RESUMO
BACKGROUND AND PURPOSE: A wide variety of metabolic changes, including an increased incidence of diabetes mellitus (DM) and dyslipidaemia, has been described in amyotrophic lateral sclerosis (ALS). The aim of this study was to investigate the associations of statin use and history of DM with onset of disease and survival in patients with ALS. METHODS: In all, 501 patients (mean age 65.2 ± 10.9 years; 58.5% male) from the ALS Registry Swabia recruited between October 2010 and April 2016 were included in this prospective cohort study. Data were collected using a standardized questionnaire. RESULTS: Statin use (n = 65) was not associated with overall survival (P = 0.62). Age of ALS onset in patients with DM was 4.2 years later (95% confidence interval 1.3-7.2 years) than in patients without DM (P < 0.01). The overall survival of patients with high body mass index at study entry (>27.0 kg/m2 , upper quartile, n = 127) was prolonged by more than 5 months compared to patients with low body mass index (<22.0 kg/m2 , lower quartile, n = 123; P = 0.04). CONCLUSIONS: This study supports the view that statin use is not associated with overall survival of ALS patients, suggesting that statins are not harmful and should not be discontinued in ALS. Furthermore, the delayed onset of ALS in patients with DM may mirror the potentially protective metabolic profile associated with type 2 DM. Consistently, this study provides further evidence that high body mass index is a positive prognostic factor in ALS.
Assuntos
Esclerose Lateral Amiotrófica , Idoso , Esclerose Lateral Amiotrófica/epidemiologia , Diabetes Mellitus/epidemiologia , Feminino , Alemanha/epidemiologia , Humanos , Inibidores de Hidroximetilglutaril-CoA Redutases/uso terapêutico , Masculino , Pessoa de Meia-Idade , Prognóstico , Estudos Prospectivos , Sistema de RegistrosRESUMO
Real-world observational datasets that record and quantify pressure-stressor-response linkages between effluent discharges and natural aquatic systems are rare. With global wastewater volumes increasing at unprecedented rates, it is urgent that the present dataset is available to provide the necessary information about microbial community structure and functioning. Field studies were performed at two time-points in the Austral summer. Single-species and microbial community whole effluent toxicity (WET) testing was performed at a complete range of effluent concentrations and two salinities, with accompanying environmental data to provide new insights into nutrient and organic matter cycling, and to identify ecotoxicological tipping points. The two salinity regimes were chosen to investigate future scenarios based on a predicted salinity increase at the study site, typical of coastal regions with rising sea levels globally. Flow cytometry, amplicon sequencing of 16S and 18S rRNA genes and micro-fluidic quantitative polymerase-chain reactions (MFQPCR) were used to determine chlorophyll-a and total bacterial cell numbers and size, as well as taxonomic and functional diversity of pelagic microbial communities. This strong pilot dataset could be replicated in other regions globally and would be of high value to scientists and engineers to support the next advances in microbial ecotoxicology, environmental biomonitoring and estuarine water quality modelling.
Assuntos
Ecotoxicologia/métodos , Microbiota/efeitos dos fármacos , Águas Residuárias/toxicidade , Bactérias/classificação , Bactérias/efeitos dos fármacos , SalinidadeRESUMO
Plasma polymer films that contain amine groups (NH2-PPFs) are known to degrade over time, particularly in aqueous environments. To reduce such aging effects, a vertical chemical gradient regarding the amine group density was explored ranging over a few nanometers at the coating surface. The gradient-containing nanofilms were formed in low-pressure plasma by tuning plasma conditions while keeping the plasma "switched on". The coating process started with a more cross-linked NH2-PPF (70 W, 4:7 NH3/C2H4), followed by the deposition of a few nanometers of a less cross-linked yet more functional NH2-PPF (50 W, 7:7 NH3/C2H4). Characterization of the prepared gradient coatings showed that the chemical composition depends on the NH3/C2H4 gas flow ratio, as observed by different analytical methods: plasma diagnostics during deposition and depth profiling analyses of the deposited coating. Finally, surface chemistry was analyzed during air and water aging, showing a similar aging process of the NH2-PPF single layer and NH2-PPF with a vertical chemical gradient in air, while the stability of the gradient coating was found to be enhanced under aqueous conditions maintaining an [NH2]/[C] amount of â¼1%.
