RESUMO
OBJECTIVES: Venous thromboembolism (VTE) is a potentially serious complication of hospitalization and immobilization. The use of anticoagulant prophylaxis in acutely ill medical inpatients is still under debate. New data including a recent meta-analysis have recently been published. We aim at studying the efficacy and safety of anticoagulant prophylaxis in acutely ill medical inpatients, and demonstrate differences between meta-analyses due to different data extraction from the heterogeneous studies included. SUBJECTS: The Cochrane Library, MEDLINE and EMBASE were searched from 1980 to present. Manual searches were performed regarding abstracts from major meetings. Seven blinded randomized controlled clinical trials assessing the prophylactic effect of heparin in acutely ill medical patients were identified and included in the meta-analysis. RESULTS: Low-molecular weight heparin (LMWH) prophylaxis prevented 48% of symptomatic pulmonary embolism (PE), 48% of symptomatic deep vein thrombosis (DVT) (not significant) and 51% of asymptomatic DVT. A nonsignificant trend towards higher bleeding risk during LMWH prophylaxis was found. Death was not significantly affected. We compared our data with a recent meta-analysis with different study selection and data extraction and found similar results. CONCLUSIONS: As DVT and PE are manifestations of the same illness, VTE, one can argue that anticoagulant prophylaxis prevents approximately half of the expected events. Most medical inpatients have short hospital stays, and a low risk of VTE. The important task for the clinician is to identify patients with a sufficiently high risk of symptomatic VTE to warrant LMWH prophylaxis. Despite differences in study selection and data extraction, our study shows results similar to a recent meta-analysis.
Assuntos
Anticoagulantes/uso terapêutico , Heparina de Baixo Peso Molecular/uso terapêutico , Complicações Pós-Operatórias/prevenção & controle , Embolia Pulmonar/prevenção & controle , Trombose Venosa/prevenção & controle , Anticoagulantes/efeitos adversos , Seguimentos , Hemorragia/induzido quimicamente , Heparina de Baixo Peso Molecular/efeitos adversos , Humanos , Ensaios Clínicos Controlados Aleatórios como AssuntoRESUMO
A deficiency of the enzyme iduronate-2-sulfatase (IDS) is the cause of Hunter syndrome (mucopolysaccharidosis type II). Here, we report a study of the human IDS locus at Xq28. An unexpected finding was an IDS-related region (IDS2) which is located on the telomeric side of the IDS gene within 80 kb. We have identified sequences in this locus that are homologous to exons 2 and 3 as well as sequences homologous to introns 2, 3 and 7 of the IDS gene. The exon 3 sequences in the IDS gene and in the IDS2 locus showed 100% identity. The overall identities of the other identified regions were 96%. A locus for DXS466 was also found to be located close to IDS2. The existence of the IDS2 locus complicates the diagnosis of mutations in genomic DNA from patients with Hunter syndrome. However, information about the IDS2 locus makes it possible to analyze the IDS gene and the IDS2 locus separately after PCR amplification.
Assuntos
Iduronato Sulfatase/genética , Mucopolissacaridose II/genética , Mutação , Cromossomo X , Sequência de Bases , Mapeamento Cromossômico , DNA , Análise Mutacional de DNA , Éxons , Humanos , Dados de Sequência Molecular , TelômeroRESUMO
OBJECTIVE: To describe cognitive functions and functional outcome in young patients with isolated infratentorial infarcts. BACKGROUND: Contemporary knowledge implies a cerebellar contribution to cognitive behavior. Neuropsychological examination of patients with selective cerebellar lesions provides an opportunity to document the existence and nature of clinically relevant cognitive manifestations from lesions of the cerebellum. METHODS: Prospective case series. The patients were assessed acutely and at 4 and 12 months after onset. Twenty-four patients from a consecutive series of 105 patients aged 18 to 44 years with cerebral infarction had a brain stem or cerebellar infarction. Fourteen age-matched controls were used for neuropsychological comparisons. Evaluation included MRI, angiography, and transesophageal echocardiography. Disability and neurologic dysfunction were assessed by the modified Rankin scale, NIH stroke scale, and maximal working capacity. A comprehensive neuropsychological battery was performed at baseline in 20 of the 24 patients. RESULTS: Eighteen patients had a cerebellar infarct. Two patients had lateral medullary infarcts, and two isolated pontine infarcts. Twenty-two patients had a favorable outcome according to the modified Rankin scale (grade 0-2) and the NIH scale. In contrast, 12 patients were granted full or partial sick leave at the 4 months follow-up, and 10 patients at 12 months. Patients generally performed worse than controls in various aspects of cognitive function, especially in tasks concerning working memory, the temporary storage of complex information, and cognitive flexibility. Measures of verbal IQ (r = -0.74) and performance IQ (r = -0.78) were related to the size of the infarct. The block design task performance in the early poststroke period predicted maximal working capacity at 12 months. CONCLUSIONS: Cerebellar damage impairs central aspects of attention and visuospatial skills. In contrast, intelligence and episodic memory remain unchanged. When the lesion involves large portions of the cerebellar hemispheres, changes concerning broad areas of intelligence may occur. The prognosis is favorable for neurologic dysfunction, but cognitive deficits may prevent return to work.
