RESUMO
A methodology for the synthesis of sulfonyl hydrazides mediated by hypervalent iodine is described. Taking advantage of the umpolung properties of hypervalent iodine reagents, the polarity of sodium sulfinate salts is reversed, and a key intermediate is generated and reacted with mono- and disubstituted hydrazines. To highlight the practical utility of this protocol, a diverse range of sulfonyl hydrazides were synthesized in yields up to 62%. Furthermore, a gram-scale reaction was performed, showing the robustness of the procedure. Mechanistic studies, including DFT calculations, were performed and the bioactivity of the generated compounds was evaluated.
RESUMO
This work focuses on evaluating the spatial variability of chemical attributes of soils under different agricultural use and native forest, indicating which are the possible indicator attributes of changes in environmental, through the use and management of the soil. The study was carried out in the southern region of the Amazonas state, in an Argissolo Vermelho-Amarelo (Ultisol). Sampling grids were established measuring: 90 m × 70 m with regular soil collection spacing of 10 m for the guarana and forest areas; 90 m × 56 m spaced at 10 m × 8 m for annatto area; and 54 m × 42 m with spacing between points of 6 m for the cupuaçu area, totaling 80 sampling points in each area, with soil samples collected at depths of 0.0-0.05; 0.05-0.10 m and 0.10-0.20 m. The following attributes were determined: pH, Al3+, K+, Ca2+, Mg2+, P, H + Al, CEC, V% and m%. Descriptive, geostatistical and multivariate statistical analyzes were performed. The results show that it is possible to state that the descriptive, geostatistical and multivariate statistical techniques were able to identify the difference between the spatial variability of the attributes according to each specific use of individual soils. The multivariate analysis made it possible to select the attributes that most contribute to the variability of these soils, and with that, it was found that the forest showed less spatial variability in the surface layer, with higher reach values by scaled semivariograms.
Assuntos
Monitoramento Ambiental , Solo , Brasil , Agricultura , FlorestasRESUMO
The amplitude of the coronavirus disease 2019 (COVID-19) pandemic motivated global efforts to find therapeutics that avert severe forms of this illness. The urgency of the medical needs privileged repositioning of approved medicines. Methylene blue (MB) has been in clinical use for a century and proved especially useful as a photosensitizer for photodynamic disinfection (PDI). We describe the use of MB to photo-inactivate SARS-CoV-2 in samples collected from COVID-19 patients. One minute of treatment can reduce the percentage inhibition of amplification by 99.99% under conditions of low cytotoxicity. We employed a pseudotyped lentiviral vector (LVs) encoding the luciferase reporter gene and exhibiting the S protein of SARS-CoV-2 at its surface, to infect human ACE2-expressing HEK293T cells. Pre-treatment of LVs with MB-PDI prevented infection at low micromolar MB concentrations and 1 min of illumination. These results reveal the potential of MB-PDI to reduce viral loads in the nasal cavity and oropharynx in the early stages of COVID-19, which may be employed to curb the transmission and severity of the disease.
Assuntos
Tratamento Farmacológico da COVID-19 , SARS-CoV-2 , Desinfecção/métodos , Células HEK293 , Humanos , Azul de Metileno/farmacologiaRESUMO
Neutrophil activation and neutrophil extracellular traps (NETs) have been associated with the pathogenesis of venous thromboembolism (VTE). Considering VTE-associated chronic sequelae, which suggest that some pathological mechanisms remain after the acute episode, we investigated whether neutrophil activation is increased in patients with a prior VTE at least one year before this investigation. Thirty-seven patients with prior VTE and 37 individuals with no history of VTE were included. Neutrophil activity was evaluated by the expression of the adhesive molecule activation-specific epitopes LFA-1 (CD11a) and MAC-1 (CD11b), chemotaxis, reactive oxygen species (ROS) and by MPO-DNA complexes as markers of NETs. The adhesive molecules sICAM-1 and sVCAM-1, involved in the cross talk between neutrophil and endothelial cells, were also evaluated. Patient neutrophils presented increased CD11a expression before and after TNF-α stimulus, whereas increased CD11b expression was observed only after TNF-α stimulus, as compared to controls. Neutrophil chemotaxis on both, basal state and after IL-8 stimulus, on circulating levels of sICAM-1 and sVCAM-1, and on MPO-DNA complexes were also increased in VTE patients. ROS release was similar between patients and controls. This is, to our knowledge, the first study to investigate neutrophil inflammatory activity in VTE patients a long period after an acute event (approximately 2 years). The results showed altered neutrophil activation patterns in these patients. While activated neutrophils can cause endothelial activation and injury, the activated endothelium can induce the release of NETs with consequent endothelial cytotoxicity, creating a vicious cycle of activation between neutrophils and endothelium that can lead to thrombosis. VTE patients (approximately 2 years after the clinical event) present an altered neutrophil activation state evidenced by increased activity of the LFA-1 and Mac-1 adhesive molecules, as well as increased chemotaxis and circulating levels of NETs remnants. Circulating levels of ICAM-1 and VCAM-1, which are endothelial adhesive molecules, are also increased in VTE patients, suggesting not only an exacerbated endothelial activation and dysfunction, but also an interaction of the neutrophil adhesive molecules with their endothelial ligands, favoring the migration process of neutrophil.
