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1.
Euro Surveill ; 26(43)2021 10.
Artigo em Inglês | MEDLINE | ID: mdl-34713798

RESUMO

BackgroundDetailed information on symptom duration and temporal course of patients with mild COVID-19 was scarce at the beginning of the COVID-19 pandemic.AimWe aimed to determine the longitudinal course of clinical symptoms in non-hospitalised COVID-19 patients in Berlin, Germany.MethodsBetween March and May 2020, 102 confirmed COVID-19 cases in home isolation notified in Berlin, Germany, were sampled using total population sampling. Data on 25 symptoms were collected during telephone consultations (a maximum of four consultations) with each patient. We collected information on prevalence and duration of symptoms for each day of the first 2 weeks after symptom onset and for day 30 and 60 after symptom onset.ResultsMedian age was 35 years (range 18-74), 57% (58/102) were female, and 37% (38/102) reported having comorbidities. During the first 2 weeks, most common symptoms were malaise (94%, 92/98), headache (71%, 70/98), and rhinitis (69%, 68/98). Malaise was present for a median of 11 days (IQR 7-14 days) with 35% (34/98) of cases still reporting malaise on day 14. Headache and muscle pain mostly occurred during the first week, whereas dysosmia and dysgeusia mostly occurred during the second week. Symptoms persisted in 41% (39/95) and 20% (18/88) of patients on day 30 and 60, respectively.ConclusionOur study shows that a significant proportion of non-hospitalised COVID-19 cases endured symptoms for at least 2 months. Further research is needed to assess the frequency of long-term adverse health effects in non-hospitalised COVID-19 patients.


Assuntos
COVID-19 , Adolescente , Adulto , Idoso , Berlim , Feminino , Alemanha/epidemiologia , Humanos , Estudos Longitudinais , Pessoa de Meia-Idade , Pandemias , SARS-CoV-2 , Adulto Jovem
2.
Infection ; 49(4): 703-714, 2021 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-33890243

RESUMO

PURPOSE: Adequate patient allocation is pivotal for optimal resource management in strained healthcare systems, and requires detailed knowledge of clinical and virological disease trajectories. The purpose of this work was to identify risk factors associated with need for invasive mechanical ventilation (IMV), to analyse viral kinetics in patients with and without IMV and to provide a comprehensive description of clinical course. METHODS: A cohort of 168 hospitalised adult COVID-19 patients enrolled in a prospective observational study at a large European tertiary care centre was analysed. RESULTS: Forty-four per cent (71/161) of patients required invasive mechanical ventilation (IMV). Shorter duration of symptoms before admission (aOR 1.22 per day less, 95% CI 1.10-1.37, p < 0.01) and history of hypertension (aOR 5.55, 95% CI 2.00-16.82, p < 0.01) were associated with need for IMV. Patients on IMV had higher maximal concentrations, slower decline rates, and longer shedding of SARS-CoV-2 than non-IMV patients (33 days, IQR 26-46.75, vs 18 days, IQR 16-46.75, respectively, p < 0.01). Median duration of hospitalisation was 9 days (IQR 6-15.5) for non-IMV and 49.5 days (IQR 36.8-82.5) for IMV patients. CONCLUSIONS: Our results indicate a short duration of symptoms before admission as a risk factor for severe disease that merits further investigation and different viral load kinetics in severely affected patients. Median duration of hospitalisation of IMV patients was longer than described for acute respiratory distress syndrome unrelated to COVID-19.


Assuntos
COVID-19/epidemiologia , COVID-19/virologia , SARS-CoV-2/fisiologia , COVID-19/terapia , Estudos de Coortes , Alemanha/epidemiologia , Hospitalização , Humanos , Hipertensão/complicações , Cinética , Estudos Prospectivos , Respiração Artificial , Fatores de Risco , Centros de Atenção Terciária , Fatores de Tempo , Carga Viral , Eliminação de Partículas Virais
3.
Blood ; 138(15): 1293-1303, 2021 Oct 14.
Artigo em Inglês | MEDLINE | ID: mdl-33876222

RESUMO

Anemia of inflammation is a hallmark of tuberculosis. Factors controlling iron metabolism during anemia of inflammation and its resolution are uncertain. Whether iron supplements should be given during antituberculosis treatment to support hemoglobin (Hb) recovery is unclear. Before and during treatment of tuberculosis, we assessed iron kinetics, as well as changes in inflammation and iron metabolism indices. In a 26-week prospective study, Tanzanian adults with tuberculosis (N = 18) were studied before treatment and then every 2 weeks during treatment; oral and intravenous iron tracers were administered before treatment and after intensive phase (8/12 weeks) and complete treatment (24 weeks). No iron supplements were given. Before treatment, hepcidin and erythroferrone (ERFE) were greatly elevated, erythrocyte iron utilization was high (∼80%), and iron absorption was negligible (<1%). During treatment, hepcidin and interleukin-6 levels decreased ∼70% after only 2 weeks (P< .001); in contrast, ERFE did not significantly decrease until 8 weeks (P< .05). ERFE and interleukin-6 were the main opposing determinants of hepcidin (P< .05), and greater ERFE was associated with reticulocytosis and Hb repletion (P< .01). Dilution of baseline tracer concentration was 2.6-fold higher during intensive phase treatment (P< .01), indicating enhanced erythropoiesis. After treatment completion, iron absorption increased ∼20-fold (P< .001), and Hb increased ∼25% (P< .001). In tuberculosis-associated anemia of inflammation, our findings suggest that elevated ERFE is unable to suppress hepcidin, and iron absorption is negligible. During treatment, as inflammation resolves, ERFE may remain elevated, contributing to hepcidin suppression and Hb repletion. Iron is well absorbed only after tuberculosis treatment, and supplementation should be reserved for patients remaining anemic after treatment. This trial was registered at www.clinicaltrials.gov as #NCT02176772.

