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In chronic diseases, mobile health apps may help to (i) improve clinical management and (ii) provide valuable real-world scientific evidence. In allergic rhinitis, a market research study has only identified four mHealth apps which were multilingual, resulted in scientific publications and displayed a comprehensive list of medications. Ot those, MASK-air® was the app with the highest number of scientific publications. MASK-air® has been launched in 2015 and is currently available in 30 countries, having collected data from more than 30,000 users. It comprises a daily monitoring questionnaire, allowing patients to register (i) their daily allergy symptoms by means of visual analogue scales, and (ii) their medication use. The achievements of MASK-air® include the development of two digital biomarkers for daily monitoring of rhinitis and asthma (combined symptom-medication score and electronic daily asthma control score). In addition, MASK-air® data have allowed to assess patients' behaviours, suggesting that patients do not follow guideline recommendations, but rather treat themselves (and often use co-medication) whenever feeling worse. Using MASK-air® data, it has also been possible to quantify the impact of allergic diseases in quality-of-life, school and work productivity. MASK-air® real-world data is being used as a source of evidence for the Allergic Rhinitis and its Impact on Asthma 2024 guidelines, in an innovative process of incorporation of mobile health data into guidelines. This review discusses the clinical and scientific contributions of MASK-air® for person-centred care of rhinitis and asthma, providing an illustrative example on the use of mobile health in chronic diseases.
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Plant species vary under different climatic conditions and the distribution of pollen in the air. Trends in pollen distribution can be used to assess the impact of climate change on public health. In 2015, the Mobile Airways Sentinel networK for rhinitis and asthma (MASK-air®) was launched as a project of the European Innovation Partnership on Active and Healthy Ageing (EIP-on-AHA, DG Santé and DG CONNECT). This project aimed to develop a warning system to inform patients about the onset of the pollen season, namely, the System for Integrated modeLling of Atmospheric coMposition (SILAM). A global-to-meso-scale dispersion model was developed by the Finnish Meteorological Institute (FMI). It provides quantitative information on atmospheric pollution of anthropogenic and natural origins, particularly on allergenic pollens. Impact of Air Pollution on Asthma and Rhinitis (POLLAR, EIT Health) has combined MASK-air clinical data with SILAM forecasts. A new Horizon Europe grant (Climate Action to Advance HeaLthY Societies in Europe [CATALYSE]; grant agreement number 101057131), which came into force in September 2022, aims to improve our understanding of climate change and help us find ways to counteractit. One objective of this project is to develop early warning systems and predictive models to improve the effectiveness of strategies for adapting to climate change. One of the warning systems is focused on allergic rhinitis (CATALYSE Task 3.2), with a collaboration between the FMI (Finland), Porto University (Portugal), MASK-air SAS (France), ISGlobal (Spain), Hertie School (Germany), and the University of Zurich (Switzerland). It is to be implemented with the support of the European Academy of Allergy and Clinical Immunology. This paper reports the planning of CATALYSE Task 3.2.
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Asma , Rinite Alérgica , Humanos , Alérgenos , Asma/epidemiologia , Asma/etiologia , Europa (Continente)/epidemiologia , CatáliseRESUMO
OBJECTIVES: Patients with laboratory criteria for anti-phospholipid syndrome (APS) but presenting only 'non-criteria' clinical manifestations are scarcely characterized in the literature. We aimed to analyse a cohort of these patients regarding the most prevalent manifestations, antibody profile, and treatments, while establishing a comparison with definite APS patients. METHOD: A retrospective analysis was conducted of individuals fulfilling APS laboratory criteria assessed in two tertiary European hospitals between 2005 and 2020. Patients without clinical criteria but with non-criteria manifestations (termed 'clinical non-criteria') and age-/gender-matched controls were included. RESULTS: Altogether, 75 clinical non-criteria patients were analysed, with haematological (thrombocytopenia, haemolytic anaemia) and 'mild' neurological manifestations (white-matter lesions, migraine) as the most prevalent non-obstetric involvements. These patients displayed more thrombocytopenia [odds ratio (OR) = 3.6, 95% confidence interval (CI) 1.7-7.6; p = 0.001] than controls with APS, but severe manifestations, such as valvular heart disease (p < 0.001), livedoid vasculopathy, seizures, chorea, transverse myelitis, bone necrosis, and alveolar haemorrhage, occurred only in definite APS patients. Corticosteroids were required by 40% of patients with thrombocytopenia. Manifestations in anticoagulated patients included white-matter lesions, nephropathy, superficial vein thrombosis, amaurosis fugax, and livedoid vasculopathy. Suspicion of progression towards systemic lupus erythematosus (SLE) occurred in 19% of non-SLE individuals. CONCLUSION: 'Clinical non-criteria' patients displayed significant treatment use, predominantly haematological involvement, and less severe manifestations than definite APS controls. Some patients may additionally progress to future SLE. The impact of certain manifestations flags them as potential future contributors to classifying individuals as definite APS.