Assuntos
Armadilhas Extracelulares , Tromboembolia Venosa , Células Endoteliais/metabolismo , Armadilhas Extracelulares/metabolismo , Humanos , Ativação de Neutrófilo , Neutrófilos/metabolismoRESUMO
Studies on the effects of azadirachtin treatment, ecdysone supplementation and ecdysone therapy on both the ultrastructural organization of the rectum in 5th-instar nymph of Rhodnius prolixus and the ex vivo attachment behavior of Trypanosoma cruzi under these experimental conditions were carried out. Control insects had a typical and significant organization of the rectum cuticle consisted of four main layers (procuticle, inner epicuticle, outer epicuticle, and wax layer) during the entire period of the experiment. Both azadirachtin treatment and ecdysone supplementation avoid the development of both outer epicuticle and wax layer. Oral therapy with ecdysone partially reversed the altered organization and induce the development of the four main rectal cuticle layers. In the same way, the ex vivo attachment of T. cruzi to rectal cuticle was blocked by azadirachtin treatment but ecdysone therapy also partially recovered the parasite adhesion rates to almost those detected in control insects. These results point out that ecdysone may be a factor responsible - directly or indirectly - by the modulation of rectum ultrastructural arrangement providing a superficial wax layer to the attachment followed by metacyclogenesis of T. cruzi in the rectum of its invertebrate hosts.
Assuntos
Doença de Chagas , Rhodnius , Trypanosoma cruzi , Animais , Doença de Chagas/tratamento farmacológico , Ecdisona/farmacologia , Ninfa , Reto/parasitologia , Reto/ultraestrutura , Rhodnius/parasitologiaRESUMO
Triggering receptor expressed on myeloid cells 2 (TREM2) is an innate immune cell surface receptor that regulates microglial function and is involved in the pathophysiology of several neurodegenerative diseases. Its soluble form (sTREM2) results from shedding of the TREM2 ectodomain. The role of TREM2 in prion diseases, a group of rapidly progressive dementias remains to be elucidated. In the present study, we analysed the expression of TREM2 and its main sheddase ADAM10 in the brain of sporadic Creutzfeldt-Jakob disease (sCJD) patients and evaluated the role of CSF and plasma sTREM2 as a potential diagnostic marker of prion disease. Our data indicate that, compared to controls, TREM2 is increased in sCJD patient brains at the mRNA and protein levels in a regional and subtype dependent fashion, and expressed in a subpopulation of microglia. In contrast, ADAM10 is increased at the protein, but not the mRNA level, with a restricted neuronal expression. Elevated CSF sTREM2 is found in sCJD, genetic CJD with mutations E200K and V210I in the prion protein gene (PRNP), and iatrogenic CJD, as compared to healthy controls (HC) (AUC = 0.78-0.90) and neurological controls (AUC = 0.73-0.85), while CSF sTREM2 is unchanged in fatal familial insomnia. sTREM2 in the CSF of cases with Alzheimer's disease, and multiple sclerosis was not significantly altered in our series. CSF sTREM2 concentrations in sCJD are PRNP codon 129 and subtype-related, correlate with CSF 14-3-3 positivity, total-tau and YKL-40, and increase with disease progression. In plasma, sTREM2 is increased in sCJD compared with HC (AUC = 0.80), displaying positive correlations with plasma total-tau, neurofilament light, and YKL-40. We conclude that comparative study of TREM2 in brain and biological fluids of prion diseases reveals TREM2 to be altered in human prion diseases with a potential value in target engagement, patient stratification, and disease monitoring.
