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1.
Nature ; 540(7631): 104-108, 2016 11 30.
Artigo em Inglês | MEDLINE | ID: mdl-27905442

RESUMO

The majority of the Earth's terrestrial carbon is stored in the soil. If anthropogenic warming stimulates the loss of this carbon to the atmosphere, it could drive further planetary warming. Despite evidence that warming enhances carbon fluxes to and from the soil, the net global balance between these responses remains uncertain. Here we present a comprehensive analysis of warming-induced changes in soil carbon stocks by assembling data from 49 field experiments located across North America, Europe and Asia. We find that the effects of warming are contingent on the size of the initial soil carbon stock, with considerable losses occurring in high-latitude areas. By extrapolating this empirical relationship to the global scale, we provide estimates of soil carbon sensitivity to warming that may help to constrain Earth system model projections. Our empirical relationship suggests that global soil carbon stocks in the upper soil horizons will fall by 30 ± 30 petagrams of carbon to 203 ± 161 petagrams of carbon under one degree of warming, depending on the rate at which the effects of warming are realized. Under the conservative assumption that the response of soil carbon to warming occurs within a year, a business-as-usual climate scenario would drive the loss of 55 ± 50 petagrams of carbon from the upper soil horizons by 2050. This value is around 12-17 per cent of the expected anthropogenic emissions over this period. Despite the considerable uncertainty in our estimates, the direction of the global soil carbon response is consistent across all scenarios. This provides strong empirical support for the idea that rising temperatures will stimulate the net loss of soil carbon to the atmosphere, driving a positive land carbon-climate feedback that could accelerate climate change.


Assuntos
Atmosfera/química , Ciclo do Carbono , Carbono/análise , Geografia , Aquecimento Global , Solo/química , Bases de Dados Factuais , Ecossistema , Retroalimentação , Modelos Estatísticos , Reprodutibilidade dos Testes , Temperatura
2.
Ecology ; 99(11): 2506-2514, 2018 11.
Artigo em Inglês | MEDLINE | ID: mdl-30144047

RESUMO

Intensifying drought is increasingly linked to global forest diebacks. Improved understanding of drought impacts on individual trees has provided limited insight into drought vulnerability in part because tree moisture access and depletion is difficult to quantify. In forests, moisture reservoir depletion occurs through water use by the trees themselves. Here, we show that drought impacts on tree fitness and demographic performance can be predicted by tracking the moisture reservoir available to trees as a mass balance, estimated in a hierarchical state-space framework. We apply this model to multiple seasonal droughts with tree transpiration measurements to demonstrate how species and size differences modulate moisture availability across landscapes. The depletion of individual moisture reservoirs can be tracked over the course of droughts and linked to biomass growth and reproductive output. This mass balance approach can predict individual moisture deficit, tree demographic performance, and drought vulnerability throughout forest stands based on measurements from a sample of trees.


Assuntos
Secas , Árvores , Biomassa , Florestas , Água
3.
Nat Genet ; 16(4): 364-7, 1997 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-9241273

RESUMO

Ischaemic stroke is a complex disorder caused by a combination of genetic and environmental factors. Clinical and epidemiological studies have provided strong evidence for genetic influences in the development of human stroke and several mendelian traits featuring stroke have been described. The genetic analysis of the non-mendelian, common ischaemic stroke in humans is hindered by the late onset of the disease and the mode of inheritance, which is complex, polygenic and multifactorial. An important approach to the study of such polygenic diseases is the use of appropriate animal models in which individual contributing factors can be recognized and analysed. The spontaneously hypertensive stroke-prone rat (SHRSP) is an experimental model of stroke characterized by a high frequency of spontaneous strokes as well as an increased sensitivity to experimentally induced focal cerebral ischaemia. Rubattu et al. performed a genomewide screen in an F2 cross obtained by mating SHRSP and SHR, in which latency to stroke on Japanese rat diet was used as a phenotype. This study identified three major quantitative trait loci (QTLs), STR-1-3. Of these, STR-2 and 3 conferred a protective effect against stroke in the presence of SHRSP alleles and STR-2 co-localized with the genes encoding for atrial natriuretic and brain natriuretic factors. Our investigation was designed to identify the genetic component responsible for large infarct volumes in the SHRSP in response to a focal ischaemic insult by performance of a genome scan in an F2 cross derived from the SHRSP and the normotensive reference strain, WKY rat. We identified a highly significant QTL on rat chromosome 5 with a lod score of 16.6 which accounts for 67% of the total variance, co-localizes with the genes encoding atrial and brain natriuretic factor and is blood pressure independent.


