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1.
J Dairy Sci ; 102(2): 1594-1600, 2019 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-30594355

RESUMO

Serum samples were obtained from Holstein dairy control cows and cows naturally infected with Mycobacterium avium ssp. paratuberculosis (MAP) to evaluate the effects of disease status on serum 25-hydroxyvitamin D3 (25OHD3) levels. Disease status was stratified for infected cows into asymptomatic, subclinical infection (n = 25), and cows demonstrating clinical signs (n = 20), along with noninfected control (n = 12) cows for comparison. In addition, portions of the ileocecal valve were taken from a subsample of cows (n = 5 per treatment group) at necropsy and processed for RNA sequencing gene transcription studies. Genes associated with vitamin D metabolism were queried to determine any association between infection and gene expression. Serum 25OHD3 levels were significantly lower in cows in the clinical stage of disease compared with either cows in the subclinical stage and noninfected control cows. Differential expression for genes associated with the vitamin D pathway such as CYP27A1, CYP27B1, vitamin D-binding protein (DBP), and IFNG was dependent upon infection status. An upregulation of CYP27A1 was noted for cows in subclinical status, whereas CYP27B1 expression was enhanced for clinical cows. Increased expression of vitamin D-binding protein was observed for infected cattle, regardless of infection status. In summary, decreases in circulating 25OHD3 for animals with clinical disease may suggest that these cows have reduced innate immune responses, thereby influencing the ability of animals to fight infection.


Assuntos
Calcifediol/sangue , Doenças dos Bovinos/fisiopatologia , Paratuberculose/fisiopatologia , Vitaminas/sangue , Animais , Bovinos , Doenças dos Bovinos/genética , Feminino , Expressão Gênica , Mycobacterium avium subsp. paratuberculosis/fisiologia , Vitamina D/genética , Vitaminas/genética
2.
BMJ Open ; 5(7): e008857, 2015 Jul 17.
Artigo em Inglês | MEDLINE | ID: mdl-26187121

RESUMO

INTRODUCTION: Only 30-40% of depressed patients treated with medication achieve full remission. Studies that change medication or augment it by psychotherapy achieve only limited benefits, in part because current treatments are not designed for chronic and complex patients. Previous trials have excluded high-risk patients and those with comorbid personality disorder. Radically Open Dialectical Behaviour Therapy (RO-DBT) is a novel, transdiagnostic treatment for disorders of emotional over-control. The REFRAMED trial aims to evaluate the effectiveness and cost-effectiveness of RO-DBT for patients with treatment-resistant depression. METHODS AND ANALYSIS: REFRAMED is a multicentre randomised controlled trial, comparing 7 months of individual and group RO-DBT treatment with treatment as usual (TAU). Our primary outcome measure is depressive symptoms 12 months after randomisation. We shall estimate the cost-effectiveness of RO-DBT by cost per quality-adjusted life year. Causal analyses will explore the mechanisms by which RO-DBT is effective. ETHICS AND DISSEMINATION: The National Research Ethics Service (NRES) Committee South Central - Southampton A first granted ethical approval on 20 June 2011, reference number 11/SC/0146. TRIAL REGISTRATION NUMBER: ISRCTN85784627.


Assuntos
Terapia Comportamental/métodos , Depressão/terapia , Terapia Comportamental/economia , Análise Custo-Benefício , Depressão/tratamento farmacológico , Depressão/economia , Resistência a Medicamentos , Humanos , Anos de Vida Ajustados por Qualidade de Vida , Projetos de Pesquisa , Retratamento
3.
Int J Hypertens ; 2013: 329602, 2013.
Artigo em Inglês | MEDLINE | ID: mdl-23984047

RESUMO

We examined 33 hypertensive (22 with comorbid type 2 diabetes mellitus (T2DM)) and 29 normotensive (8 with T2DM) middle-aged and elderly adults, comparable in age and education. Relative to normotensive participants, those with hypertension, in addition to a higher prevalence of periventricular white matter (WM) lesions, had significantly lower WM microstructural integrity of major fiber tracts as seen with MRI-based diffusion tensor imaging. Among participants with hypertension, those with co-morbid T2DM (n = 22) had more widespread WM pathology than those without T2DM (n = 11). Furthermore and consistent with previous research, both hypertension and T2DM were related to decreased retinal arterial diameter. Further exploratory analysis demonstrated that the observed retinal arteriolar narrowing among individual with hypertension was associated with widespread subclinical losses in WM microstructural integrity and these associations were present predominantly in the frontal lobe. We found that T2DM adds to the damaging effects of hypertension on cerebral WM, and notably these effects were independent of age and body mass index. Given that the decrease in retinal arteriolar diameter may be a biomarker for parallel pathology in cerebral arterioles, our data suggest that the frontal lobe may be particularly vulnerable to microvascular damage in the presence of hypertension and T2DM.

