. A number of studies have appeared in the recent literature on the identification of molecular frameworks, which correspond to the minimum structural subunit, in several drugs or lead-compounds, able of providing ligand points for more than one type of bioreceptor. Since Evans first introduced the concept of “privileged structure”, privileged-based drug discovery has emerged as a fruitful approach in medicinal chemistry. Privileged scaffolds increase hit rates for biological targets of interest, leading to the discovery of other biologically active targets and generating leads with enhanced drug-like properties. Consequently, medicinal chemists value privileged structures as core scaffolds for viable starting points in exploration design and synthesis. Despite the identification of numerous recurring molecular frameworks in bioactive molecules, there is a restricted availability of privileged structures. Toward this concern, a subject of great fascination and importance, dealing with the need to identify novel chemotypes, have been addressed the studies conducted during this PhD thesis. Research into drug-like and lead-like concepts has explored a range of ideas looking at structural characteristics and physicochemical properties. The selected structures might represent potential replacements of frequently occurring structural motifs. The development of efficient methodologies for the synthesis of the identified compounds has provided the suitable tools to open up an investigation about the behaviour of such a kind of molecules towards biological systems

Molecular characterization of the NRAMP1 gene in buffalo

NRAMP1 (natural-resistance-associated macrophage protein) gene influences the initial phase of bacterial cellular infections, regulating macrophage activation. Recent literature on buffalo has attempted to associate the genotypes at the polymorphic microsatellite, that is located in the 3'-UTR of the gene, with either susceptibility to brucellosis or improved macrophage function. However, contradictory results were reported. In the present work, we have sequenced the whole coding region, as well as part of the introns and UTRs, of the NRAMP1 gene in 49 Mediterranean buffaloes, including both serologically positive and negative animals to Brucella abortus test. We have detected 12 mutations. Nineteen haplotypes were built from the detected variant alleles, so demonstrating the high variability of this gene in buffalo, but no significant differences in haplotype frequencies were found between serologically positive/negative animals

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

Pooled analysis of WHO Surgical Safety Checklist use and mortality after emergency laparotomy

Background The World Health Organization (WHO) Surgical Safety Checklist has fostered safe practice for 10 years, yet its place in emergency surgery has not been assessed on a global scale. The aim of this study was to evaluate reported checklist use in emergency settings and examine the relationship with perioperative mortality in patients who had emergency laparotomy. Methods In two multinational cohort studies, adults undergoing emergency laparotomy were compared with those having elective gastrointestinal surgery. Relationships between reported checklist use and mortality were determined using multivariable logistic regression and bootstrapped simulation. Results Of 12 296 patients included from 76 countries, 4843 underwent emergency laparotomy. After adjusting for patient and disease factors, checklist use before emergency laparotomy was more common in countries with a high Human Development Index (HDI) (2455 of 2741, 89.6 per cent) compared with that in countries with a middle (753 of 1242, 60.6 per cent; odds ratio (OR) 0.17, 95 per cent c.i. 0.14 to 0.21, P <0001) or low (363 of 860, 422 per cent; OR 008, 007 to 010, P <0.001) HDI. Checklist use was less common in elective surgery than for emergency laparotomy in high-HDI countries (risk difference -94 (95 per cent c.i. -11.9 to -6.9) per cent; P <0001), but the relationship was reversed in low-HDI countries (+121 (+7.0 to +173) per cent; P <0001). In multivariable models, checklist use was associated with a lower 30-day perioperative mortality (OR 0.60, 0.50 to 073; P <0.001). The greatest absolute benefit was seen for emergency surgery in low- and middle-HDI countries. Conclusion Checklist use in emergency laparotomy was associated with a significantly lower perioperative mortality rate. Checklist use in low-HDI countries was half that in high-HDI countries.Peer reviewe