Assuntos
Tronco Encefálico/irrigação sanguínea , Cerebelo/irrigação sanguínea , Infarto Cerebral/psicologia , Transtornos Cognitivos/etiologia , Adolescente , Adulto , Estudos de Casos e Controles , Feminino , Seguimentos , Humanos , Imageamento por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Testes Neuropsicológicos , Estudos Prospectivos , Tomografia Computadorizada por Raios X , Resultado do TratamentoRESUMO
Increased activity of the hypothalamic-pituitary-adrenal (HPA) axis is common early after stroke. Hypercortisolism is a prominent manifestation. Normally the secretion of cortisol is regulated by adrenocorticotrophic hormone (ACTH), but recently an ACTH/cortisol dissociation after stroke was reported. Cytokines may influence the HPA axis, and plasma IL-6 levels are elevated following stroke. We investigated correlations between cortisol, ACTH, and cytokines, and between blood pressure and blood hormone levels early after stroke in seven stroke patients. All had neurological symptoms secondary to brain infarctions. Blood samples for analysis of cortisol, ACTH, IL-6, TNF alpha, norepinephrine, and epinephrine were collected four times daily, and 24-h blood pressure was measured. Plasma IL-6, but not ACTH, correlated significantly to serum cortisol. Catecholamine levels correlated with cytokine and cortisol levels. This study suggests that several routes for HPA-axis dysregulation is present early after stroke. Cytokine release may play an important role in this situation.
Assuntos
Transtornos Cerebrovasculares/fisiopatologia , Citocinas/fisiologia , Hidrocortisona/metabolismo , Sistema Hipotálamo-Hipofisário/fisiopatologia , Sistema Hipófise-Suprarrenal/fisiopatologia , Hormônio Adrenocorticotrópico/sangue , Idoso , Idoso de 80 Anos ou mais , Ritmo Circadiano/fisiologia , Citocinas/sangue , Feminino , Humanos , Interleucina-6/sangue , Masculino , Taxa SecretóriaRESUMO
To test the hypothesis that magnesium depletion might be of importance for the development of vascular complications in diabetes mellitus we performed a randomized, double-blind, placebo-controlled study during 12 months with 20-30 mmol/day of oral magnesium hydroxide in 28 type 1 diabetic patients. Urinary albumin excretion, Cr-EDTA-clearance and certain blood cardiovascular risk factors were measured. At the end of the study there were no significant differences of these parameters between the two groups, except that serum triglyceride values increased in three magnesium treated patients who either showed an increase in blood glycosylated hemoglobin values or body weight during the study.
