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1.
Scand J Med Sci Sports ; 34(1): e14553, 2024 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-38268074

RESUMO

Low energy availability (LEA) is a health concern for athletes, although it may paradoxically lead to improved cardiometabolic health in the general population. We investigated the associations between LEA, body composition, and serum cardiometabolic profile in 23 physique athletes (DIET) and 21 controls (CONT) during a 5-month pre-competition diet (MID), followed by 1 week of increased energy availability (COMP) and a 5-month weight regain period (POST). Quantification of 250 serum metabolome variables was conducted by NMR spectroscopy, body composition by dual-energy x-ray absorptiometry, dietary intake by food diaries, and exercise levels by training logs. Body fat percentage decreased from 19.5 ± 7.0% to 8.3 ± 5.3% (p < 0.001) in DIET through increased exercise levels and decreased energy intake, while CONT maintained those constant. In MID, DIET had increased (FDR < 0.01) HDL cholesterol, HDL particle size and number, and decreased (FDR < 0.05) VLDL lipids, serum triglycerides, and low-grade inflammation (glycoprotein acetyls) compared to baseline and CONT. The changes were associated with reduced android fat mass (-78 ± 13%) and energy intake (-28 ± 10%). In COMP, most of the metabolic changes found in MID persisted, except for altered triglycerides in all lipoprotein classes. After weight regain in POST, serum metabolome, body composition, energy intake, and exercise levels had reverted to baseline levels. In conclusion, fat loss and LEA may have beneficial yet transient effects on the serum cardiometabolic profile of lean individuals. Especially the HDL lipidome and lipoprotein triglycerides offer potential novel biomarkers for detecting LEA in athletes.


Assuntos
Atletas , Doenças Cardiovasculares , Humanos , HDL-Colesterol , Triglicerídeos , Aumento de Peso
2.
Phys Rev Lett ; 118(24): 242002, 2017 Jun 16.
Artigo em Inglês | MEDLINE | ID: mdl-28665642

RESUMO

We report the first beam-target double-polarization asymmetries in the γ+n(p)→π^{-}+p(p) reaction spanning the nucleon resonance region from invariant mass W=1500 to 2300 MeV. Circularly polarized photons and longitudinally polarized deuterons in solid hydrogen deuteride (HD) have been used with the CEBAF Large Acceptance Spectrometer (CLAS) at Jefferson Lab. The exclusive final state has been extracted using three very different analyses that show excellent agreement, and these have been used to deduce the E polarization observable for an effective neutron target. These results have been incorporated into new partial wave analyses and have led to significant revisions for several γnN^{*} resonance photocouplings.

3.
Oecologia ; 184(2): 317-326, 2017 06.
Artigo em Inglês | MEDLINE | ID: mdl-28584941

RESUMO

Amino acid nitrogen isotopic analysis is a relatively new method for estimating trophic position. It uses the isotopic difference between an individual's 'trophic' and 'source' amino acids to determine its trophic position. So far, there is no accepted explanation for the mechanism by which the isotopic signals in 'trophic' and 'source' amino acids arise. Yet without a metabolic understanding, the utility of nitrogen isotopic analyses as a method for probing trophic relations, at either bulk tissue or amino acid level, is limited. I draw on isotopic tracer studies of protein metabolism, together with a consideration of amino acid metabolic pathways, to suggest that the 'trophic'/'source' groupings have a fundamental metabolic origin, to do with the cycling of amino-nitrogen between amino acids. 'Trophic' amino acids are those whose amino-nitrogens are interchangeable, part of a metabolic amino-nitrogen pool, and 'source' amino acids are those whose amino-nitrogens are not interchangeable with the metabolic pool. Nitrogen isotopic values of 'trophic' amino acids will reflect an averaged isotopic signal of all such dietary amino acids, offset by the integrated effect of isotopic fractionation from nitrogen cycling, and modulated by metabolic and physiological effects. Isotopic values of 'source' amino acids will be more closely linked to those of equivalent dietary amino acids, but also modulated by metabolism and physiology. The complexity of nitrogen cycling suggests that a single identifiable value for 'trophic discrimination factors' is unlikely to exist. Greater consideration of physiology and metabolism should help in better understanding observed patterns in nitrogen isotopic values.