4.
J Med Chem ; 63(23): 14576-14593, 2020 12 10.
Artigo em Inglês | MEDLINE | ID: mdl-33252239

RESUMO

MALT1 plays a central role in immune cell activation by transducing NF-κB signaling, and its proteolytic activity represents a key node for therapeutic intervention. Two cycles of scaffold morphing of a high-throughput biochemical screening hit resulted in the discovery of MLT-231, which enabled the successful pharmacological validation of MALT1 allosteric inhibition in preclinical models of humoral immune responses and B-cell lymphomas. Herein, we report the structural activity relationships (SARs) and analysis of the physicochemical properties of a pyrazolopyrimidine-derived compound series. In human T-cells and B-cell lymphoma lines, MLT-231 potently and selectively inhibits the proteolytic activity of MALT1 in NF-κB-dependent assays. Both in vitro and in vivo profiling of MLT-231 support further optimization of this in vivo tool compound toward preclinical characterization.


Assuntos
Inibidores de Caspase/uso terapêutico , Proteína de Translocação 1 do Linfoma de Tecido Linfoide Associado à Mucosa/antagonistas & inibidores , Neoplasias/tratamento farmacológico , Ureia/análogos & derivados , Ureia/uso terapêutico , Animais , Antineoplásicos/síntese química , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Inibidores de Caspase/síntese química , Inibidores de Caspase/farmacologia , Descoberta de Drogas , Feminino , Humanos , Imunidade Humoral/efeitos dos fármacos , Masculino , Camundongos Endogâmicos BALB C , Estrutura Molecular , Pirazóis/síntese química , Pirazóis/farmacologia , Pirazóis/uso terapêutico , Pirimidinas/síntese química , Pirimidinas/farmacologia , Pirimidinas/uso terapêutico , Ratos Sprague-Dawley , Relação Estrutura-Atividade , Linfócitos T/efeitos dos fármacos , Ureia/farmacologia , Ensaios Antitumorais Modelo de Xenoenxerto
5.
PLoS Negl Trop Dis ; 14(10): e0008752, 2020 10.
Artigo em Inglês | MEDLINE | ID: mdl-33119632

RESUMO

BACKGROUND: Chagas disease (CD) is highly endemic in the Bolivian Chaco. The municipality of Monteagudo has been targeted by national interventions as well as by Médecins Sans Frontières to reduce infection rates, and to decentralize early diagnosis and treatment. This study seeks to determine the knowledge and attitudes of a population with increased awareness and to identify remaining factors and barriers for sustained vector control, health care seeking behaviour, and access, in order to improve future interventions. METHODOLOGY/PRINCIPAL FINDINGS: A cross-sectional survey was conducted among approximately 10% (n = 669) of the municipality of Monteagudo's households that were randomly selected. Additionally, a total of 14 in-depth interviews and 2 focus group discussions were conducted with patients and key informants. Several attitudes and practices were identified that could undermine effective control against (re-)infection. Knowledge of clinical symptoms and secondary prevention was limited, and revealed specific misconceptions. Although 76% of the participants had been tested for CD, only 18% of those who tested positive concluded treatment with benznidazole (BNZ). Sustained positive serologies after treatment led to perceived ineffectiveness of BNZ. Moreover, access barriers such as direct as well as indirect costs, BNZ stock-outs and a fear of adverse reactions triggered by other community members made patients opt for alternative treatments against CD such as veterinary ivermectin, used by 28% of infected participants in our study. The lack of accessible care for chronic complications as well as socioeconomic consequences, such as the exclusion from both job opportunities and bank loans contributed to the ongoing burden of CD. CONCLUSIONS/SIGNIFICANCE: Large scale interventions should be accompanied by operational research in order to identify misconceptions and unintended consequences early on, to generate accessible data for future interventions, and for rigorous evaluation. An integrated, community-based approach tackling social determinants and including both traditional and animal health sectors might help to overcome current barriers and advocate for patients' rights.