Assuntos
Diabetes Mellitus Tipo 1/tratamento farmacológico , Fibrinogênio/metabolismo , Rim/efeitos dos fármacos , Lipídeos/sangue , Magnésio/uso terapêutico , Adulto , Albuminúria/metabolismo , Creatina/metabolismo , Método Duplo-Cego , Feminino , Fibrinogênio/efeitos dos fármacos , Hemoglobinas/efeitos dos fármacos , Hemoglobinas/metabolismo , Humanos , Magnésio/sangue , Magnésio/urina , Masculino , Pessoa de Meia-Idade , Triglicerídeos/sangueRESUMO
OBJECTIVE: To find out about the experiences of stroke patients concerning their falling ill, their stay in hospital, discharge and homecoming. DESIGN: Qualitative methods using in-depth interviews. SUBJECTS AND SETTING: Nine strategically chosen patients and in five cases near family members were interviewed in their homes four months post stroke and following care at the Stroke Centre, University Hospital of Northern Sweden, Umeå. RESULTS: Three main categories with subcategories were brought to the fore from the interviews: 'Responsible and implicated', 'Depersonalized object for caring measures' and 'The striving for repersonalization and autonomy'. The patients got the most important insights and understanding about their state and the consequences when they came home. CONCLUSION: The three main categories that were found mirror the crisis which becoming ill entails and the process gone through when the individual takes control again of his or her life. The patients saw coming home as an important factor for their recovery and rehabilitation. The health care system needs to develop strategies to make use of the power of this attitude with the patients and to use the patients' own milieu in rehabilitation after stroke.
Assuntos
Pacientes Internados/psicologia , Acontecimentos que Mudam a Vida , Acidente Vascular Cerebral/psicologia , Adaptação Psicológica , Idoso , Feminino , Humanos , Controle Interno-Externo , Entrevistas como Assunto , Masculino , Pessoa de Meia-Idade , Avaliação das Necessidades , Autonomia Pessoal , Autocuidado/psicologia , SuéciaRESUMO
BACKGROUND AND PURPOSE: Patients with acute stroke are often found to have high blood pressures at hospital admission. Previous studies have shown variable results regarding the prognostic value of high blood pressure in acute stroke. The aim of this study was to investigate the prognostic value of admission blood pressure in a population-based sample of patients with acute stroke. METHODS: Eighty-five patients with intracerebral hemorrhage and 831 with ischemic disease were included in the study. The relations between admission blood pressure and 30-day mortality were studied by logistic regression analyses. RESULTS: High blood pressure in patients with impaired consciousness on hospital admission was significantly related to 30-day mortality in patients with intracerebral hemorrhage (P = .037) and in patients with ischemic disease (P < .0001). In patients without impaired consciousness, high blood pressure at time of admission was not related to increased mortality at 30 days. CONCLUSIONS: High admission blood pressure in alert stroke patients was not related to increased mortality. Stroke patients with impaired consciousness showed higher mortality rates with increasing blood pressure. However, this does not provide a basis for recommending antihypertensive therapy for such patients.
Assuntos
Pressão Sanguínea , Transtornos Cerebrovasculares/mortalidade , Admissão do Paciente , Idoso , Idoso de 80 Anos ou mais , Hemorragia Cerebral/mortalidade , Hemorragia Cerebral/fisiopatologia , Transtornos Cerebrovasculares/fisiopatologia , Estado de Consciência , Feminino , Humanos , Ataque Isquêmico Transitório/mortalidade , Ataque Isquêmico Transitório/fisiopatologia , Masculino , Pessoa de Meia-Idade , Prognóstico , Fatores de TempoRESUMO
In clinical practice, patients with acute stroke often have high blood pressure. The aim of this study was to investigate factors correlated with blood pressure elevation in 843 consecutive stroke patients on hospital admission to a nonintensive stroke unit. Using a multivariate analysis model, we analyzed the influence on admission blood pressure of sex, age, previous hypertension, cardiac failure, diabetes, type of stroke, impaired consciousness, and latency between onset of symptoms and admission. Previous hypertension was the strongest predictor (p less than 0.001) of elevated blood pressure on admission, followed by the presence of intracerebral hemorrhage (p less than 0.001). The latency between onset of symptoms and admission showed no correlation with blood pressure levels at hospitalization. Previously, high blood pressure levels on hospital admission have been shown to decline within a few days in hospital. We therefore hypothesize that mental stress on hospital admission may be a major factor in the blood pressure elevation seen in acute stroke.