RESUMO
The soil substrate membrane system (SSMS) is a novel micro-culturing technique targeted at terrestrial soil systems. We applied the SSMS to pristine and diesel fuel spiked polar soils, along with traditional solid media culturing and culture independent 454 tag pyrosequencing to elucidate the effects of diesel fuel on the soil community. The SSMS enriched for up to 76% of the total soil diversity within high diesel fuel concentration soils, in contrast to only 26% of the total diversity for the control soils. The majority of organisms originally recovered with the SSMS were lost in the transfer to solid media, with all 300 isolates belonging to Proteobacteria, Firmicutes, Actinobacteria or Bacteroidetes, the four phyla most frequently associated with soil culturing efforts. The soils spiked with high diesel fuel concentrations exhibited reduced species richness, diversity and a selection towards heterotrophs and hydrocarbon degraders in comparison to the control soils. Based on these observations and the unusually high level of overlap in microbial taxa observed between methods, we suggest the SSMS holds potential to exploit hydrocarbon degraders and other targets within simplified bacterial systems, yet is inadequate for soil ecology and ecotoxicology studies where identifying rare oligotrophic species is paramount.
RESUMO
BACKGROUND: There is increasing evidence that amyotrophic lateral sclerosis (ALS) has to be regarded as multisystem degeneration rather than as purely a motor neuron disease, as it also includes various dnonmotor symptoms. This modern view has been confirmed by neuropathological and imaging findings. OBJECTIVES: To review recent findings supporting the idea of multisystem degeneration and to describe the implications for diagnostics and therapy. METHODS: A discussion of recent clinical, imaging, and neuropathological findings is presented. RESULTS: Symptoms of ALS include not only motor symptoms but also cognitive impairment, oculomotor abnormalities, and extrapyramidal and sensory symptoms. As a neuropathological correlate, a systematic spreading of "transactive response DNA binding protein 43 kDa" (TDP-43) over functionally connected cortical structures has been described. CONCLUSIONS: Nonmotor symptoms are regularly seen in ALS, although they usually do not dominate the clinical picture. Recent neuropathological findings offer new perspectives for diagnostics and therapy in ALS.
Assuntos
Esclerose Lateral Amiotrófica/diagnóstico , Esclerose Lateral Amiotrófica/terapia , Transtornos Cognitivos/diagnóstico , Transtornos Cognitivos/terapia , Transtornos da Motilidade Ocular/diagnóstico , Transtornos da Motilidade Ocular/terapia , Diagnóstico Diferencial , Medicina Baseada em Evidências , Humanos , Avaliação de Sintomas/métodosRESUMO
A large proportion of "universal" 16S PCR primers lack sequence homology to many of the "candidate" divisions, severely limiting bacterial diversity assessments. We designed a primer set that offers a 50% increase in silico in coverage of the domain Bacteria over the commonly used primer combination 27F/519R. Comparisons using pyrosequencing on soil environments showed a significant increase in recovery of taxonomic diversity with around a 3-fold increase in recovery of sequences from candidate divisions.
Assuntos
Bactérias/classificação , Bactérias/genética , Genes de RNAr , Variação Genética , Metagenômica/métodos , Reação em Cadeia da Polimerase/métodos , RNA Ribossômico 16S/genética , Primers do DNA/genética , DNA Bacteriano/química , DNA Bacteriano/genética , DNA Ribossômico/química , DNA Ribossômico/genética , Análise de Sequência de DNA , Microbiologia do SoloRESUMO
OBJECTIVE: On the basis of attachment, the study combines results in relationship and psychosomatic research. A buffering hypothesis of a secure attachment in patients with chronic skin diseases is checked. METHODS: Patients with atopic dermatitis (n = 21) and psoriasis (n = 22) were tested with various questionnaires: the German questionnaire for partnership attributes (PFB) and problem list (PL), questionnaire for psychosomatic complaints (BEB), Relationship Scales Questionnaire (RSQ), and a self-designed questionnaire. RESULTS: Unsecurely attached patients with atopic dermatitis feel mentally more disturbed and report more coherence between mental strains and changes in skin surface than securely attached psoriasis patients. There are tendencies to the assumed buffering effects. The study shows hints of the importance of attachment theory in psychosomatic skin diseases. CONCLUSION: In the treatment of patients with chronic skin diseases psychosocial aspects should be taken into consideration. Partnership factors might be used as a resource.