Assuntos
Doença de Chagas/tratamento farmacológico , Conhecimentos, Atitudes e Prática em Saúde , Nitroimidazóis/uso terapêutico , Aceitação pelo Paciente de Cuidados de Saúde/psicologia , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Animais , Bolívia/epidemiologia , Doença de Chagas/economia , Doença de Chagas/epidemiologia , Doença de Chagas/prevenção & controle , Estudos Transversais , Características da Família , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Nitroimidazóis/economia , Fatores Socioeconômicos , Inquéritos e Questionários , Adulto Jovem
6.
Infection ; 48(4): 619-626, 2020 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-32535877

RESUMO

PURPOSE: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has spread worldwide causing a global health emergency. Pa-COVID-19 aims to provide comprehensive data on clinical course, pathophysiology, immunology and outcome of COVID-19, to identify prognostic biomarkers, clinical scores, and therapeutic targets for improved clinical management and preventive interventions. METHODS: Pa-COVID-19 is a prospective observational cohort study of patients with confirmed SARS-CoV-2 infection treated at Charité - Universitätsmedizin Berlin. We collect data on epidemiology, demography, medical history, symptoms, clinical course, and pathogen testing and treatment. Systematic, serial blood sampling will allow deep molecular and immunological phenotyping, transcriptomic profiling, and comprehensive biobanking. Longitudinal data and sample collection during hospitalization will be supplemented by long-term follow-up. RESULTS: Outcome measures include the WHO clinical ordinal scale on day 15 and clinical, functional, and health-related quality-of-life assessments at discharge and during follow-up. We developed a scalable dataset to (i) suit national standards of care, (ii) facilitate comprehensive data collection in medical care facilities with varying resources, and (iii) allow for rapid implementation of interventional trials based on the standardized study design and data collection. We propose this scalable protocol as blueprint for harmonized data collection and deep phenotyping in COVID-19 in Germany. CONCLUSION: We established a basic platform for harmonized, scalable data collection, pathophysiological analysis, and deep phenotyping of COVID-19, which enables rapid generation of evidence for improved medical care and identification of candidate therapeutic and preventive strategies. The electronic database accredited for interventional trials allows fast trial implementation for candidate therapeutic agents. TRIAL REGISTRATION: Registered at the German registry for clinical studies (DRKS00021688).


Assuntos
Infecções por Coronavirus/fisiopatologia , Pneumonia Viral/fisiopatologia , Sistema de Registros , Berlim/epidemiologia , Betacoronavirus , Bancos de Espécimes Biológicos , COVID-19 , Infecções por Coronavirus/epidemiologia , Gerenciamento Clínico , Humanos , Estudos Observacionais como Assunto , Pandemias , Fenótipo , Pneumonia Viral/epidemiologia , Estudos Prospectivos , Medição de Risco , Fatores de Risco , SARS-CoV-2 , Fatores de Tempo , Resultado do Tratamento , Organização Mundial da Saúde
7.
Obesity (Silver Spring) ; 28(8): 1382-1385, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32352652

RESUMO

OBJECTIVE: The aim of this study was to test the hypothesis that youths with obesity, when removed from structured school activities and confined to their homes during the coronavirus disease 2019 pandemic, will display unfavorable trends in lifestyle behaviors. METHODS: The sample included 41 children and adolescents with obesity participating in a longitudinal observational study located in Verona, Italy. Lifestyle information including diet, activity, and sleep behaviors was collected at baseline and 3 weeks into the national lockdown during which home confinement was mandatory. Changes in outcomes over the two study time points were evaluated for significance using paired t tests. RESULTS: There were no changes in reported vegetable intake; fruit intake increased (P = 0.055) during the lockdown. By contrast, potato chip, red meat, and sugary drink intakes increased significantly during the lockdown (P value range, 0.005 to < 0.001). Time spent in sports activities decreased by 2.30 (SD 4.60) h/wk (P = 0.003), and sleep time increased by 0.65 (SD 1.29) h/d (P = 0.003). Screen time increased by 4.85 (SD 2.40) h/d (P < 0.001). CONCLUSIONS: Recognizing these adverse collateral effects of the coronavirus disease 2019 pandemic lockdown is critical in avoiding depreciation of weight control efforts among youths afflicted with excess adiposity. Depending on duration, these untoward lockdown effects may have a lasting impact on a child's or adolescent's adult adiposity level.


Assuntos
Infecções por Coronavirus/epidemiologia , Dieta , Estilo de Vida , Obesidade Pediátrica/fisiopatologia , Pneumonia Viral/epidemiologia , Isolamento Social , Adolescente , Betacoronavirus , COVID-19 , Criança , Exercício Físico , Comportamento Alimentar , Feminino , Alimentos , Humanos , Itália/epidemiologia , Estudos Longitudinais , Masculino , Pandemias , SARS-CoV-2 , Sono , Inquéritos e Questionários
8.
J Travel Med ; 27(4)2020 Jul 14.
Artigo em Inglês | MEDLINE | ID: mdl-32442249

