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1.
Public Health ; 190: 173-175, 2021 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-33309006

RESUMO

OBJECTIVES: The aim of this study was to discuss the status of and perspective for biomarker validation in view of the challenges imposed on national healthcare systems due to an increasing number of citizens with chronic diseases and new expensive drugs with effects that are sometimes poorly documented. The demand for a paradigm shift toward stratification of patients or even 'personalized medicine' (PM) is rising, and the implementation of such novel strategies has the potential to increase patient outcomes and cost efficiency of treatments. The implementation of PM depends on relevant and reliable biomarkers correlated to disease states, prognosis, or effect of treatment. Beyond biomarkers of disease, personalized prevention strategies (such as individualized nutrition guidance) are likely to depend on novel biomarkers. STUDY DESIGN: We discuss the current status of the use of biomarkers and the need for standardization and integration of biomarkers based on multi-omics approaches. METHODS: We present representative cases from laboratory medicine, oncology, and nutrition, where present and emerging biomarkers have or may present opportunities for PM or prevention. RESULTS: Biomarkers vary greatly in complexity, from single genomic mutations to metagenomic analyses of the composition of the gut microbiota and comprehensive analyses of metabolites, metabolomics. Using biomarkers for decision-making has previously often relied on measurements of single biomolecules. The current development now moves toward the use of multiple biomarkers requiring the use of machine learning or artificial intelligence. Still, the usefulness of biomarkers is often challenged by suboptimal validation, and the discovery of new biomarkers moves much faster than standardization efforts. To reap the potential benefits of personalization of treatment and prevention, healthcare systems and regulatory authorities need to focus on validation and standardization of biomarkers. CONCLUSION: There is a great public health need for better understanding of the usefulness, but also limitations, of biomarkers among policy makers, clinicians, and scientists, and efforts securing effective validation are key to the future use of novel sets of complex biomarkers.


Assuntos
Biomarcadores/sangue , Metabolômica , Estado Nutricional , Medicina de Precisão/tendências , Atenção à Saúde , Humanos , Metagenômica , Nutrigenômica
2.
Food Chem Toxicol ; 80: 137-143, 2015 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-25792266

RESUMO

Recent epidemiological studies show a positive association between cancer incidence and high intake of processed meat. N-nitrosamines (NAs) in these products have been suggested as one potential causative factor. Most volatile NAs (VNAs) are classified as probable human carcinogens, whereas the carcinogenicity for the majority of the non-volatile NA (NVNA) remains to be elucidated. Danish adults (15-75 years) and children (4-6 years) consume 20 g and 16 g of processed meat per day (95th percentile), respectively. The consumption is primarily accounted for by sausages, salami, pork flank (spiced and boiled) and ham. This consumption results in an exposure to NVNA of 33 and 90 ng kg bw(-1) day(-1) for adults and children, respectively. The exposure to VNA is significantly lower amounting to 0.34 and 1.1 ng kg bw(-1) day(-1) for adults and children, respectively. Based on a BMDL10 of 29 µg kg bw(-1) day(-1) a MOE value ≥17,000 was derived for the exposure to NA known to be carcinogenic (VNA including NSAR), indicating an exposure of low concern. The exposure to the NVNA is substantially higher and if found to be of toxicological significance the exposure may be of concern.


Assuntos
Dieta , Produtos da Carne/análise , Nitrosaminas/toxicidade , Compostos Orgânicos Voláteis , Adolescente , Adulto , Idoso , Animais , Criança , Pré-Escolar , Dinamarca , Contaminação de Alimentos , Humanos , Pessoa de Meia-Idade , Nitrosaminas/química , Fatores de Risco , Adulto Jovem
3.
Eur J Neurol ; 22(5): 781-8, e49-50, 2015 May.
Artigo em Inglês | MEDLINE | ID: mdl-25598324

RESUMO

BACKGROUND AND PURPOSE: A number of studies have suggested associations between dementia and depression in older adults. One reason could be that these disorders share structural correlates, such as white matter lesions (WMLs) and cortical atrophy. No study has examined whether these lesions precede both dementia and depression independently of each other in the general population. METHODS: Whether WMLs and cortical atrophy on computed tomography predict dementia and depression was investigated in a population-based sample of 70-year-olds (n = 380) followed over 10 years. Exclusion criteria were dementia, major depression, history of stroke and a Mini-Mental State Examination score below 26 at baseline in 2000-2001. Dementia was diagnosed according to the Diagnostic and Statistical Manual of Mental Disorders, third edition, revised, and depression according to the Diagnostic and Statistical Manual of Mental Disorders, fifth edition. Primary outcomes included dementia and major depression at 10-year follow-up. RESULTS: Adjusted logistic regression models, including both WMLs and temporal lobe atrophy, showed that moderate to severe WMLs [odds ratio (OR) 3.96, 95% confidence interval (CI) 1.23-12.76] and temporal lobe atrophy (OR 2.93, 95% CI 1.13-7.60) predicted dementia during a 10-year follow-up independently of major depression. Similarly, both moderate to severe WMLs (OR 3.84, 95% CI 1.25-11.76) and temporal lobe atrophy (OR 2.52, 95% CI 1.06-5.96) predicted depression even after controlling for incident dementia. CONCLUSION: White matter lesions and temporal lobe atrophy preceded 10-year incidence of both dementia and depression in 70-year-olds. Shared structural correlates could explain the reported associations between dementia and depression. These brain changes may represent independent and complementary pathways to dementia and depression. Strategies to slow progression of vascular pathology and neurodegeneration could indirectly prevent both dementia and depression in older adults.