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Síndrome Antifosfolipídica , Vasculopatia Livedoide , Lúpus Eritematoso Sistêmico , Trombocitopenia , Doenças Vasculares , Humanos , Síndrome Antifosfolipídica/diagnóstico , Estudos Retrospectivos , Lúpus Eritematoso Sistêmico/complicações , Lúpus Eritematoso Sistêmico/diagnóstico , Trombocitopenia/diagnóstico , Trombocitopenia/etiologiaRESUMO
Chronic rhinosinusitis with nasal polyps (CRSwNP) affects 1.0-2.6% of the population (1) and results in relevant direct and indirect costs. Recently, several randomized controlled trials (RCTs) with Type 2-targeting biologicals (anti-IL4Rα, anti-IL5R, anti-IL5 and anti-IgE) opened a new treatment field for patients refractory to first-line treatments (2,3).
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Produtos Biológicos , Pólipos Nasais , Rinite , Sinusite , Humanos , Rinite/tratamento farmacológico , Produtos Biológicos/uso terapêutico , Pólipos Nasais/tratamento farmacológico , Sinusite/tratamento farmacológico , Doença CrônicaRESUMO
Evaluation of expression profile in autism spectrum disorder (ASD) patients is an important approach to understand possible similar functional consequences that may underlie disease pathophysiology regardless of its genetic heterogeneity. Induced pluripotent stem cell (iPSC)-derived neuronal models have been useful to explore this question, but larger cohorts and different ASD endophenotypes still need to be investigated. Moreover, whether changes seen in this in vitro model reflect previous findings in ASD postmortem brains and how consistent they are across the studies remain underexplored questions. We examined the transcriptome of iPSC-derived neuronal cells from a normocephalic ASD cohort composed mostly of high-functioning individuals and from non-ASD individuals. ASD patients presented expression dysregulation of a module of co-expressed genes involved in protein synthesis in neuronal progenitor cells (NPC), and a module of genes related to synapse/neurotransmission and a module related to translation in neurons. Proteomic analysis in NPC revealed potential molecular links between the modules dysregulated in NPC and in neurons. Remarkably, the comparison of our results to a series of transcriptome studies revealed that the module related to synapse has been consistently found as upregulated in iPSC-derived neurons-which has an expression profile more closely related to fetal brain-while downregulated in postmortem brain tissue, indicating a reliable association of this network to the disease and suggesting that its dysregulation might occur in different directions across development in ASD individuals. Therefore, the expression pattern of this network might be used as biomarker for ASD and should be experimentally explored as a therapeutic target.
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Transtorno do Espectro Autista , Células-Tronco Pluripotentes Induzidas , Transtorno do Espectro Autista/genética , Humanos , Neurônios , Proteômica , Transcriptoma/genéticaRESUMO
BACKGROUND: Allergic diseases appear to be associated with mood disorders. However, particularly regarding allergic rhinitis (AR), such association has not been adequately systematically reviewed. Therefore, we conducted a systematic review and meta-analysis to quantify the association between AR and depression and anxiety. METHODOLOGY: We performed an electronic search of PubMed, Web of Science and Scopus for observational studies assessing the association between AR and depression and anxiety. Such association was quantified by means of random-effects meta-analysis, with estimation of pooled odds ratio (OR). Sources of heterogeneity were explored by subgroup analysis. RESULTS: We included a total of 24 primary studies, of which 23 assessed depression and 11 assessed anxiety. Of these, 12 studies presented OR from multivariable regression models and were included in our meta-analysis. AR was associated with higher odds of depression and anxiety. CONCLUSIONS: AR appears to be associated with high risk of depression and anxiety. While our results point to the importance of mental comorbidities among patients with AR, longitudinal studies are needed adopting uniform definitions and presenting results stratified by AR severity.