Assuntos
Fator Natriurético Atrial/genética , Isquemia Encefálica/genética , Mapeamento Cromossômico , Proteínas do Tecido Nervoso/genética , Animais , Pressão Sanguínea , Artérias Cerebrais/cirurgia , Transtornos Cerebrovasculares/genética , Cruzamentos Genéticos , Modelos Animais de Doenças , Feminino , Humanos , Masculino , Peptídeo Natriurético Encefálico , Ratos , Ratos Endogâmicos SHR , Ratos Endogâmicos WKY
4.
Science ; 292(5514): 95-8, 2001 Apr 06.
Artigo em Inglês | MEDLINE | ID: mdl-11292871

RESUMO

We determined the reproductive response of 19-year-old loblolly pine (Pinus taeda) to 4 years of carbon dioxide (CO2) enrichment (ambient concentration plus 200 microliters per liter) in an intact forest. After 3 years of CO2 fumigation, trees were twice as likely to be reproductively mature and produced three times as many cones and seeds as trees at ambient CO2 concentration. A disproportionate carbon allocation to reproduction under CO2 enrichment results in trees reaching maturity sooner and at a smaller size. This reproductive response to future increases in atmospheric CO2 concentration is expected to change loblolly dispersal and recruitment patterns.


Assuntos
Dióxido de Carbono , Cycadopsida/fisiologia , Ecossistema , Árvores/fisiologia , Atmosfera , Dióxido de Carbono/metabolismo , Dióxido de Carbono/farmacologia , Cycadopsida/crescimento & desenvolvimento , Efeito Estufa , North Carolina , Fotossíntese , Probabilidade , Reprodução , Sementes/metabolismo , Especificidade da Espécie , Árvores/crescimento & desenvolvimento
5.
Science ; 293(5530): 657-60, 2001 Jul 27.
Artigo em Inglês | MEDLINE | ID: mdl-11474103

RESUMO

Planning and decision-making can be improved by access to reliable forecasts of ecosystem state, ecosystem services, and natural capital. Availability of new data sets, together with progress in computation and statistics, will increase our ability to forecast ecosystem change. An agenda that would lead toward a capacity to produce, evaluate, and communicate forecasts of critical ecosystem services requires a process that engages scientists and decision-makers. Interdisciplinary linkages are necessary because of the climate and societal controls on ecosystems, the feedbacks involving social change, and the decision-making relevance of forecasts.


Assuntos
Ecossistema , Previsões , Agricultura , Animais , Tomada de Decisões , Surtos de Doenças , Ecologia , Epidemiologia , Humanos , Formulação de Políticas , Crescimento Demográfico , Processos Estocásticos
6.
J Physiol Pharmacol ; 70(2)2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-31356179

RESUMO

Antiplatelet therapy resistance against acetylsalicylic acid (ASA) and/or clopidogrel in coronary heart disease (CHD) is common with diabetes mellitus. One factor might involve platelet receptor ITGB3 gene polymorphism. We aimed to assess resistance together with platelet reactivity parameters, the polymorphism, plus diabetes type 2 coexistence. The study included 185 patients with CHD, including 58 diabetics, aged 62.3 ± 8.2 years. Patients were treated long-term with ASA, plus clopidogrel, both 75 mg/d. Platelet aggregation was measured with arachidonic acid (ASPI test; ASA-response assessment) or ADP (ADP test; clopidogrel-response assessment). Thromboxane B2 (TXB2) and fibrinogen concentrations were measured and ITGB3 PIA1>A2 variants identified. Increases in PLT, glucose and SBP were demonstrated with dual resistance or to clopidogrel. Regardless of response, diabetics (versus non-diabetics) had elevated platelet aggregation with the ADP test (P = 0.0198), higher TXB2 (P = 0.0501), BMI (P = 0.0003) and SBP (P = 0.0627). ITGB3 PIA1/A1 homozygotes had higher platelet aggregation with the ASPI test (P = 0.0513), and fibrinogen concentrations (P = 0.0133), relative to A2 allele carriers. Significant associations of diabetes with clopidogrel resistance (P = 0.0011) and PIA1/A1 homozygotes with ASA resistance (P = 0.0518) were found. Higher concentrations of TXB2 (P = 0.0223) and higher SBP (P = 0.0063) were found with diabetes (versus non-diabetic) in PIA1/A1 homozygotes. We concluded that diabetes with CHD weakens response to antiplatelet drugs, especially to clopidogrel; and hyperglycaemia, hypertension and obesity might also play an important role. Diabetics' resistance to ASA is associated with increased platelet reactivity, perhaps related to the more frequent ITGB3 PIA1 allele and increased TXB2 generation. The PIA1 allele may be a potential factor for aspirin resistance with elevated fibrinogen concentration.


Assuntos
Plaquetas/efeitos dos fármacos , Doença da Artéria Coronariana/tratamento farmacológico , Doença da Artéria Coronariana/genética , Diabetes Mellitus Tipo 2/genética , Inibidores da Agregação Plaquetária/uso terapêutico , Complexo Glicoproteico GPIIb-IIIa de Plaquetas/genética , Polimorfismo Genético/genética , Clopidogrel/uso terapêutico , Feminino , Fibrinogênio/genética , Humanos , Integrina beta3/genética , Masculino , Pessoa de Meia-Idade , Agregação Plaquetária/efeitos dos fármacos , Agregação Plaquetária/genética , Testes de Função Plaquetária/métodos , Estudos Prospectivos , Tromboxano B2/genética
7.
J Physiol Pharmacol ; 69(4)2018 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-30552303