Assuntos
Aminoácidos , Cadeia Alimentar , Isótopos de Nitrogênio , Animais , Isótopos de Carbono , Dieta , Nitrogênio , Estado Nutricional , Proteínas/metabolismo
4.
Emerg Radiol ; 22(2): 117-23, 2015 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-24993583

RESUMO

Increased use of CT Pulmonary angiography in suspected pulmonary embolism (PE) has driven research to minimize radiation dose while maintaining image quality and diagnostic accuracy. Following institutional review board approval, we performed a retrospective comparison study in patients with suspected PE. Patients were scanned using an ultra high pitch dual source technique (pitch = 2.6) using 120 kV (SVCTPA) (n = 54) or 100 kV (RV-CTPA) (n = 52). SV-CTPA images were reconstructed using filtered back projection (SV-wFBP) and RV-CTPA images were reconstructed using both FBP (RV-wFBP) and Iterative Reconstruction (RV-IR). Comparison of radiation dose, diagnostic ability, subjective image noise, quality, and sharpness, diagnostic agreement, signal to noise (SNR) and contrast to noise ratios (CNR) were performed. Mean effective dose was 2.56 ± 0.19 mSv for the RV protocol compared to 5.36 ± 0.60 mSv for the SV. The RV-CTPA protocol resulted in a mean DLP reduction of 52 % and mean CTDI reduction of 51 %. Pulmonary artery SNR and CNR were significantly higher on RV-IR images than SV-wFBP (p = 0.007, p = 0.003). Mean subjective image noise, quality and sharpness scores did not differ significantly between the SV-wFBP and RVIR images (p > 0.05). Subjective quality scores were significantly better for the RV-IR group compared to the RV-wFBP group (p < 0.001). Agreement between readers for presence or absence of pulmonary emboli on RV-IR images was almost perfect (κ = 0.891, p < 0.001). Iterative reconstruction complements ultra high pitch dual source CTPA examinations acquired using a reduced voltage resulting in higher mean pulmonary artery SNR and CNR when compared to both RV-wFBP and SV-CTPA.


Assuntos
Angiografia/métodos , Embolia Pulmonar/diagnóstico por imagem , Interpretação de Imagem Radiográfica Assistida por Computador/métodos , Tomografia Computadorizada por Raios X/métodos , Adulto , Idoso , Idoso de 80 Anos ou mais , Meios de Contraste , Feminino , Humanos , Pessoa de Meia-Idade , Artéria Pulmonar/diagnóstico por imagem , Doses de Radiação , Estudos Retrospectivos , Razão Sinal-Ruído , Ácidos Tri-Iodobenzoicos
5.
Am J Phys Anthropol ; 154(4): 535-43, 2014 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-24888560

RESUMO

Patterns of water consumption by past human populations are rarely considered, yet drinking behavior is socially mediated and access to water sources is often socially controlled. Oxygen isotope analysis of archeological human remains is commonly used to identify migrants in the archeological record, but it can also be used to consider water itself, as this technique documents water consumption rather than migration directly. Here, we report an oxygen isotope study of humans and animals from coastal regions of Croatia in the Iron Age, Roman, and Early Medieval periods. The results show that while faunal values have little diachronic variation, the human data vary through time, and there are wide ranges of values within each period. Our interpretation is that this is not solely a result of mobility, but that human behavior can and did lead to human oxygen isotope ratios that are different from that expected from consumption of local precipitation.


Assuntos
Dieta/etnologia , Dieta/história , Ingestão de Líquidos/etnologia , Animais , Croácia/etnologia , História Antiga , História Medieval , Humanos , Isótopos de Oxigênio/análise , Dente/química , Abastecimento de Água/história
6.
Sci Rep ; 14(1): 158, 2024 01 02.
Artigo em Inglês | MEDLINE | ID: mdl-38168495

RESUMO

Movement of resources was essential to the survival and success of early complex societies. The sources and destinations of goods and the means of transportation - be it by boats, carts and/or foot - can often be inferred, but the logistics of these movements are inherently more difficult to ascertain. Here, we use strontium isotopic analysis to test hypotheses about the role of animal and animal-powered transport in medium and long-distance movement and exchange, using the Indus Civilization as a case study. Across the wide geographical spread of the Indus Civilisation, there is strong evidence for long-distance exchange of raw materials and finished objects and this process is presumed to involve boats and animal-driven transport, although there is little evidence as to the relative importance of each mode of movement. Strontium isotopic analysis of animal remains from four sites analysed for this study combined with results from nine other sites indicates limited long-distance animal movement between different geological zones within the Indus Civilisation. These findings suggest that individual animals primarily moved short- or medium-distances, though there are several significant exceptions seen in some pigs and cattle found at two large urban sites. We infer that long-distance transport of goods, be it raw materials, finished objects, other goods, or the animals themselves, could have occurred through the use of boats and waterways, by traction animals moving over long distances that did not end up in the archaeological record, and/or by different animals participating in many short to medium-distance movements.