4.
Clin Radiol ; 68(7): e391-6, 2013 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-23537577

RESUMO

AIM: To evaluate radiation exposure for 64-row computed tomography (CT) of the cervical spine comparing two optimized protocols using filtered back projection (FBP) and adaptive statistical iterative reconstruction (ASIR), respectively. MATERIALS AND METHODS: Sixty-seven studies using FBP (scanner 1) were retrospectively compared with 80 studies using ASIR (scanner 2). The key scanning parameters were identical (120 kV dose modulation, 64 × 0.625 mm collimation, pitch 0.531:1). In protocol 2, the noise index (NI) was increased from 5 to 25, and ASIR and the high-definition (HD) mode were used. The scan length, CT dose index (CTDI), and dose-length product (DLP) were recorded. The image quality was analysed subjectively by using a three-point scale (0; 1; 2), and objectively by using a region of interest (ROI) analysis. Mann-Whitney U and Wilcoxon's test were used. RESULTS: In the FBP group, the mean CTDI was 21.43 mGy, mean scan length 186.3 mm, and mean DLP 441.15 mGy cm. In the ASIR group, the mean CTDI was 9.57 mGy, mean scan length 195.21 mm, and mean DLP 204.23 mGy cm. The differences were significant for CTDI and DLP (p < 0.001) and scan length (p = 0.01). There was no significant difference in the subjective image quality (p > 0.05). The estimated mean effective dose decreased from 2.38 mSv (FBP) to 1.10 mSv (ASIR). CONCLUSION: The radiation dose of 64-row MDCT can be reduced to a level comparable to plain radiography without loss of subjective image quality by implementation of ASIR in a dedicated cervical spine trauma protocol. These results might contribute to an improved relative risk-to-benefit ratio and support the justification of CT as a first-line imaging tool to evaluate cervical spine trauma.


Assuntos
Vértebras Cervicais/lesões , Tomografia Computadorizada Multidetectores/métodos , Vértebras Cervicais/diagnóstico por imagem , Vértebras Cervicais/efeitos da radiação , Protocolos Clínicos , Feminino , Humanos , Processamento de Imagem Assistida por Computador/métodos , Masculino , Pessoa de Meia-Idade , Doses de Radiação , Estudos Retrospectivos , Razão Sinal-Ruído , Estatísticas não Paramétricas
5.
Diabetes Metab Res Rev ; 28(1): 76-83, 2012 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-21695767

RESUMO

BACKGROUND: Type 2 diabetes mellitus (T2DM) has been shown to result in medical complications on several organ systems including the kidneys, eyes, cardiovascular system, and most recently described the brain, including the hippocampus. There is also evidence that females are disproportionately affected by these medical complications. Brain volume reductions have also been associated with chronic low-grade inflammation and dyslipidaemia. This study investigated the relationships among T2DM, gender, inflammation, dyslipidaemia, and hippocampal volumes. METHOD: Participant groups consisted of 40 obese adults with T2DM and 47 lean adults, group-matched on age, gender, race, and education. Each participant underwent medical examination including a standard panel of blood tests, a magnetic resonance imaging, and cognitive evaluation. RESULTS: We show that there is a gender difference in the association of T2DM and hippocampal volumes: diabetic women are most affected despite having better glucose control than their male counterparts. Although females with T2DM had disproportionately lower high density lipoprotein as well as better haemoglobin A1c, neither of these results explained why females with T2DM had the smallest hippocampal volumes. CONCLUSIONS: These important findings indicate that in addition to the higher rate of traditional medical complication, females with T2DM are likely to suffer more brain complications than males. These observations, if supported by larger studies, suggest that in the future gender could be considered when customizing diabetes treatment.


Assuntos
Diabetes Mellitus Tipo 2/patologia , Hipocampo/patologia , Idoso , Diabetes Mellitus Tipo 2/complicações , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Tamanho do Órgão , Fatores Sexuais
6.
J Psychopharmacol ; 23(6): 697-707, 2009 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-18562420

RESUMO

This study aimed to investigate the effects of treatment with haloperidol, olanzapine and risperidone on cardiovascular variability in patients with recent-onset schizophrenia by means of spectral analysis. Unmedicated patients (n = 18) had a higher mean heart rate and a tendency for a lower high-frequency power of heart rate variability than healthy control subjects (n = 57), indicating a decreased cardiac vagal control in unmedicated patients with schizophrenia. Patients treated with haloperidol (n = 10) showed significantly lower low-frequency power of heart rate and systolic blood pressure variability compared with olanzapine-treated patients, suggesting that haloperidol attenuated sympathetic functioning. On the contrary, olanzapine-treated patients (n = 10) showed the highest power in the low-frequency range of heart rate and systolic blood pressure variability, suggesting an increased sympathetic cardiac functioning. No significant effects of risperidone (n = 13) were found. None of the antipsychotic agents differed in their parasympathetic cardiovascular effects. We conclude that young, unmedicated patients with schizophrenia differed from controls in their parasympathetic functioning, but the antipsychotic agents haloperidol, risperidone and olanzapine induced only minor cardiovascular side effects.