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Depressão , Rinite Alérgica , Ansiedade/epidemiologia , Transtornos de Ansiedade/epidemiologia , Comorbidade , Depressão/epidemiologia , Humanos , Rinite Alérgica/complicações , Rinite Alérgica/epidemiologiaRESUMO
BACKGROUND: Drooling is a major morbidity in several neurological diseases. Intraglandular botulinum neurotoxin (BoNT) injections have been used to manage this condition. However, by decreasing salivary flow, BoNT injections may result in an increased risk of caries and other oral adverse effects. In this study, we aimed to assess whether, in patients with drooling, intraglandular BoNT injections are associated with increased dental caries development, modifications on salivary composition (oral pH, buffering capacity and osmolality) and cariogenic bacterial load. MATERIAL AND METHODS: We performed a systematic review, searching PubMed, CENTRAL, Web of Science, and Scopus for all experimental and observational studies reporting on adverse effects of intraglandular BoNT injections in patients with drooling. Primary study selection, quality assessment, and data extraction were independently performed by two researchers. No studies were excluded based on their language, publication status or date of publication. Studies' quality was based on revised Cochrane Risk of Bias tools. Meta-analysis was not performed. RESULTS: We retrieved 1025 studies, of which 5 were included. Two studies were two randomized controlled trials and three quasi-experimental studies. None of the included studies found BoNT injections to be associated with dental caries development or with significant reductions in oral pH. One of the included primary studies even observed an increase in salivary buffer capacity. One study found an increase in Lactobacilli counts. As for the risk of bias, two studies were classified as having a critical risk, two as high risk and one as having some concerns. CONCLUSIONS: Currently, there is no evidence that, in patients with drooling, BoNT injections associate with increased risk of dental caries or disturbances in oral pH or salivary buffering capacity. However, the included primary studies had important limitations and differences in their methodologies.
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Toxinas Botulínicas Tipo A , Paralisia Cerebral , Cárie Dentária , Fármacos Neuromusculares , Sialorreia , Toxinas Botulínicas Tipo A/efeitos adversos , Humanos , Saúde Bucal , Sialorreia/induzido quimicamente , Sialorreia/tratamento farmacológicoRESUMO
BACKGROUND: LupusPRO is a SLE specific patient reported outcomes measure developed and validated in the USA. This study aimed to validate the Hindi version of LupusPRO in systemic lupus erythematosus (SLE) patients in India. METHODS: Disease activity and damage were assessed using SELENA-SLEDAI and SLICC/ACR damage Index respectively. Demographic and clinical features were recorded. The Hindi Version of LupusPRO and 36-Item Short Form Health Survey (SF-36) were administered for assessment of quality of life. Depression, anxiety and fatigue were assessed using Patient Health Questionnaire 9 (PHQ9), Generalized Anxiety Disorder 7 (GAD7) and Fatigue Severity Scale (FSS) respectively. Internal consistency reliability, test-retest reliability, convergent and discriminant validity (against corresponding domains of the SF-36, fatigue, depression and anxiety), criterion validity (against disease activity and damage) and known group validity were tested. RESULTS: A total of 144 (140 females) patients with SLE with a mean age of 32.48 ± 7.26 years participated in the study. The median (interquartile range) SELENA SLEDAI was 2 (5.5). The internal consistency reliability of the LupusPRO domains was >0.7 for most domains (except for lupus symptoms, lupus medication, procreation and social support).We noted good convergent validity of LupusPRO domains with corresponding domains of SF-36, pain vitality with fatigue (FSS) and emotional health domain with depression (PHQ9) and anxiety (GAD7). Criterion validity of lupus symptoms with disease activity was observed. Known group validity of the LupusPRO domains with patient reported health status was observed. Confirmatory factor analysis showed a good fit. CONCLUSION: The Hindi LupusPRO has fair psychometric properties among Indian patients with SLE.