Assuntos
Casco e Garras , Animais , Bovinos , Suínos , Isótopos de Estrôncio , Arqueologia , Meios de Transporte , Civilização , Movimento
7.
Occup Med (Lond) ; 63(5): 365-8, 2013 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-23703780

RESUMO

BACKGROUND: Long-term sickness absence can have negative consequences for individuals and for their employers. Occupational health has an important role in assisting workplace rehabilitation in such cases. AIMS: To investigate long-term sickness absence referrals in the Irish Civil Service in terms of epidemiological profile, illness categories and eventual outcomes. METHODS: A retrospective review of consecutive new long-term sickness absence cases referred between January 2008 and April 2008 and followed up to July 2010, using review of electronic and paper medical records and personnel department data to establish case outcomes. RESULTS: Three hundred and one cases were available for analysis. There were more long-term sickness absence cases among older employees, with female employees and clerical officer grades more likely to be referred. The principal diagnostic groups were mental health issues (30%), musculoskeletal disorders (13%) and cancer (11%). The eventual outcomes were the following: return to work (83%) and ill-health retirement (8%); 2% were still on sick leave and the remaining 7% had left civil service employment for other reasons at the end of the study period. CONCLUSIONS: The final outcome in a large majority of case referrals was to resume work, with only a small proportion retiring on ill-health grounds. Mental health disorders, musculoskeletal disorders and cancers were the principal reasons for absence.


Assuntos
Transtornos Mentais/epidemiologia , Doenças Musculoesqueléticas/epidemiologia , Neoplasias/epidemiologia , Saúde Ocupacional , Ocupações , Retorno ao Trabalho/estatística & dados numéricos , Licença Médica/estatística & dados numéricos , Feminino , Humanos , Irlanda/epidemiologia , Masculino , Transtornos Mentais/reabilitação , Pessoa de Meia-Idade , Doenças Musculoesqueléticas/reabilitação , Neoplasias/reabilitação , Saúde Ocupacional/estatística & dados numéricos , Serviços de Saúde do Trabalhador , Encaminhamento e Consulta , Aposentadoria , Estudos Retrospectivos , Fatores de Tempo , Local de Trabalho
8.
Am J Phys Anthropol ; 148(4): 543-56, 2012 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-22552855

RESUMO

Food is well-known to encode social and cultural values, for example different social groups use different consumption patterns to act as social boundaries. When societies and cultures change, whether through drift, through population replacement or other factors, diet may also alter despite unchanging resource availability within a region. This study investigates the extent to which dietary change coincides with cultural change, to understand the effects of large-scale migrations on the populations' diets. Through stable carbon and nitrogen isotope analysis of Iron Age, Roman, and Early Medieval human bone collagen, we show that in Croatia large-scale cultural change led to significant changes in diet. The isotopic evidence indicates that Iron Age diet consisted of C(3) foodstuffs with no isotopic evidence for the consumption of C(4) or marine resources. With the Roman conquest, marine resources were added to the diet, although C(3) foodstuffs continued to play an important role. In the Early Medieval period, this marine component was lost and varying amounts of C(4) foodstuffs, probably millet, were added to the otherwise C(3) diet. In both of these transitions it is likely that the changes in diet are related to the arrival of a new people into the area.