Assuntos
Dermatite Atópica/psicologia , Relações Interpessoais , Neurodermatite/psicologia , Apego ao Objeto , Psoríase/psicologia , Adaptação Psicológica , Adolescente , Adulto , Criança , Comportamento Cooperativo , Feminino , Humanos , Comportamento de Doença , Comunicação Interdisciplinar , Masculino , Pessoa de Meia-Idade , Transtornos Psicofisiológicos/psicologia , Papel do Doente , Apoio Social , Estatística como Assunto , Estresse Psicológico/complicações , Inquéritos e Questionários , Adulto JovemRESUMO
Weight loss is a common phenomenon and an independent prognostic factor in amyotrophic lateral sclerosis (ALS). Several potential causal mechanisms, including intrinsic hypermetabolism and deficient food intake, have been discussed. We investigated the influence of fasting serum glucose, cholesterol, and triglyceride levels at time of diagnosis on survival in ALS. Serum cholesterol (LDL, HDL, and LDL/HDL ratio), triglycerides, and glucose were investigated in 488 patients (age of onset = 57.6 ± 12.6 years) in relation to survival and revised Amyotrophic Lateral Sclerosis Functional Rating Scale (ALS-FRS) data. High serum levels of both fasting cholesterol and triglycerides had a significantly positive effect on survival (p < 0.05). We found a median prolonged life expectancy by 14 months for patients with serum triglyceride levels above the median of 1.47 mmol/l. The results suggest that the lipid metabolism and the nutritional status of ALS patients are important prognostic factors. These parameters should be thoroughly monitored during the clinical management of these patients. In case of progressive loss of body weight, a diet rich in lipids and calories should be considered. However, the final decision whether a lipid-rich diet should be recommended to ALS patients can only be based on a double-blind placebo-controlled interventional trial. Our results further imply that lipid-lowering drugs, e.g., statins, should be applied carefully in ALS patients although individual risk considerations must be made.
Assuntos
Esclerose Lateral Amiotrófica/sangue , Esclerose Lateral Amiotrófica/mortalidade , Colesterol/sangue , Triglicerídeos/sangue , Adulto , Idoso , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Análise de SobrevidaRESUMO
Here we illustrate a 74-year-old patient presenting with clinical signs of slowly progressive motor neuron disease. After electromyography demonstrated myopathic changes, a skeletal muscle biopsy was performed showing histological signs of granulomatous myositis. In extensive diagnostic workup underlying primary granulomas forming diseases were excluded and corticoid therapy was initiated, but without clinical effect. We want to point out that granulomatous myositis should be considered in the differential diagnosis of slowly progressive motor neuron diseases, especially in atypical clinical presentations.
Assuntos
Granuloma/diagnóstico , Miosite/diagnóstico , Idoso , Biópsia , Diagnóstico Diferencial , Feminino , Granuloma/metabolismo , Humanos , Imageamento por Ressonância Magnética , Doença dos Neurônios Motores/diagnóstico , Doença dos Neurônios Motores/patologia , Músculo Esquelético/patologia , Miosite/metabolismo , Neurônios/metabolismo , Sarcoidose/diagnósticoRESUMO
RATIONALE: Functional transcranial Doppler sonography (fTCD) during word generation is well established for language lateralization. In this study, we evaluated a fTCD paradigm to reliably identify the non-dominant hemisphere. METHODS: Twenty-nine right-handed healthy subjects (27.1+/-7.6 years) performed the 'cube perspective test' [Stumpf, H., & Fay, E. (1983). Schlauchfiguren: Ein Test zur Beurteilung des räumlichen Vorstellungsvermögens. Verlag für Psychologie Dr. C. J. Hogrefe, Göttingen, Toronto, Zürich] a spatial orientation task, while the cerebral blood flow velocity (CBFV) was simultaneously measured in both middle cerebral arteries (MCAs). In addition, the established word generation paradigm for language lateralization was performed. Subjects with atypical language representation were excluded. Data were analysed offline with the software Average, which performed a heart-cycle integration and a baseline-correction and calculated a lateralization index (LI) with its standard error of the mean increase in CBFV separately for both MCAs. RESULTS: Twenty-one of 29 subjects (72.4%) lateralized to the right hemisphere (chi2=5.828, p=0.016). The mean LI of the spatial orientation paradigm pointed to the right hemisphere (x =-1.9+/-3.2) and was different from the LI of word generation (x =3.9+/-2.2;p<0.001). There was no correlation between the LI of spatial orientation and word generation (R=0.095, p=0.624). Age of the subjects did not correlate with the LI during spatial orientation (p>0.05) but negatively with the LI during word generation (R=-0.468, p=0.010). The maximum increase of CBFV was greater in the spatial orientation (14.0%+/-3.6%) than in the word generation paradigm (9.4%+/-4.0%; p<0.001). CONCLUSIONS: In more than two thirds of the subjects with left-sided language dominance, the spatial orientation paradigm was able to identify the non-dominant hemisphere. The results suggest both paradigms to be independent of each other. The spatial orientation paradigm, therefore, appears to be a non-verbal fTCD paradigm with possible clinical relevance.