Assuntos
Proteína ADAM10 , Encéfalo , Glicoproteínas de Membrana , Doenças Priônicas , Receptores Imunológicos , Proteína ADAM10/sangue , Proteína ADAM10/líquido cefalorraquidiano , Proteína ADAM10/metabolismo , Doença de Alzheimer/metabolismo , Animais , Biomarcadores/metabolismo , Encéfalo/metabolismo , Modelos Animais de Doenças , Humanos , Glicoproteínas de Membrana/sangue , Glicoproteínas de Membrana/líquido cefalorraquidiano , Glicoproteínas de Membrana/genética , Glicoproteínas de Membrana/metabolismo , Camundongos , Microglia/metabolismo , Doenças Priônicas/genética , Doenças Priônicas/metabolismo , Doenças Priônicas/patologia , Proteínas Priônicas/metabolismo , Receptores Imunológicos/sangue , Receptores Imunológicos/genética , Receptores Imunológicos/metabolismoRESUMO
AIM: Antiretroviral therapy (ART) development has reduced the severity of neurological complications of the human immunodeficiency virus (HIV), but they remain prevalent and need prompt recognition. Acute inflammatory demyelinating polyneuropathy (AIDP) is a rare complication of human immunodeficiency virus (HIV) infection that may appear at any stage of the disease. In this case, AIDP represents a late presentation of HIV infection. METHODS: Descriptive study. Patient data were collected from their medical records and by health assessment interviews. RESULTS: We report a case of a 52-year-old male with acute lower limb weakness. Given the suggestive clinical presentation of AIDP and a positive HIV test, intravenous immunoglobulin (IVIG) was administered along with antiretroviral therapy. Progressive weakness to the upper limbs, autonomic dysfunction, and pain was observed. The second regimen of IVIG plus corticosteroids was administered. Muscle strength improved after three weeks. CONCLUSIONS: Screening for HIV in a patient with AIDP may provide a better outcome because of the early start of ART with good central nervous system penetration in HIV-infected patients.
Assuntos
Corticosteroides/uso terapêutico , Terapia Antirretroviral de Alta Atividade , Síndrome de Guillain-Barré/complicações , Infecções por HIV/tratamento farmacológico , Imunoglobulinas Intravenosas/uso terapêutico , Debilidade Muscular/etiologia , Disautonomias Primárias , Corticosteroides/administração & dosagem , Síndrome de Guillain-Barré/diagnóstico , Síndrome de Guillain-Barré/tratamento farmacológico , Infecções por HIV/complicações , Humanos , Imunoglobulinas Intravenosas/administração & dosagem , Masculino , Pessoa de Meia-Idade , Debilidade Muscular/tratamento farmacológico , Resultado do TratamentoRESUMO
Agriculture needs methodologies that assist in the determination of soil attributes and variability mapping attributes with greater levels of detail. Therefore, the objective of this research was to evaluate magnetic susceptibility as auxiliary variable for estimating soil attributes in areas of Indian Black Earths in the south of Amazonas State. Three Indian Black Earth areas are located in the municipalities of Apuí and Manicoré - Amazonas, under uses with coffee, cocoa and pasture. The soils were collected at the crossing points in the depth of 0.00 - 0.20 m, making a total of 88 sampling points/area, and totaling 264 samples. The points were georeferenced for geostatistical modeling. After that, physical and chemical analyzes were performed to obtain the values ââof soil and magnetic susceptibility attributes. Descriptive statistics, Pearson correlation, linear regression and geostatistical analyzes were applied for Pedotransfer Function modeling and the spatial variability of the analyzed attributes. Magnetic susceptibility showed a high degree of spatial dependence in the study areas, high range values, correlating with most of the assessed attributes, mainly physical, indicating potential in the prediction of the attributes in these environments. Pedotransfer functions vary among IBE's sites in attribute prediction, ensuring moderate estimates for predicting soil attributes in IBE's areas.