Assuntos
Antipsicóticos/efeitos adversos , Benzodiazepinas/efeitos adversos , Haloperidol/efeitos adversos , Hemodinâmica/efeitos dos fármacos , Risperidona/efeitos adversos , Esquizofrenia/fisiopatologia , Adulto , Antipsicóticos/uso terapêutico , Benzodiazepinas/uso terapêutico , Pressão Sanguínea/efeitos dos fármacos , Eletrocardiografia/efeitos dos fármacos , Feminino , Haloperidol/uso terapêutico , Frequência Cardíaca/efeitos dos fármacos , Humanos , Masculino , Olanzapina , Escalas de Graduação Psiquiátrica , Risperidona/uso terapêutico , Esquizofrenia/tratamento farmacológico , Caracteres Sexuais , Fumar/psicologia , Adulto Jovem
7.
Heredity (Edinb) ; 99(4): 414-22, 2007 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-17551520

RESUMO

In early 1992, the European bumblebee, Bombus terrestris, was first seen in Tasmania and currently has spread to most of the island. Here, we report on the genetic structure, using micro-satellites, of the invading population from samples collected in the years 1998-2000, a few years after the first sighting of the species in its new area. The data show that the Tasmanian population has a very low genetic diversity, with less than half of the allelic richness (Richness=2.89 alleles; H(exp)=0.591) and lower levels of heterozygosity as compared to populations in New Zealand (4.24 alleles; H(exp)=0.729) and Europe (5.08 alleles; H(exp)=0.826). In addition, the genetic data suggest that the invasion must have happened once, probably around late 1991, and was the result of very few, perhaps only two, individuals arriving in Tasmania. Furthermore, these founders came from the New Zealand population. Today, the population in the south of Tasmania seems to act as a source population from which individuals migrate into other parts of the state. A similar source-sink structure seems also the case for New Zealand. The data show that B. terrestris is a highly invasive species capable of establishing itself even after a dramatic genetic bottleneck. B. terrestris may be an invasive species due to the haplo-diploid sex determination system, which exposes recessive, deleterious mutations to selection. Offspring of such purged lines may then be able to tolerate high levels of inbreeding.


Assuntos
Abelhas/genética , Abelhas/fisiologia , Modelos Genéticos , Alelos , Animais , Análise por Conglomerados , Cruzamentos Genéticos , Diploide , Variação Genética , Genética Populacional , Geografia , Heterozigoto , Repetições de Microssatélites/genética , Nova Zelândia , Filogenia , Tasmânia
8.
Poult Sci ; 85(11): 1980-6, 2006 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-17032833

RESUMO

The objective of this study was to explore the homeostatic response of jejunal and renal epithelia regarding the inorganic phosphate (P(i)) transport capacities to variations in dietary total phosphorus (tP) supply in hens. Adaptive processes were determined by quantitative measures of intake and excretion, P(i) transport studies across brush border membranes, and semiquantitative detection of sodium-dependent phosphate transporters (NaPi II) based on mRNA expression in the jejunum and kidney. Twelve hens (4/group) were adapted to 3 tP feeding levels in a pair-fed manner (60 g/d): low P diet with 0.073% tP, medium P diet with 0.204% tP, and high P diet with 0.343% tP. Excretion was measured during the last 5 d of a 16-d feeding period. After slaughtering, jejunal mucosa and renal cortex were removed. Tissues were used for (32)P uptake studies in brush-border membrane vesicles by rapid filtration technique and NaPi II mRNA expression studies by northern analyses. Plasma P(i) concentrations were additionally measured. The NaPi II transporter mRNA could specifically be detected in chicken jejunum and kidney. Functional parameters of Na(+)-dependent P(i) transport indicated that these transporters were involved in chicken P(i) transport across the apical membranes of jejunal and renal epithelia. Increased tP intake resulted in an increased overall tP excretion. Correlating individual data from all animals by linear regression highlighted that the adaptive decrease of renal P(i) transport capacity and NaPi IIa mRNA expression was associated with an increase in plasma P(i) levels and resulted in a higher tP excretion. Jejunal P(i) transport capacity and NaPi IIb mRNA expression did not react to variations in dietary tP supply. In conclusion, the homeostatic response was mainly based on the adaptive capacity of the kidney in hens.