Assuntos
Pressão Sanguínea , Transtornos Cerebrovasculares/fisiopatologia , Doença Aguda , Idoso , Hemorragia Cerebral/fisiopatologia , Infarto Cerebral/fisiopatologia , Transtornos Cerebrovasculares/classificação , Feminino , Humanos , Embolia e Trombose Intracraniana/fisiopatologia , Ataque Isquêmico Transitório/fisiopatologia , Masculino , Análise de Regressão , Estudos RetrospectivosRESUMO
We report on a patient with hypokalaemia and severe ventricular tachycardia of torsades de pointes type which turned out to be caused by an apparent mineralocorticoid excess syndrome associated with liquorice consumption. The patient, a 44-year-old woman, attended the hospital because of irregular heart rhythm and she displayed repeated episodes of life-threatening torsades de pointes ventricular tachycardia. The initial serum potassium was low: 2.3 mmol L-1. The patient was treated with potassium and magnesium infusions, and the dysrhythmias eventually ceased. Endocrinological investigations showed no indication of Cushing's syndrome or hyperaldosteronism. After some time it became clear that the patient had ingested moderately large amounts of liquorice every day for 4 months. After the patient stopped this habit the hypokalaemia and dysrhythmias did not recur and after more than 1 year there are no signs of cardiac illness.
Assuntos
Glycyrrhiza/efeitos adversos , Hipopotassemia/induzido quimicamente , Hipopotassemia/complicações , Plantas Medicinais , Torsades de Pointes/etiologia , Adulto , Eletrocardiografia , Feminino , Humanos , Hipopotassemia/fisiopatologia , Torsades de Pointes/fisiopatologiaRESUMO
BACKGROUND AND PURPOSE: Elevated fibrinogen levels and abnormalities in the fibrinolytic system are related to the occurrence of cardiovascular events. However, the role of these factors in the evolution of cerebrovascular disease has received less attention, in particular in young stroke patients. The aim of this study was to evaluate possible abnormalities in plasma fibrinogen levels and the state of the fibrinolytic system in young adults with a first-ever ischemic stroke. METHODS: This study is based on 102 consecutive patients aged 18 to 44 years admitted between January 1991 and May 1996 as a result of a first ischemic stroke. Forty-one healthy controls were recruited. Evaluations of anthropometric/metabolic variables, plasma fibrinogen levels, and the fibrinolytic system were undertaken >/=3 months (mean, 5.4+/-2.0 months) after admission. RESULTS: Patients had lower tissue plasminogen activator activity and increased plasminogen activator inhibitor type 1 activity at baseline, as well as increased tissue plasminogen activator mass concentration both at baseline and after a venous occlusion test. Overall, there were no significant differences between the main etiologic subgroups regarding plasma fibrinogen levels and fibrinolytic variables. Baseline fibrinolytic variables were strongly correlated with body mass index, serum triglycerides, and cholesterol levels. After adjustments in multivariate models, fibrinogen levels and tissue plasminogen activator mass concentration both at baseline and after venous occlusion test remained significantly increased in patients. Logistic multiple regression analyses indicated that plasma fibrinogen was a strong predictor of ischemic stroke (odds ratio, 11.25; 95% CI, 3.27 to 38. 69). CONCLUSIONS: Increased fibrinogen levels and tissue plasminogen activator mass concentration are independently associated with ischemic stroke in young adults. Metabolic perturbations are closely interrelated with aberrations in tissue plasminogen activator and plasminogen activator inhibitor type 1 activity in these patients, findings consistent with an acquired hypofibrinolysis.
Assuntos
Isquemia Encefálica/metabolismo , Transtornos Cerebrovasculares/metabolismo , Fibrinogênio/metabolismo , Fibrinólise/fisiologia , Adolescente , Adulto , Isquemia Encefálica/complicações , Isquemia Encefálica/epidemiologia , Transtornos Cerebrovasculares/epidemiologia , Transtornos Cerebrovasculares/etiologia , Colesterol/sangue , Feminino , Fibrinogênio/análise , Humanos , Modelos Logísticos , Masculino , Ativadores de Plasminogênio/análise , Ativadores de Plasminogênio/metabolismo , Fatores de Risco , Triglicerídeos/sangueRESUMO
Iduronate-2-sulfatase (IDS) is involved in the degradation of heparan sulfate and dermatan sulfate in the lysosomes, and a deficiency in this enzyme results in Hunter syndrome. A 2.3-kb cDNA clone that contains the entire coding sequence of IDS has previously been reported. Here we describe the identification of a 1.4-kb transcript that may encode an IDS-like enzyme. The predicted protein is identical to the previously described enzyme, except for the absence of the 207-amino-acid COOH-terminal domain, which is replaced by 7 amino-acids. Our data suggest that there might exist an additional form of the IDS enzyme in humans. The results from this study may have implications for the pathogenesis of the Hunter syndrome.