Assuntos
Encéfalo/fisiologia , Dominância Cerebral/fisiologia , Orientação/fisiologia , Percepção Espacial/fisiologia , Ultrassonografia Doppler Transcraniana/métodos , Adulto , Fatores Etários , Velocidade do Fluxo Sanguíneo/fisiologia , Encéfalo/irrigação sanguínea , Circulação Cerebrovascular/fisiologia , Distribuição de Qui-Quadrado , Feminino , Humanos , Idioma , Masculino , Pessoa de Meia-Idade , Artéria Cerebral Média/diagnóstico por imagem , Testes Psicológicos/estatística & dados numéricos , Desempenho Psicomotor/fisiologia , Percepção Visual/fisiologia , Adulto JovemRESUMO
Granulomatous myositis is a rare neuromuscular disorder histologically characterized by the development of endomyseal and/or perimyseal granulomas. Clinical hallmarks are generalized muscle weakness, myalgias, and bulbar symptoms. The association of granulomatous myositis with sarcoidosis is well known; less recognized is the association with several infectious diseases, inflammatory bowel diseases, malignancy, thymoma, graft-vs-host disease, and myasthenia gravis. In absence of sarcoidosis or other underlying disorders, the diagnosis of isolated or primary granulomatous myositis must be considered. Therapeutic strategies focus on immunosuppression, whereas the therapy response is unpredictable. Here we discuss the clinical features, diagnosis, and differential diagnosis and therapeutic strategies of primary and secondary granulomatous myositis.
Assuntos
Granuloma/diagnóstico , Miosite/diagnóstico , Idoso , Biópsia , Transtornos de Deglutição/etiologia , Diagnóstico Diferencial , Feminino , Granuloma/etiologia , Granuloma/patologia , Humanos , Imageamento por Ressonância Magnética , Cãibra Muscular/etiologia , Debilidade Muscular/etiologia , Músculo Esquelético/patologia , Miosite/etiologia , Miosite/patologia , Exame Neurológico , Fatores de RiscoRESUMO
We previously discovered a novel missense mutation (Lys650Met) in the tyrosine kinase domain of the fibroblast growth factor receptor 3 (FGFR3) gene in four unrelated individuals with a condition we called "severe achondroplasia with developmental delay and acanthosis nigricans" (SADDAN) [Tavormina et al., 1999: Am. J. Hum. Genet. 64:722-731]. Here we present a more detailed clinical account of the SADDAN phenotype. The FGFR3 Lys650Met mutation results in severe disturbances in endochondral bone growth that approach and overlap those observed in thanatophoric dysplasia, type I. However, this mutation is most often compatible with survival into adulthood. Other unusual bone deformities, such as femoral bowing with reverse (i.e., posterior apex) tibial and fibular bowing and "ram's horn" bowing of the clavicle, are also seen in some patients. In addition to skeletal dysplasia, progressive acanthosis nigricans, and central nervous system structural anomalies, seizures and severe developmental delays are observed in surviving SADDAN patients. Despite its location within the same FGFR3 codon as the thanatophoric dysplasia type II mutation (Lys650Glu) and a similar effect on constitutive activation of the FGFR3 tyrosine kinase, the Lys650Met is not associated with cloverleaf skull or craniosynostosis.