Assuntos
Demência , Transtorno Depressivo Maior , Lobo Temporal/patologia , Substância Branca/patologia , Idoso , Atrofia/epidemiologia , Atrofia/patologia , Comorbidade , Demência/diagnóstico , Demência/epidemiologia , Demência/patologia , Transtorno Depressivo Maior/diagnóstico , Transtorno Depressivo Maior/epidemiologia , Transtorno Depressivo Maior/patologia , Feminino , Seguimentos , Humanos , Incidência , Masculino , Radiografia , Lobo Temporal/diagnóstico por imagem , Fatores de Tempo , Substância Branca/diagnóstico por imagem
4.
Neurology ; 76(10): 879-86, 2011 Mar 08.
Artigo em Inglês | MEDLINE | ID: mdl-21383324

RESUMO

BACKGROUND: Individuals aged 80 years and older is the fastest growing segment of the population worldwide. To understand the biology behind increasing longevity, it is important to examine factors related to survival in this age group. The relationship between brain atrophy and survival after age 85 remains unclear. METHODS: A population-based sample (n = 239) had head CT scans at age 85 and was then followed until death. Cortical atrophy and ventricular size were assessed. Statistical analyses included Cox proportional hazards models with time to death as the outcome and considering a large number of possible confounders, including baseline cognitive function, incident dementia, and somatic disorders. RESULTS: Mean survival time (±SD) was 5.0 ± 3.6 years (range 0.10-19.8 years). Decreased survival was associated with temporal, and frontal atrophy, sylvian fissure width and a number of ventricular measures after adjustment for potential confounders. In participants without dementia at baseline (n = 135), decreased survival was associated with temporal lobe atrophy and bifrontal ratio. In those with dementia (n = 104), decreased survival was associated with third ventricle width, cella media ratio, and ventricle-to-brain and ventricle-to-cranial ratio. CONCLUSIONS: Several indices of brain atrophy were related to decreased survival after age 85, regardless of dementia status. Brain atrophy is rarely mentioned as a significant indicator of survival in the elderly, independent of traditional predictors such as cardiovascular disease or cancer. The biology behind the influence of brain atrophy on survival needs to be further scrutinized.


Assuntos
Encéfalo/patologia , Demência/patologia , Doenças Neurodegenerativas/epidemiologia , Doenças Neurodegenerativas/patologia , Fatores Etários , Idoso de 80 Anos ou mais , Atrofia/patologia , Planejamento em Saúde Comunitária , Demência/diagnóstico por imagem , Demência/epidemiologia , Demência/mortalidade , Depressão/diagnóstico , Humanos , Estudos Longitudinais , Doenças Neurodegenerativas/diagnóstico por imagem , Doenças Neurodegenerativas/mortalidade , Modelos de Riscos Proporcionais , Escalas de Graduação Psiquiátrica , Análise de Sobrevida , Tomografia Computadorizada por Raios X/métodos
5.
Diabetologia ; 48(3): 561-8, 2005 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-15700136

RESUMO

AIMS/HYPOTHESIS: Extracellular matrix modifications and linear medial calcifications are elements of diabetic macroangiopathy. We hypothesised that the bone-related protein osteoprotegerin (OPG) may occur in altered amounts in the arterial wall in diabetes, putatively associated with altered synthesis from vascular cells. METHODS: The amount of OPG in the thoracic aorta, obtained at autopsy from 21 diabetic and 42 sex- and age-matched controls, was measured in tissue extracts by an ELISA. The production of OPG was estimated in conditioned media by an ELISA, and OPG mRNA was estimated by RT-PCR in vascular cells grown in vitro. RESULTS: The content of OPG was increased in tunica media samples from diabetic individuals. No differences between diabetic and non-diabetic subjects were observed in tunica intima. Human vascular smooth muscle cells (HVSMCs) produced approximately 30 times more OPG than human umbilical vein endothelial cells. The OPG production into the medium decreased dose- and time-dependently after insulin treatment (maximal effect approximately 60% of control) in HVSMCs, whereas TNF-alpha supplement gave rise to increased OPG synthesis in a time- and dose-dependent manner (maximal effect approximately 200% of control). Similar effects on OPG mRNA expression were observed. Addition of growth hormone (10 ng/ml) or extra glucose (25 mmol/l) to the growth medium had no effect. CONCLUSIONS/INTERPRETATION: Increased OPG concentrations in the arterial wall in diabetes may be part of generalised matrix alterations, putatively related to the development of vascular calcifications. Altered arterial OPG content may be a consequence of the effects of hormones and cytokines, like insulin and TNF-alpha.