Assuntos
Processamento Alternativo , Hominidae/genética , Iduronato Sulfatase/genética , Sequência de Aminoácidos , Animais , Sequência de Bases , Northern Blotting , Clonagem Molecular , Primers do DNA , DNA Complementar , Éxons , Humanos , Dados de Sequência Molecular , Mucopolissacaridose II/enzimologia , Mucopolissacaridose II/genética , Reação em Cadeia da Polimerase , RNA Mensageiro/biossíntese , RNA Mensageiro/isolamento & purificação , Homologia de Sequência do Ácido Nucleico , Transcrição GênicaRESUMO
BACKGROUND AND PURPOSE: Many comprehensive descriptions of the clinical spectrum of infratentorial infarcts in elderly patients and with a retrospective design have been published. The aim of this study was to describe the clinical characteristics and prognosis in young patients with isolated infratentorial infarcts. METHODS: In a prospective series of 105 patients aged 18-44 years with cerebral infarction 24 had a brainstem or cerebellar infarction. The patient selection was validated in a population-based epidemiological survey. The patients were assessed acutely and at 4 and 12 months after onset. Extensive evaluation included CT and MRI scans, angiography, ultrasonic duplex scanning, transesophageal echocardiography and a chemistry panel including hematologic testing. The modified Rankin scale and NIH stroke scale were used for assessment of disability and neurological dysfunction. RESULTS: Eighteen patients had a cerebellar infarct (posterior inferior cerebellar artery territory in 9 patients, superior cerebellar artery in 6, anterior inferior cerebellar artery in 2, nonterritorial in 1). Two patients had lateral medullary infarcts and 2 isolated pontine infarcts. In 2 patients MRI was normal despite repeated investigations. Hearing loss and tinnitus were the only explicit symptoms for superior cerebellar artery infarcts, but it was otherwise impossible to classify each case to a vascular territory according to clinical characteristics. The age-specific incidence of isolated cerebellar infarction was 1.8/100,000/year. The presumed causes were arterial dissection in 8 patients, idiopathic in 7, cardioembolic in 5, oral contraceptive use in 3 and protein S deficiency in 1 patient. One patient died during the acute phase and another developed a locked-in syndrome. At follow-up, 1 patient had a transitory ischemic attack and 1 a silent cerebral infarction. Twenty-two patients had a favorable outcome according to the modified Rankin scale (grade 0-2) and the NIH scale. CONCLUSIONS: Cerebellar infarctions are frequent among young stroke patients in northern Sweden. Arterial dissection is the prevailing stroke mechanism in infratentorial infarcts. The prognosis is favorable regarding motor impairment but cognitive deficits may prevent return to work.
Assuntos
Doenças Cerebelares/diagnóstico , Infarto Cerebral/diagnóstico , Bulbo/patologia , Ponte/patologia , Adolescente , Adulto , Doenças Cerebelares/epidemiologia , Infarto Cerebral/epidemiologia , Feminino , Pesquisas sobre Atenção à Saúde , Humanos , Imageamento por Ressonância Magnética , Masculino , Prognóstico , Fatores de RiscoRESUMO
BACKGROUND AND PURPOSE: The aim of this study was to conduct a population-based epidemiological survey among young adults aged 18 to 44 years in Northern Sweden and furthermore to gain further insight into the etiology of ischemic stroke in this age group. METHODS: Two studies were done. In the first part, epidemiological data were collected to calculate incidence and mortality from 1991 through 1994. This was based on the World Health Organization Northern Sweden MONICA register of acute stroke events. Eighty-eight first-ever ischemic stroke patients were identified during that period. In the second part, 107 consecutive patients aged 18 to 44 years with ischemic stroke referred to a university hospital were studied prospectively during a 5-year period and were extensively evaluated according to a standardized protocol. On the basis of modified Trial of ORG 10172 in Acute Stroke Treatment (TOAST) criteria, the patients were classified into eight subtypes of ischemic stroke. RESULTS: The average population-based annual incidence rate for ischemic stroke (cases per 100,000 per year) was 11.3 (95% confidence interval, 6.7 to 16.1). The case-fatality rate was 5.7%. According to the modified TOAST criteria, a probable cause of ischemic stroke was identified in 36% and remained unexplained in 21% of cases. Spontaneous cervical arterial dissection was the leading probable etiology (13%). Patent foramen ovale or atrial septal aneurysm was a possible cause of stroke in 28% of cases. The percentages of ischemic stroke attributed to IgG anticardiolipin antibodies (4.7%), atherothrombotic vasculopathy (3.7%), oral contraceptive use (7%), and migraine (1%) were lower than reported in recent clinical series. CONCLUSIONS: The incidence rate for ischemic stroke was higher than previously reported from most countries in Western Europe. The higher incidence was not explained by a higher prevalence of premature atherosclerotic vasculopathy. Without the additional diagnostic information derived from advanced cardiac imaging, the proportion of indeterminate cases would have constituted 37% of the patients.