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Lúpus Eritematoso Sistêmico/fisiopatologia , Medidas de Resultados Relatados pelo Paciente , Qualidade de Vida , Inquéritos e Questionários , Adulto , Comparação Transcultural , Estudos Transversais , Feminino , Humanos , Índia , Lúpus Eritematoso Sistêmico/psicologia , Masculino , Psicometria , Reprodutibilidade dos Testes , Índice de Gravidade de DoençaRESUMO
The primary sweet sensor in mammalian taste cells for sugars and noncaloric sweeteners is the heteromeric combination of type 1 taste receptors 2 and 3 (T1R2+T1R3, encoded by Tas1r2 and Tas1r3 genes). However, in the absence of T1R2+T1R3 (e.g., in Tas1r3 KO mice), animals still respond to sugars, arguing for the presence of T1R-independent detection mechanism(s). Our previous findings that several glucose transporters (GLUTs), sodium glucose cotransporter 1 (SGLT1), and the ATP-gated K(+) (KATP) metabolic sensor are preferentially expressed in the same taste cells with T1R3 provides a potential explanation for the T1R-independent detection of sugars: sweet-responsive taste cells that respond to sugars and sweeteners may contain a T1R-dependent (T1R2+T1R3) sweet-sensing pathway for detecting sugars and noncaloric sweeteners, as well as a T1R-independent (GLUTs, SGLT1, KATP) pathway for detecting monosaccharides. However, the T1R-independent pathway would not explain responses to disaccharide and oligomeric sugars, such as sucrose, maltose, and maltotriose, which are not substrates for GLUTs or SGLT1. Using RT-PCR, quantitative PCR, in situ hybridization, and immunohistochemistry, we found that taste cells express multiple α-glycosidases (e.g., amylase and neutral α glucosidase C) and so-called intestinal "brush border" disaccharide-hydrolyzing enzymes (e.g., maltase-glucoamylase and sucrase-isomaltase). Treating the tongue with inhibitors of disaccharidases specifically decreased gustatory nerve responses to disaccharides, but not to monosaccharides or noncaloric sweeteners, indicating that lingual disaccharidases are functional. These taste cell-expressed enzymes may locally break down dietary disaccharides and starch hydrolysis products into monosaccharides that could serve as substrates for the T1R-independent sugar sensing pathways.
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Dissacarídeos/farmacologia , Regulação Enzimológica da Expressão Gênica/fisiologia , Papilas Gustativas/enzimologia , Paladar/fisiologia , alfa-Glucosidases/biossíntese , Animais , Proteínas Facilitadoras de Transporte de Glucose/genética , Proteínas Facilitadoras de Transporte de Glucose/metabolismo , Camundongos , Camundongos Transgênicos , Receptores Acoplados a Proteínas G/genética , Receptores Acoplados a Proteínas G/metabolismo , Transportador 1 de Glucose-Sódio/genética , Transportador 1 de Glucose-Sódio/metabolismo , alfa-Glucosidases/genéticaRESUMO
BACKGROUND: Uncontrolled proteolysis contributes to cell injury and organ dysfunction in animal models of circulatory shock. We investigated in humans the relationship between septic shock, proteolysis, and outcome. METHODS: Intensive care patients with septic shock (n=29) or sepsis (n=6) and non-hospitalised subjects (n=9) were recruited as part of the prospective observational trial 'ShockOmics' (ClinicalTrials.gov Identifier NCT02141607). A mass spectrometry-based approach was used to analyse the plasma peptidomes and the origin of circulating peptides from proteolysis in the enrolled subjects. RESULTS: Evidence of systemic proteolysis was indicated by a larger number of circulating peptides in septic shock patients, compared with septic patients and non-hospitalised healthy subjects. The peptide count and abundance in the septic shock patients were greater in patients who died (n=6) than in survivors (n=23), suggesting an association between magnitude of proteolysis and outcome. In silico analysis of the peptide sequences and of the sites of cleavage on the proteins of origin indicated a predominant role for serine proteases, such as chymotrypsin, and matrix metalloproteases in causing the observed proteolytic degradation. CONCLUSIONS: Systemic proteolysis is a novel fundamental pathological mechanism in septic shock. Plasma peptidomics is proposed as a new tool to monitor clinical trajectory in septic shock patients. CLINICAL TRIAL REGISTRATION: NCT02141607.
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Peptídeos/sangue , Proteólise , Choque Séptico/metabolismo , Choque Séptico/mortalidade , Adulto , Idoso , Idoso de 80 Anos ou mais , Quimotripsina/sangue , Simulação por Computador , Cuidados Críticos , Feminino , Mortalidade Hospitalar , Humanos , Masculino , Metaloproteinases da Matriz/sangue , Pessoa de Meia-Idade , Estudos Prospectivos , Sepse/sangue , Sepse/metabolismo , Sepse/mortalidade , Choque Séptico/sangue , Análise de Sobrevida , Resultado do Tratamento , Adulto JovemRESUMO
Interventions offering peer mentoring programmes promoting moderate-to-vigorous physical activity (MVPA) have shown improvements in MVPA and well-being from baseline; however, research is limited. The purpose of this study was to compare the physical activity (PA) levels and psychosocial well-being of coaches and participants at baseline and following a 12-week intervention. Breast cancer survivors (<5 years) were recruited and randomised into either exercise (Reach-to-Recovery (RTR) + PA) or control (RTR Control). Participants in both groups were individually assigned one of the 18 available coaches who delivered either the MVPA intervention or the control condition via telephone. PA (7-Day PA Recall), psychosocial well-being, fatigue and mood were assessed at baseline and intervention completion. Seventy-six breast cancer survivors (average age = 55.62 (±9.55)) were randomised. At baseline, all participants showed significantly lower MVPA (p = .001) and well-being (p < .05) as compared to coaches. However, post-intervention showed significant improvement in PA and well-being in RTR + PA, so that they were no longer significantly different from the coaches. Post-intervention, MVPA (p < .01), quality of life (p < .05) and fatigue (p < .05) remained significantly lower in RTR Controls compared to coaches. Future interventions should consider the behavioural patterns not only of the participants, but also of those who deliver the interventions.