Assuntos
Aclimatação , Galinhas/metabolismo , Jejuno/metabolismo , Córtex Renal/metabolismo , Fosfatos/metabolismo , Fósforo na Dieta/administração & dosagem , Animais , Relação Dose-Resposta a Droga , Feminino , Mucosa Intestinal/metabolismo , Fosfatos/administração & dosagem , Fosfatos/farmacocinética , Radioisótopos de Fósforo , Fósforo na Dieta/metabolismo , Fósforo na Dieta/farmacocinética , RNA Mensageiro/metabolismo , Distribuição Aleatória , Proteínas Cotransportadoras de Sódio-Fosfato/metabolismo , Simportadores
9.
Br Poult Sci ; 47(3): 311-21, 2006 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-16787855

RESUMO

1. The objective was to study the effects of a supplementation of a 6-phytase derived from the Peniophora lycii gene in the White Pekin duck. 2. In two balance studies, low-phosphorus (P) diets consisting mainly of maize, solvent extracted soybean meal and solvent extracted sunflower meal were supplemented with phytase up to concentrations of 1500 U/kg (Study 1) or 2000 U/kg (Study 2). Each diet (phytase level) was fed to 8 to 10 individually penned ducks. The intake and excretion of each animal was measured for 5 consecutive days when ducks were in their third week of life. Responses were described by nonlinear regression. 3. Although the basal diets from the two studies were similar in ingredient composition, efficiencies of P utilisation (P accretion/P intake x 100) for the unsupplemented basal diets were 39% in Study 1 and 30% in Study 2. Phytase supplementation significantly improved P utilisation up to levels of about 55% in both studies. A plateau in P utilisation with an increase in phytase supplementation was achieved in Study 2, but not in Study 1. The enzyme was more efficient in Study 2 than in Study 1 at low rates of supplementation. Utilisation of calcium (Ca) was significantly improved by phytase supplementation. Accretions of P and Ca increased at a constant ratio. 4. In a 5-week growth study, diets with an intentionally marginal P level were used. Diets were fed either unsupplemented or supplemented with 1000 or 10,000 U/kg of phytase. Eight pens of 10 sex-separated ducks each (4 pens per sex) were allocated to each dietary treatment. 5. Phytase significantly improved the growth of ducks of both sexes between d 1 and 21, but not between d 22 and 35. Feed conversion rate was not affected by treatment. Blood serum phosphate concentrations, but not calcium, were significantly increased by phytase supplementation. Blood concentrations of creatinine, aspartate aminotransferase and lactate dehydrogenase remained unaffected while alanine aminotransferase was significantly reduced by phytase supplementation. 6. It was concluded that the efficacy of a microbial phytase varies even under similar experimental conditions. Differences in intrinsic phytase activity of maize/soybean meal-based diets may be responsible for this. The 6-phytase used has the potential to improve the utilisation of plant P in duck feeding. A plateau in response was reached above 1500 U/kg.


Assuntos
6-Fitase/farmacologia , Cálcio/sangue , Cálcio/metabolismo , Patos/crescimento & desenvolvimento , Fósforo/sangue , Fósforo/metabolismo , Aumento de Peso/efeitos dos fármacos , Ração Animal , Animais , Dieta , Suplementos Nutricionais , Relação Dose-Resposta a Droga , Patos/sangue , Feminino , Masculino
10.
Adv Ther ; 22(3): 263-77, 2005.
Artigo em Inglês | MEDLINE | ID: mdl-16236687

RESUMO

Only a minority of patients treated for hypertension achieve controlled blood pressure (BP) levels. Therapy with fixed-dose combinations of an angiotensinreceptor blocker (ARB) and low-dose hydrochlorothiazide (HCTZ) is commonly prescribed but not always sufficient to achieve the target BP. The efficacy and safety of the fixed-dose combination of valsartan 160 mg and HCTZ 25 mg was evaluated in patients in whom BP had not been controlled with a fixed-dose combination of another ARB and low-dose HCTZ (12.5 mg) in a multicenter trial. After a wash-out period for antihypertensive drugs, patients with a mean sitting diastolic BP (DBP) at trough (3)100 mm Hg but <110 mm Hg were treated with candesartan cilexetil 16 mg plus HCTZ 12.5 mg or telmisartan 80 mg plus HCTZ 12.5 mg for 4 weeks (phase 1). Patients whose BP was still uncontrolled (DBP (3)90 mm Hg) after 4 weeks of therapy were then given valsartan 160 mg plus HCTZ 25 mg for an additional 4 weeks (phase 2). The primary efficacy parameter was the reduction in DBP between week 4 and week 8 in the intention-to-treat (ITT) population. BP reduction during phase 1 was -14.3+/-11.3/-7.5+/-3.9 mm Hg. DBP was controlled in 26% of the patients after phase 1. In patients treated with valsartan 160 mg plus HCTZ 25 mg during phase 2, DBP decreased by an additional 10.3+/-6.5 mm Hg and the mean sitting systolic BP (SBP) by an additional 11.0+/-11.7 mm Hg. The additional decrease was significant (P<.0001) for both parameters and independent of the fixed-dose combination used during phase 1. Among patients whose BP remained uncontrolled during phase 1, 74% achieved a controlled DBP after phase 2. The incidence of adverse events during both phases was comparably low and the results of laboratory tests were unremarkable. Treatment with valsartan 160 mg/HCTZ 25 mg offered a substantial benefit for patients with hypertension not controlled with the combination of candesartan cilexetil 16 mg or telmisartan 80 mg and low dose HCTZ, while maintaining a comparable safety and tolerability profile.