Assuntos
Isquemia Encefálica/epidemiologia , Isquemia Encefálica/etiologia , Transtornos Cerebrovasculares/epidemiologia , Transtornos Cerebrovasculares/etiologia , Adolescente , Adulto , Isquemia Encefálica/mortalidade , Transtornos Cerebrovasculares/classificação , Feminino , Humanos , Incidência , Masculino , Mortalidade , SuéciaRESUMO
OBJECTIVE: To evaluate a computerized decision support system (DSS) for drug treatment of hypertension, regarding quality, safety, and cost compared to actual antihypertensive drug treatment. DESIGN: The medical profiles of 338 hypertensive patients treated with drugs against hypertension were processed by the DSS. The drug treatment proposed by the system was then compared to actual treatment given by their physician. SETTING: Four health centres in the county of Västerbotten, in Sweden. SUBJECTS: A list of hypertensive patients was extracted from the computerized medical records of each health centre and every fifth patient's medical profile was assessed by the system. INTERVENTIONS: None. MAIN OUTCOME MEASURES: Drug used, drug used in relation to certain major diseases such as diabetes mellitus, asthma, ischaemic heart disease (IHD), and previous myocardial infarction. Adherence to hypertension guidelines, safety, and cost. RESULTS: The DSS suggested significantly more thiazides and significantly fewer calcium antagonists than the physicians had prescribed, with a total cost reduction of 33-40%, depending on doses chosen. The DSS drug profile was more adherent to guidelines in patients with major complicating diseases, suggesting an improvement in treatment quality for these patients by the DSS. CONCLUSION: The DSS which fully implements current guidelines may improve the quality of antihypertensive treatment, concurrently leading to a considerable reduction in drug costs.
Assuntos
Anti-Hipertensivos/economia , Anti-Hipertensivos/uso terapêutico , Redução de Custos , Sistemas de Apoio a Decisões Clínicas , Hipertensão/tratamento farmacológico , Hipertensão/economia , Idoso , Pressão Sanguínea/efeitos dos fármacos , Análise Custo-Benefício , Tomada de Decisões Assistida por Computador , Custos de Medicamentos , Feminino , Fidelidade a Diretrizes , Humanos , Hipertensão/fisiopatologia , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Suécia , Resultado do TratamentoRESUMO
Mucopolysaccharidosis type II (Hunter syndrome) is an X-linked lysosomal storage disorder. A novel mutation is described in an MPS II patient in whom the disorder is caused by a 43.6 kb deletion. Southern blot analysis, PCR analysis and subsequent sequencing of the deletion junction revealed that the deletion spans exons 1-7 of the iduronate-2-sulfatase (IDS) gene, the IDS-2 locus and exons 3-5 of the recently identified gene W. Short direct repeats of 12 bp were identified at both deletion breakpoints, suggesting that the deletion is the result of an illegitimate recombination event. A sequence motif (TGAGGA) which is identical to a consensus sequence frequently associated with deletions in man was identified at both breakpoints. This further supports the notion that this motif is a hot spot for recombination. Gene expression studies by RT-PCR analysis of total RNA derived from fibroblasts of the patient revealed the presence of a novel fusion transcript. DNA sequence analysis of the cDNA demonstrated that it consists of exons derived from both the gene W and the IDS gene. A similar but longer fusion transcript containing exons 2-4 of the gene W and exons 4-9 of the IDS gene could also be detected in RNA of normal cell lines originating from different tissues. This result further demonstrates the complex gene expression profile of the IDS region, which may contribute to the observed genomic instability of this region.