Assuntos
Acantose Nigricans/genética , Deficiências do Desenvolvimento/genética , Osteocondrodisplasias/genética , Mutação Puntual , Proteínas Tirosina Quinases , Receptores de Fatores de Crescimento de Fibroblastos/genética , Feminino , Humanos , Recém-Nascido , Lisina/genética , Masculino , Metionina/genética , Fenótipo , Radiografia , Receptor Tipo 3 de Fator de Crescimento de Fibroblastos , Crânio/diagnóstico por imagem , Crânio/patologiaRESUMO
In the framework of a project aimed at the elucidation of the nature of the functional importance of the N-glycosylation of the alpha-subunit of the glycoprotein hormones human lutropin and human chorionic gonadotropin, the structural element alpha-Neu p5Ac-(2-->6)-beta-D-GalpNac-(1-->4)- beta-D-GlcpNAc-(1-->2)-alpha-D-Manp, which is part of the carbohydrate chains of human lutropin, has been prepared by chemical and chemo-enzymatic synthesis in the form of its propyl glycoside. Condensation of 4-O- acetyl-3,6-di-O-benzyl-2-deoxy-2-phthalimido-alpha/beta-D-glucopyranosyl trichloroacetimidate with allyl 3,4,6-tri-O-benzyl-alpha-D-mannopyranoside gave after deacetylation allyl (3,6-di-O-benzyl-2-deoxy-2-phthalimido-beta-D-glucopyranosyl) -(1-->2)-3,4,6-tri-O-benzyl-alpha-D-mannopyranoside. Ethyl 3-O-benzyl-2-deoxy-2-phthalimido-l-thio-beta-D-glucopyranoside was converted into the galacto-derivative ethyl 4,6-di-O-acetyl-3-O-benzyl-2-deoxy-2-phthalimido-1-thio-beta-D -galactopyranoside via an oxidation-reduction route, as well as via SN2-type substitution with acetate. The use of this galacto thioglycoside, after its conversion into the corresponding bromide, as GaIN donor for condensation with the mentioned disaccharide derivative yielded after deacetylation allyl (3-O-benzyl-2-deoxy-2-phthalimido-beta-D-galactopyranosyl)-(1-->4) -(3,6-di-O-benzyl-2-deoxy-2-phthalimido-beta-D-glucopyranosyl)-(1-->2) -3,4,6-tri-O-benzyl-alpha-D-mannopyranoside. Methylsulfenyl bromide-silver triflate promoted sialylation of this trisaccharide derivative with O-ethyl S-[methyl (5-acetamido-4,7,8,9-tetra-O-acetyl-3,5-dideoxy-D -glycero-alpha-D-galacto-non-2-ulopyranosyl)onate] dithiocarbonate and subsequent deprotection resulted into the aimed tetrasaccharide structural element. Alternatively, this compound was prepared via a block synthesis, which, however, was not superior to the linear strategy. Finally, a stereose lective sialylation of synthetically prepared beta-D-GalpNAc-(1-->4)-beta-D-GlcpNAc-(1-->2)-alpha-D-Manp-(1-->O) CH2CH2CH3 with CMP-Neu5Ac and rat liver alpha-2,6-sialyltransferase was accomplished affording the same tetrasaccharide structural element.
Assuntos
Carboidratos/síntese química , Hormônio Luteinizante/química , Oligossacarídeos/síntese química , Animais , Sequência de Carboidratos , Carboidratos/química , Humanos , Hormônio Luteinizante/síntese química , Dados de Sequência Molecular , Oligossacarídeos/química , RatosRESUMO
Seven analogues of the trisaccharide beta-D-Galp-(1-->4)-beta-D-GlcpNAc-(1-->2)-alpha-D-Manp-(1-->O)(CH 2)7CH3 have been synthesized as potential substrates for glycosyltransferases involved in the chain-termination of N-acetyllactosamine-type N-glycans. These compounds include: 3-O-methyl-beta-D-Galp-(1-->4)-beta-D-GlcpNAc-(1-->2)-alpha-D-Manp -(1-->O) (CH2)7CH3, 3-deoxy-beta-D-Galp-(1-->4)-beta-D-GlcpNAc-(1-->2)-alpha-D-Manp-(1 -->O) (CH2)7CH3, 3-deoxy-3-fluoro-beta-D-Galp-(1-->4)-beta-D-GlcpNAc-(1-->2)-alpha-D-M anp- (1-->O)(CH2)7Ch3, 3-amino-3-deoxy-beta-D-Galp-(1-->4)-beta-D-GlcpNAc-(1-->2)-alpha-D-Ma np- (1-->O)(CH2)7CH3, beta-D-Gulp-(1-->4)-beta-D-GlcpNAc-(1-->2)-alpha-D-Manp-(1-- >O)(CH2)7CH3, beta-L-Galp-(1-->4)-beta-D-GlcpNAc-(1-->2)-alpha-D-Manp-(1-->O)(CH 2)7CH3, and alpha-L-Altp-(1-->4)-beta-D-GlcpNAc-(1-->2)-alpha-D-Manp-(1- ->O) (CH2)7CH3. All trisaccharides were obtained by condensation of suitably modified glycosyl donors based on imidates or thioglycosides with the same disaccharide acceptor, octyl 3,4,6-tri-O-benzyl-2-O-(3,6-di-O-benzyl-2-deoxy-2-phthalimido-beta-D- glucopyranosyl)-alpha-D-mannopyranoside, followed by deprotection.