Assuntos
Antropologia Física , Evolução Cultural , Dieta/história , Osso e Ossos/química , Isótopos de Carbono/análise , Colágeno Tipo I/química , Croácia/etnologia , Dieta/etnologia , Grão Comestível , História Antiga , História Medieval , Humanos , Isótopos de Nitrogênio/análise , Alimentos Marinhos
9.
Am J Phys Anthropol ; 149(3): 426-34, 2012 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-23042579

RESUMO

The "trophic level enrichment" between diet and body results in an overall increase in nitrogen isotopic values as the food chain is ascended. Quantifying the diet-body Δ(15) N spacing has proved difficult, particularly for humans. The value is usually assumed to be +3-5‰ in the archaeological literature. We report here the first (to our knowledge) data from humans on isotopically known diets, comparing dietary intake and a body tissue sample, that of red blood cells. Samples were taken from 11 subjects on controlled diets for a 30-day period, where the controlled diets were designed to match each individual's habitual diet, thus reducing problems with short-term changes in diet causing isotopic changes in the body pool. The Δ(15) N(diet-RBC) was measured as +3.5‰. Using measured offsets from other studies, we estimate the human Δ(15) N(diet-keratin) as +5.0-5.3‰, which is in good agreement with values derived from the two other studies using individual diet records. We also estimate a value for Δ(15) N(diet-collagen) of ≈6‰, again in combination with measured offsets from other studies. This value is larger than usually assumed in palaeodietary studies, which suggests that the proportion of animal protein in prehistoric human diet may have often been overestimated in isotopic studies of palaeodiet.


Assuntos
Antropologia Física , Dieta , Eritrócitos/química , Isótopos de Nitrogênio/análise , Adulto , Idoso , Biomarcadores/sangue , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Isótopos de Nitrogênio/metabolismo , Estatísticas não Paramétricas
10.
Bone ; 137: 115374, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32330695

RESUMO

Taurine has been shown to have positive effects on bone mass, which are thought to be due in part to its cytoprotective effects on osteoblasts and here we show that taurine also protects osteocytes against cell death due to reactive oxygen species. Using the IDG-SW3 cell line, the expression of the taurine uptake transporter Taut/Slc6a6 is increased during osteoblast to osteocyte differentiation. Taurine had no effect on genes associated with osteoblast to osteocyte differentiation such as Dmp1, Phex or osteocalcin, even at high doses, but a slight yet significant inhibition of alkaline phosphatase was observed at the highest dose (50 mM). No effect was seen on the osteoclast regulatory genes Rankl and Opg, however the wnt antagonist Sost/sclerostin was potently and dose-dependently downregulated in response to taurine supplementation. Taurine also significantly inhibited Dkk1 mRNA expression, but only at 50 mM. Interestingly, osteocytes were found to also be able to synthesize taurine intracellularly, potentially as a self-protective mechanism, but do not secrete the metabolite. A highly significant increase in the expression of cysteine dioxygenase (Cdo), a key enzyme necessary for the production of taurine, was observed with osteoblast to osteocyte differentiation along with a decrease in methionine, the precursor of taurine. For the first time, we describe the synthesis of taurine by osteocytes, potentially to preserve viability and to regulate bone formation through inhibition of sclerostin.


Assuntos
Osteócitos , Via de Sinalização Wnt , Morte Celular , Diferenciação Celular , Osteoblastos , Estresse Oxidativo , Taurina/farmacologia
11.
J Cell Biol ; 104(2): 263-75, 1987 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-3543023

RESUMO

Human mesothelial cells, endothelial cells, and type II kidney epithelial cells growing in culture devote approximately 3% of their total protein synthesis to the production of an Mr approximately 46-kD, pI 7.1, secreted glycoprotein (designated Sp46). Fibroblasts make about 1/10th as much Sp46 as these cell types, and their synthesis is dependent upon hydrocortisone. Keratinocytes, urothelial cells, conjunctival epithelial cells, and mammary epithelial cells do not make detectable amounts of Sp46. Mesothelial cells secrete Sp46 onto the substratum, and from there it is subsequently released into the medium. Immunofluorescence analysis using specific antisera discloses that Sp46 is deposited beneath cells as a fine coating on the substratum. In sparse cultures, Sp46 is detected in trails behind motile cells. In contrast, secreted fibronectin coalesces into fibers, most of which remain in contact with and on top of the cells; thus Sp46 does not preferentially bind to fibronectin. About 6 kD of the mass of human Sp46 is N-linked oligosaccharide, which is terminally sialated before secretion. Sp46 has a low glycine content, indicating that it is not a collagenlike protein. Its NH2-terminal sequence over the first 40 amino acids does not resemble any protein for which sequence information is available. Sp46 appears to be a novel extracellular glycoprotein, high-level constitutive expression of which is restricted to mesoderm-derived epithelial and endothelial cells. We therefore propose for it the name "mesosecrin."