Assuntos
Poluentes do Solo , Solo , Agricultura , Brasil , Monitoramento Ambiental , Poluentes do Solo/análise , Análise EspacialRESUMO
The main cause of physical degradation in pasture areas is overgrazing, and when combined with poorly productive soils, it causes the loss of millions of hectares of agricultural soils a year. Thus, work is needed to indicate which physical attributes are most sensitive to degradation, generating information so that soil management can be proposed, with a view to economic, social, and environmental aspects. Therefore, the objective of the work was to evaluate the impacts caused on the physical attributes of the soil, in forests converted to pastures in northern Rondônia, Brazil. The study was carried out in three areas within the municipality of Porto Velho, Rondônia, one area with forest and two with pastures (brachiaria and mombaça grass). In the field, deformed soil samples were collected at a depth of 0.00-0.10 and 0.10-0.20 m in the three study areas. In the laboratory, physical analyses of texture, aggregates and porosity, compaction, and an additional analysis of soil organic carbon were carried out. Then, univariate, bivariate, and multivariate analyses were performed, as well as geostatistical analysis. The conversion of forest to pasture had a negative impact on aggregates, compaction, porosity, and accumulation of organic carbon in the soil. The studied environments are influenced by the high levels of sand and clay, which interfere in the aggregation, compaction, porosity, and accumulation of organic carbon in the soil. We observed greater spatial variability of physical attributes in the environment with mombaça grass and attributed this to the greater grazing and trampling intensity of the animals.
Assuntos
Carbono , Solo , Brasil , Monitoramento Ambiental , FlorestasRESUMO
OBJECTIVES: Currently, the exact reasons why different α-synucleinopathies exhibit variable pathologies and phenotypes are still unknown. A potential explanation may be the existence of distinctive α-synuclein conformers or strains. Here, we intend to analyze the seeding activity of dementia with Lewy bodies (DLB) and Parkinson's disease (PD) brain-derived α-synuclein seeds by real-time quaking-induced conversion (RT-QuIC) and to investigate the structure and morphology of the α-synuclein aggregates generated by RT-QuIC. METHODS: A misfolded α-synuclein-enriched brain fraction from frontal cortex and substantia nigra pars compacta tissue, isolated by several filtration and centrifugation steps, was subjected to α-synuclein/RT-QuIC analysis. Our study included neuropathologically well-characterized cases with DLB, PD, and controls (Ctrl). Biochemical and morphological analyses of RT-QuIC products were conducted by western blot, dot blot analysis, Raman spectroscopy, atomic force microscopy, and transmission electron microscopy. RESULTS: Independently from the brain region, we observed different seeding kinetics of α-synuclein in the RT-QuIC in patients with DLB compared to PD and Ctrl. Biochemical characterization of the RT-QuIC product indicated the generation of a proteinase K-resistant and fibrillary α-synuclein species in DLB-seeded reactions, whereas PD and control seeds failed in the conversion of wild-type α-synuclein substrate. INTERPRETATION: Structural variances of α-synuclein seeding kinetics and products in DLB and PD indicated, for the first time, the existence of different α-synuclein strains in these groups. Therefore, our study contributes to a better understanding of the clinical heterogeneity among α-synucleinopathies, offers an opportunity for a specific diagnosis, and opens new avenues for the future development of strain-specific therapies. Ann Neurol 2019;85:691-703.