Assuntos
Glicosiltransferases/metabolismo , Trissacarídeos/síntese química , Configuração de Carboidratos , Sequência de Carboidratos , Galactose/análogos & derivados , Glicosídeos/química , Glicosilação , Espectroscopia de Ressonância Magnética , Sondas Moleculares , Dados de Sequência Molecular , Estrutura Molecular , Especificidade por Substrato , Trissacarídeos/química , Trissacarídeos/metabolismoRESUMO
The acceptor specificities of rat liver Gal(beta 1-4)GlcNAc alpha-2,6-sialyltransferase, recombinant full-length human liver Gal(beta 1-4)GlcNAc alpha-2,6-sialyltransferase, and a soluble form of recombinant rat liver Gal(beta 1-3/4)GlcNAc alpha-2,3-sialyltransferase were studied with a panel of analogues of the trisaccharide Gal(beta 1-4)GlcNAc(beta 1-2)Man(alpha 1-O)(CH2)7CH3. These analogues contain structural variants of D-galactose, modified at either C3, C4 or C5 by deoxygenation, fluorination, O-methylation, epimerization, or by the introduction of an amino group. In addition, the enantiomer of D-galactose is included. The alpha-2,6-sialyltransferases tolerated most of the modifications at the galactose residue to some extent, whereas the alpha-2,3-sialyltransferase displayed a narrower specificity. Molecular dynamics simulations were performed in order to correlate enzymatic activity to three-dimensional structure. Ineffective acceptors for rat liver alpha-2,6-sialyltransferase were shown to be inhibitory towards the enzyme; likewise, the alpha-2,3-sialyltransferase was found to be inhibited by all non-substrates. Modified sialyloligosaccharides were obtained on a milligram scale by incubation of effective acceptors with one of each of the three enzymes, and characterized by 500-MHz 1H-NMR spectroscopy.
Assuntos
Sialiltransferases/metabolismo , Animais , Simulação por Computador , Cinética , Fígado/enzimologia , Espectroscopia de Ressonância Magnética , Conformação Molecular , Ratos , Proteínas Recombinantes , Especificidade por Substrato , Trissacarídeos/metabolismo , beta-D-Galactosídeo alfa 2-6-Sialiltransferase , beta-Galactosídeo alfa-2,3-SialiltransferaseRESUMO
Five trisaccharide derivatives designed for detailed exploration of the acceptor specificity of glycosyltransferases involved in termination of N-acetyllactosamine-type structures have been synthesized: beta-D-Gal p-(1-->4)-beta-D-Glc pNAc-(1-->2)-alpha-D-Man p-(1-->0)(CH2)7CH3 (1), 4-deoxy-beta-D-Gal p-(1-->4)-beta-D-Glc pNAc-(1-->2)-alpha-D-Man p-(1-->O)(CH2)7CH3 (2), 4-O-methyl-beta-D-Gal p-(1-->4)-beta-D-Glc pNAc-(1-->2)-alpha-D-Man p-(1-->O)(CH2)7CH3 (3), 4-deoxy-4-fluoro-beta-D-Gal p-(1-->4)-beta-D-Glc pNAc-(1-->2)-alpha-D-Man p(1-->O)(CH2)7CH3 (4), and beta-D-Glc p-(1-->4)-beta-D-Glc pNAc-(1-->2)-alpha-D-Man p-(1-->O)(CH2)7CH3 (5). A general disaccharide acceptor octyl 3,4,6-tri-O-benzyl-2-O-(3,6-di-O-benzyl-2-deoxy-2-phthalimido-beta-D -glucopyranosyl)-alpha-D-mannopyranoside was synthesized by condensation of 4-O-acetyl-3,6-di-O-benzyl-2-deoxy-2-phthalimido-alpha, beta-D-glucopyranosyl trichloroacetimidate with octyl 3,4,6-tri-O-benzyl-alpha-D-mannopyranoside, followed by deacetylation. 2,3,4,6-Tetra-O-acetyl-alpha-D-galactopyranosyl trichloroacetimidate and 2,3,4,6-tetra-O-acetyl-alpha-D-glucopyranosyl trichloroacetimidate were used as the glycosyl donors in the syntheses of 1 and 5. The modified galactosyl derivatives required subtle anomeric activation. Suitable donors for 2 turned out to be 2,3,6-tri-O-acetyl-4-deoxy-alpha-D-xylo-hexopyranosyl trichloroacetimidate and ethyl 2,3,6-tri-O-acetyl-4-deoxy-1-thio-alpha, beta-D-xylo-hexopyranoside; for 3, ethyl 2,3,6-tri-O-acetyl-4-O-methyl-1-thio-alpha, beta-D-galactopyranoside; and for 4, 2,3,6-tri-O-acetyl-4-deoxy-4-fluoro-alpha-D-galactopyranosyl trichloroacetimidate. It was concluded that thioglycosides were most appropriate for stereoselective coupling of activated synthons (carrying deoxy or O-methyl groups), whereas trichloroacetimidates gave high yields with deactivated (fluorine-containing) synthons.