Assuntos
Bloqueadores do Receptor Tipo 1 de Angiotensina II/administração & dosagem , Anti-Hipertensivos/administração & dosagem , Hidroclorotiazida/administração & dosagem , Hipertensão/tratamento farmacológico , Tetrazóis/administração & dosagem , Valina/análogos & derivados , Adulto , Idoso , Bloqueadores do Receptor Tipo 1 de Angiotensina II/efeitos adversos , Anti-Hipertensivos/efeitos adversos , Anti-Hipertensivos/farmacologia , Benzimidazóis/administração & dosagem , Benzimidazóis/farmacologia , Benzoatos/administração & dosagem , Benzoatos/farmacologia , Compostos de Bifenilo , Estudos Cross-Over , Relação Dose-Resposta a Droga , Combinação de Medicamentos , Feminino , Humanos , Hidroclorotiazida/efeitos adversos , Hidroclorotiazida/farmacologia , Masculino , Pessoa de Meia-Idade , Telmisartan , Tetrazóis/efeitos adversos , Tetrazóis/farmacologia , Valina/administração & dosagem , Valina/efeitos adversos , Valsartana
11.
Mol Ecol ; 12(6): 1599-605, 2003 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-12755887

RESUMO

Social insect colonies provide model systems for the examination of conflicts among parties with different genetic interests. As such, they have provided the best tests of inclusive fitness theory. However, much remains unknown about in which party's favour such conflicts are resolved, partly as a result of the only recent advent of the molecular tools needed to examine the outcome of these conflicts. Two key conflicts in social insect colonies are over control of the reproductive sex ratio and the production of male offspring. Most studies have examined only one of these conflicts but in reality they occur in tandem and may influence each other. Using microsatellite analyses, the outcome of conflict over sex ratios and male production was examined in the bumble bee, Bombus hypnorum. The genotypes were determined for mother queens, their mates and males for each of 10 colonies. In contrast to other reports of mating frequency in this species, all of the queens were singly mated. The population sex ratio was consistent with queen control, suggesting that queens are winning this conflict. In contrast, workers produced over 20% of all males in queen-right colonies, suggesting that they are more effective in competing over male-production. Combining these results with previous work, it is suggested that worker reproduction is a labile trait that may well impose only small costs on queen fitness.


Assuntos
Abelhas/genética , Abelhas/fisiologia , Razão de Masculinidade , Comportamento Sexual Animal/fisiologia , Predomínio Social , Alelos , Animais , Primers do DNA , Eletroforese , Feminino , Finlândia , Masculino , Repetições de Microssatélites/genética , Reprodução/fisiologia , Suécia
12.
Anal Biochem ; 297(2): 177-82, 2001 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-11673885

RESUMO

The properties of M-hirudin as a new reporter gene system were examined using rabbit reticulocyte lysate for cell-free protein expression. In contrast to the luciferase gene, in vitro translation of M-hirudin is highly robust against changes in concentrations of K+ (and Rb+). In addition, M-hirudin can be detected very sensitively using a reasonably priced fluorimetric thrombin assay. To show that the new reporter gene system is well suited for (u)HTS-applications, cell-free synthesis as well as the fluorimetric assay of M-hirudin were carried out in nanotiter and microtiter plates, respectively.


Assuntos
Avaliação Pré-Clínica de Medicamentos/métodos , Genes Reporter/genética , Hirudinas/genética , Hirudinas/metabolismo , Potássio/metabolismo , RNA Antissenso/análise , Trombina/análise , Animais , Antivirais/análise , Sistema Livre de Células/metabolismo , Fluorometria/métodos , Hirudinas/farmacologia , Luciferases/análise , Luciferases/genética , Biossíntese de Proteínas/genética , Biossíntese de Proteínas/fisiologia , RNA Viral/análise , Coelhos , Rubídio/metabolismo , Trombina/antagonistas & inibidores
13.
Drug Metab Dispos ; 29(6): 855-62, 2001 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-11353754