Assuntos
Processamento Alternativo/genética , Iduronato Sulfatase/genética , Mucopolissacaridose II/enzimologia , Mucopolissacaridose II/genética , Recombinação Genética , Deleção de Sequência , Composição de Bases , Sequência de Bases , Criança , Humanos , Recém-Nascido , Masculino , Dados de Sequência MolecularRESUMO
BACKGROUND AND PURPOSE: Data from epidemiological and case-control studies suggest that increased total homocysteine (tHcy) levels are associated with increased risk for thromboembolic disease. The mechanisms by which hyperhomocysteinemia contributes to thrombogenesis are incompletely understood. The main objectives of this study of young ischemic stroke patients were (1) to examine fasting and post-methionine load levels of tHcy, (2) to ascertain the genotype frequency of the C677CT mutation in the methylenetetrahydrofolate reductase gene (TT genotype), and (3) to study the possible interaction between plasma tHcy levels and fibrinolytic factors. METHODS: This case-control study was based on 80 consecutive patients aged 18 to 44 years admitted between January 1992 and May 1996 as a result of a first-ever ischemic stroke. Forty-one healthy control subjects were recruited. Measurement of fasting tHcy and post-methionine load levels and evaluation of the fibrinolytic system were undertaken at least 3 months (mean, 5.1+/-1. 9 months) after admission. Genotyping of the methylenetetrahydrofolate reductase gene was performed. RESULTS: Although the increase after methionine loading (ie, postload tHcy minus fasting-level tHcy) was significantly higher among patients, there was no difference in fasting and postload tHcy levels. After adjustment for conventional risk factors, elevated postload increase tHcy levels were associated with a 4.8-fold increased risk of ischemic stroke. There was no difference between patients and control subjects in either TT genotype frequency or T allele frequency. Abnormal response to methionine loading was associated with higher tissue plasminogen activator (tPA) mass concentration, higher plasminogen activator inhibitor-1 levels, and lower tPA activity. After adjustment for age, sex, body mass index, serum cholesterol, and triglycerides, an abnormal increase in postload tHcy levels remained significantly associated with tPA mass concentration levels (P=0.03). CONCLUSIONS: A moderately elevated increase in tHcy levels after methionine loading was associated with an increased risk for ischemic stroke in young adults. In contrast, fasting tHcy levels did not differ between patients and controls. A moderately elevated increase in tHcy after methionine loading may provide a additional thrombogenic risk mediated in part by interactions with the fibrinolytic system. In young stroke patients, a methionine loading test to detect hyperhomocysteinemia should always be considered in the convalescent phase of the disease.
Assuntos
Isquemia Encefálica/complicações , Transtornos Cerebrovasculares/etiologia , Fibrinólise , Hiper-Homocisteinemia/complicações , Adolescente , Adulto , Isquemia Encefálica/epidemiologia , Isquemia Encefálica/genética , Estudos de Casos e Controles , Artérias Cerebrais/enzimologia , Transtornos Cerebrovasculares/epidemiologia , Transtornos Cerebrovasculares/genética , Feminino , Genótipo , Homocisteína/sangue , Humanos , Hiper-Homocisteinemia/diagnóstico , Hiper-Homocisteinemia/genética , Masculino , Metionina , Metilenotetra-Hidrofolato Desidrogenase (NAD+) , Mutação , Oxirredutases/genética , Fatores de Risco , Vitaminas/sangueRESUMO
We have recently described the identification of a second IDS locus (IDS-2) located within 90 kb telomeric of the IDS gene (Bondeson et al. submitted). Here, we show that this region is involved in a recombination event with the IDS gene in about 13% of patients with the Hunter syndrome. Analysis of the resulting rearrangement at the molecular level showed that these patients have suffered a recombination event that results in a disruption of the IDS gene in intron 7 with an inversion of the intervening DNA. Interestingly, all of the six cases with a similar type of rearrangement showed recombination between intron 7 of the IDS gene and sequences close to exon 3 at the IDS-2 locus implying that these regions are hot spots for recombination. Analysis by nucleotide sequencing showed that the inversion is caused by recombination between homologous sequences present in the IDS gene and the IDS-2 locus. No detectable deletions or insertions were observed as a result of the recombination event. The results in this study have practical implications for diagnosis of the Hunter syndrome.