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Neoplasias da Mama/reabilitação , Sobreviventes de Câncer , Exercício Físico , Promoção da Saúde/métodos , Tutoria , Grupo Associado , Apoio Social , Afeto , Idoso , Sobreviventes de Câncer/psicologia , Exercício Físico/psicologia , Fadiga/prevenção & controle , Feminino , Humanos , Mentores/psicologia , Pessoa de Meia-Idade , Qualidade de VidaRESUMO
Influenza virus neuraminidase (NA) drug resistance is one of the challenges to preparedness against epidemic and pandemic influenza virus infections. NA N1- and N2-containing influenza viruses are the primary cause of seasonal epidemics and past pandemics. The structural and functional basis underlying drug resistance of the influenza virus N1 NA is well characterized. Yet drug resistance of the N2 strain is not well understood. Here, we confirm that replacement of N2 E119 or I222 results in multidrug resistance, and when the replacements occur together, the sensitivity to NA inhibitors (NAI) is reduced severely. Using crystallographic studies, we showed that E119 replacement results in a loss of hydrogen bonding to oseltamivir and zanamivir, whereas I222 replacement results in a change in the hydrophobic environment that is critical for oseltamivir binding. Moreover, we found that MS-257, a zanamivir-oseltamivir hybrid inhibitor, is less susceptible to drug resistance. The binding mode of MS-257 shows that increased hydrogen bonding interactions between the inhibitor and NA active site anchor the inhibitor within the active site and allow adjustments in response to active-site modifications. Such stability is likely responsible for the observed reduced susceptibility to drug resistance. MS-257 serves as a next-generation anti-influenza virus drug candidate and serves also as a scaffold for further design of NAIs. IMPORTANCE: Oseltamivir and zanamivir are the two major antiviral drugs available for the treatment of influenza virus infections. However, multidrug-resistant viruses have emerged in clinical cases, which pose a challenge for the development of new drugs. N1 and N2 subtypes exist in the viruses which cause seasonal epidemics and past pandemics. Although N1 drug resistance is well characterized, the molecular mechanisms underlying N2 drug resistance are unknown. A previous report showed that an N2 E119V/I222L dual mutant conferred drug resistance to seasonal influenza virus. Here, we confirm that these substitutions result in multidrug resistance and dramatically reduced sensitivity to NAI. We further elucidate the molecular mechanism underlying N2 drug resistance by solving crystal structures of the N2 E119V and I222L mutants and the dual mutant. Most importantly, we found that a novel oseltamivir-zanamivir hybrid inhibitor, MS-257, remains more effective against drug-resistant N2 and is a promising candidate as a next-generation anti-influenza virus drug.