RESUMO

BACKGROUND: Plasmodium falciparum malaria (P.f. malaria) is frequently imported to non-endemic countries. Recommendations on outpatient treatment differ largely due to differences in country-level guidelines and even between tropical medicine referral centres within the same country. METHODS: This survey among experts from TropNet or GeoSentinel referral centres for tropical medicine outside malaria endemic areas investigated common practices in P.f. malaria management, selection criteria for outpatient management and diagnostic procedures as a first step for developing a future common and evidence-based approach. RESULTS: A total of 44 referral centres participated. Most of the centres are located in Europe (n = 37). Overall, 27 centres (61%) treat uncomplicated P.f. malaria patients as outpatients, of which eight centres (18%) reported treating ≥75% of patients on an outpatient basis. Seventeen centres (39%) reported treating patients only as inpatients. No single criterion stands out for the decision regarding outpatient treatment, but three groups of factors were identified: (i) clinical criteria including laboratory parameters, clinical condition and tolerance of oral medication; (ii) factors such as patient compliance, reachability by phone and support at home and (iii) patient origin and place of residence as a proxy for possible underlying semi-immunity. The threshold parasitaemia for outpatient treatment varied from 0.1 to 5% with a median of 2%. A median of 0.5% of outpatients were admitted during follow-up. During the last 10 years, 33 complications were reported by nine of the 27 centres and three deaths by one centre. CONCLUSION: This study gives insight into the heterogeneous management of P.f. malaria patients outside endemic regions. Although there is no consensus among experts, the majority of centres includes outpatient treatment in their clinical routine. However, the lack of evidence-based criteria and established safety for this approach shows the need for prospective studies to define and evaluate criteria and practices for safe outpatient management.


Assuntos
Assistência Ambulatorial , Antimaláricos , Doenças Transmissíveis Importadas , Malária Falciparum , Medicina Tropical , Assistência Ambulatorial/estatística & dados numéricos , Antimaláricos/uso terapêutico , Doenças Transmissíveis Importadas/tratamento farmacológico , Europa (Continente) , Humanos , Malária Falciparum/tratamento farmacológico , Malária Falciparum/epidemiologia , Plasmodium falciparum , Estudos Prospectivos , Medicina Tropical/estatística & dados numéricos
9.
Front Immunol ; 11: 628971, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33584731

RESUMO

Clinical trials on the use of COVID-19 convalescent plasma remain inconclusive. While data on safety is increasingly available, evidence for efficacy is still sparse. Subgroup analyses hint to a dose-response relationship between convalescent plasma neutralizing antibody levels and mortality. In particular, patients with primary and secondary antibody deficiency might benefit from this approach. However, testing of neutralizing antibodies is limited to specialized biosafety level 3 laboratories and is a time- and labor-intense procedure. In this single center study of 206 COVID-19 convalescent patients, clinical data, results of commercially available ELISA testing of SARS-CoV-2 spike-IgG and -IgA, and levels of neutralizing antibodies, determined by plaque reduction neutralization testing (PRNT), were analyzed. At a medium time point of 58 days after symptom onset, only 12.6% of potential plasma donors showed high levels of neutralizing antibodies (PRNT50 ≥ 1:320). Multivariable proportional odds logistic regression analysis revealed need for hospitalization due to COVID-19 (odds ratio 6.87; p-value 0.0004) and fever (odds ratio 3.00; p-value 0.0001) as leading factors affecting levels of SARS-CoV-2 neutralizing antibody titers in convalescent plasma donors. Using penalized estimation, a predictive proportional odds logistic regression model including the most important variables hospitalization, fever, age, sex, and anosmia or dysgeusia was developed. The predictive discrimination for PRNT50 ≥ 1:320 was reasonably good with AUC: 0.86 (with 95% CI: 0.79-0.92). Combining clinical and ELISA-based pre-screening, assessment of neutralizing antibodies could be spared in 75% of potential donors with a maximal loss of 10% of true positives (PRNT50 ≥ 1:320).


Assuntos
Anticorpos Neutralizantes/imunologia , Anticorpos Antivirais/imunologia , Doadores de Sangue , COVID-19/imunologia , COVID-19/terapia , Adolescente , Adulto , Fatores Etários , Idoso , Convalescença , Feminino , Febre , Humanos , Imunização Passiva , Masculino , Pessoa de Meia-Idade , SARS-CoV-2/imunologia , Índice de Gravidade de Doença , Fatores Sexuais , Adulto Jovem
10.
Pediatr Infect Dis J ; 38(11): e295-e300, 2019 11.
Artigo em Inglês | MEDLINE | ID: mdl-31626041

RESUMO

BACKGROUND: Intravenous artesunate (ivA) is the standard treatment for severe malaria. Data systematically evaluating the use of ivA in pediatric patients outside malaria-endemic regions are limited. The aim of this case series was to summarize efficacy and safety of ivA for imported severe malaria in children in Germany. METHODS: Our retrospective case series included pediatric patients with imported severe malaria treated with at least 1 dose of ivA (Artesun, Guilin Pharmaceutical; Shanghai, China) at 4 German tertiary care centers. Severe malaria was defined according to World Health Organization criteria. RESULTS: Between 2010 and 2018, 14 children with a median [interquartile range (IQR)] age of 6 (1;9.5) years were included. All children were of African descent. All but 2 patients had Plasmodium falciparum malaria; 1 child had P. vivax malaria and 1 child had P. falciparum and P. vivax co-infection. Median (IQR) parasitemia at admission in patients with P. falciparum was 9.5% (3;16.5). Patients were treated with 1-10 [median (IQR) 3 (3;4)] doses ivA. All but one patient received a full course of oral antimalarial treatment. Parasite clearance was achieved within 2-4 days, with the exception of 1 patient with prolonged clearance of peripheral parasitemia. Three patients experienced posttreatment hemolysis but none needed blood transfusion. Otherwise ivA was safe and well tolerated. CONCLUSIONS: ivA was highly efficacious in this pediatric cohort. We observed episodes of mild to moderate posttreatment hemolysis in approximately one-third of patients. The legal status and usage of potentially lifesaving ivA should be evaluated in Europe.


