RESUMO
The identification of the causative genetic variants in quantitative trait loci (QTL) influencing phenotypic traits is challenging, especially in crosses between outbred strains. We have previously identified several QTL influencing tameness and aggression in a cross between two lines of wild-derived, outbred rats (Rattus norvegicus) selected for their behavior towards humans. Here, we use targeted sequence capture and massively parallel sequencing of all genes in the strongest QTL in the founder animals of the cross. We identify many novel sequence variants, several of which are potentially functionally relevant. The QTL contains several regions where either the tame or the aggressive founders contain no sequence variation, and two regions where alternative haplotypes are fixed between the founders. A re-analysis of the QTL signal showed that the causative site is likely to be fixed among the tame founder animals, but that several causative alleles may segregate among the aggressive founder animals. Using a formal test for the detection of positive selection, we find 10 putative positively selected regions, some of which are close to genes known to influence behavior. Together, these results show that the QTL is probably not caused by a single selected site, but may instead represent the joint effects of several sites that were targets of polygenic selection.
Assuntos
Agressão , Locos de Características Quantitativas , Seleção Genética , Alelos , Animais , Sequência de Bases , Feminino , Variação Genética , Genoma , Sequenciamento de Nucleotídeos em Larga Escala , Masculino , Análise de Sequência com Séries de Oligonucleotídeos , Fenótipo , Polimorfismo de Nucleotídeo Único , Ratos , Análise de Sequência de DNARESUMO
Haemorrhagic disorders must be excluded prior to any operation or other invasive procedure that has the potential to involve serious bleeding. When assessing the individual risk of bleeding, screening tests of hemostasis must be combined with the patient's clinical history and symptoms, and any history of bleeding must be explored under direct medical supervision using a standardized questionnaire. However, this bleeding history is neither very specific, nor is it particularly sensitive. Screening tests that have been found to be useful include platelet count, activated partial thrombo plastin time (aPTT), prothrombin time (PT) and clottable fibrinogen. No reliable, sensitive and specific screening test is however available today to screen for platelet dysfunction or von Willebrand disease. A specialized coagulation laboratory should be involved when the bleeding history or laboratory screening indicate a potential haemorrhagic disorder.
Assuntos
Procedimentos Cirúrgicos Eletivos , Hemostasia , Cuidados Pré-Operatórios , Fatores de Coagulação Sanguínea/análise , Fibrinogênio/análise , Hemorragia/prevenção & controle , Humanos , Complicações Intraoperatórias/sangue , Complicações Intraoperatórias/prevenção & controle , Anamnese , Tempo de Tromboplastina Parcial , Contagem de Plaquetas , Tempo de Protrombina , Doenças de von Willebrand/diagnósticoRESUMO
BACKGROUND: In allogeneic kidney transplantation the response to cyclosporine A (CsA) is important for graft outcome. Although CsA therapy is controlled by drug monitoring to ensure therapeutic CsA levels, the sensitivity to the effects of CsA varies among individuals. Since CsA is an antagonist of cytostatic drugs in P-glycoprotein (Pgp)-mediated transport, increased Pgp expression might contribute to an increased resistance to CsA. METHODS: The sensitivity of lymphocytes at three different concentrations of CsA was tested in a non-radioactive lymphocyte-transformation test and related to Pgp expression as determined by flow cytometry on mononuclear cells. Five groups, including healthy donors (CON; n = 25), patients on dialysis (DIAL; n = 25), patients before transplantation (PTX; n = 5) and after transplantation [short-term (ATX; n = 5) and long-term (LTX; n = 25)] were investigated. RESULTS: In LTX, the sensitivity to CsA at 400 and 1000 ng/ml was significantly different from CON and DIAL. Overall a higher sensitivity to CsA was seen in patients after transplantation. In ATX, sensitivity to CsA was significantly higher than in PTX at a concentration of 1000 ng/ml CsA. However, comparing all groups no significant changes in Pgp expression were noted. Analysing the relationship between CsA sensitivity and Pgp expression, no significant heterogeneity could be observed between the different groups. CONCLUSION: In conclusion, our data suggest that in vitro testing of CsA sensitivity prior transplantation and Pgp expression monitoring yield independent results and cannot substitute for each other as predictors of graft outcome. The differential role of each test for the evaluation of CsA sensitivity or resistance remains to be determined.