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Antivirais/farmacologia , Vírus da Influenza A/efeitos dos fármacos , Vírus da Influenza A/enzimologia , Mutação , Neuraminidase/antagonistas & inibidores , Neuraminidase/genética , Oseltamivir/farmacologia , Proteínas Virais/antagonistas & inibidores , Proteínas Virais/genética , Zanamivir/farmacologia , Substituição de Aminoácidos , Farmacorresistência Viral Múltipla/genética , Inibidores Enzimáticos/farmacologia , Humanos , Vírus da Influenza A/genética , Modelos Moleculares , Neuraminidase/química , Proteínas Virais/químicaRESUMO
An accurate estimate of the impact of toxoplasmosis on the population in Italy is not available. We performed a cross-sectional study on individuals living in Italy to assess: (1) differences in access to Toxo testing and in the prevalence of recent and past Toxoplasma gondii infection according to gender and age, and (2) the clinical impact of disease burden on the male patient subset. Reason for testing, condition of in- or outpatient and clinical data were analysed. Between-gender differences were observed in access to the test. Immunoglobulin M (IgM) prevalence was increased in males in the age range 5-34 years [odds ratio (OR) = 2.03, 95% confidence interval (CI) 1.18-3.49, p = 0.01), with a peak at 25-34 years. In females, it decreased in the age range 20-39 years (OR = 0.49, 95% CI 0.32-0.74, p = 0.0008). The attack rate of recent infection was twice as high for males than for females. Estimates pointed out 3.3 and 1.7 events in 1000 at-risk person-years in the male and female cohorts, respectively. Most IgM-positive subjects did not experience severe forms of toxoplasmosis, with 35% having lymphadenopathy. Chorioretinitis, systemic and neurological manifestations were also observed. Our findings suggest that the acute phase of toxoplasmosis is largely unapparent or clinically mild in this area. It is also possible that the disease burden for Toxoplasma infection in Italy is underestimated. Further study should focus on information acquisition and Toxo test access in hospital units for a better estimation of the real burden of mild and severe forms of the disease.
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Toxoplasmose/epidemiologia , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Anticorpos Antiprotozoários/sangue , Criança , Pré-Escolar , Estudos Transversais , Feminino , Acessibilidade aos Serviços de Saúde , Humanos , Imunoglobulina M/sangue , Lactente , Recém-Nascido , Itália/epidemiologia , Masculino , Pessoa de Meia-Idade , Prevalência , Fatores de Risco , Fatores Sexuais , Toxoplasmose/patologia , Adulto JovemRESUMO
BACKGROUND: Prophylactic antibiotics are traditionally given as a single dose for caesarean section. However, inconsistent application of recommendations and recent evidence prompted a literature review. OBJECTIVES: To assess the optimal regimen for antibiotic prophylaxis in caesarean section by comparing single versus multiple doses of the same intervention. SEARCH STRATEGY: MEDLINE, Web of Knowledge, SCOPUS, CENTRAL and ongoing trials databases were searched. Reference lists were reviewed and international groups contacted. SELECTION CRITERIA: Randomised controlled trials (RCT) comparing single with multiple dose regimens of the same antibiotic prophylaxis. Quasi-RCT and abstracts were suitable for inclusion. DATA COLLECTION AND ANALYSIS: Reviewers independently extracted data and assessed quality of evidence. A random-effects model was used and results presented as risk ratio (RR) with 95% confidence intervals (CI). MAIN RESULTS: Sixteen studies were included, involving 2695 women. Nonsignificant differences were observed between single dose and multiple dose antibiotic prophylaxis in the incidence of postpartum infectious morbidity (RR 0.95, 95% CI 0.75-1.20, I2 = 25%), endometritis (RR 1.03, 95% CI 0.74-1.42, I2 = 0%) and wound infection (RR 1.22, 95% CI 0.72-2.08, I2 = 0%). A trend towards lower risk of urinary tract infection was seen with multiple dose (RR 0.65, 95% CI 0.34-1.24, I2 = 0%). CONCLUSIONS: There was insufficient evidence to determine whether there is a difference between single and multiple dose regimens in reducing the incidence of infectious morbidity after caesarean section. The quality of evidence was very low and well-designed RCTs are needed. TWEETABLE ABSTRACT: Insufficient evidence of difference between dosage regimens of antibiotic prophylaxis in caesarean section.
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Antibacterianos/administração & dosagem , Antibioticoprofilaxia/métodos , Cesárea/efeitos adversos , Infecções/epidemiologia , Complicações Pós-Operatórias/prevenção & controle , Relação Dose-Resposta a Droga , Feminino , Humanos , Infecções/etiologia , Complicações Pós-Operatórias/epidemiologia , GravidezRESUMO
UDP-galactopyranose mutase (UGM), a key enzyme in the biosynthesis of mycobacterial cell walls, is a potential target for the treatment of tuberculosis. In this work, we investigate binding models of a non-substrate-like inhibitor, MS-208, with M.â tuberculosis UGM. Initial saturation transfer difference (STD) NMR experiments indicated a lack of direct competition between MS-208 and the enzyme substrate, and subsequent kinetic assays showed mixed inhibition. We thus hypothesized that MS-208 binds at an allosteric binding site (A-site) instead of the enzyme active site (S-site). A candidate A-site was identified in a subsequent computational study, and the overall hypothesis was supported by ensuing mutagenesis studies of the A-site. Further molecular dynamics studies led us to propose that MS-208 inhibition occurs by preventing complete closure of an active site mobile loop that is necessary for productive substrate binding. The results suggest the presence of an A-site with potential druggability, opening up new opportunities for the development of novel drug candidates against tuberculosis.