RESUMO

Antiplatelet therapy is considered as a standard procedure against atherosclerotic cardiovscular disease but this therapy has limited effect if resistance to acetylsalicylic acid or clopidogrel is present. Important factors associated with resistance are gender; or inflammation possibly associated with membrane microparticles (MP). It was decided to challenge the hypothesis that differential responses to dual antiplatelet therapy are conditioned by gender and/or proinflammatory status. The study involved 160 patients with stable coronary heart disease (118 men, 42 women) aged 65.2 ± 7.8 years. Patients were treated long-term with acetylsalicylic acid (ASA); plus clopidogrel starting 6 days before percutaneous coronary intervention (both 75 mg/day). Response was evaluated using platelet aggregation with either arachidonic acid (the ASPI test; predominantly for ASA response) or adenosine diphosphate (the ADP test; predominantly for clopidogrel response). MP levels were measured as follows: total (MP-total); with TF expression (MP-TF); or platelet-derived microparticles (PDMP), as well as proinflammatory parameters: C-reactive protein (CRP), leukocytes (WBC) and platelet numbers (PLT). Analysis of platelet-aggregation levels with regard to gender revealed higher aggregation in women: with resistance to ASA (ASPI test: P = 0.0383, ADP test: P = 0.0027); resistance to clopidogrel (ASPI test: P = 0.0003; ADP test: P = 0.0566) and with sensitivity to both drugs with the ADP test (P = 0.0190). In women relative to men, regardless of response, significantly higher CRP (P = 0.0012), WBC (P = 0.0244) and PLT numbers (P = 0.0001) were found. In contrast, in men significantly higher concentrations of MP-TF (P = 0.0286) and triglycerides (P = 0.0296) were found in the clopidogrel-resistant group. We conclude that women have an inferior response to dual antiplatelet therapy relative to men, possibly associated with higher platelet reactivity (especially when measured with the ADP test), with a more accentuated proinflammatory status. In contrast, among the factors supporting the resistance in men can be an elevated concentration of MP-TF which, together with the coexistence of hypertriglyceridemia, may constitute an important mechanism of resistance to clopidogrel.


Assuntos
Aspirina/farmacologia , Clopidogrel/farmacologia , Doença da Artéria Coronariana/sangue , Inibidores da Agregação Plaquetária/farmacologia , Idoso , Plaquetas/efeitos dos fármacos , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Agregação Plaquetária/efeitos dos fármacos , Caracteres Sexuais
8.
J Physiol Pharmacol ; 67(6): 903-910, 2016 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-28195071

RESUMO

Formation of an abdominal aortic aneurysm is a complex process involving aortic wall degradation. The matrix metalloproteinases (MMPs) mainly involved in this process are MMP-2 and MMP-9. Most aneurysms contain an intraluminal thrombus. It is suggested that the thrombus' thickness correlates with the risk of aneurysm rupture and may be a new prognostic factor. The purpose of the present study was to investigate enzyme protein levels in thick (A1) and thin (B1) segments of the thrombus and aneurysm wall sections A (adjacent to A1) and B (adjacent to B1). Aneurysm samples from one aneurism sac were collected from 36 patients that underwent aneurysm repair. MMP-2, MMP-9 and a tissue inhibitor of metalloproteinases (TIMP-1) were measured using enzyme-linked-immunosorbent assay of protein extract. MMP-9 concentrations were significantly higher in B1 samples compared with A1 (113.4 ± 118.0 versus 63.0 ± 61.2, P = 0.004), A(113.4 ± 118.0 versus 31.7 ± 30.0, P < 0.001) or B (113.4 ± 118.0 versus 39.5 ± 41.5, P < 0.001). Likewise MMP-9/TIMP-1 ratio was elevated in B1 compared with A1 (18.9 ± 27.8 versus 9.1 ± 10.6, P = 0.017), A (18.9 ± 27.8 versus 2.5 ± 2.2, P < 0.001) or B (18.9 ± 27.8 versus 3.6 ± 4.5, P < 0.001). MMP-2 and TIMP-1 were higher in A compared with A1 (18.4 ± 8.5 versus 7.2 ± 7.6, P < 0.001; 14.3 ± 5.9 versus 8.5 ± 5.4, P < 0.001, respectively) and B1 (18.4 ± 8.5 versus 5.2 ± 2.9, P < 0.001; 14.3 ± 5.9 versus 8.9 ± 4.9, P < 0.001, respectively) as well as in B compared with A1 (15.9 ± 7.3 versus 7.2 ± 7.6, P < 0.001; 13.0 ± 5.0 versus 8.5 ± 5.4, P < 0.001, respectively) and B1 (15.9 ± 7.3 versus 5.2 ± 2.9, P < 0.001; 13.0 ± 5.0 versus 8.9 ± 4.9, P = 0.003, respectively). There were significant correlations between thin thrombus TIMP-1 and thrombus thickness (ß = -0.24, P = 0.021) and between thin thrombus MMP-9/TIMP-1 ratio and thrombus thickness (ß = 1.75, P = 0.003). Our study has revealed that the presence of thrombi with thin segments in the aneurysm sac, associated with higher proteolytic activity, could possibly be used as a potential indicator of a rupture site.