RESUMO

The excretion and biotransformation of rac-alpha-lipoic acid (LA), which is used for the symptomatic treatment of diabetic polyneuropathy, were investigated following single oral dosing of [(14)C]LA to mice (30 mg/kg), rats (30 mg/kg), dogs (10 mg/kg), and unlabeled LA to humans (600 mg). More than 80% of the radioactivity given was renally excreted. Metabolite profiles obtained by radiometric high-performance liquid chromatography revealed that LA was extensively metabolized irrespective of the species. Based on a new on-line liquid chromatography/tandem mass spectroscopy assay developed for negative ions, LA and a total of 12 metabolites were identified. Mitochondrial beta-oxidation played the paramount role in the metabolism of LA. Simultaneously, the circulating metabolites were subjected to reduction of the 1,2-dithiolane ring and subsequent S-methylation. In addition, evidence is given for the first time that the methyl sulfides formed were partly oxidized to give sulfoxides, predominantly in dogs. The disulfoxide of 2,4-bismethylmercapto-butanoic acid, the most polar metabolite identified, was the major metabolite in dogs. Furthermore, new data are presented that suggest conjugation with glycine occurred as a separate metabolic pathway in competition with beta-oxidation, predominantly in mice.


Assuntos
Ácido Tióctico/farmacocinética , Animais , Cromatografia Líquida de Alta Pressão , Cães , Humanos , Espectrometria de Massas , Camundongos , Oxirredução , Ratos , Padrões de Referência , Ácido Tióctico/urina
14.
Biochem Biophys Res Commun ; 283(2): 267-72, 2001 May 04.
Artigo em Inglês | MEDLINE | ID: mdl-11327692

RESUMO

The effect of monovalent cation concentrations on the translation was examined in the rabbit reticulocyte cell-free system. The translation of standard reporter gene luciferase was studied using different concentrations of LiCl, NaCl, KCl, RbCl, CsCl, NH(4)Cl, and (CH(3))(4)NCl and the acetates of Na(+), K(+), and NH4(+). Only the salts of K(+), Rb(+), and NH4(+) and to some minor extent of Cs(+) significantly supported translation. Optimum concentrations were dependent on the cation used. Optimum concentrations ranged between 40 mM (NH(4)Ac), 80 mM (KCl, NH(4)Cl), and 100 mM (RbCl, KAc). The maximum efficiency of translation depends on the ionic radius of the cation used. KCl and RbCl were superior to all other salts tested in stimulating in vitro translation. The results were confirmed, using a second reporter system, M-hirudin. Here, however, broad optima were observed with RbCl being slightly superior to KCl in supporting translation.


Assuntos
Cátions Monovalentes/farmacologia , Biossíntese de Proteínas/efeitos dos fármacos , Reticulócitos/metabolismo , Animais , Cátions Monovalentes/química , Sistema Livre de Células , Genes Reporter , Hirudinas/genética , Técnicas In Vitro , Luciferases/genética , Coelhos
15.
Drug Metab Dispos ; 28(1): 10-20, 2000 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-10611134

RESUMO

Disposition and metabolism of cetrorelix was studied in intact and bile duct-cannulated rats and dogs after s.c. injection. An s.c. dose of 0.1 mg/kg [(14)C]cetrorelix was rapidly and completely absorbed in rats. T(max) in plasma and most tissues was at 2 h. Radioactivity at the injection site in rats declined to 10% by 24 h. The extent of (14)C absorption in rats calculated from excretion until 264 h was 94%. Exposure of the target organ pituitary gland was demonstrated with a time course similar to plasma but on a higher level. Rats excreted 69.6% of radioactivity via feces and 24. 3% into urine. Excretion was nearly complete within 48 h. No enteral reabsorption was detected. In dogs t(max) in plasma was 1.3 h. (14)C- and cetrorelix-plasma levels were similar until 24 h, indicating a negligible amount of metabolites. A dose of 1 mg/kg in dogs showed an increasing influence of a slow absorption phase (flip-flop). In dogs equal amounts of the (14)C dose were found within 192 h in feces and urine, 46 and 48%, respectively. In urine of both species, only intact cetrorelix was detected. In bile and feces of both species qualitatively the same metabolites were found, characterized as truncated peptides of the parent decapeptide. The major metabolite occurring in bile of both species was the (1-7)heptapeptide. The amounts of the (1-4)tetrapeptide in feces of rats but not in that of dogs increase with time, suggesting additional degradation of the peptide in the gastrointestinal tract of rats by enteric metabolization.