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Inibidores Enzimáticos/farmacologia , Transferases Intramoleculares/antagonistas & inibidores , Mycobacterium tuberculosis/enzimologia , Pirazóis/farmacologia , Sítios de Ligação/efeitos dos fármacos , Relação Dose-Resposta a Droga , Inibidores Enzimáticos/química , Transferases Intramoleculares/metabolismo , Espectroscopia de Ressonância Magnética , Modelos Moleculares , Estrutura Molecular , Pirazóis/química , Relação Estrutura-AtividadeRESUMO
Although several studies have reported an increase of syphilis incidence over the last decade in Western Europe, information concerning syphilis epidemiology in Portugal remains scarce. Therefore, we sought to characterise acquired syphilis-associated hospitalisations in Portugal according to demographic and clinical data. We used a database containing all hospitalisations that occurred in mainland Portugal public hospitals with discharges between 2000 and 2014. We analysed all hospitalisations associated with ICD-9-CM codes 091-097.x (corresponding to acquired syphilis diagnosis) concerning inpatients' gender, age and comorbidities. The median length of stay and in-hospital mortality rates were also studied. Between 2000 and 2014, there were a total of 8974 syphilis-related hospitalisations in mainland Portugal. The rate of acquired syphilis hospitalisations per 100,000 inhabitants increased by 33 % during the studied period. Syphilis hospitalisation rates increased by 70 % in males and 139 % among patients aged over 55 years. On the other hand, they declined by 10 % in females and 20 % among patients younger than 55 years old. The percentage of syphilis episodes presenting cardiovascular and neuropsychiatric comorbidities increased, while the percentage of syphilis episodes presenting HIV co-infection decreased by 69 %. A fatal outcome was reported in 5 % of episodes; 4.6 % of them had acquired syphilis as the main reason for hospitalisation. This study illustrates that, despite being a preventable infection, syphilis remains a public health problem. The analysis of hospitalisation and administrative data helps to understand syphilis epidemiology and provides a supplement to traditional case notifications.
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Mortalidade Hospitalar , Hospitalização/estatística & dados numéricos , Sífilis/epidemiologia , Adolescente , Adulto , Idoso , Coinfecção , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Portugal/epidemiologia , Sífilis/microbiologia , Sífilis/mortalidade , Treponema pallidum , Adulto JovemRESUMO
This manuscript describes a novel class of derivatives based on a bicyclo[3.1.0]hexane scaffold, proposed as mimics of sialic acid in a distorted boat conformation that is on the catalytic pathway of neuraminidases (sialidases). A general synthetic route for these constrained-ring molecules was developed using a photochemical reaction followed by a Johnson-Corey-Chaykovsky cyclopropanation. Functionalization with the goal of occupying the 150-cavity was also exploited. Inhibition assays demonstrated low micromolar inhibition against both group-1 (H5N1) and group-2 (H9N2) influenza neuraminidase subtypes, indicating good affinity for the alpha and beta sialic acid mimics and 150-cavity-targeted derivatives. These results provide a validation of a bicyclo[3.1.0]hexane scaffold as a mimic of a distorted sialic acid bound in the neuraminidase active site during catalysis.