Assuntos
Aorta Abdominal/metabolismo , Aneurisma da Aorta Abdominal/metabolismo , Metaloproteinase 2 da Matriz/metabolismo , Metaloproteinase 9 da Matriz/metabolismo , Trombose/metabolismo , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Inibidor Tecidual de Metaloproteinase-1/metabolismo
9.
Hypertension ; 36(1): 110-5, 2000 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-10904021

RESUMO

The present study was designed to assess vascular smooth muscle cell (VSMC) proliferation and apoptosis in primary cultured VSMCs prepared from the aortic tunica media of adult (4 to 5 months old) age- and gender-matched groups of stroke-prone spontaneously hypertensive rats (SHRSP) and the normotensive reference strain, Wistar-Kyoto (WKY) rats. In the present study, VSMC proliferation was assessed with measurement of DNA synthesis in response to stimulation of G(0)/G(1) arrested VSMCs with 10% serum, whereas apoptosis was measured in response to serum deprivation. Apoptosis in aortic VSMCs was assessed in vitro with the technique of Annexin V binding in combination with propidium iodide exclusion with bivariate flow cytometric analysis. The percentage of necrotic VSMCs in the cell populations was assessed simultaneously. The light-scattering properties of the cells were assessed to provide further information on cell shrinkage and chromatin condensation. Results of the present study have shown enhanced DNA synthesis in VSMCs from SHRSP (n=10; 5.2+/-0.9 cpmx10(3)/mg protein) compared with WKY (n=12; 2.4+/-0.7 cpmx10(3) /mg protein; P<0.05, 95% CI, -5271 to -296). In addition, the results of the present study have demonstrated the role of serum in the survival of VSMCs in vitro, because SHRSP VSMCs underwent significantly more apoptosis in response to insult by serum deprivation (n=13; 10.21+/-1.8%) than WKY VSMCs (n=7; 3.44+/-1.4%; P<0.01, 95% CI, -11.5 to -2.0). Thus, it appears that both proliferation and apoptosis are enhanced in synthetic phenotype aortic medial VSMCs from the SHRSP in vitro.


Assuntos
Apoptose , DNA/biossíntese , Hipertensão/patologia , Músculo Liso Vascular/patologia , Animais , Divisão Celular , Feminino , Hipertensão/genética , Masculino , Ratos , Ratos Endogâmicos SHR , Ratos Endogâmicos WKY , Receptor Tipo 1 de Angiotensina , Receptor Tipo 2 de Angiotensina , Receptores de Angiotensina/fisiologia , Timidina/metabolismo
10.
Hypertension ; 35(1 Pt 2): 164-72, 2000 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-10642293

RESUMO

Human essential hypertension is a complex, multifactorial, quantitative trait under a polygenic control. Several strategies have been developed over the last decade to dissect genetic determinants of hypertension. Of these, the most successful have been studies that identified rare mendelian syndromes in which a single gene mutation causes high blood pressure. The attempts to identify multiple genes, each with a small contribution to the common polygenic form of hypertension, have been less successful. Several laboratories focused their attention on rat models of genetic hypertension, which can be considered as a reductionist paradigm for human disease. Using numerous crosses between hypertensive and normotensive strains, investigators identified several quantitative trait loci (QTL) for blood pressure subphenotypes and for cardiovascular complications such as left ventricular hypertrophy, kidney failure, stroke, and insulin resistance. Furthermore, congenic strains have been produced to confirm the existence of some of these QTL and to narrow down the chromosomal regions of interest. A number of interesting strategies have been developed, including a "speed" congenic strategy perfected by our group in Glasgow. However, the limit of congenic strategy is estimated at 1 cM, which corresponds to 2x10(6) base pairs of DNA and approximately 50 candidate genes. It is envisaged that gene expression profiling with cDNA microarrays might allow a quick progression toward the gene identification within cardiovascular QTL. In parallel experimental effort, several laboratories have been developing gene transfer/therapy strategies with adenoviral or adeno-associated viral vectors used, for example, to overexpress protective vascular genes such as vascular endothelial growth factor or endothelial nitric oxide synthase. It is anticipated that further developments in positional cloning of susceptibility and severity genes in hypertension and its complications will lead to a direct transfer of these discoveries to essential hypertension in humans and will ultimately produce novel targets for local and systemic gene therapy in cardiovascular disease.