Unconventional therapies for hidradenitis suppurativa

Hidradenitis suppurativa (HS) is a chronic, inflammatory, and debilitating skin disease, which usually occurs after puberty with painful, deep-seated, inflammatory lesions in the apocrine gland-bearing areas of the body. Several pharmacologic agents have been described to reduce lesion activity and inflammation in HS. However, conventional treatment may not always get the desired results. Therefore, unconventional therapies must be taken into account. Areas covered: Recently, the better understanding of HS pathogenesis has been used to improve treatment strategies with many emerging conventional and unconventional therapeutics options. Adalimumab is the only FDA-approved biologic available for therapy of moderate-to-severe HS. Nevertheless, novel therapeutic approach, including both topical and systemic as well as novel laser device, showed good clinical outcome. Several molecules, such as tumor necrosis factor-alpha (TNF-α), interleukin-1 (IL-1), IL-17, IL-12, IL-23, phosphodiesterase 4 (PDE4), lymphocyte function-associated antigen 1 (LFA-1), and complement component 5a (C5a), are modulated by such new biologic agents in HS. Expert commentary: In the next years, many therapeutic options for HS will be available. Clinical trials showed the efficacy of several biologic drugs, antibiotics, laser light device. Novel therapeutic options seem to be promising, but dermatologists will have to evaluate their effectiveness and safety in daily clinical practice

Sialyloligosaccharides Content in Mature Milk of Different Cow Breeds

Sialyloligosaccharides (SOS) are bioactive molecules that play an important role in brain development and the increase in immunity in infants. In adults, they act as prebiotics, enhancing protection against microbial pathogens. In the present work, we aimed to analyze the levels of SOS in mature milk, at days 60 and 120 after calving in four cow breeds: Holstein (HO), Simmental &times; Holstein (SM &times; HO), Simmental (SM), all fed with total mixed ration (TMR) in intensive production, and Podolica (POD) raised on pasture in an extensive system. The concentrations of SOS (3&prime;-sialyllactose = 3&prime;-SL, 6&prime;-sialyllactose = 6&prime;-SL, 6&prime;-Sialyl-N-acetyllactosamine = 6&prime;-SLN, disialyllactose = DSL, expressed in mg/L) were determined using HPAEC-PAD, a high-performance anion-exchange chromatography with pulsed amperometric detection. Results showed both breed and lactation effects. The contents of 3&prime;-SL, 6&prime;-SL, 6&prime;-SLN, and DSL were higher at 60 than 120 days (p &lt; 0.001), as well as in POD, as compared to the other breeds (p &lt; 0.001). Furthermore, SM showed a significantly greater level of 3&prime;-SL than HO (p &lt; 0.001), as well as a significantly higher level of 6&prime;-SLN in SM than HO (p &lt; 0.001) and SM &times; HO (p &lt; 0.001). Our findings may have implications for several areas of sustainability that might be used in the cattle management system

Sialyloligosaccharides Content in Mature Milk of Different Cow Breeds

Sialyloligosaccharides (SOS) are bioactive molecules that play an important role in brain development and the increase in immunity in infants. In adults, they act as prebiotics, enhancing protection against microbial pathogens. In the present work, we aimed to analyze the levels of SOS in mature milk, at days 60 and 120 after calving in four cow breeds: Holstein (HO), Simmental × Holstein (SM × HO), Simmental (SM), all fed with total mixed ration (TMR) in intensive production, and Podolica (POD) raised on pasture in an extensive system. The concentrations of SOS (3′-sialyllactose = 3′-SL, 6′-sialyllactose = 6′-SL, 6′-Sialyl-N-acetyllactosamine = 6′-SLN, disialyllactose = DSL, expressed in mg/L) were determined using HPAEC-PAD, a high-performance anion-exchange chromatography with pulsed amperometric detection. Results showed both breed and lactation effects. The contents of 3′-SL, 6′-SL, 6′-SLN, and DSL were higher at 60 than 120 days (p p p p p < 0.001). Our findings may have implications for several areas of sustainability that might be used in the cattle management system