Assuntos
Aorta Torácica/fisiopatologia , Diabetes Mellitus Tipo 1/fisiopatologia , Diabetes Mellitus Tipo 2/fisiopatologia , Endotélio Vascular/metabolismo , Glicoproteínas/genética , Insulina/farmacologia , Músculo Liso Vascular/fisiopatologia , Receptores Citoplasmáticos e Nucleares/genética , Receptores do Fator de Necrose Tumoral/genética , Aorta Torácica/efeitos dos fármacos , Autopsia , Células Cultivadas , Endotélio Vascular/efeitos dos fármacos , Glicoproteínas/sangue , Humanos , Osteoprotegerina , RNA Mensageiro/genética , Receptores Citoplasmáticos e Nucleares/sangue , Receptores do Fator de Necrose Tumoral/sangue , Valores de Referência , Fator de Necrose Tumoral alfa/farmacologia , Veias Umbilicais
6.
Phys Rev E Stat Nonlin Soft Matter Phys ; 68(1 Pt 2): 016307, 2003 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-12935246

RESUMO

It is pointed out that for the case of (compressible) magnetohydrodynamics (MHD) with the fields v(y)(y,t) and Bx(y,t), one can have equations of the Burgers type which are integrable. We discuss the solutions. It turns out that the propagation of the nonlinear effects is governed by the initial velocity (as in Burgers case) as well as by the initial Alfvén velocity. Many results previously obtained for the Burgers equation can be transferred to the MHD case. We also discuss equipartition v(y)=+/-Bx. It is shown that an initial localized small scale magnetic field will end up in fields moving to the left and the right, thus transporting energy from smaller to larger distances.

7.
Exp Eye Res ; 74(2): 217-29, 2002 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-11950232

RESUMO

The protein-bound chromophores, which increase with aging in the human lens, act as UVA sensitizers, producing almost exclusively singlet oxygen in vitro. Direct irradiation of whole, aged human lenses with high intensity UVA light (200 mW cm(-2) for 24 hr), however, failed to produce singlet oxygen damage, as evidenced by the lack of either His or Trp photodestruction. Total homogenates of human lenses prepared in a cuvette under air did show destruction of His and Trp residues by UVA light, but no destruction was seen when equivalent homogenates were prepared under argon. These data are consistent with the idea that the low oxygen levels in the lens prevent singlet oxygen damage in vivo.UVA irradiation of aged human lenses in culture caused an extensive photobleaching of the yellow chromophores. A time course indicated that the photobleaching increased with time, with significant color loss apparent after 6 hr. Homogenization of the irradiated and dark control lenses in 6 M guanidine-HCl, followed by determination of the difference spectrum, showed approximately 50% bleaching of compounds with a lambda(max) at 355 nm. Similarly, fluorophores with a lambda(max) for excitation of 355 nm and for emission of 420 nm were 50% destroyed by the UVA light. Similar results were obtained in vitro by the anaerobic irradiation of a sonication-solubilized WI fraction from type II brunescent cataracts and from aged human lenses. In this system, there was an initial bleaching of 15% after 30 min of irradiation, followed by a slow increase over the next 6 hr to a final bleaching of 30%. The addition of 1.0 m M ascorbic acid, but not 1.0 m M glutathione (GSH), increased the photobleaching to 60% under argon, and the loss of ascorbate could be detected under these anaerobic conditions. In the presence of air, UVA light produced no photobleaching, but rather caused a three-fold increase in absorbance at 345 nm, which was prevented by the inclusion of 1.0 m M ascorbic acid and almost 50% inhibited by 1.0 m M GSH. The data are consistent with the conversion of the triplet state of the sensitizers to anion and cation radicals in the absence of oxygen. Photobleaching may occur either by dismutation of the anion radical or by reduction of the anion radical by ascorbate via type I chemistry. UVA irradiation of an enriched fraction of sensitizers from a proteolytic digest from type II cataract lenses produced a 63% bleaching at 330 nm in the absence of oxygen, and the almost complete loss of the A(330) absorbing and 350/450 nm fluorescent peaks upon HPLC separation. This loss correlated with the loss of the ability of the irradiated fraction to produce singlet oxygen in vitro upon subsequent UVA irradiation.