Assuntos
Hormônio Liberador de Gonadotropina/análogos & derivados , Hormônio Liberador de Gonadotropina/antagonistas & inibidores , Antagonistas de Hormônios/farmacocinética , Absorção , Animais , Radioisótopos de Carbono/metabolismo , Cães , Feminino , Hormônio Liberador de Gonadotropina/administração & dosagem , Hormônio Liberador de Gonadotropina/farmacocinética , Antagonistas de Hormônios/administração & dosagem , Injeções Subcutâneas , Masculino , Ratos , Ratos Wistar , Distribuição Tecidual
16.
Drug Metab Dispos ; 27(5): 613-22, 1999 May.
Artigo em Inglês | MEDLINE | ID: mdl-10220491

RESUMO

Retigabine (D-23129, N-(2-amino-4-(4-fluorobenzylamino)-phenyl) carbamic acid ethyl ester) is a potent anticonvulsant in a variety of animal models. Rats metabolized [14C]retigabine mainly through glucuronidation and acetylation reactions. Glucuronides were detected in incubates with liver microsomes or slices, in plasma, and in bile and feces but were absent in urine (0-24 h) that contained about 2% of the dose as retigabine and approximately 29% of the dose in > 20 metabolites, which are derived mainly from acetylation reactions. About 67% of the radioactivity was excreted into feces, approximately 10% of the dose as glucuronide. The metabolite pattern in the urine (0-24 h) of dogs was comparatively simple in that retigabine (13%), retigabine-N-glucuronide (5%), and retigabine-N-glucoside (1%) were present. In the same 24-h interval, about 39% of unchanged retigabine was excreted into feces. Plasma profiling and spectroscopic analysis (liquid chromatography with tandem mass spectrometry NMR) of two isolated urinary metabolites obtained after single oral dosing of 600 mg retigabine in healthy volunteers indicated that both acetylation and glucuronidation are major metabolic pathways of retigabine in humans. We found that in vitro assays with liver slices from rat and humans reveal the major circulating metabolites in vivo.


Assuntos
Anticonvulsivantes/metabolismo , Carbamatos/metabolismo , Fenilenodiaminas/metabolismo , Animais , Bile/metabolismo , Radioisótopos de Carbono , Cromatografia Líquida de Alta Pressão , Cães , Glucuronatos/metabolismo , Humanos , Masculino , Microssomos Hepáticos/metabolismo , Ressonância Magnética Nuclear Biomolecular , Radiometria , Ratos , Ratos Wistar
17.
J Neurosci Res ; 50(5): 729-42, 1997 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-9418961

RESUMO

It has previously been shown that nerve growth factor (NGF) is of functional significance for mature pig oligodendrocytes (OLs) in culture. The present data give evidence for the expression of TrkA, the so-called high-affinity NGF receptor, and of p75NTR, the so-called low-affinity NGF receptor. TrkA is upregulated during culturing, in contrast to the p75 receptor. Exposure of OLs to NGF induces an autophosphorylation of TrkA via its intrinsic tyrosine kinase. K-252a inhibits the TrkA autophosphorylation, which reduces the OL process formation to control levels. To the tyrosine-phosphorylated sites of TrkA several proteins, such as phospholipase C-gamma1, the adaptor protein SHC, the phosphotyrosine phosphatase SH-PTP2 (SYP) associate via their SH2 phosphotase SH-PTP2 domain. The association of SHC to TrkA is shown by co-immunoprecipitation. Indirect evidence for a possible activation of PLC-gamma1 is given by an NGF-induced increase of oligodendroglial [Ca2+]i. Downstream from TrkA, a mitogen-activated protein kinase cascade, which includes Erk1 and Erk2, is operating. An in-gel myelin basic protein kinase assay revealed that NGF activates predominantly Erk1. Finally, it is shown that NGF stimulates expression of c-fos.


Assuntos
Encéfalo/fisiologia , Fatores de Crescimento Neural/farmacologia , Oligodendroglia/fisiologia , Proteínas Proto-Oncogênicas/fisiologia , Receptores Proteína Tirosina Quinases/fisiologia , Receptores de Fator de Crescimento Neural/fisiologia , Transdução de Sinais/efeitos dos fármacos , Animais , Cálcio/metabolismo , Proteínas Quinases Dependentes de Cálcio-Calmodulina/metabolismo , Carbazóis/farmacologia , Células Cultivadas , Quinase 3 da Glicogênio Sintase , Alcaloides Indólicos , Peptídeos e Proteínas de Sinalização Intracelular , Isoenzimas/metabolismo , Oligodendroglia/citologia , Oligodendroglia/efeitos dos fármacos , Fosforilação , Proteína Quinase C/metabolismo , Proteína Tirosina Fosfatase não Receptora Tipo 11 , Proteína Tirosina Fosfatase não Receptora Tipo 6 , Proteínas Tirosina Fosfatases/metabolismo , Proteínas Tirosina Quinases/metabolismo , Proteínas Proto-Oncogênicas/biossíntese , Proteínas Proto-Oncogênicas c-fos/biossíntese , Receptores Proteína Tirosina Quinases/biossíntese , Receptor de Fator de Crescimento Neural , Receptor trkA , Receptores de Fator de Crescimento Neural/biossíntese , Suínos , Regulação para Cima
18.
J Mass Spectrom ; 31(12): 1371-81, 1996 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-8990520