Assuntos
Compostos Bicíclicos com Pontes/síntese química , Compostos Bicíclicos com Pontes/farmacologia , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/farmacologia , Virus da Influenza A Subtipo H5N1/enzimologia , Vírus da Influenza A Subtipo H9N2/enzimologia , Neuraminidase/antagonistas & inibidores , Compostos Bicíclicos com Pontes/química , Técnicas de Química Sintética , Desenho de Fármacos , Inibidores Enzimáticos/química , Modelos Moleculares , Neuraminidase/química , Conformação ProteicaRESUMO
In humans, four different enzymes mediate the digestion of ingested carbohydrates. First salivary and pancreatic α-amylases, the two endoacting retaining glucosidases, break down the complex starch molecules into smaller linear maltose-oligomers (LM) and branched α-limit dextrins (αLDx). Then two retaining exoglucosidases, maltase-glucoamylase (MGAM) and sucrase-isomaltase (SI), convert those molecules into glucose in the small intestine. The small intestinal brush-border epithelial cells anchor MGAM and SI, and each contains a catalytic N- and C-terminal subunit, ntMGAM, ctMGAM, ntSI, and ctSI, respectively. All four catalytic domains have, to varying extents, α-1,4-exohydrolytic glucosidase activity and belong to the glycoside hydrolase family 31 (GH31). ntSI and ctSI show additional activity toward α-1,6 (isomaltose substrates) and α-1,2 (sucrose) glycosidic linkages, respectively. Because they mediate the final steps of starch digestion, both MGAM and SI are important target enzymes for the treatment of type-2 diabetes. Because of their potent inhibitory activities against the mammalian intestinal α-glucosidases, sulfonium-ion glucosidase inhibitors isolated from the antidiabetic herbal extracts of various Salacia species have received considerable attention recently. Thus far, researchers have isolated eight sulfonium-ion glucosidase inhibitors from Salacia species: salaprinol, salacinol, ponkoranol, kotalanol, and four of their corresponding de-O-sulfonated compounds, the structures of which comprise a 1,4-anhydro-4-thio-d-arabinitol and a polyhydroxylated acyclic side chain. Some of these compounds more strongly inhibit human intestinal α-glucosidases than the currently available antidiabetic drugs, acarbose and miglitol, and could serve as lead candidates in the treatment of type-2 diabetes. In this Account, we summarize progress in the field since 2010 with this class of inhibitors, with particular focus on their selective inhibitory activities against the intestinal glucosidases. Through structure-activity relationship (SAR) studies, we have modified the natural compounds to derive more potent, nanomolar inhibitors of human MGAM and SI. This structural optimization also yielded the most potent inhibitors known to date for each subunit. Furthermore, we observed that some of our synthetic inhibitors selectively blocked the activity of some mucosal α-glucosidases. Those results led to our current working hypothesis that selective inhibitors can dampen the action of a fast digesting subunit or subunits which places the burden of digestion on slower digesting subunits. That strategy can control the rate of starch digestion and glucose release to the body. Decreasing the initial glucose spike after a carbohydrate-rich meal and extending postprandial blood glucose delivery to the body can be desirable for diabetics and patients with other metabolic syndrome-associated diseases.
Assuntos
Produtos Biológicos/farmacologia , Inibidores Enzimáticos/farmacologia , Glucosidases/antagonistas & inibidores , Hipoglicemiantes/farmacologia , Compostos de Enxofre/farmacologia , Animais , Produtos Biológicos/química , Inibidores Enzimáticos/química , Humanos , Hipoglicemiantes/química , Relação Estrutura-Atividade , Compostos de Enxofre/químicaRESUMO
UDP-galactopyranose mutase (UGM) is an enzyme involved in the biosynthesis of the Mycobacterium tuberculosis cell wall, and is essential for the growth and survival of the organism. A micromolar inhibitor developed by tetrafluorination of the UGM substrate has been previously studied by saturation transfer difference (STD) NMR spectroscopy. To elucidate the bioactive conformation of the inhibitor bound to UGM, we employ molecular dynamics (MD) simulations to construct a structural model. The MD model is subsequently validated by a good fit between experimental and theoretical STD effects, the latter calculated by a complete relaxation and conformational exchange matrix (CORCEMA) analysis. This structural model is used to explain the relative binding affinities of the inhibitor and the parent substrate.
Assuntos
Inibidores Enzimáticos/química , Transferases Intramoleculares/antagonistas & inibidores , Simulação de Dinâmica Molecular , Sítios de Ligação , Inibidores Enzimáticos/metabolismo , Transferases Intramoleculares/metabolismo , Klebsiella pneumoniae/enzimologia , Espectroscopia de Ressonância Magnética , Ligação Proteica , Estrutura Terciária de ProteínaRESUMO
The synthesis of 1-[5-O-(α-D-galactopyranosyl)-D-glucityl]pyrimidine-2,4(3H)-dione and 1-[(5-O-(ß-D-galactopyranosyl)-D-glucityl]pyrimidine-2,4(3H)-dione as non-ionic substrate mimics of UDP-Galp are described. UDP-Galp is a precursor of Galf, which is a primary component of the cell-wall glycans of several microorganisms. The interconversion of UDP-Galp and UDP-Galf is catalyzed by UDP galactopyranose mutase (UGM); its inhibition comprises a mode of compromising the microorganisms. The nonionic polyhydroxylated chain was intended to mimic the ionic pyrophosphate group and the ribose moiety in UDP-Galp and increase the bioavailabilities of the candidate inhibitors. Inhibition assays with UGM of Mycobacterium tuberculosis showed only weak inhibition of the enzyme by these compounds.