Assuntos
Cristalino/metabolismo , Oxigênio/metabolismo , Pigmentos Biológicos/efeitos da radiação , Raios Ultravioleta/efeitos adversos , Idoso , Ácido Ascórbico/farmacologia , Catarata/metabolismo , Cromatografia Líquida de Alta Pressão , Técnicas de Cultura , Humanos , Pessoa de Meia-Idade
8.
Curr Opin Drug Discov Devel ; 4(4): 471-8, 2001 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-11727312

RESUMO

It is now half a century since Friedman introduced the term bioisosterism for the similar biological activity of structurally related compounds. Since then, the concept has been used extensively and successfully in the optimization of lead compounds in drug discovery. The number of chemical lead compounds has expanded enormously in recent years due to the expression of an increasing number of recombinant proteins, and the screening of these new protein targets against a large number of compounds in high-throughput screens. For the fine-tuning of lead compounds to obtain candidates suitable for clinical trials, which is in most circumstances still a tedious process, the use of bioisosteric replacement can be of significant value. This is especially the case in optimizing for selectivity for a specific target and in improving the pharmacokinetic properties of lead compounds. The use of bioisosteres in lead optimization is illustrated by some recent examples from the literature.


Assuntos
Desenho de Fármacos , Animais , Humanos , Conformação Molecular , Estereoisomerismo
9.
Biochem J ; 360(Pt 2): 363-70, 2001 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-11716764

RESUMO

The expression of monocyte adhesion molecules, such as VCAM-1 (vascular cell adhesion molecule-1) and E-selectin, on the surface of the endothelium is an important step in the initiation and progression of atherosclerotic lesions. We hypothesized that the inhibition of 3-hydroxy-3-methylglutaryl-CoA (HMG-CoA) reductase in endothelial cells could influence the expression of VCAM-1 and E-selectin. Using cultured human umbilical vein endothelial cells, we found that mevastatin (0.1-1 microM) significantly reduced the expression of VCAM-1 protein in cells activated by tumour necrosis factor-alpha (TNF-alpha) for 7 h. In contrast, TNF-alpha-induced E-selectin protein expression was augmented after mevastatin treatment. Mevastatin inhibited the mRNA expression of both VCAM-1 and E-selectin in TNF-alpha-stimulated endothelial cells. The activity of the transcription factor nuclear factor-kappa B, which is known to regulate the transcription of VCAM-1 and E-selectin, was significantly reduced after incubation with mevastatin. Analysis of the time-dependent variation in the TNF-alpha-induced expression of E-selectin, and estimation of the rate of surface disappearance of E-selectin together with measurement of the amounts of E-selectin molecules secreted, indicated that mevastatin inhibited the surface removal of E-selectin. This is compatible with the observed increase in E-selectin expression after statin treatment. All observed effects of mevastatin were reversed by mevalonate, the product of the HMG-CoA reductase reaction. In conclusion, inhibition of HMG-CoA reductase in endothelial cells attenuates VCAM-1 expression, but increases E-selectin expression, after cytokine induction. These diverse effects are associated with changes in the transcriptional regulation of the two adhesion molecule genes and modulation of the surface removal of E-selectin.


Assuntos
Selectina E/biossíntese , Endotélio Vascular/metabolismo , Hidroximetilglutaril-CoA Redutases/metabolismo , Inibidores de Hidroximetilglutaril-CoA Redutases/farmacologia , Lovastatina/análogos & derivados , Molécula 1 de Adesão de Célula Vascular/biossíntese , Membrana Celular/efeitos dos fármacos , Membrana Celular/enzimologia , Membrana Celular/metabolismo , Células Cultivadas , Citocinas/antagonistas & inibidores , Citocinas/farmacologia , Selectina E/genética , Selectina E/metabolismo , Endotélio Vascular/enzimologia , Meia-Vida , Humanos , Hidroximetilglutaril-CoA Redutases/fisiologia , Lovastatina/farmacologia , Proteínas de Membrana/antagonistas & inibidores , Proteínas de Membrana/metabolismo , Ácido Mevalônico/farmacologia , NF-kappa B/antagonistas & inibidores , NF-kappa B/metabolismo , RNA Mensageiro/antagonistas & inibidores , RNA Mensageiro/biossíntese , Fatores de Tempo , Fator de Necrose Tumoral alfa/antagonistas & inibidores , Fator de Necrose Tumoral alfa/farmacologia , Molécula 1 de Adesão de Célula Vascular/genética , Molécula 1 de Adesão de Célula Vascular/metabolismo
10.
Coron Artery Dis ; 12(4): 285-93, 2001 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-11428537