Assuntos
Membro 1 da Subfamília B de Cassetes de Ligação de ATP/análise , Ciclosporina/farmacologia , Imunossupressores/farmacologia , Transplante de Rim , Ativação Linfocitária/efeitos dos fármacos , Diálise Renal , Humanos , Técnicas In VitroRESUMO
Cyclosporine (CSA)-associated arteriolopathy (CAA) is the second most frequent morphological diagnosis in renal allografts and its final outcome remains unclear. The present study was performed to clarify the morphological outcome of CAA by follow-up histological analysis after stopping CSA. Furthermore, the clinical management of patients showing CAA is discussed. Most of the patients came from our early experience with CSA between 1981-1983 when CSA doses and trough levels were high. Twenty recipients were divided into two groups according to the presence of CAA after stopping CSA: group A (n = 9) showed persistent CAA and group B (n = 11) showed no CAA. The majority of the patients, including five incomplete remission in group A, showed obvious improvement of CAA even if the arterioles were severely affected. Improvement of CAA was noted a few months after stopping CSA or after lower dose CSA therapy. There were no significant differences in CSA blood levels or duration of CSA therapy between the groups. The severity of preexistent CAA was significantly greater in group A. Only two patients who died from malignant tumor showed exacerbation of CAA. Eight patients died and eight grafts were lost, seven due to vascular rejection and one to hemolytic uremic syndrome-like CAA. Poor renal function was also noted in four cases with functioning graft owing to vascular rejection even though the improvement of CAA was evident. The complete regression of CAA and the remodelling of arterioles showing well preserved vascular patency were frequently found after stopping or reducing the dose of CSA.(ABSTRACT TRUNCATED AT 250 WORDS)
Assuntos
Ciclosporina/efeitos adversos , Transplante de Rim/patologia , Rim/irrigação sanguínea , Doenças Vasculares/induzido quimicamente , Adulto , Arteríolas/patologia , Biópsia , Ciclosporina/uso terapêutico , Seguimentos , Sobrevivência de Enxerto , Humanos , Rim/patologia , Pessoa de Meia-Idade , Fatores de Tempo , Resultado do Tratamento , Doenças Vasculares/epidemiologia , Doenças Vasculares/patologiaRESUMO
Thrombogenicity is the property of a foreign surface to induce clotting processes or formation of aggregates after contact with blood. Beside the sort of anticoagulation patient's prethrombotic state, rheological factors as well as physicochemical properties of foreign membranes decisively influence thrombogenicity. We examined the influence of chronic renal failure and different hemodialyzers and blood transfusion therapy during hemodialysis on hemorheological parameters. Different membranes cannot be discriminated by the used hemorheological parameters. We clearly could demonstrate the close relationship between the hemofiltration rate and an increase of viscosity. Blood transfusion therapy or elevated hematocrit in combination with increased hemofiltration rate have influence on the flow behaviour of blood, especially in disturbed microcirculation.
Assuntos
Materiais Biocompatíveis , Membranas Artificiais , Diálise Renal , Reologia , Sangue , Transfusão de Sangue , Viscosidade Sanguínea/fisiologia , Feminino , Hemofiltração , Humanos , Falência Renal Crônica/fisiopatologia , Falência Renal Crônica/terapia , Masculino , Microscopia Eletrônica de Varredura , Pessoa de Meia-IdadeRESUMO
Despite the apparent robustness of language learning in humans, a large number of children still fail to develop appropriate language skills despite adequate means and opportunity. Most cases of language impairment have a complex etiology, with genetic and environmental influences. In contrast, we describe a three-generation German family who present with an apparently simple segregation of language impairment. Investigations of the family indicate auditory processing difficulties as a core deficit. Affected members performed poorly on a nonword repetition task and present with communication impairments. The brain activation pattern for syllable duration as measured by event-related brain potentials showed clear differences between affected family members and controls, with only affected members displaying a late discrimination negativity. In conjunction with psychoacoustic data showing deficiencies in auditory duration discrimination, the present results indicate increased processing demands in discriminating syllables of different duration. This, we argue, forms the cognitive basis of the observed language impairment in this family. Genome-wide linkage analysis showed a haplotype in the central region of chromosome 12 which reaches the maximum possible logarithm of odds ratio (LOD) score and fully co-segregates with the language impairment, consistent with an autosomal dominant, fully penetrant mode of inheritance. Whole genome analysis yielded no novel inherited copy number variants strengthening the case for a simple inheritance pattern. Several genes in this region of chromosome 12 which are potentially implicated in language impairment did not contain polymorphisms likely to be the causative mutation, which is as yet unknown.