Assuntos
Química Encefálica/fisiologia , Encéfalo/metabolismo , Sinucleinopatias/metabolismo , alfa-Sinucleína/análise , alfa-Sinucleína/metabolismo , Idoso , Idoso de 80 Anos ou mais , Encéfalo/patologia , Feminino , Humanos , Masculino , Isoformas de Proteínas/análise , Isoformas de Proteínas/metabolismo , Análise Espectral Raman/métodos , Sinucleinopatias/patologiaRESUMO
BACKGROUND: /Objectives: Evaluation of the local and systemic effects of aging on the severity of acute pancreatitis (AP) in an experimental rat model in elderly animals. METHODS: AP was induced in Wistar rats by intraductal 2.5% taurocholate injection and divided into two groups: Young (3 month old) and Aged (18 month old). Two and 24â¯h after AP induction blood samples were collected for determinations of amylase, AST, ALT, urea, creatinine, glucose, and of plasma I-FABP. TNF-α and IL-6 levels were determined in serum and ascitic fluid. Liver mitochondrial function and malondialdehyde (MDA) contents, pancreas histological analysis, and pulmonar myeloperoxidade (MPO) activity were performed. Bacterial translocation was evaluated by bacterial cultures of pancreas. RESULTS: A significant increase in serum amylase, AST, ALT, urea, creatinine, glucose, I-FABP, and IL-6 levels, and a reduction in serum and ascitic fluid TNF-α levels were observed in the aged group compared to the young group. Liver mitochondrial dysfunction, MDA contents, and pulmonary MPO activity were increased in the Aged AP group compared to the Young AP group. Positive bacterial cultures obtained from pancreas tissue in aged group were significantly increased compared to the young group. Acinar necrosis was also increased in aged AP group when compared to young AP group. CONCLUSION: Aging worsens the course of acute pancreatitis evidenced by increased local and systemic lesions and increased bacterial translocation.
Assuntos
Envelhecimento/patologia , Pancreatite/patologia , Doença Aguda , Animais , Citocinas/sangue , Proteínas de Ligação a Ácido Graxo/metabolismo , Infecções/complicações , Infecções/fisiopatologia , Peroxidação de Lipídeos , Masculino , Mitocôndrias Hepáticas/metabolismo , Necrose , Oxirredução , Pancreatite/cirurgia , Peroxidase/metabolismo , Fosforilação , Ratos , Ratos WistarRESUMO
The role of digital technologies for fostering sustainability and efficiency in forest-based supply chains is well acknowledged and motivated several studies in the scope of precision forestry. Sensor technologies can collect relevant data in forest-based supply chains, comprising all activities from within forests and the production of the woody raw material to its transformation into marketable forest-based products. Advanced planning systems can help to support decisions of the various entities in the supply chain, e.g., forest owners, harvest companies, haulage companies, and forest product processing industry. Such tools can help to deal with the complex interdependencies between different entities, often with opposing objectives and actions-which may increase efficiency of forest-based supply chains. This paper analyzes contemporary literature dealing with digital technologies in forest-based supply chains and summarizes the state-of-the-art digital technologies for real-time data collection on forests, product flows, and forest operations, as well as planning systems and other decision support systems in use by supply chain actors. Higher sustainability and efficiency of forest-based supply chains require a seamless information flow to foster integrated planning of the activities over the supply chain-thereby facilitating seamless data exchange between the supply chain entities and foster new forms of collaboration. Therefore, this paper deals with data exchange and multi-entity collaboration aspects in combination with interoperability challenges related with the integration among multiple process data collection tools and advanced planning systems. Finally, this interdisciplinary review leads to the discussion of relevant guidelines that can guide future research and integration projects in this domain.
Assuntos
Agricultura Florestal/tendências , Tomada de Decisões , Agricultura Florestal/métodos , Florestas , Tecnologia , Madeira/químicaRESUMO
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 JovemRESUMO
Seborrheic dermatitis is an inflammatory and chronic disease with a high incidence and prevalence (1% to 3% in the general population, 3% to 5% in young adults, and 40% to 80% in HIV-positive individuals). Although the condition was first described in 1887, its clinical aspects and clinical forms have still not been well individualized, nor has its etiopathogenesis been fully elucidated. The disease, despite having clinical features similar to dermatitis, does not have the same histopathologic features or the same progressive clinical behavior. This contribution reviews the history of seborrheic dermatitis.