RESUMO

BACKGROUND: Vascular remodeling is the major cause of restenosis after coronary balloon angioplasty but the pathophysiology of this process is not known. OBJECTIVE: To examine the time courses of vascular remodeling, formation of neointima and adventitial changes after coronary angioplasty. DESIGN: An experimental study on pigs using coronary angiography, intravascular ultrasound (IVUS), and histology. METHODS: Deep vessel-wall injury was induced by conventional balloon angioplasty in the circumflex and right coronary arteries, and by retraction of a chain-encircled balloon in the left anterior descending artery. Angiography in all three arteries and IVUS measurements in circumflex and left anterior descending arteries were performed before and after angioplasty, and at follow-up on days 0, 1, 4, 7, 14, 28, and 56 (n = 5 in each group). Serial IVUS measurements were used to determine vascular remodeling. Formation of neointima and neoadventitia was measured by histomorphometry. RESULTS: Angiographically evident loss of lumen and ultrasonographically detectable constrictive remodeling occurred between day 7 and day 28. IVUS measurements showed that late loss of lumen (days 28 and 56) was correlated to vascular remodeling but not to the increase in wall area (neointima plus media). Histomorphometry revealed that neointima was present from day 7 and that amount of neointima increased up to day 28. Area of adventitia increased during the first 4 days and remained unchanged thereafter. Adventitial neovascularization by vasa vasorum was observed from day 4 onward. CONCLUSIONS: Formation of neoadventitia precedes late loss of lumen, constrictive remodeling, and formation of neointima. The time course of vascular remodeling coincides with growth of neointima rather than with changes in the adventitia.


Assuntos
Angioplastia Coronária com Balão , Doença da Artéria Coronariana/terapia , Vasos Coronários/fisiologia , Endotélio Vascular/fisiologia , Animais , Doença da Artéria Coronariana/diagnóstico por imagem , Doença da Artéria Coronariana/fisiopatologia , Modelos Animais de Doenças , Suínos , Fatores de Tempo , Túnica Íntima/fisiologia , Ultrassonografia
11.
J Comput Aided Mol Des ; 15(3): 247-58, 2001 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-11289078

RESUMO

A study of a series of compounds with agonistic effect at the alpha4beta2 nicotinic acetylcholine receptors resulted in an improved pharmacophore model as well as a CoMFA model. The pharmacophore was composed of three pharmacophoric elements: (1) a site point (a) corresponding to a protonated nitrogen atom, (2) a site point (b) corresponding to an electronegative atom capable of forming a hydrogen bond, and (3) the centre of a heteroaromatic ring or a C=O bond (c). The pharmacophoric elements were related by the following parameters: (a-b) 7.3-8.0 A, (a-c) 6.5-7.4 A, and the angle between the two distance vectors (delta bac) 30.4-35.8 degrees. In addition to this, a stereoselective CoMFA model was developed, which showed good predictability even for compound classes not present in the training set.


Assuntos
Agonistas Nicotínicos/química , Agonistas Nicotínicos/farmacologia , Receptores Colinérgicos/efeitos dos fármacos , Animais , Carbacol/análogos & derivados , Carbacol/metabolismo , Córtex Cerebral/metabolismo , Desenho Assistido por Computador , Desenho de Fármacos , Técnicas In Vitro , Modelos Químicos , Relação Quantitativa Estrutura-Atividade , Ratos , Receptores Colinérgicos/metabolismo , Estereoisomerismo , Trítio
12.
Curr Med Chem ; 8(6): 651-74, 2001 May.
Artigo em Inglês | MEDLINE | ID: mdl-11281847

RESUMO

Agonists of the alpha4beta2 nicotinic acetylcholine receptors have been synthesised as potential drugs for treatment of a variety of diseases. In this review, the published nicotinic agonists are presented and, on the basis of the molecular structure, the compounds are divided into three compound classes, nicotinoids (structurally close to nicotine), bicyclic compounds (structurally close to epibatidine and anatoxin-a), and analogues of imidacloprid (structurally close to the insecticide imidacloprid). The structure-activity relationships are discussed within and in between the classes. On the basis of computational studies of ligands for the nicotinic acetylcholine receptors the structure-activity relationships are discussed and a possible binding mode suggested. The binding mode encompasses: (A) an interaction between an anionic site in the receptor and the protonated nitrogen atom in the ligand, (B) a hydrogen bond between a hydrogen bond donor in the receptor and a hydrogen bond acceptor in the ligand, (C) an interaction between a pi-system (heteroaromatic ring, carbonyl bond) in the ligand and another pi-system or a positively charged amino acid residue in the binding site, (D) a pi-cation interaction between aromatic residues in the receptor binding site and the protonated nitrogen atom in the ligand, and (E) steric interactions of positive and negative character around the aliphatic and the heteroaromatic part of the ligand.