Assuntos
Inversão Cromossômica , Iduronato Sulfatase/genética , Mucopolissacaridose II/genética , Recombinação Genética , Sequência de Bases , Mapeamento Cromossômico , DNA , Humanos , Dados de Sequência Molecular , Reação em Cadeia da PolimeraseRESUMO
We have previously shown that patients with the Hunter syndrome frequently have suffered from a recombination event between the IDS gene and its putative pseudogene, IDS-2, resulting in an inversion of the intervening DNA. The inversion, which might be the consequence of an intrachromosomal mispairing, is caused by homologous recombination between sequences located in intron 7 of the IDS gene and sequences located distal of exon 3 in IDS-2. In order to gain insight into the mechanisms causing the inversion, we have isolated both inversion junctions in six unrelated patients. DNA sequence analysis of the junctions showed that all recombinations have taken place within a 1 kb region where the sequence identity is >98%. An interesting finding was the identification of regions with alternating IDS gene and IDS-2 sequences present at one inversion junction, suggesting that the recombination event has been initiated by a double-strand break in intron 7 of the IDS gene. The results from this study suggest that homologous recombination in man could be explained by mechanisms similar to those described for Saccharomyces cerevisiae. The results also have practical implications for diagnosis of patients with the Hunter syndrome.
Assuntos
Inversão Cromossômica , Iduronato Sulfatase/genética , Mucopolissacaridose II/genética , Recombinação Genética/genética , Mapeamento Cromossômico , DNA/metabolismo , Humanos , Masculino , Modelos Genéticos , Dados de Sequência Molecular , Reação em Cadeia da Polimerase , Polimorfismo Genético/genética , Pseudogenes/genética , Saccharomyces/genética , Análise de Sequência de DNA , Cromossomo XRESUMO
Hunter syndrome is an X-linked lysosomal storage disorder caused by a deficiency of the lysosomal enzyme iduronate-2-sulfatase (IDS). The IDS deficiency can be caused by several different types of mutations in the IDS gene. We have performed a molecular and mutation analysis of a total 19 unrelated MPS II patients of different ethnic origin and identified 19 different IDS mutations, 9 of which were novel and unique. SSCP analysis followed by DNA sequencing revealed four novel missense mutations: S143F, associated with the 562C-->T polymorphism, C184W, D269V and Y348H. Two novel nonsense mutations were found: Y103X (433C-->A) and Y234X (826C-->G). In two patients two novel minor insertions (42linsA and 499insA) were identified. In one patient a complete IDS deletion was found, extending from locus DXS1185 to locus DXS466).
Assuntos
Iduronato Sulfatase/genética , Mucopolissacaridose II/enzimologia , Mucopolissacaridose II/genética , Mutação/genética , HumanosRESUMO
A novel mutation has been identified in a patient with the Hunter syndrome (mucopolysaccharidosis type II), in whom the disorder is associated with two distinct deletions separated by 30 kb. The deletions were characterized by Southern blot and PCR analyses, and the nucleotide sequences at both junctions were determined. The first deletion, corresponding to a loss of 3152 bp of DNA, included exons 5 and 6 of the iduronate-2-sulfatase (IDS) gene. The second deletion was 3603 bp long and included exons 3 and 4 of gene W, which is located in the DXS466 locus telomeric of the IDS gene. Both deletions are the result of nonhomologous (illegitimate) recombination events between short direct repeats at the deletion breakpoints. An interesting finding was the presence of the heptamer sequence 5'-TACTCTA-3' present at both deletion junctions, suggesting that this motif might be a hot spot for recombination. We propose that the double deletion is the result of homology-associated nonhomologous recombinations caused by the presence of large duplicated regions in Xq27.3-q28.