Assuntos
Antimaláricos/uso terapêutico , Artesunato/uso terapêutico , Malária Falciparum/tratamento farmacológico , Malária Vivax/tratamento farmacológico , Doença Aguda/terapia , Administração Intravenosa , Adolescente , Antimaláricos/administração & dosagem , Artesunato/administração & dosagem , Criança , Pré-Escolar , Doenças Transmissíveis Importadas/tratamento farmacológico , Doenças Transmissíveis Importadas/parasitologia , Feminino , Alemanha , Humanos , Lactente , Masculino , Parasitemia/tratamento farmacológico , Estudos Retrospectivos , Centros de Atenção Terciária
11.
J Med Chem ; 61(18): 8120-8135, 2018 09 27.
Artigo em Inglês | MEDLINE | ID: mdl-30137981

RESUMO

Chronic myelogenous leukemia (CML) arises from the constitutive activity of the BCR-ABL1 oncoprotein. Tyrosine kinase inhibitors (TKIs) that target the ATP-binding site have transformed CML into a chronic manageable disease. However, some patients develop drug resistance due to ATP-site mutations impeding drug binding. We describe the discovery of asciminib (ABL001), the first allosteric BCR-ABL1 inhibitor to reach the clinic. Asciminib binds to the myristate pocket of BCR-ABL1 and maintains activity against TKI-resistant ATP-site mutations. Although resistance can emerge due to myristate-site mutations, these are sensitive to ATP-competitive inhibitors so that combinations of asciminib with ATP-competitive TKIs suppress the emergence of resistance. Fragment-based screening using NMR and X-ray yielded ligands for the myristate pocket. An NMR-based conformational assay guided the transformation of these inactive ligands into ABL1 inhibitors. Further structure-based optimization for potency, physicochemical, pharmacokinetic, and drug-like properties, culminated in asciminib, which is currently undergoing clinical studies in CML patients.


Assuntos
Descoberta de Drogas , Proteínas de Fusão bcr-abl/antagonistas & inibidores , Leucemia Mielogênica Crônica BCR-ABL Positiva/tratamento farmacológico , Niacinamida/análogos & derivados , Inibidores de Proteínas Quinases/farmacologia , Pirazóis/farmacologia , Regulação Alostérica , Animais , Cães , Proteínas de Fusão bcr-abl/genética , Humanos , Leucemia Mielogênica Crônica BCR-ABL Positiva/enzimologia , Leucemia Mielogênica Crônica BCR-ABL Positiva/patologia , Masculino , Camundongos , Modelos Moleculares , Estrutura Molecular , Mutação , Niacinamida/química , Niacinamida/farmacologia , Fosforilação , Conformação Proteica , Inibidores de Proteínas Quinases/química , Pirazóis/química , Ratos , Ratos Sprague-Dawley , Células Tumorais Cultivadas , Ensaios Antitumorais Modelo de Xenoenxerto
12.
Bioorg Med Chem Lett ; 28(12): 2153-2158, 2018 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-29759726

RESUMO

Starting from a weak screening hit, potent and selective inhibitors of the MALT1 protease function were elaborated. Advanced compounds displayed high potency in biochemical and cellular assays. Compounds showed activity in a mechanistic Jurkat T cell activation assay as well as in the B-cell lymphoma line OCI-Ly3, which suggests potential use of MALT1 inhibitors in the treatment of autoimmune diseases as well as B-cell lymphomas with a dysregulated NF-κB pathway. Initially, rat pharmacokinetic properties of this compound series were dominated by very high clearance which could be linked to amide cleavage. Using a rat hepatocyte assay a good in vitro-in vivo correlation could be established which led to the identification of compounds with improved PK properties.