Assuntos
Nicotina/análogos & derivados , Agonistas Nicotínicos/farmacologia , Receptores Nicotínicos/efeitos dos fármacos , Animais , Humanos , Modelos Moleculares , Nicotina/farmacologia , Agonistas Nicotínicos/química , Agonistas Nicotínicos/metabolismo , Receptores Nicotínicos/química , Receptores Nicotínicos/metabolismo , Relação Estrutura-Atividade
13.
Coron Artery Dis ; 12(1): 53-9, 2001 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-11211166

RESUMO

BACKGROUND: Coronary angioscopy has been reported to be superior to angiography and intravascular ultrasound for detecting intracoronary thrombus. However, in-vivo histopathologic validation of angioscopic detection of intracoronary thrombus had not been performed. OBJECTIVE: To perform histopathologic validation of in-vivo angioscopic detection of coronary thrombus. DESIGN: An experimental, blinded comparison of angioscopy and histopathology. METHODS: Coronary angioscopy was performed from 0 to 14 days after angioplasty in 39 porcine coronary arteries. When thrombus was detected by angioscopy, it was subclassified into white, mixed red-white, or red thrombus according to color. By histopathology the presence of thrombus was determined and subclassified into platelet-rich, mixed platelet-erythrocyte, or erythrocyte-rich thrombus. RESULTS: Angioscopy correctly classified 19 of 21 coronary thrombi (sensitivity 90%) but incorrectly classified nine of 18 arteries without formation of thrombus as having a thrombus (specificity 50%). Positive and negative predictive values were 68 and 82%, respectively. The angioscopic subclassification of thrombus into white, mixed red-white, or red thrombi was not correlated to the corresponding histopathologic morphology (platelet-rich, mixed platelet-erythrocyte, or erythrocyte-rich) of the observed thrombi (chi2 test: P = 0.5). CONCLUSIONS: Angioscopic detection of thrombus in vivo had high sensitivity and negative predictive value but low-to-moderate specificity and positive predictive value. Visual assessment of color of angioscopically detected thrombi seemed not to reflect histopathologic morphology of thrombus according to the definitions used in the present study.


Assuntos
Angioplastia com Balão , Angioscopia , Trombose Coronária/diagnóstico , Trombose Coronária/terapia , Animais , Trombose Coronária/patologia , Valor Preditivo dos Testes , Sensibilidade e Especificidade , Suínos
14.
Bioorg Med Chem ; 8(6): 1443-50, 2000 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-10896121

RESUMO

Bioisosteric replacement of the isoxazole heterocycle in (3-methyl-5-isoxazolyl)methylene-azacyclic compounds with pyridine, oxadiazole, or an acyl group resulted in ligands with high to moderate affinity for the central nicotinic cholinergic receptors (IC50 = 2.0 to IC50 > 1000 nM) labeled by [3H]methylcarbamylcholine. Additionally, further support of an important distance parameter for high-affinity nicotinic compounds has been provided.


Assuntos
Compostos Aza/síntese química , Compostos Bicíclicos com Pontes/síntese química , Receptores Nicotínicos/efeitos dos fármacos , Compostos Aza/química , Compostos Aza/farmacologia , Compostos Bicíclicos com Pontes/química , Compostos Bicíclicos com Pontes/farmacologia , Espectroscopia de Ressonância Magnética , Espectrometria de Massas
15.
Meat Sci ; 56(4): 357-68, 2000 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-22062166

RESUMO

The influence of the yeast starter cultures Debaryomyces hansenii and Candida utilis on fermented meat aroma was studied in model minces and in commercial-type fermented sausages. Volatile compounds from model minces and sausages were collected using diffusive and dynamic headspace sampling respectively and were identified by gas chromatography/mass spectrometry (GC/MS). A triangle test was carried out on the sausages to detect whether the yeast influenced the sausage odour. C. utilis demonstrated high metabolic activity in the model minces, producing several volatile compounds, in particularly esters. C. utilis also seemed to ferment the amino acids valine, isoleucine and leucine into compounds important for the aroma of sausages. D. hansenii on the contrary, had very little effect on the production of volatile compounds in the model minces. In the sausage experiment both yeast cultures died out before the ripening process ended and the sensory analysis showed only a slight difference between the sausages. A fungistatic test of the garlic powder added to the sausages indicated that garlic inhibits the growth of the yeast starter cultures.