Assuntos
Glicosiltransferases/metabolismo , Trissacarídeos/síntese química , Amino Açúcares/síntese química , Amino Açúcares/química , Amino Açúcares/metabolismo , Configuração de Carboidratos , Sequência de Carboidratos , Glicosídeos/síntese química , Glicosídeos/metabolismo , Espectroscopia de Ressonância Magnética , Manosídeos/síntese química , Manosídeos/metabolismo , Dados de Sequência Molecular , Estrutura Molecular , Especificidade por Substrato , Trissacarídeos/metabolismoRESUMO
UDP-GlcNAc:Man alpha 1-6R beta(1-2)-N-acetylglucosaminyltransferase II (GlcNAc-T II; EC 2.4.1.143) is a key enzyme in the synthesis of complex N-glycans. We have tested a series of synthetic analogues of the substrate Man"'alpha 1-6(GlcNAc"beta 1-2Man'alpha 1-3)Man beta-O-octyl as substrates and inhibitors for rat liver GlcNAc-T II. The enzyme attaches N-acetylglucosamine in beta 1-2 linkage to the 2"'-OH of the Man"'alpha 1-6 residue. The 2"'-deoxy analogue is a competitive inhibitor (Ki = 0.13 mM). The 2"'-O-methyl compound does not bind to the enzyme presumably due to steric hindrance. The 3"'-, 4"'- and 6"'-OH groups are not essential for binding or catalysis since the 3"'-, 4"'- and 6"'-deoxy and -O-methyl derivatives are all good substrates. Increasing the size of the substituent at the 3"'-position to pentyl and substituted pentyl groups causes competitive inhibition (Ki = 1.0-2.5 mM). We have taken advantage of this effect to synthesize two potentially irreversible GlcNAc-T II inhibitors containing a photolabile 3"'-O-(4,4-azo)pentyl group and a 3"'-O-(5-iodoacetamido)pentyl group respectively. The data indicate that none of the hydroxyls of the Man"'alpha 1-6 residue are essential for binding although the 2"'- and 3"'-OH face the catalytic site of the enzyme. The 4-OH group of the Man beta-O-octyl residue is not essential for binding or catalysis since the 4-deoxy derivative is a good substrate; the 4-O-methyl derivative does not bind.(ABSTRACT TRUNCATED AT 250 WORDS)
Assuntos
N-Acetilglucosaminiltransferases/metabolismo , Animais , Metabolismo dos Carboidratos , Sequência de Carboidratos , Carboidratos/síntese química , Fígado/enzimologia , Dados de Sequência Molecular , N-Acetilglucosaminiltransferases/antagonistas & inibidores , Ratos , Especificidade por SubstratoRESUMO
Wildlife has a considerable and highly varied impact on the environment. Furthermore, in transforming the environment, man has indirectly altered some of the many links which associate animals with the environment. Food chains are an essential link, for they associate animals to plants (in the case of depredators such as herbivores, fruit- and grain-eaters) and to other animals (in the case of predators). Food chains determine the equilibrium of populations in their habitat. The various roles and activity of animals within different ecosystems are described. Birds are discussed at some length, given their role in pollination and the dissemination of plants, and also their potential for acting as reservoirs or carriers of pathogens. Mention is also made of disturbances to the environment resulting from the introduction, by humans, of various species which can threaten the ecological balance of the host region. These topics form a basis for further reflection on the conservation of particularly endangered natural resources.