Assuntos
Antineoplásicos/farmacologia , Proteína de Translocação 1 do Linfoma de Tecido Linfoide Associado à Mucosa/antagonistas & inibidores , Piperidinas/farmacologia , Animais , Antineoplásicos/síntese química , Antineoplásicos/química , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Relação Dose-Resposta a Droga , Hepatócitos/efeitos dos fármacos , Humanos , Células Jurkat , Microssomos/efeitos dos fármacos , Estrutura Molecular , Proteína de Translocação 1 do Linfoma de Tecido Linfoide Associado à Mucosa/metabolismo , Piperidinas/síntese química , Piperidinas/química , Proteólise/efeitos dos fármacos , Ratos , Relação Estrutura-Atividade
13.
Chemistry ; 24(21): 5551-5561, 2018 Apr 11.
Artigo em Inglês | MEDLINE | ID: mdl-29383765

RESUMO

Syntheses and molecular structures of the dimeric tin-platinum complex [LSnPtCl2 (SMe2 )]2 (2), the tin-platinum clusters [{LSnPtCl(SMe2 )}2 SnCl2 )] (3) and [(LSn)3 (PtCl2 )(PtClSnCl)(LSnOHCl)] (6) (L=MeN(CH2 CMe2 O- )2 ), and of the unprecedented tin(II) aminoalkoxide-tin oxide chloride complex [O(SnCl)2 ⋅(SnL)2 ] (5) are reported. The compounds were characterized by NMR spectroscopy (1 H, 13 C, 119 Sn, 195 Pt), 119 Sn Mössbauer spectroscopy (1-3, 6), electrospray ionization mass spectrometry, elemental analyses, and single-crystal X-ray diffraction analyses (2⋅CH2 Cl2 , 3⋅2 C4 H8 O, 5, 6⋅3CH2 Cl2 ). The tin(II) aminoalkoxide [MeN(CH2 CMe2 O)2 Sn]2 (1) behaves like a neutral ligand, inserts into a Pt-Cl bond, or is involved in rearrangement reactions with the different behavior occurring even within one compound (3, 6). DFT calculations show that the tin-platinum compounds behave like electronic chameleons.

14.
BMC Pulm Med ; 18(1): 11, 2018 Jan 19.
Artigo em Inglês | MEDLINE | ID: mdl-29351754

RESUMO

BACKGROUND: Chronic obstructive pulmonary disease is a global problem and available data from sub-Saharan Africa is very limited. METHODS: A cross-sectional facility-based pilot study among patients and visitors to an urban and a rural primary healthcare facility was conducted in coastal Tanzania. The primary outcome was the prevalence of chronic airflow obstruction. RESULTS: The final analysis included 598 participants with valid post-bronchodilator spirometry. Applying ATS/ERS spirometric criteria, chronic airflow obstruction was found in n = 24 (4%, CI95 2.7-5.9) participants and in n = 30 (5%, CI95 3.5-7.1) applying GOLD spirometric criteria. To analyse risk factors for chronic airflow obstruction including those not meeting ATS/ERS or GOLD criteria, FEF25-75 and FEV1% predicted was analysed in participants without evidence of pulmonary restriction among those exposed or not exposed to risk factors (n = 552). FEV1% predicted, but in particular FEF25-75 decreased with increasing symptom severity of shortness of breath as well as limitations in daily activities of participants. Cooking in general and cooking with biomass fuels vs. gas or electricity was associated with significantly lower FEF25-75, but not with lower FEV1% predicted. Participants having refrained from taking a job because of shortness of breath exhibited lower FEF25-75 (p < 0.01). A history of prior active TB was the most relevant risk factor associated with a decrease in FEF25-75 as well as FEV1% predicted. CONCLUSION: This study demonstrated a relevant prevalence of chronic airflow obstruction in primary healthcare attendants and healthy visitors of a Tanzanian hospital. Using the baseline data provided, larger and population-based studies are needed to validate these findings. TB may have more impact on development of chronic airway obstruction than smoking in Africa. Due to the influence of age on the GOLD definition of chronic airflow obstruction, studies should report results using both ATS/ERS and GOLD definitions and include age-stratified analysis. Analysis of FEV1 and in particular FEF25-75 may yield additional information on risk factors and earlier stages of chronic airflow obstruction.


Assuntos
Culinária , Doença Pulmonar Obstrutiva Crônica/epidemiologia , Doença Pulmonar Obstrutiva Crônica/fisiopatologia , Tuberculose Pulmonar/fisiopatologia , Atividades Cotidianas , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Estudos Transversais , Dispneia/etiologia , Dispneia/fisiopatologia , Feminino , Volume Expiratório Forçado , Humanos , Masculino , Fluxo Máximo Médio Expiratório , Pessoa de Meia-Idade , Prevalência , Doença Pulmonar Obstrutiva Crônica/complicações , Fatores de Risco , Tanzânia/epidemiologia , Tuberculose Pulmonar/epidemiologia , Adulto Jovem
15.
Am J Trop Med Hyg ; 97(2): 567-574, 2017 08.
Artigo em Inglês | MEDLINE | ID: mdl-28722637

RESUMO

Schistosomiasis remains one of the most prevalent parasitic diseases worldwide and the infection is frequently found in travelers and migrants. The European Network for Tropical Medicine and Travel Health conducted a sentinel surveillance study on imported schistosomiasis between 1997 and 2010. This report summarizes epidemiological and clinical data from 1,465 cases of imported schistosomiasis. Direct pathogen detection and serology were the main diagnostic tools applied. Of these, 486 (33%) cases were identified among European travelers, 231 (16%) among long-term expatriates, and 748 (51%) among non-European immigrants. Overall, only 18.6% of travelers had received pretravel advice; 95% of infections were acquired in the African region. On species level, Schistosoma mansoni was identified in 570 (39%) and Schistosoma haematobium in 318 (22%) cases; 57.5% of patients were symptomatic. Acute symptoms were reported in 27% of patients leading to earlier presentation within 3 months. Praziquantel was used in all patients to treat schistosomiasis. Many infections were detected in asymptomatic patients. In 47.4% of asymptomatic patients infection was detected by microscopy and in 39% by serology or antigen testing. Schistosomiasis remains a frequent infection in travelers and migrants to Europe. Travelers should be made aware of the risk of schistosomiasis infection when traveling to sub-Saharan Africa. Posttravel consultations particularly for returning expatriates are useful given the high potential for detecting asymptomatic infections.