Assuntos
Mapeamento Cromossômico , Técnicas de Transferência de Genes , Hipertensão/genética , Hipertensão/terapia , Animais , Modelos Animais de Doenças , Endotélio Vascular/fisiologia , Humanos
11.
Hypertension ; 35(1 Pt 2): 179-87, 2000 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-10642295

RESUMO

The identification of any quantitative trait locus (QTL) via a genome scan is only the first step toward the ultimate goal of gene identification. The next step is the production of congenic strains by which the existence of a QTL may be verified and the implicated chromosomal region be reduced to a size applicable to positional cloning of the causal gene. We used a speed congenic breeding protocol previously verified in mice for 2 blood pressure QTLs on rat chromosome 2. Four congenic strains were produced through introgression of various segments of chromosome 2 from Wistar-Kyoto rats from Glasgow colonies [WKY((Gla)) rats] into the recipient stroke-prone spontaneously hypertensive rats from Glasgow colonies [SHRSP((Gla))], and vice versa. The number of backcross generations required for each strain to achieve complete homozygosity at 83 background genetic markers in a "best" male varied between 3 and 4. Transfer of the region of rat chromosome 2 containing both QTLs from WKY((Gla)) into an SHRSP((Gla)) genetic background lowered both baseline and salt-loaded systolic blood pressure by approximately 20 and approximately 40 mm Hg in male congenic rats compared with the SHRSP parental strain (F=53.4, P<0.005; F=28.0, P< 0.0005, respectively). In contrast, control animals for stowaway heterozygosity presented no deviation from the blood pressure values recorded for the SHRSP((Gla)), indicating that if such heterozygosity exists, its effect on blood pressure is negligible. A reciprocal strategy in which 1 or both QTLs on rat chromosome 2 were transferred from SHRSP((Gla)) into a WKY((Gla)) genetic background resulted in statistically significant but smaller blood pressure increases for 1 of these QTLs. These results confirm the existence of blood pressure QTLs on rat chromosome 2 and demonstrate the applicability of a speed congenic strategy in the rat and emphasize the important role of the genetic background.


Assuntos
Pressão Sanguínea/genética , Hipertensão/genética , Característica Quantitativa Herdável , Ratos Endogâmicos SHR/genética , Animais , Mapeamento Cromossômico , Ritmo Circadiano , DNA Satélite/análise , Feminino , Marcadores Genéticos , Genótipo , Homozigoto , Masculino , Ratos , Ratos Endogâmicos WKY , Especificidade da Espécie , Acidente Vascular Cerebral/genética
12.
Hypertension ; 33(2): 681-5, 1999 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-10024327

RESUMO

We have investigated genetic transmission of increased sensitivity to focal cerebral ischemia and the influence of gender in the stroke-prone spontaneously hypertensive rat (SHRSP). Halothane-anesthetized, 3- to 5-month-old male and female Wistar-Kyoto rats (WKY), SHRSP, and the first filial generation rats (F1 crosses 1 and 2) underwent distal (2 mm) permanent middle cerebral artery occlusion (MCAO) by electrocoagulation. Infarct volume was measured by using hematoxylin-eosin-stained sections and image analysis 24 hours after ischemia and expressed as a percentage of the volume of the ipsilateral hemisphere. Infarct volume in males and females grouped together were significantly larger in SHRSP, F1 cross 1 (SHRSP father), and F1 cross 2 (WKY father), at 36.6+/-2.3% (mean+/-SEM, P<0.001, n=15), 25.4+/-2.4% (P<0.01, n=14), and 33. 9+/-1.6% (P<0.001, n=18), respectively, compared with WKY (14+/-2%, n=17). Male F1 cross 1 (18.9+/-2.4%, n=6) developed significantly smaller infarcts than male F1 cross 2 (32.8+/-2%, n=8, P<0.005). Females, which underwent ischemia during metestrus, developed larger infarcts than respective males. A group of females in which the cycle was not controlled for developed significantly smaller infarcts than females in metestrus. Thus, the increased sensitivity to MCAO in SHRSP is retained in both F1 cross 1 and cross 2 hybrids, suggesting a dominant or codominant trait; response to cerebral ischemia appears to be affected by gender and stage in the estrous cycle. In addition, the male progenitor of the cross (ie, SHRSP versus WKY) influences stroke sensitivity in male F1 cohorts.


Assuntos
Isquemia Encefálica/genética , Isquemia Encefálica/fisiopatologia , Hipertensão/complicações , Animais , Transtornos Cerebrovasculares/genética , Transtornos Cerebrovasculares/fisiopatologia , Feminino , Hipertensão/genética , Hipertensão/fisiopatologia , Masculino , Ratos , Ratos Endogâmicos SHR , Ratos Endogâmicos WKY , Fatores Sexuais
13.
Hypertension ; 28(5): 898-906, 1996 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-8901842

RESUMO

We performed a total genome screen in an F2 cross derived from the stroke-prone spontaneously hypertensive rat and the normotensive Wistar-Kyoto rat. Blood pressure at baseline and after 1% NaCl was measured by radiotelemetry; other phenotypes included heart rate, motor activity, left ventricle weight to body weight ratio, and vascular smooth muscle cell polyploidy, a measure of vascular hypertrophy. Quantitative trait loci affecting a given phenotype were mapped relative to microsatellite markers by using the MAPMAKER/QTL 1.1 computer package. We identified three blood pressure quantitative trait loci, two on rat chromosome 2 and one on rat chromosome 3. The quantitative trait loci close to genetic markers D2Mgh12 ("suggestive" linkage, with a maximal logarithm of the odds [LOD] score of 3.1) and D3Mgh16 (significant linkage, with a maximal LOD score of 5.6) showed possible sex specificity in the male F2 cohort only. This was confirmed by the likelihood ratio test for the difference in locus effects between the sexes. We also identified a new quantitative trait locus for LV hypertrophy on rat chromosome 14 ("suggestive" linkage, with a maximal LOD score of 3.1). The sex specificity of blood pressure quantitative trait loci will be important in designing congenic strains and substrains for fine genetic mapping and for identifying genes that regulate blood pressure.