16.
J Med Chem ; 42(24): 4970-80, 1999 Dec 02.
Artigo em Inglês | MEDLINE | ID: mdl-10585207

RESUMO

A series of (isoxazole)methylene-1-azacyclic compounds was prepared. The compounds were tested for affinity to central nicotinic acetylcholine receptors (nAChRs) and central muscarinic receptors. The compounds covered a broad range of affinities for the nAChRs (IC(50) = 0.32 to >1000 nM), with selectivities for the nAChRs over the muscarinic receptors in the range of 3-183. The high-affinity compound (Z)-26 (3-(4-methyl-5-isoxazolyl)methylene-1-azabicyclo[2.2. 2]octane, IC(50) = 3.2 nM) having only one energy minimum was used as the reference structure in a computational study. This ligand has enabled definition of an important distance parameter, and the existence of this parameter was supported by showing that other potent nicotinic ligands (for example, nicotine and epibatidine) fit the model.


Assuntos
Isoxazóis/síntese química , Modelos Moleculares , Nicotina/química , Quinuclidinas/síntese química , Relação Estrutura-Atividade , Animais , Córtex Cerebral/metabolismo , Fenômenos Químicos , Físico-Química , Ligação de Hidrogênio , Isoxazóis/metabolismo , Masculino , Conformação Molecular , Estrutura Molecular , Nicotina/metabolismo , Nitrogênio/química , Quinuclidinas/metabolismo , Ratos , Ratos Wistar , Receptores Muscarínicos/metabolismo , Receptores Nicotínicos/metabolismo , Eletricidade Estática , Termodinâmica
17.
J Med Chem ; 42(11): 1999-2006, 1999 Jun 03.
Artigo em Inglês | MEDLINE | ID: mdl-10354408

RESUMO

Two new series of 1-(1,2,5-thiadiazol-4-yl)-4-azatricyclo[2.2.1.0(2, 6)]heptanes were synthesized and evaluated for their in vitro activity in cell lines transfected with either the human M1 or M2 receptor. 3-Phenyl-2-propyn-1-yloxy and -1-ylthio analogues substituted with halogen in the meta position showed high functional potency, efficacy, and selectivity toward the M1 receptor subtype. A quite unique functional M1 receptor selectivity was observed for compounds 8b, 8d, 8f, 9b, 9d, and 9f. Bioavailability studies in rats indicated an oral bioavailability of about 20-30%, with the N-oxide as the only detected metabolite.


Assuntos
Compostos Aza/química , Heptanos/química , Agonistas Muscarínicos/química , Receptores Muscarínicos/efeitos dos fármacos , Tiadiazóis/química , Animais , Compostos Aza/síntese química , Compostos Aza/farmacocinética , Compostos Aza/farmacologia , Ligação Competitiva , Disponibilidade Biológica , Células CHO , Linhagem Celular , Córtex Cerebral/metabolismo , Cricetinae , AMP Cíclico/biossíntese , Heptanos/síntese química , Heptanos/farmacocinética , Heptanos/farmacologia , Humanos , Hidrólise , Técnicas In Vitro , Camundongos , Agonistas Muscarínicos/síntese química , Agonistas Muscarínicos/farmacocinética , Agonistas Muscarínicos/farmacologia , Fosfatidilinositóis/metabolismo , Ensaio Radioligante , Ratos , Receptor Muscarínico M1 , Receptor Muscarínico M2 , Receptores Muscarínicos/metabolismo , Relação Estrutura-Atividade , Tiadiazóis/síntese química , Tiadiazóis/farmacocinética , Tiadiazóis/farmacologia , Transfecção
18.
Life Sci ; 64(6-7): 527-34, 1999.
Artigo em Inglês | MEDLINE | ID: mdl-10069519

RESUMO

The role of muscarinic receptors in schizophrenia was investigated using the muscarinic agonist PTAC. PTAC was highly selective for muscarinic receptors, was a partial agonist at muscarinic M2/M4 receptors and an antagonist at M1, M3 and M5 receptors. PTAC was highly active in animal models predictive of antipsychotic behavior including inhibition of conditioned avoidance responding in rats and blockade of apomorphine-induced climbing behavior in mice. d-Amphetamine-induced Fos expression in rat nucleus accumbens was inhibited by PTAC, thus directly demonstrating the ability of PTAC to modulate DA activity. In electrophysiological studies in rats, PTAC acutely inhibited the firing of A10 DA cells and after chronic administration decreased the number of spontaneously firing DA cells in the A10 brain area. However, PTAC did not appreciably alter the firing of A9 DA cells. Thus, PTAC appears to have novel antipsychotic-like activity and these data suggest that muscarinic compounds such as PTAC may represent a new class of antipsychotic agents.