RESUMO

A new specific HPLC-TSP-MS/MS assay for identification of beta-blocking drug talinolol and its metabolites in urinary samples of man, dog, rat and mouse after single oral administration has been developed. Centrifuged urines were directly injected into the HPLC-TSP-MS system. Based on thermospray MS/MS studies of 10 reference compounds, several selective CID-MS/MS reactions were found, which were typical of substructure elements of potential phase I metabolites. In this way the differentiation of various stereochemical positions of the hydroxyl group in the cyclohexyl ring moiety of metabolites was possible. Renal metabolic profiles for all investigated species were generated by HPLC-multiple reaction monitoring (MRM). The detected metabolites were characterized by TSP full scan and MS/MS analysis in relation to synthesized reference compounds. The major metabolic pathway in all species results in the hydroxylation of the cyclohexylring moiety of talinolol. In dog urine, a phase II metabolite, the O-glucuronide of talinolol (I) was found. In order to identify this structure, the use of electrospray ionization was also necessary.


Assuntos
Antagonistas Adrenérgicos beta/urina , Propanolaminas/urina , Antagonistas Adrenérgicos beta/química , Antagonistas Adrenérgicos beta/farmacocinética , Animais , Biotransformação , Cromatografia Líquida de Alta Pressão , Cães , Humanos , Hidrólise , Espectrometria de Massas , Camundongos , Propanolaminas/química , Propanolaminas/farmacocinética , Ratos , Espectrofotometria Ultravioleta
19.
J Am Board Fam Pract ; 5(5): 483-7, 1992.
Artigo em Inglês | MEDLINE | ID: mdl-1414449

RESUMO

BACKGROUND: Increasing seat belt use represents an ideal opportunity for preventive health care in family practice. Little evidence exists, however, that primary care physicians can increase safety belt use. METHODS: Three hundred twenty-six patients seen in a rural primary care center were randomized to either a control or intervention group. Before their health care examination, patients completed a short questionnaire concerning seat belt use and then viewed a 6-minute videotape explaining reasons to wear seat belts (intervention) or espousing general preventive health care guidelines with no mention of seat belts (control). In 6 months the questionnaire was again administered with no further intervention. RESULTS: Two hundred forty-three (74.5 percent) patients completed both baseline and 6-month questionnaires. Seat belt use increased significantly from baseline to 6 months for the intervention (22 to 37.3 percent, P = 0.00052) and control (20 to 33.6 percent, P = 0.00085) groups; however, the difference between the increase in the intervention (37.3 percent) and control (33.6 percent) groups at 6 months was insignificant (P = 0.641). The most common reasons for not using seat belts were forgetfulness (40.3 percent), fear of being trapped (26.7 percent), and lack of comfort (21.8 percent). CONCLUSIONS: Seat belt use increased in this study, although the intervention videotape was no better than the control videotape at increasing restraint use. This increase in use supports office-based intervention to improve seat belt use, but further research is needed to clarify the mechanism and extent of change possible.


Assuntos
Medicina de Família e Comunidade/normas , Educação de Pacientes como Assunto/normas , Cintos de Segurança/estatística & dados numéricos , Adulto , Medicina de Família e Comunidade/métodos , Feminino , Humanos , Masculino , Educação de Pacientes como Assunto/métodos , Saúde da População Rural , Inquéritos e Questionários , Gravação de Videoteipe/normas
20.
South Med J ; 83(12): 1426-32, 1990 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-2251531

RESUMO

We assessed two interventions designed to improve the care of patients with diabetes mellitus by documenting the complications of their disease. These were a flow sheet, included with outpatient medical records, and a weekly patient education clinic, in which a nurse educator provided individualized instruction to patients with diabetes. Physician compliance with recommendations of the National Diabetes Advisory Board for diabetes care was measured before (n = 45) and after (n = 158) these interventions. The numbers of referrals to ophthalmologists increased from 22% to 46%, urinalyses increased from 58% to 77%, and lower extremity examinations increased from 36% to 61%. Nutrition education documentation increased from 51% to 69%, and diabetes education documentation increased from 31% to 61%. These results suggest that a significant improvement in physicians' documentation of care of patients with diabetes can be achieved by using a flow sheet and a diabetes patient education clinic.


Assuntos
Instituições de Assistência Ambulatorial , Complicações do Diabetes , Medicina de Família e Comunidade/normas , Anamnese/normas , Prontuários Médicos/normas , Educação de Pacientes como Assunto/métodos , Adulto , Diabetes Mellitus/terapia , Diabetes Mellitus/urina , Retinopatia Diabética/terapia , Retinopatia Diabética/urina , Estudos de Avaliação como Assunto , Feminino , Doenças do Pé/etiologia , Doenças do Pé/terapia , Doenças do Pé/urina , Humanos , Masculino , Pessoa de Meia-Idade , Fenômenos Fisiológicos da Nutrição , Oftalmologia , Cooperação do Paciente , Encaminhamento e Consulta , Estudos Retrospectivos
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