Assuntos
Pressão Sanguínea/genética , Hipertensão/genética , Animais , Pressão Sanguínea/efeitos dos fármacos , Cromossomos Humanos Par 2 , Cromossomos Humanos Par 3 , Cruzamentos Genéticos , Feminino , Marcadores Genéticos , Genótipo , Humanos , Hipertensão/etiologia , Masculino , Fenótipo , Ratos , Ratos Endogâmicos SHR , Ratos Endogâmicos WKY , Fatores Sexuais , Cloreto de Sódio/efeitos adversos , Especificidade da Espécie
14.
Hypertension ; 33(1 Pt 2): 290-7, 1999 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-9931119

RESUMO

-Previous studies suggested that atrial natriuretic peptide gene (Anp) and brain natriuretic peptide gene (Bnp) are plausible candidate genes for susceptibility to stroke and for sensitivity to brain ischemia in the stroke-prone spontaneously hypertensive rat (SHRSP). We performed structural and functional analyses of these 2 genes in SHRSP from Glasgow colonies (SHRSPGla) and Wistar-Kyoto rats from Glasgow colonies (WKYGla) and developed a radiation hybrid map of the relevant region of rat chromosome 5. Sequencing of the coding regions of the Anp and Bnp genes revealed no difference between the 2 strains. Expression studies in brain tissue showed no differences at baseline and at 24 hours after middle cerebral artery occlusion. Plasma concentrations of atrial natriuretic peptide (ANP) did not differ between the SHRSPGla and WKYGla, whereas concentrations of brain natriuretic peptide were significantly higher in the SHRSPGla as compared with the WKYGla (n=11 to 14; 163+/-21 pg/mL and 78+/-14 pg/mL; 95% confidence interval 31 to 138, P=0.003). We did not detect any attenuation of endothelium-dependent relaxations to bradykinin or ANP in middle cerebral arteries from the SHRSPGla; indeed the sensitivity to ANP was significantly increased in arteries harvested from this strain (WKYGla: n=8; pD2=7. 3+/-0.2 and SHRSPGla: n=8; pD2=8.2+/-0.15; P<0.01). Moreover, radiation hybrid mapping and fluorescence in situ hybridization allowed us to map the Anf marker in the telomeric position of rat chromosome 5 in close proximity to D5Rat48, D5Rat47, D5Mgh15, and D5Mgh16. These results exclude Anp and Bnp as candidate genes for the sensitivity to brain ischemia and pave the way to further congenic and physical mapping strategies.


Assuntos
Fator Natriurético Atrial/genética , Isquemia Encefálica/genética , Encéfalo/metabolismo , Transtornos Cerebrovasculares/genética , Mapeamento Cromossômico , Predisposição Genética para Doença , Hipertensão/genética , Peptídeo Natriurético Encefálico/genética , Mutação Puntual , Substituição de Aminoácidos , Animais , Fator Natriurético Atrial/sangue , Sequência de Bases , Células Cultivadas , Primers do DNA , Éxons , Marcadores Genéticos , Íntrons , Masculino , Músculo Liso Vascular/metabolismo , Peptídeo Natriurético Encefálico/sangue , Reação em Cadeia da Polimerase , Ratos , Ratos Endogâmicos SHR , Ratos Endogâmicos WKY , Ratos Sprague-Dawley
15.
Am Nat ; 157(5): 537-54, 2001 May.
Artigo em Inglês | MEDLINE | ID: mdl-18707261

RESUMO

For populations having dispersal described by fat-tailed kernels (kernels with tails that are not exponentially bounded), asymptotic population spread rates cannot be estimated by traditional models because these models predict continually accelerating (asymptotically infinite) invasion. The impossible predictions come from the fact that the fat-tailed kernels fitted to dispersal data have a quality (nondiscrete individuals and, thus, no moment-generating function) that never applies to data. Real organisms produce finite (and random) numbers of offspring; thus, an empirical moment-generating function can always be determined. Using an alternative method to estimate spread rates in terms of extreme dispersal events, we show that finite estimates can be derived for fat-tailed kernels, and we demonstrate how variable reproduction modifies these rates. Whereas the traditional models define spread rate as the speed of an advancing front describing the expected density of individuals, our alternative definition for spread rate is the expected velocity for the location of the furthest-forward individual in the population. The asymptotic wave speed for a constant net reproductive rate R0 is approximated as (1/T)(piuR)/2)(1/2) m yr(-1), where T is generation time, and u is a distance parameter (m2) of Clark et al.'s 2Dt model having shape parameter p = 1. From fitted dispersal kernels with fat tails and infinite variance, we derive finite rates of spread and a simple method for numerical estimation. Fitted kernels, with infinite variance, yield distributions of rates of spread that are asymptotically normal and, thus, have finite moments. Variable reproduction can profoundly affect rates of spread. By incorporating the variance in reproduction that results from variable life span, we estimate much lower rates than predicted by the standard approach, which assumes a constant net reproductive rate. Using basic life-history data for trees, we show these estimated rates to be lower than expected from previous analytical models and as interpreted from paleorecords of forest spread at the end of the Pleistocene. Our results suggest reexamination of past rates of spread and the potential for future response to climate change.