Assuntos
Endotélio/metabolismo , Glicoproteínas/biossíntese , Rim/metabolismo , Sequência de Aminoácidos , Células Cultivadas , Epitélio/metabolismo , Fibroblastos/metabolismo , Fibronectinas/biossíntese , Imunofluorescência , Glicoproteínas/isolamento & purificação , Humanos , Cinética , Metionina/metabolismo , Peso Molecular , Inibidor 1 de Ativador de Plasminogênio , Radioisótopos de Enxofre
12.
Biochim Biophys Acta ; 1208(1): 171-8, 1994 Sep 21.
Artigo em Inglês | MEDLINE | ID: mdl-8086432

RESUMO

3H-NMR spectroscopy of specifically tritiated and tritiated/deuterated derivatives of tosylchymotrypsin has been used to examine the behavior of the tosyl group in this protein at pH 7. The presence of several tritiated isotopomers complicates analysis of experiments and extensive computer simulations of T1 relaxation, line widths, and various nuclear Overhauser experiments for the collection of tritiated species present in the samples were used to the interpret the observations made. These analyses suggests that the tosyl group of tosylchymotrypsin at pH 7 is largely retained within the substrate specificity pocket observed in the crystal structure. This outcome is in strong contrast to the situation observed at pH 4, where the tosyl group is mobile enough to be found outside the specificity pocket an appreciable fraction of the time, and may be the result of protein association at pH 7.


Assuntos
Quimotripsina/química , Espectroscopia de Ressonância Magnética , Sítios de Ligação , Cristalização , Deutério , Concentração de Íons de Hidrogênio , Especificidade por Substrato , Trítio
13.
J Mol Biol ; 262(2): 283-93, 1996 Sep 20.
Artigo em Inglês | MEDLINE | ID: mdl-8831794

RESUMO

Twisted conformations of two- and three-stranded antiparallel beta-sheet models containing alanine, glycine and valine with three or five residues per strand have been studied by molecular dynamics simulations. Free molecular dynamics and free energy simulations have been carried out to characterize the dynamics and energetics of the conformational change from a flat sheet to a twisted sheet. By altering the charges on the model in the free energy simulations, we have been able to analyze the contributions to the twist from electrostatic and van der Waals interactions. We have found that alanine and valine beta-sheets prefer conformations with a right-handed twist. In contrast, model glycine sheets do not have a pronounced preference to twist. Single beta-strands are found to be easily twisted, but to not have a strong preference for twisted conformations. Hence, the driving forces for the right-handed twist of beta-sheets must come principally from interactions between strands. These results disagree with several previous theoretical studies and constitute a different paradigm of the origin of beta-sheet twist observed in proteins.


Assuntos
Simulação por Computador , Estrutura Secundária de Proteína , Alanina , Entropia , Glicina , Modelos Moleculares , Valina
14.
Endocrinology ; 134(2): 899-905, 1994 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-8299585

RESUMO

In this report, we demonstrate a significant inverse correlation between contractility and serum 1,25-dihydroxyvitamin D3 [1,25-(OH)2D3] levels and no correlation between contractility and serum levels of calcium, phosphate, or PTH. We also examined myosin isozyme distribution in vitamin D3-deficient rats, because myosin isozyme distribution can alter contractility. There was a significant increase in the levels of the V1 myosin isozyme in animals raised on a vitamin D3-deficient diet that maintained normal serum calcium and phosphate levels. There was no difference in the relative myosin isozyme distribution in animals raised on a hypocalcemia-yielding vitamin D3-deficient diet vs. animals raised on a control diet. As increased contractility has been observed in both groups of vitamin D3-deficient animals, a shift in myosin isozyme distribution cannot solely explain the increase in contractility previously observed in the vitamin D3-deficient rat heart. To determine whether 1,25-(OH)2D3 directly regulates myosin isozyme levels, we analyzed myosin isozyme distribution in primary cultures of ventricular myocytes. We found that 1,25-(OH)2D3 reduces total myosin levels, but does not alter myosin isozyme distribution. Thus, we show that the influence of vitamin D3 status on myosin isozyme expression in the intact rat involves a complex regulatory system of direct and indirect effects.