Assuntos
Anti-Helmínticos/uso terapêutico , Praziquantel/uso terapêutico , Esquistossomose/diagnóstico , Adolescente , Adulto , África ao Sul do Saara/epidemiologia , Idoso , Idoso de 80 Anos ou mais , Animais , Criança , Pré-Escolar , Europa (Continente)/epidemiologia , Feminino , Humanos , Lactente , Recém-Nascido , Masculino , Pessoa de Meia-Idade , Prevalência , Esquistossomose/tratamento farmacológico , Esquistossomose/epidemiologia , Migrantes/estatística & dados numéricos , Viagem/estatística & dados numéricos , Adulto Jovem
16.
Malar J ; 16(1): 57, 2017 01 31.
Artigo em Inglês | MEDLINE | ID: mdl-28143519

RESUMO

BACKGROUND: Malaria remains one of the most serious infections for travellers to tropical countries. Due to the lack of harmonized guidelines a large variety of treatment regimens is used in Europe to treat severe malaria. METHODS: The European Network for Tropical Medicine and Travel Health (TropNet) conducted an 8-year, multicentre, observational study to analyse epidemiology, treatment practices and outcomes of severe malaria in its member sites across Europe. Physicians at participating TropNet centres were asked to report pseudonymized retrospective data from all patients treated at their centre for microscopically confirmed severe Plasmodium falciparum malaria according to the 2006 WHO criteria. RESULTS: From 2006 to 2014 a total of 185 patients with severe malaria treated in 12 European countries were included. Three patients died, resulting in a 28-day survival rate of 98.4%. The majority of infections were acquired in West Africa (109/185, 59%). The proportion of patients treated with intravenous artesunate increased from 27% in 2006 to 60% in 2013. Altogether, 56 different combinations of intravenous and oral drugs were used across 28 study centres. The risk of acute renal failure (36 vs 17% p = 0.04) or cerebral malaria (54 vs 20%, p = 0.001) was significantly higher in patients ≥60 years than in younger patients. Respiratory distress with the need for mechanical ventilation was significantly associated with the risk of death in the study population (13 vs 0%, p = 0.001). Post-artemisinin delayed haemolysis was reported in 19/70 (27%) patients treated with intravenous artesunate. CONCLUSION: The majority of patients with severe malaria in this study were tourists or migrants acquiring the infection in West Africa. Intravenous artesunate is increasingly used for treatment of severe malaria in many European treatment centres and can be given safely to European patients with severe malaria. Patients treated with intravenous artesunate should be followed up to detect and manage late haemolytic events.


Assuntos
Antimaláricos/uso terapêutico , Malária Falciparum/tratamento farmacológico , Malária Falciparum/epidemiologia , Adulto , Idoso , Antimaláricos/classificação , Europa (Continente)/epidemiologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Resultado do Tratamento , Adulto Jovem
17.
J Med Chem ; 60(5): 1946-1958, 2017 03 09.
Artigo em Inglês | MEDLINE | ID: mdl-28157311

RESUMO

Chronic dysregulation of alternative complement pathway activation has been associated with diverse clinical disorders including age-related macular degeneration and paroxysmal nocturnal hemoglobinurea. Factor D is a trypsin-like serine protease with a narrow specificity for arginine in the P1 position, which catalyzes the first enzymatic reaction of the amplification loop of the alternative pathway. In this article, we describe two hit finding approaches leading to the discovery of new chemical matter for this pivotal protease of the complement system: in silico active site mapping for hot spot identification to guide rational structure-based design and NMR screening of focused and diverse fragment libraries. The wealth of information gathered by these complementary approaches enabled the identification of ligands binding to different subpockets of the latent Factor D conformation and was instrumental for understanding the binding requirements for the generation of the first known potent noncovalent reversible Factor D inhibitors.