16.
J Hypertens ; 16(12 Pt 2): 1859-69, 1998 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-9886870

RESUMO

Experimental models of genetic hypertension are used to develop paradigms to study human essential hypertension while removing some of the complexity inherent in the study of human subjects. Since 1991 several quantitative trait loci responsible for blood pressure regulation have been identified in various rat crosses. More recently, a series of interesting quantitative trait loci influencing cardiac hypertrophy, stroke, metabolic syndrome and renal damage has also been described. It is recognized that the identification of large chromosomal regions containing a quantitative trait locus is only a first step towards gene identification. The next step is the production of congenic strains and substrains to confirm the existence of the quantitative trait locus and to narrow down the chromosomal region of interest. Several congenic strains have already been produced, with further refinement of the methodology currently in progress. The ultimate goal is to achieve positional cloning of the causal gene, a task which has so far been elusive. There are several areas of cross-fertilization between experimental and human genetics of hypertension, with a successful transfer of two loci directly from rats to humans and with new pharmacogenetic approaches which may be utilized in both experimental and clinical settings.


Assuntos
Hipertensão/genética , Animais , Anti-Hipertensivos/uso terapêutico , Pressão Sanguínea/genética , Mapeamento Cromossômico , Modelos Animais de Doenças , Humanos , Hipertensão/tratamento farmacológico , Camundongos , Fenótipo , Característica Quantitativa Herdável , Ratos , Especificidade da Espécie
17.
J Hypertens ; 13(2): 211-8, 1995 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-7615951

RESUMO

OBJECTIVE: To quantify vascular smooth muscle polyploidy and growth kinetics in aortic cells from stroke-prone spontaneously hypertensive rats (SHRSP) and from normotensive Wistar-Kyoto (WKY) rats, and to examine the effects of treatment with the angiotensin converting enzyme (ACE) inhibitor perindopril on these parameters. DESIGN: The following experimental groups were used: young (age < 20 weeks) and old (age > 20 weeks) untreated WKY rats and untreated SHRSP; SHRSP treated with perindopril, and age- and sex-matched control SHRSP; and SHRSP treated with hydralazine and hydrochlorothiazide and age- and sex-matched control SHRSP. The effects of treatment of the SHRSP with perindopril for 30 days on vascular smooth muscle polyploidy and growth kinetics were measured and compared with the effects of equivalent antihypertensive doses of hydralazine and hydrochlorothiazide. METHODS: Vascular smooth muscle polyploidy was measured using flow-cytometry DNA analysis of freshly harvested cells. Growth curves were performed on cultured aortic cells. Plasma renin activity was measured by an antibody-trapping method, plasma angiotensin II (Ang II) by radioimmunoassay and plasma ACE activity by a colorimetric method. Cardiac hypertrophy was evaluated by measuring the heart weight:body weight and left ventricle + septum weight:body weight ratios. RESULTS: The SHRSP had markedly and significantly elevated G2 + M phase of the cell cycle. Treatment with perindopril resulted in a significant reduction in polyploidy in the SHRSP, whereas treatment with hydralazine and hydrochlorothiazide had no effect on the percentage of cells in the G2 + M phase of the cell cycle. The regression of polyploidy after treatment with perindopril was associated with a significant reduction in the concentration of Ang II and ACE activity, and with a significant regression of cardiac hypertrophy. Increased mitogenesis of cultured vascular smooth muscle cells from the SHRSP was not altered by treatment with perindopril. CONCLUSIONS: ACE inhibition reduces vascular smooth muscle polyploidy in large conduit arteries. This type of vascular protection is mediated by the reduced Ang II and possibly by increased kinins level, rather than by the hypotensive effect alone.