Assuntos
Calcitriol/farmacologia , Regulação da Expressão Gênica/fisiologia , Coração/fisiologia , Isoenzimas/biossíntese , Contração Miocárdica , Miocárdio/metabolismo , Miosinas/biossíntese , Hormônio Paratireóideo/sangue , Deficiência de Vitamina D/metabolismo , Animais , Cálcio/sangue , Cálcio/metabolismo , Células Cultivadas , Regulação da Expressão Gênica/efeitos dos fármacos , Coração/efeitos dos fármacos , Coração/fisiopatologia , Isoenzimas/isolamento & purificação , Masculino , Miosinas/isolamento & purificação , Ratos , Ratos Sprague-Dawley , Deficiência de Vitamina D/sangue , Deficiência de Vitamina D/fisiopatologia
15.
Endocrinology ; 136(2): 482-8, 1995 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-7835280

RESUMO

The signals that regulate cardiac myocyte maturation in the neonatal heart are not completely understood. In our study we examined the effects of 1,25-dihydroxyvitamin D3 [1,25-(OH)2D3] on primary cultures of ventricular myocytes isolated from neonatal rat hearts. Our data show that 1,25-(OH)2D3 inhibited an increase in both the muscle-specific form of creatine kinase and V1 myosin isoenzyme levels in myocytes induced to mature by serum withdrawal. Thus, in contrast to other cell types studied to date, in the heart, 1,25-(OH)2D3 blocks cell maturation. Treating cultures with phorbol 12-myristate 13-acetate induced a decrease in the muscle-specific isoenzyme of creatine kinase similar to the effects of 1,25-(OH)2D3. Interestingly, we found that staurosporine, a protein kinase-C inhibitor, blunts the effects of 1,25-(OH)2D3 and has the opposite effect of phorbol 12-myristate 13-acetate on cultured myocytes induced to mature by serum withdrawal. Thus, our data identify a novel role for 1,25-(OH)2D3 in the regulation of myocardial development and suggest that 1,25-(OH)2D3 may be acting through a protein kinase-dependent mechanism to maintain cardiac myocytes in an immature state.


Assuntos
Calcitriol/farmacologia , Creatina Quinase/biossíntese , Miocárdio/metabolismo , Alcaloides/farmacologia , Animais , Diferenciação Celular/efeitos dos fármacos , Células Cultivadas , Meios de Cultura , Ventrículos do Coração/efeitos dos fármacos , Isoenzimas/biossíntese , Miocárdio/citologia , Miosinas/biossíntese , Ratos , Estaurosporina , Acetato de Tetradecanoilforbol/farmacologia
16.
Endocrinology ; 137(10): 4154-60, 1996 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-8828471

RESUMO

The steroid hormone 1,25-dihydroxyvitamin D3[1,25-(OH)2D3] induces maturation of many cells, including HL-60 promyelocytic leukemia cells that are differentiated to monocytes/macrophages. This process involves changes in transcription of genes such as c-myc. We investigated the effects of 1,25-(OH)2D3 on nuclear protein binding to the c-myc intron element (MIE), a region of DNA within the c-myc gene. A mutation in this MIE sequence has been shown to be associated with uncontrolled expression of the c-myc gene in various cell lines. In this report, we demonstrate for the first time that 1,25-(OH)2D3 induces increased binding of nuclear proteins to this MIE in HL-60 cells. The major MIE-binding proteins were approximately 32 kDa in size. Interestingly, phorbol 12-myristate 13-acetate induced a similar increase in binding of the 32-kDa doublet protein to the MIE. In addition, we showed that the level of 138-kDa MIE-binding protein was increased by 1,25-(OH)2D3 and phorbol 12-myristate 13-acetate. However, the extent of MIE binding by the 138-kDa protein is significantly less than that of the 32-kDa doublet binding species. MIE binding by the 32-kDa doublet protein was significantly increased within 12 h of 1,25-(OH)2D3 treatment. The time course of this increase was similar to that of 1,25-(OH)2D3-induced inhibition of c-myc gene transcription. We also demonstrated that dephosphorylation of the 32-kDa doublet protein inhibited its binding to the MIE. Thus, this study shows that the mechanism employed by 1,25-(OH)2D3 for regulation of c-myc expression may involve an increase in protein binding to the MIE, which has been shown to be the site for control of c-myc gene expression.