Assuntos
Transtornos da Percepção Auditiva/genética , Cromossomos Humanos Par 12/genética , Dislexia/genética , Predisposição Genética para Doença/genética , Transtornos do Desenvolvimento da Linguagem/genética , Adolescente , Adulto , Idoso , Criança , Pré-Escolar , Mapeamento Cromossômico , Feminino , Ligação Genética , Genótipo , Humanos , Transtornos do Desenvolvimento da Linguagem/fisiopatologia , Escore Lod , Masculino , Núcleo Familiar , LinhagemAssuntos
Procedimentos Cirúrgicos Cardíacos , Doenças Cardiovasculares/complicações , Angiografia Coronária , Falência Renal Crônica/complicações , Transplante de Rim , Doenças Cardiovasculares/diagnóstico , Doenças Cardiovasculares/terapia , Doença das Coronárias/complicações , Doença das Coronárias/diagnóstico , Humanos , Falência Renal Crônica/terapia , Diálise RenalAssuntos
Complexos Cardíacos Prematuros/fisiopatologia , Eletrocardiografia , Falência Renal Crônica/fisiopatologia , Diálise Renal , Taquicardia/fisiopatologia , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Ventrículos do Coração/fisiopatologia , Humanos , Masculino , Pessoa de Meia-Idade , Fatores de RiscoAssuntos
Cálcio/uso terapêutico , Distúrbio Mineral e Ósseo na Doença Renal Crônica/prevenção & controle , Citratos/uso terapêutico , Diálise Renal , Sódio/uso terapêutico , Distúrbio Mineral e Ósseo na Doença Renal Crônica/terapia , Humanos , Falência Renal Crônica/terapia , Equilíbrio HidroeletrolíticoRESUMO
PURPOSE: To evaluate the diagnostic benefit of contrast-enhanced ultrasound for the differential diagnosis of liver tumors in clinical practice. MATERIALS AND METHODS: From May 2004 to December 2006 1349 patients (male 677, female 672) with a hepatic tumor lacking a definite diagnosis based on B-mode ultrasound and power Doppler ultrasound were examined at 14 hospitals by contrast-enhanced ultrasound using a standardized protocol (pulse/phase inversion imaging, mechanical index < 0.4). The Tumor status was assessed based on the vascularity pattern and contrast enhancement seen in focal lesions during the arterial, portal, and late phase. The diagnosis established after contrast-enhanced ultrasound was compared to histology (> 75% cases) or in some cases to CT or MRI. RESULTS: The final diagnosis of hepatic tumors included 573 benign hepatic tumors (hemangiomas n = 242, focal nodular hyperplasia n = 170, hepatocellular adenoma n = 19, other benign lesions n = 142) and 755 malignant hepatic tumors (metastases n = 383, hepatocellular carcinoma n = 279, other malignant lesions n= 93). The overall diagnostic accuracy of contrast-enhanced ultrasound in comparison to the correct final diagnosis based on the combined gold standard was 90.3%. Contrast-enhanced ultrasound was able to correctly assess 723/755 malignant lesions (sensitivity 95.8%) and 476/573 benign lesions (specificity 83.1%). The positive predictive value of contrast-enhanced ultrasound for the diagnosis of a malignant tumor was 95.4% and the negative predictive value of contrast-enhanced ultrasound was 95.7%. CONCLUSION: Contrast-enhanced ultrasound clearly improves the differential diagnosis of hepatic tumors and is very helpful in clinical practice when B-scan or power Doppler morphological criteria are missing.
Assuntos
Neoplasias Hepáticas/diagnóstico por imagem , Meios de Contraste , Humanos , Aumento da Imagem , Neoplasias Hepáticas/patologia , Estadiamento de Neoplasias , Valor Preditivo dos Testes , Estudos Prospectivos , Reprodutibilidade dos Testes , Sensibilidade e Especificidade , UltrassonografiaRESUMO
As a risk factor, arterial hypertension favors the progression of renal failure and promotes cardiovascular complications, leading to early death. Progressive renal failure can be delayed or halted in glomerular diseases, and damage to other end organs can be avoided, by effective measures to lower blood pressure. Calcium antagonists and angiotensin-converting enzyme (ACE) inhibitors appear to be especially suitable as antihypertensive medications, because they may have specific renoprotective properties. Diuretics are required when a volume expansion caused by retention of salt and water occurs in more severe restriction of the glomerular filtrate. After ruling out contraindications and with cautious individualized dosages of antihypertensives (especially ACE inhibitors), deterioration of kidney function resulting from therapy is very rare.