Assuntos
Inibidores de Proteases/farmacologia , Domínio Catalítico , Fator D do Complemento/química , Desenho de Fármacos , Humanos , Espectroscopia de Ressonância Magnética , Estrutura Molecular , Inibidores de Proteases/química
18.
Euro Surveill ; 22(1)2017 Jan 05.
Artigo em Inglês | MEDLINE | ID: mdl-28080959

RESUMO

We describe the epidemiological pattern and genetic characteristics of 242 acute dengue infections imported to Europe by returning travellers from 2012 to 2014. The overall geographical pattern of imported dengue (South-east Asia > Americas > western Pacific region > Africa) remained stable compared with 1999 to 2010. We isolated the majority of dengue virus genotypes and epidemic lineages causing outbreaks and epidemics in Asia, America and Africa during the study period. Travellers acted as sentinels for four unusual dengue outbreaks (Madeira, 2012-13; Luanda, 2013; Dar es Salaam, 2014; Tokyo, 2014). We were able to characterise dengue viruses imported from regions where currently no virological surveillance data are available. Up to 36% of travellers infected with dengue while travelling returned during the acute phase of the infection (up to 7 days after symptom onset) or became symptomatic after returning to Europe, and 58% of the patients with acute dengue infection were viraemic when seeking medical care. Epidemiological and virological data from dengue-infected international travellers can add an important layer to global surveillance efforts. A considerable number of dengue-infected travellers are viraemic after arrival back home, which poses a risk for dengue introduction and autochthonous transmission in European regions where suitable mosquito vectors are prevalent.


Assuntos
Vírus da Dengue/isolamento & purificação , Dengue/epidemiologia , Dengue/transmissão , Surtos de Doenças , Vigilância de Evento Sentinela , Viagem , África/epidemiologia , América/epidemiologia , Ásia Sudeste/epidemiologia , Dengue/diagnóstico , Vírus da Dengue/genética , Europa (Continente)/epidemiologia , Genótipo , Humanos , Incidência , Filogenia , Reação em Cadeia da Polimerase Via Transcriptase Reversa/métodos , Medicina de Viagem/métodos
19.
EMBO Mol Med ; 8(11): 1325-1339, 2016 11.
Artigo em Inglês | MEDLINE | ID: mdl-27729388

RESUMO

Accumulating evidence from experimental animal models suggests that antibodies play a protective role against tuberculosis (TB). However, little is known about the antibodies generated upon Mycobacterium tuberculosis (MTB) exposure in humans. Here, we performed a molecular and functional characterization of the human B-cell response to MTB by generating recombinant monoclonal antibodies from single isolated B cells of untreated adult patients with acute pulmonary TB and from MTB-exposed healthcare workers. The data suggest that the acute plasmablast response to MTB originates from reactivated memory B cells and indicates a mucosal origin. Through functional analyses, we identified MTB inhibitory antibodies against mycobacterial antigens including virulence factors that play important roles in host cell infection. The inhibitory activity of anti-MTB antibodies was directly linked to their isotype. Monoclonal as well as purified serum IgA antibodies showed MTB blocking activity independently of Fc alpha receptor expression, whereas IgG antibodies promoted the host cell infection. Together, the data provide molecular insights into the human antibody response to MTB and may thereby facilitate the design of protective vaccination strategies.


Assuntos
Anticorpos Antibacterianos/imunologia , Anticorpos Monoclonais/imunologia , Formação de Anticorpos , Linfócitos B/imunologia , Isotipos de Imunoglobulinas/imunologia , Mycobacterium tuberculosis/imunologia , Tuberculose Pulmonar/imunologia , Anticorpos Antibacterianos/isolamento & purificação , Anticorpos Monoclonais/isolamento & purificação , Humanos
20.
Emerg Infect Dis ; 22(8): 1381-6, 2016 08.
Artigo em Inglês | MEDLINE | ID: mdl-27434054

RESUMO

Episodes of delayed hemolysis 2-6 weeks after treatment of severe malaria with intravenous artesunate have been described. We performed a prospective observational study of patients with uncomplicated malaria to investigate whether posttreatment hemolysis also occurs after oral artemisinin-based combination therapy. Eight of 20 patients with uncomplicated malaria who were given oral artemisinin-based combination therapy met the definition of posttreatment hemolysis (low haptoglobin level and increased lactate dehydrogenase level on day 14). Five patients had hemolysis persisting for 1 month. Patients with posttreatment hemolysis had a median decrease in hemoglobin level of 1.3 g/dL (interquartile range 0.3-2.0 g/dL) in the posttreatment period, and patients without posttreatment hemolysis had a median increase of 0.3 g/dL (IQR -0.1 to 0.7 g/dL; p = 0.002). These findings indicate a need for increased vigilance for hemolytic events in malaria patients, particularly those with predisposing factors for anemia.


Assuntos
Artemisininas/efeitos adversos , Artemisininas/uso terapêutico , Hemólise/efeitos dos fármacos , Malária Falciparum/tratamento farmacológico , Administração Oral , Adolescente , Adulto , Anemia/induzido quimicamente , Antimaláricos/administração & dosagem , Antimaláricos/efeitos adversos , Antimaláricos/uso terapêutico , Artemeter , Artemisininas/administração & dosagem , Criança , Quimioterapia Combinada , Etanolaminas/administração & dosagem , Etanolaminas/uso terapêutico , Feminino , Fluorenos/administração & dosagem , Fluorenos/uso terapêutico , Humanos , Lumefantrina , Masculino , Estudos Prospectivos , Quinolinas/administração & dosagem , Quinolinas/uso terapêutico
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