Assuntos
Dermatite Seborreica/história , Dermatite Seborreica/diagnóstico , Dermatite Seborreica/etiologia , Dermatite Seborreica/patologia , Eczema/diagnóstico , História do Século XIX , História do Século XX , História do Século XXI , Humanos , Terminologia como AssuntoRESUMO
Artificial light at night (ALAN), producing light pollution (LP), is not a matter restricted to astronomy anymore. Light is part of modern societies and, as a consequence, the natural cycle day-night (bright-dark) has been interrupted in a large segment of the global population. There is increasing evidence that exposure to certain types of light at night and beyond threshold levels may produce hazardous effects to humans and the environment. The concept of "dark skies reserves" is a step forward in order to preserve the night sky and a means of enhancing public awareness of the problem of spread of light pollution worldwide. The aim of this study was to assess the skyglow at two sites in Portugal, the Peneda-Gerês National Park (PNPG) and the region now known as Dark Sky Alqueva Reserve. The latter site was classified as a "Starlight Tourism Destination" by the Starlight Foundation (the first in the world to achieve this classification) following a series of night sky measurements in situ described herein. The measurements at PNPG also contributed to the new set of regulations concerning light pollution at this national park. This study presents the first in situ systematic measurements of night sky brightness, showing that at the two sites the skies are mostly in levels 3 to 4 of the Bortle 9-level scale (with level 1 being the best achievable). The results indicate that the sources of light pollution and skyglow can be attributed predominantly to contamination from nearby urban regions.
Assuntos
Escuridão , Monitoramento Ambiental , Poluição Ambiental/análise , Iluminação , Humanos , Parques Recreativos , PortugalRESUMO
The aim of this study was to determine the net requirements of calcium (Ca), phosphorus (P), magnesium (Mg), and sulphur (S) for weight gain of non-descript breed hair lambs (NDBL) of different sex classes reared under Brazilian semiarid conditions. Sixty NDBL (20 intact males, 20 castrated males, and 20 females), with an average initial body weight of 18.1 ± 0.4 kg and average age of 5 months were used. The macromineral requirements were determined by the differences in body composition through comparative slaughter direct method. The animals were confined for 58 days, and the average fasting body weight (FBW) and average daily gain (ADG) of lambs fed ad libitum were 29.2 ± 0.6 and 0.19 ± 0.01 kg, respectively. The net requirements of macrominerals for gain of NDBL did not differ between sex classes (P > 0.05), and ranged from 1.83 to 1.46 g/day of Ca, 1.21 to 1.01 g/day of P, 37 to 30 mg/day of Mg, and 0.31 to 0.28 g/day of S, for lambs with an ADG of 0.200 kg and 15 or 30 kg of FBW, respectively (P < 0.05). The N to S net ratio reduced and increased, respectively, as the body weight and ADG increase. The net requirements of Ca, P, Mg, and S for gain of NDBL slaughtered young and at the same age did not differ between sex classes and decreased as the body weight increased. The net requirements for gain of Ca and P were similar to those recommended by NRC (2007).
Assuntos
Ração Animal/análise , Criação de Animais Domésticos , Fenômenos Fisiológicos da Nutrição Animal , Dieta/veterinária , Ovinos/crescimento & desenvolvimento , Animais , Composição Corporal , Peso Corporal , Brasil , Cálcio/administração & dosagem , Clima Desértico , Feminino , Magnésio/administração & dosagem , Masculino , Fósforo/administração & dosagem , Enxofre/administração & dosagem , Aumento de PesoRESUMO
Intravenous artesunate improves survival in severe malaria, but clinical trial data from nonendemic countries are scarce. The TropNet severe malaria database was analyzed to compare outcomes of artesunate vs quinine treatment. Artesunate reduced parasite clearance time and duration of intensive care unit and hospital treatment in European patients with imported severe malaria.