Assuntos
Inibidores da Enzima Conversora de Angiotensina/uso terapêutico , Anti-Hipertensivos/uso terapêutico , Bloqueadores dos Canais de Cálcio/uso terapêutico , Diuréticos/uso terapêutico , Insuficiência Renal/tratamento farmacológico , Inibidores da Enzima Conversora de Angiotensina/farmacologia , Anti-Hipertensivos/farmacologia , Pressão Sanguínea/efeitos dos fármacos , Bloqueadores dos Canais de Cálcio/farmacologia , Humanos , Hipertensão/complicações , Hipertensão/tratamento farmacológico , Rim/efeitos dos fármacos , Rim/fisiopatologia , Insuficiência Renal/etiologiaRESUMO
The pharmacokinetics and pharmacodynamics of nilvadipine, a new dihydropyridine calcium antagonist, were examined in 16 patients divided into two different population groups. The first group of eight patients had arterial hypertension with limited renal function (creatinine clearance of 15-50 ml/min). The second group of eight patients had arterial hypertension with no concomitant renal dysfunction (creatinine clearance over 80 ml/min). Following a 1-week placebo washout period, all patients were given 8 mg of nilvadipine once daily for 10 days. The diastolic blood pressure (24-h postdose) fell in group I from a mean of 100.5 to 91.5 mm Hg and in group II from a mean of 106.7 to 88.2 mm Hg, which was significant in comparison to the placebo period. In neither group was there a significant change in heart rate, renin and aldosterone plasma levels, serum electrolytes, or sodium and potassium excretion. The pharmacokinetics of the unchanged nilvadipine were not significantly different between group I and group II. Neither group showed unchanged nilvadipine in urine. There was a slight increase in plasma levels of the inactive main metabolites M3 and M7; there was correspondingly less M3 found in the urine of group I patients. Nilvadipine appears to be an effective hypotensive agent at single daily doses of 8 mg. This dosage was well tolerated. The findings of this study did not suggest that lower doses need to be given to patients with limited renal function, at least not those with a creatinine clearance between 15 and 50 ml/min.
Assuntos
Anti-Hipertensivos/farmacocinética , Hipertensão/metabolismo , Nefropatias/metabolismo , Nifedipino/análogos & derivados , Adulto , Idoso , Aldosterona/sangue , Anti-Hipertensivos/farmacologia , Pressão Sanguínea/efeitos dos fármacos , Creatinina/urina , Feminino , Frequência Cardíaca/efeitos dos fármacos , Humanos , Testes de Função Renal , Masculino , Pessoa de Meia-Idade , Nifedipino/farmacocinética , Nifedipino/farmacologia , Renina/sangueRESUMO
We examined the possibility that haemoperfusion with coated activated charcoal might be used in the therapy of alkyl phosphate intoxications. The criterion used was the effect of haemoperfusion on the elimination of alkyl phosphates from the blood. Clearance values for haemoperfusion of nitrostigmine, demeton-S-methyl sulfoxide and dimethoate were determined in vitro. Very good clearance values were ascertained at a blood flow rate of 100ml/min (mitrostigmine 59.20ml/min, demeton-S-methyl sulfoxide 83.70 ml/min, dimethoate 87.84 ml/min). Measurements of the nitrostigmine clearance as a function of various nitrostigmine concentrations in plasma showed that haemoperfusion is effective over a concentration range covering two powers of ten. A 7-h haemoperfusion with coated activated charcoal was performed on a suicide patient with severe nitrostigmine intoxication (Folidol-öl). Clearance values were obtained which were to be expected on the basis of the in vitro investigations. The nitrostigmine concentrations in the extracorporeal blood plasma fell as a result of haemoperfusion to a mid-value of 55 per cent of the initial level. In the patient the level of nitrostigmine in the blood rose showing that there had been a redistribution of nitrostigmine from the tissue or a subsequent absorption from the gastrointestinal tract into the vessels. The results support the use of haemoperfusion with coated activated charcoal in very severe cases of alkyl phosphate intoxication or where standard therapy fails.
Assuntos
Paration/intoxicação , Perfusão/métodos , Adulto , Sangue , Velocidade do Fluxo Sanguíneo , Carvão Vegetal , Dimetoato/sangue , Filtração , Humanos , Masculino , Paration/sangue , Paration/metabolismo , Sulfóxidos/sangueRESUMO
An abnormal fibrinogen was identified in a man with suspicious prolonged prothrombin time and a mild bleeding tendency. Coagulation studies showed marked prolonged thrombin and reptilase clotting times and a discrepancy between functional fibrinogen test and fibrinogen antigen. The rate of fibrinopeptide B release by thrombin was slightly delayed while the release of fibrinopeptide A was only half the normal amount. DNA sequencing revealed a heterozygous C to T point mutation in position 1202 of exon 2 of the Aalpha chain, resulting in the substitution of Arg-->Cys at position 16, the thrombin cleavage site. This mutation was found also in his 2 children. Both had a mild bleeding tendency too.