Assuntos
Calcitriol/farmacologia , Íntrons , Proteínas Nucleares/metabolismo , Proteínas Proto-Oncogênicas c-myc/genética , Proteínas Proto-Oncogênicas c-myc/metabolismo , Fosfatase Alcalina/farmacologia , Proteínas de Transporte/metabolismo , Relação Dose-Resposta a Droga , Eletroforese , Células HL-60 , Humanos , Fatores de Tempo , Transcrição Gênica/efeitos dos fármacos
17.
J Med Chem ; 43(19): 3541-8, 2000 Sep 21.
Artigo em Inglês | MEDLINE | ID: mdl-11000008

RESUMO

Gold(III) complexes generally exhibit interesting cytotoxic and antitumor properties, but until now, their development has been heavily hampered by their poor stability under physiological conditions. To enhance the stability of the gold(III) center, we prepared a number of gold(III) complexes with multidentate ligands - namely [Au(en)(2)]Cl(3), [Au(dien)Cl]Cl(2), [Au(cyclam)](ClO(4))(2)Cl, [Au(terpy)Cl]Cl(2), and [Au(phen)Cl(2)]Cl - and analyzed their behavior in solution. The solution properties of these complexes were monitored by visible absorption spectroscopy, mass spectrometry, and chloride-selective potentiometric measurements; the electrochemical properties were also studied by cyclic voltammetry and coulometry. Since all the investigated compounds exhibited sufficient stability under physiological conditions, their cytotoxic properties were tested in vitro, via the sulforhodamine B assay, on the representative human ovarian tumor cell line A2780, either sensitive or resistant to cisplatin. In most cases the investigated compounds showed relevant cell-killing properties with IC(50) values falling in the 0.2-10 microM range; noticeably most investigated gold(III) complexes were able to overcome, to a large extent, resistance to cisplatin when tested on the corresponding cisplatin-resistant cell line. The cytotoxic properties of the free ligands were also determined under the same solution conditions. Ethylenediamine, diethylenetriamine, and cyclam were virtually nontoxic (IC(50) values > 100 microM) so that the relevant cytotoxic effects observed for [Au(en)(2)]Cl(3) and [Au(dien)Cl]Cl(2) could be quite unambiguously ascribed to the presence of the gold(III) center. In contrast the phenanthroline and terpyridine ligands turned out to be even more cytotoxic than the corresponding gold(III) complexes rendering the interpretation of the cytotoxicity profiles of the latter complexes less straightforward. The implications of the present findings for the development of novel gold(III) complexes as possible cytotoxic and antitumor drugs are discussed.


Assuntos
Antineoplásicos/síntese química , Ouro , Compostos Organometálicos/síntese química , Antineoplásicos/química , Antineoplásicos/farmacologia , Cisplatino/farmacologia , Resistencia a Medicamentos Antineoplásicos , Ensaios de Seleção de Medicamentos Antitumorais , Eletroquímica , Humanos , Espectrometria de Massas , Compostos Organometálicos/química , Compostos Organometálicos/farmacologia , Potenciometria , Soluções , Relação Estrutura-Atividade , Células Tumorais Cultivadas
18.
Biochem Pharmacol ; 54(8): 909-15, 1997 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-9354591