Assuntos
Antipsicóticos/farmacologia , Compostos Bicíclicos com Pontes/farmacologia , Receptores Muscarínicos/fisiologia , Esquizofrenia/tratamento farmacológico , Tiadiazóis/farmacologia , Animais , Antipsicóticos/administração & dosagem , Antipsicóticos/metabolismo , Antipsicóticos/uso terapêutico , Comportamento Animal/efeitos dos fármacos , Ligação Competitiva , Compostos Bicíclicos com Pontes/administração & dosagem , Compostos Bicíclicos com Pontes/metabolismo , Compostos Bicíclicos com Pontes/uso terapêutico , Células CHO , Catalepsia/induzido quimicamente , Cricetinae , Dopamina/metabolismo , Dopaminérgicos/farmacologia , Relação Dose-Resposta a Droga , Eletrofisiologia , Agonistas Muscarínicos/farmacologia , Antagonistas Muscarínicos/farmacologia , Neurônios/efeitos dos fármacos , Neurônios/fisiologia , Proteínas Proto-Oncogênicas c-fos/metabolismo , Ratos , Receptores Muscarínicos/metabolismo , Esquizofrenia/fisiopatologia , Sistemas do Segundo Mensageiro/efeitos dos fármacos , Tiadiazóis/administração & dosagem , Tiadiazóis/metabolismo , Tiadiazóis/uso terapêutico
19.
Cardiovasc Pathol ; 8(3): 123-31, 1999.
Artigo em Inglês | MEDLINE | ID: mdl-10722234

RESUMO

Thrombus organization has been suggested to play a major role in late neointimal formation after coronary angioplasty. We sought to describe the time sequence of lesion formation after angioplasty in porcine coronary arteries and to quantify the relation between early thrombosis and late neointimal formation. Deep vessel wall injury was induced by conventional balloon angioplasty in the circumflex (CX) and right coronary (RCA) arteries and by retraction of a chain-encircled balloon in the left anterior descendent artery (LAD). Lesions were assessed by histomorphometry at days 0, 1, 4, 7, 14, 28, and 56 after angioplasty. A response-to-injury index (lesion area/injury length) was determined for each artery. Angioplasty led to rupture/removal of media. Thrombus was present at the exposed adventitia at days 0, 1, and 4. From day 7, neointima was observed on the luminal side of the arterial wall. All thrombus had disappeared at day 28, at which only neointima was observed. Histomorphometry revealed that lesion formation after angioplasty was a gradually increasing process from day 0 to day 28 with no further growth from day 28 to day 56. Maximal thrombus size (day 4, RCA: 0.07+/-0.04 mm, CX: 0.23+/-0.16 mm, LAD: 0.15+/-0.11 mm) was significantly smaller than late neointimal formation (day 28, RCA: 0.68+/-0.18 mm, CX: 0.63+/-0.23 mm, LAD: 0.71+/-0.18 mm) in all three arteries (p < .03). Lesion formation after angioplasty is a gradually increasing process for 4 weeks. Maximal thrombus size is about four times smaller than late neointimal formation. Thus, thrombus organization plays no major role in late neointimal formation.


Assuntos
Angioplastia Coronária com Balão/efeitos adversos , Trombose Coronária/patologia , Vasos Coronários/patologia , Túnica Íntima/patologia , Animais , Trombose Coronária/etiologia , Vasos Coronários/lesões , Modelos Animais de Doenças , Ruptura , Suínos , Túnica Íntima/lesões , Tempo de Coagulação do Sangue Total
20.
Bioorg Med Chem ; 6(9): 1623-9, 1998 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-9801833

RESUMO

A novel class of central nicotinic acetylcholine receptor ligands, 3-(5-alkylamino-4-isoxazolyl)-1,2,5,6-tetrahydropyridine 4a-f, was synthesized. Several of the compounds showed high affinity for central nicotinic receptors (4c: IC50 = 50 nM), with more than a 100-fold selectivity for nicotinic over muscarinic receptors. The compounds showed up to a 10-fold selectivity for the central nicotinic subtype combination alpha 4 beta 2 (4c: IC50 = 4.6 nM), as compared to the major ganglionic subtype composed of alpha 3 containing subunits (4c: IC50 = 48 nM). The compounds were further evaluated in a dopamine release assay in vitro, and in a drug discrimination assay in vivo. Compound 4a is an effective nicotinic agonist with a potency 50-100 times lower than nicotine. Extending the alkylamino chain beyond one, compound (4b-f), changed the pharmacological profile of the compounds in an antagonistic direction.


Assuntos
Piridinas/metabolismo , Receptores Nicotínicos/metabolismo , Animais , Córtex Cerebral/metabolismo , Técnicas In Vitro , Ligantes , Espectroscopia de Ressonância Magnética , Masculino , Espectrometria de Massas , Ratos , Ratos Wistar , Spodoptera
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