Assuntos
Antimaláricos/administração & dosagem , Artemisininas/administração & dosagem , Malária/tratamento farmacológico , Administração Intravenosa , Adulto , Artesunato , Europa (Continente) , Feminino , Humanos , Masculino , Quinina/administração & dosagem , Estudos Retrospectivos , Fatores de Tempo , Resultado do TratamentoRESUMO
BACKGROUND: In chronic granulomatous disease allogeneic haemopoietic stem-cell transplantation (HSCT) in adolescents and young adults and patients with high-risk disease is complicated by graft-failure, graft-versus-host disease (GVHD), and transplant-related mortality. We examined the effect of a reduced-intensity conditioning regimen designed to enhance myeloid engraftment and reduce organ toxicity in these patients. METHODS: This prospective study was done at 16 centres in ten countries worldwide. Patients aged 0-40 years with chronic granulomatous disease were assessed and enrolled at the discretion of individual centres. Reduced-intensity conditioning consisted of high-dose fludarabine (30 mg/m(2) [infants <9 kg 1·2 mg/kg]; one dose per day on days -8 to -3), serotherapy (anti-thymocyte globulin [10 mg/kg, one dose per day on days -4 to -1; or thymoglobuline 2·5 mg/kg, one dose per day on days -5 to -3]; or low-dose alemtuzumab [<1 mg/kg on days -8 to -6]), and low-dose (50-72% of myeloablative dose) or targeted busulfan administration (recommended cumulative area under the curve: 45-65 mg/Lâ×âh). Busulfan was administered mainly intravenously and exceptionally orally from days -5 to -3. Intravenous busulfan was dosed according to weight-based recommendations and was administered in most centres (ten) twice daily over 4 h. Unmanipulated bone marrow or peripheral blood stem cells from HLA-matched related-donors or HLA-9/10 or HLA-10/10 matched unrelated-donors were infused. The primary endpoints were overall survival and event-free survival (EFS), probabilities of overall survival and EFS at 2 years, incidence of acute and chronic GVHD, achievement of at least 90% myeloid donor chimerism, and incidence of graft failure after at least 6 months of follow-up. FINDINGS: 56 patients (median age 12·7 years; IQR 6·8-17·3) with chronic granulomatous disease were enrolled from June 15, 2003, to Dec 15, 2012. 42 patients (75%) had high-risk features (ie, intractable infections and autoinflammation), 25 (45%) were adolescents and young adults (age 14-39 years). 21 HLA-matched related-donor and 35 HLA-matched unrelated-donor transplants were done. Median time to engraftment was 19 days (IQR 16-22) for neutrophils and 21 days (IQR 16-25) for platelets. At median follow-up of 21 months (IQR 13-35) overall survival was 93% (52 of 56) and EFS was 89% (50 of 56). The 2-year probability of overall survival was 96% (95% CI 86·46-99·09) and of EFS was 91% (79·78-96·17). Graft-failure occurred in 5% (three of 56) of patients. The cumulative incidence of acute GVHD of grade III-IV was 4% (two of 56) and of chronic graft-versus-host disease was 7% (four of 56). Stable (≥90%) myeloid donor chimerism was documented in 52 (93%) surviving patients. INTERPRETATION: This reduced-intensity conditioning regimen is safe and efficacious in high-risk patients with chronic granulomatous disease. FUNDING: None.
Assuntos
Doença Granulomatosa Crônica/terapia , Transplante de Células-Tronco Hematopoéticas/métodos , Condicionamento Pré-Transplante/métodos , Adolescente , Adulto , Alemtuzumab , Anticorpos Monoclonais Humanizados/administração & dosagem , Soro Antilinfocitário/administração & dosagem , Bussulfano/administração & dosagem , Criança , Pré-Escolar , Quimioterapia Combinada , Sobrevivência de Enxerto/efeitos dos fármacos , Doença Enxerto-Hospedeiro/prevenção & controle , Antígenos HLA , Humanos , Imunossupressores/administração & dosagem , Lactente , Estudos Prospectivos , Quimeras de Transplante/fisiologia , Resultado do Tratamento , Vidarabina/administração & dosagem , Vidarabina/análogos & derivados , Adulto JovemRESUMO
Azaindole scaffold is a privileged structure in medicinal chemistry and some derivatives have demonstrated to be potential anticancer drugs. Herein, a set of novel azaindoles, comprising the four regioisomers, bearing a morpholine (azaindoles 3a-d) and N-methyl-N-benzylamine (azaindoles 4a-d) groups were prepared. Among these compounds, azaindoles 4 exhibited higher cytotoxicity against the ovarian cancer cell line A2780 and normal dermal fibroblasts compared to azaindoles 3. Furthermore, azaindoles 4b and 4c promoted a delay in the cell cycle of the cancer cell line, inspiring an investigation into the intracellular localization of these derivatives.