RESUMO

The hormone 1,25-dihydroxyvitamin D3 [1,25-(OH)2D3] promotes differentiation of a number of cell types including HL-60 promyelocytic leukemia cells. It is now established that protein kinase Cbeta (PKCbeta) plays a critical role in HL-60 cell maturation to a monocyte/macrophage phenotype. In the present study, we investigated the importance of PKCbeta levels and activation in 1,25-(OH)2D3-mediated differentiation of HL-60 cells. Cell differentiation promoted by 1,25-(OH)2D3 at 48 hr was 39 +/- 3% (mean +/- SEM) nitroblue tetrazolium (NBT) positive and at 72 hr it was 35 +/- 2% NBT positive and 70% CD14 positive. Thus, promotion of cell differentiation by 20 nM 1,25-(OH)2D3 treatment was maximal at 48-72 hr. When PKCbeta levels and cell differentiation were assayed at 72 hr, treatment with 20 nM 1,25-(OH)2D3 for the initial 6 hr increased PKCbeta levels by 175% but had little effect on cell differentiation (7 +/- 2% NBT positive; 11% CD14 positive). The effect of ionomycin, a calcium ionophore, on PKCbeta levels and cell differentiation also was examined. Alone, 5 microM ionomycin promoted few cells (3% CD14 positive) to differentiate. In contrast, cells treated with 5 microM ionomycin for 66 hr after a 6-hr pretreatment with 20 nM 1,25-(OH)2D3 resulted in 34 +/- 5% NBT positive cells and 73% CD14 positive cells. Quantitatively, this induction of differentiation was identical to that observed in cultures continuously treated with 1,25-(OH)2D3 (35 +/- 2% NBT positive; 70% CD14 positive). Therefore, ionomycin seemed to replace the requirement for the continuous presence of 1,25-(OH)2D3. Chelerythrine chloride (3 microM), a specific PKC inhibitor, blocked differentiation promoted by 1,25-(OH)2D3 alone (82 +/- 2% inhibition) or in sequence with ionomycin (86 +/- 3% inhibition). Taken together, our data show that the capacity of 1,25-(OH)2D3 to both increase PKCbeta levels and activate PKC is utilized to promote HL-60 cell differentiation. These data further suggest that 1,25-(OH)2D3 has a genomic action to increase PKCbeta levels and also a nongenomic action requiring its continuous presence to promote HL-60 cell differentiation.


Assuntos
Calcitriol/farmacologia , Células HL-60/efeitos dos fármacos , Proteína Quinase C/metabolismo , Diferenciação Celular/efeitos dos fármacos , Ativação Enzimática/efeitos dos fármacos , Células HL-60/citologia , Humanos , Imunofenotipagem , Ionomicina/farmacologia , Ionóforos/farmacologia , Receptores de Lipopolissacarídeos/metabolismo , Explosão Respiratória
19.
J Thorac Cardiovasc Surg ; 72(1): 94-6, 1976 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-132582

RESUMO

A case of a fibrosarcoma arising in association with a Dacron prosthetic graft is reported. This is the second report of such an association. Animal studies have shown that polymeric substances can induce similar sarcomas and that pore size between the polymeric strands is an important consideration in determining carcinogenicity. Grafts with pore size less than 0.4 mu in diameter should be avoided in man until they are absolutely proved incapable of tumorogenesis.


Assuntos
Aorta Abdominal , Prótese Vascular/efeitos adversos , Polietilenotereftalatos/efeitos adversos , Sarcoma/etiologia , Amputação Cirúrgica , Aorta Abdominal/patologia , Aneurisma Aórtico/cirurgia , Arteriopatias Oclusivas/diagnóstico por imagem , Artéria Femoral/diagnóstico por imagem , Artéria Femoral/cirurgia , Humanos , Masculino , Pessoa de Meia-Idade , Radiografia , Sarcoma/diagnóstico por imagem , Sarcoma/cirurgia , Trombose/diagnóstico por imagem , Trombose/cirurgia
20.
Int J Epidemiol ; 30(2): 298-301, 2001 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-11369732

RESUMO

BACKGROUND: The objective of this study was to estimate the prevalence of hepatitis B virus exposure (HBV) in the population of the Republic of Ireland, by using oral fluid (saliva) collection by post for hepatitis B anti-core antibody (anti-HBc). This paper discusses the methodological approach used and the strategies that were adopted to improve response rates. METHODS: The sampling frame used was the Register of Electors for Irish parliamentary elections. A multistage stratified cluster sample was taken, and a total of 962 households were selected nationally. A four-letter approach was employed for sample collection. Households received an initial letter outlining the purpose of the study. This was followed by a letter containing six swabs for oral fluid collection, along with easy-to-follow instructions. Non-respondents received two reminder letters, and were also telephoned where possible. A telephone helpline was provided. All testing was anonymous and unlinked. RESULTS: The study achieved a good household response rate (60.4%), and more than 98% of the 1738 specimens received were suitable for testing. The prevalence of anti-HBc in the Irish population was estimated to be 0.51%. The observed design effect was 1.29. DISCUSSION: From a review of the literature, this is the first study where a representative sample of a national population was asked to self-collect oral fluid samples and return these by post for serological testing. The technique may have many future applications in epidemiological research.


Assuntos
Hepatite B/epidemiologia , Vigilância da População/métodos , Serviços Postais , Saliva/virologia , Adulto , Humanos , Irlanda/epidemiologia , Estudos Soroepidemiológicos
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