Assuntos
Hipertensão/patologia , Indóis/farmacologia , Músculo Liso Vascular/patologia , Poliploidia , Inibidores da Enzima Conversora de Angiotensina/farmacologia , Angiotensinas/sangue , Animais , Aorta/patologia , Pressão Sanguínea , Núcleo Celular/patologia , Células Cultivadas , Feminino , Citometria de Fluxo , Frequência Cardíaca , Hipertensão/metabolismo , Masculino , Peptidil Dipeptidase A/sangue , Perindopril , Ratos , Ratos Endogâmicos SHR , Ratos Endogâmicos WKY , Renina/sangue
18.
Immunol Lett ; 31(3): 279-83, 1992 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-1347754

RESUMO

The quantitative distribution and phenotype of gamma/delta lymphocytes in the peripheral blood (PBL), tumour draining lymph node (LNL) and tumour infiltrating lymphocytes (TIL) from breast carcinoma patients were determined by one- and two-colour flow cytometry. The TCR-gamma/delta + cells generally expressed the T cell lineage antigen CD3. The proportions of such cells were variable but generally small from all the three sources. Phenotypic analysis revealed that the CD8 marker was consistently and predominantly observed on gamma/delta + CD3+ cells in the tumour infiltrate, whereas CD4 expression, while generally low, was noted on a significant percentage (median 10%) of LNL gamma/delta + lymphocytes. In both PBL and LNL the predominant gamma/delta cell population was CD4-8-.


Assuntos
Neoplasias da Mama/imunologia , Carcinoma Intraductal não Infiltrante/imunologia , Linfócitos do Interstício Tumoral/imunologia , Receptores de Antígenos de Linfócitos T gama-delta/imunologia , Linfócitos T/imunologia , Anticorpos Monoclonais , Antígenos de Diferenciação de Linfócitos T/imunologia , Axila , Complexo CD3 , Linfócitos T CD4-Positivos/imunologia , Feminino , Citometria de Fluxo , Humanos , Imunofenotipagem , Linfonodos/imunologia , Receptores de Antígenos de Linfócitos T/imunologia , Linfócitos T Reguladores/imunologia
19.
Immunol Lett ; 35(3): 229-34, 1993 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-8390399

RESUMO

Lymphocytes from matched pairs of tumour-invaded and tumour-free lymph nodes from 22 stage II breast cancer patients have been analysed for expression of phenotypic and activation markers by flow cytometry. Although the relative proportions of T and B lymphocytes were similar in the two nodes, significant differences in the distribution of T cell subsets were observed between nodes that were invaded and those that were not. The CD4/CD8 ratio was markedly depressed in tumour invaded nodes (P < 0.001). This was due to an increase in the number of CD8+ T cells (P < 0.001) and a decrease in the CD4+ T cell population (P = 0.008) in invaded nodes in comparison with tumour-free nodes. The percentage of CD8+ T cells expressing HLA DR (P = 0.023) and IL-2 receptors (Tac) (P = 0.029) was significantly higher in invaded nodes and, while CD4+ T cells expressing HLA DR (P = 0.036) were also in a higher proportion of Tac expressing CD4+ T cells failed to reach significance. Although invaded nodes in a few patients were found to have a higher percentage of IgG-expressing B cells, no significant differences were observed between the two groups of nodes. These results suggest that the presence of metastatic tumour cells in a lymph node is associated with specific alterations in the T cell population.


Assuntos
Neoplasias da Mama/patologia , Carcinoma Intraductal não Infiltrante/patologia , Linfonodos/patologia , Linfócitos T , Linfócitos B/imunologia , Neoplasias da Mama/imunologia , Relação CD4-CD8 , Carcinoma Intraductal não Infiltrante/imunologia , Feminino , Antígenos HLA-DR/análise , Humanos , Imunofenotipagem , Metástase Linfática , Ativação Linfocitária , Receptores de Interleucina-2/análise , Linfócitos T/imunologia , Linfócitos T Reguladores/imunologia
20.
Cancer Lett ; 66(3): 193-200, 1992 Oct 21.
Artigo em Inglês | MEDLINE | ID: mdl-1360329

RESUMO

DNA aneuploidy and p53 or c-erbB-2 expression were simultaneously measured in 29 breast tumours by two-colour flow cytometry. (i) The majority of tumours had some cells expressing either p53 (5-68%) or c-erbB-2 (1-56%). (ii) Expression of p53 and c-erbB-2 was observed mainly in the aneuploid population of mixed aneuploid and diploid tumours but there was no significant correlation with a specific DNA index. Aneuploid tumours contained higher percentages of c-erbB-2 positive cells (average 25%) than purely diploid tumours (average 15%) but this just failed to reach significance (P = 0.074). No relevant trends were noted for p53 expression. (iii) Significantly increased c-erbB-2 expression was observed in stage 2 tumours (26%) compared to stage 1 tumours (12%) (P = 0.001) with no trend evident for p53 expression. (iv) The metastatic tumour in the axillary node contained similar or slightly higher percentages of positive cells than the matched primary tumour.


Assuntos
Aneuploidia , Neoplasias da Mama/genética , DNA de Neoplasias/genética , Genes p53 , Proteínas Proto-Oncogênicas/análise , Proto-Oncogenes , Proteína Supressora de Tumor p53/análise , Neoplasias da Mama/patologia , Neoplasias da Mama/cirurgia , DNA de Neoplasias/análise , Feminino , Humanos , Excisão de Linfonodo , Metástase Linfática , Metástase Neoplásica , Estadiamento de Neoplasias , Proteínas Tirosina Quinases/análise , Proteínas Tirosina Quinases/genética , Proteínas Proto-Oncogênicas/genética , Receptor ErbB-2 , Proteína Supressora de Tumor p53/genética
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