Assuntos
Animais Selvagens/fisiologia , Aves/fisiologia , Meio Ambiente , Insetos/fisiologia , Mamíferos/fisiologia , Animais , HumanosRESUMO
A multicenter, prospective randomized controlled trial was performed comparing the efficacy of a single intratracheal dose of modified bovine surfactant extract (Survanta, 100 mg/kg, Abbott Laboratory, North Chicago, IL) with air placebo in preventing respiratory distress syndrome. Infants were enrolled if they were estimated to be between 24 and 30 weeks' gestation, weighed between 750 and 1250 g, and were intubated and stabilized within 15 minutes after birth. A total of 160 infants were treated (79 with surfactant, 81 with air placebo) between 4 and 37 minutes after birth (median time 12 minutes). Of these, 5 infants were excluded from the final analysis. The 72-hour average values for the arterial-alveolar oxygen ratio, fraction of inspired oxygen, and mean airway pressure were calculated from the area under the curve of scheduled values measured throughout 72 hours. Clinical status was classified using five ordered categories (no supplemental oxygen or assisted ventilation, supplemental oxygen only, continuous positive airway pressure or assisted ventilation with intermittent mandatory ventilation less than or equal to 6 breaths/min, assisted ventilation with intermittent mandatory ventilation greater than 6 breaths/min, death). Chest radiographs at 24 hours were graded for severity of respiratory distress syndrome. Infants receiving Survanta had less severe radiographic changes at 24 hours of age and decreased average fraction of inspired oxygen (31% vs 42%, P = .002) compared with control infants. No differences were noted in the average arterial-alveolar oxygen ratio, mean airway pressure, or clinical status on days 7 and 28. A beneficial effect was noted in the incidence of pneumothorax (P = .057) and an increase was noted in the incidence of necrotizing enterocolitis (P = .052). No differences in incidence of patent ductus arteriosus, intraventricular hemorrhage, sepsis, or bronchopulmonary dysplasia were seen. According to results of a secondary analysis, there was improvement in the fraction of inspired oxygen and a greater number of survivors without bronchopulmonary dysplasia in the subgroup of infants weighing less than 1000 g who were treated with surfactant. It was concluded that a single dose of Survanta given shortly after birth resulted in decreased severity of chest radiographic findings 24 hours after treatment and improved oxygenation during 72 hours after treatment, but did not improve other acute measures of disease severity or clinical status later in the neonatal period. The group at highest risk for respiratory distress syndrome (infants with birth weights between 750 and 999 g) may benefit the most from preventive therapy.
Assuntos
Surfactantes Pulmonares/administração & dosagem , Síndrome do Desconforto Respiratório do Recém-Nascido/prevenção & controle , Animais , Bovinos , Combinação de Medicamentos , Humanos , Recém-Nascido de Baixo Peso , Recém-Nascido , Minnesota , Estudos Multicêntricos como Assunto , Cidade de Nova Iorque , Oxigênio/sangue , Ácido Palmítico , Ácidos Palmíticos/administração & dosagem , Estudos Prospectivos , Ensaios Clínicos Controlados Aleatórios como Assunto , Síndrome do Desconforto Respiratório do Recém-Nascido/sangue , Síndrome do Desconforto Respiratório do Recém-Nascido/diagnóstico , Rhode Island , Texas , Fatores de Tempo , Triglicerídeos/administração & dosagemRESUMO
Osteogenesis imperfecta is the common term for a heterogeneous group of heritable disorders of connective tissue with lethal and nonlethal forms. Prenatal diagnosis presents difficult medical and ethical issues. Of concern are the following: 1) the certainty of diagnosis, 2) the severity of disease, 3) the prognosis for survival and ambulation, and 4) the appropriate mode of delivery. A case of nonlethal fetal osteogenesis imperfecta managed by vaginal delivery is discussed.