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D Leys

Publications and source records attributed to D Leys.

At least 55 records · Page 3Linked to original sources
PubMed2003

The TB structural genomics consortium: a resource for Mycobacterium tuberculosis biology.

The TB Structural Genomics Consortium is an organization devoted to encouraging, coordinating, and facilitating the determination and analysis of structures of proteins from Mycobacterium tuberculosis. The Consortium members hope to work together with other M. tuberculosis researchers to identify M. tuberculosis proteins for which structural information could provide important biological information, to analyze and interpret structures of M. tuberculosis proteins, and to work collaboratively to test ideas about M. tuberculosis protein function that are suggested by structure or related to structural information. This review describes the TB Structural Genomics Consortium and some of the proteins for which the Consortium is in the progress of determining three-dimensional structures.

Amino Acid Sequence↗
PubMed2003

Cytochromes P450: novel drug targets in the war against multidrug-resistant Mycobacterium tuberculosis.

Novel drug strategies are desperately needed to combat the global threat posed by multidrug-resistant strains of Mycobacterium tuberculosis (Mtb). The genome sequence of Mtb has revealed an unprecedented number of cytochrome P450 enzymes in a prokaryote, suggesting fundamental physiological roles for many of these enzymes. Several azole drugs (known inhibitors of cytochromes P450) have been shown to have potent anti-mycobacterial activity, and the most effective azoles have extremely tight binding constants for one of the Mtb P450s (CYP121). The structure of CYP121 has been determined at atomic resolution, revealing novel features of P450 structure, including mixed haem conformations and putative proton-relay pathways from protein surface to haem iron. The structure provides both a platform for investigation of structure/mechanism of cytochrome P450, and for design of inhibitor molecules as novel anti-tubercular agents.

Antitubercular Agents↗
PubMed2003

[Sub-acute phase of cerebral ischemia: value of MRI].

MRI is the examination of choice for the evaluation of ischemic brain injury. At the acute phase, this examination may differentiate infarcted tissue from hypoperfused tissue. At the subacute phase, MRI allows to confirm the diagnosis of ischemia, exclude other diagnoses, recognize the rare appearances of cerebral ischemia, distinguish the different aspects of infarct and detect some rare diseases at the origin of the ischemic event.

Acute Disease↗
PubMed2003

[Peripheral haemosiderosis of the central nervous system].

We report 2 cases of patients with hemosiderosis of the central nervous system. The diagnosis was made in 1999 in a stroke unit. The patients had both deafness, but their clinical presentation was different, due to heterogeneous features of this pathology. Hemosiderosis of the central nervous system is due to chronic subarachnoidal hemorrhage. Magnetic resonance imaging is extremely sensitive to the presence of hemosiderin and is the investigation of choice enabling diagnosis and sometimes bleeding source (50 p. cent). The interest of our observations concerned the source of bleeding. In the first patient, diagnostic work-up was negative. For the second one, the deposition of hemosiderin was explained by 3 possible sources. If a bleeding source can be identified, surgery is the optimal treatment. Copper chelation, like Trientine can be used, but there is no evidence-based for using this treatment.

Adolescent↗
PubMed2002

Clinical outcome in 287 consecutive young adults (15 to 45 years) with ischemic stroke.

OBJECTIVE: To determine the 3-year outcome in 287 young adults (15 to 45 years old) consecutively admitted between 1992 and 1996 for an ischemic stroke. METHODS: Follow-up was obtained with clinical examinations or telephone interviews, and data were recorded about risk factors, associated disorders, causes of stroke, and current treatments. Functional outcomes were classified with the modified Rankin Scale (mRS). Endpoints were stroke recurrence, myocardial infarction, epileptic seizures, and death. RESULTS: After a mean follow-up of 3 years, no patient was lost to follow-up; 25.4% of the follow-up visits were performed by telephone interview. The authors found 1) an annual mortality rate of 4.5% during the first year and then of 1.6%; 2) an annual stroke recurrence rate of 1.4% during the first year and then of 1.0%; 3) a 0.2% annual rate of myocardial infarct; 4) epileptic seizures occurring in 6.6% of patients, during the first year in most patients; 5) independence (mRS = 0 to 2) in 94.0% of patients; 6) 4.2% of patients lost their job after stroke despite an mRS score of < or =1; 7) 7.0% of patients reported divorce; and 8) only 22.2% of smokers gave up smoking. CONCLUSION: Although young patients who experience ischemic strokes have a low risk of stroke recurrence and myocardial infarction, some patients do not regain independence.

Adolescent↗
PubMed2002

[Giant arteriovenous malformation of the vein of Galen in a 50 year old man].

True malformations of the vein of Galen are usually diagnosed within the first weeks of life. They represent less than 1 p. 100 of the cerebral arteriovenous malformations. These true malformations are exceptional in adults but should be known as an endovascular treatment could be performed. The most frequent clinical presentation is a severe cardiac failure leading to death. We report a giant arteriovenous malformation of the vein of Galen in a right-handed, 50 year-old man. During childhood, he suffered from a compensated cardiac failure which remained of unknown cause. Neurological examination showed kinetic and static cerebellar syndrome and a Parinaud syndrome. A cerebral MRI scan revealed a giant vascular malformation of the vein of Galen with a normal posterior fossa. The angiography enabled the diagnosis of a true malformation of the vein of Galen in its choroidian form. Its high blood flow entails cardiac failure because of a steal phenomenon. An endovascular treatment was declined because of numerous arterial afferences and the potential risks of peroperative haemorrhage.

Cardiac Output, Low↗
PubMed2001

Kinetic and crystallographic analysis of the key active site acid/base arginine in a soluble fumarate reductase.

There is now overwhelming evidence supporting a common mechanism for fumarate reduction in the respiratory fumarate reductases. The X-ray structures of substrate-bound forms of these enzymes indicate that the substrate is well positioned to accept a hydride from FAD and a proton from an arginine side chain. Recent work on the enzyme from Shewanella frigidimarina [Doherty, M. K., Pealing, S. L., Miles, C. S., Moysey, R., Taylor, P., Walkinshaw, M. D., Reid, G. A., and Chapman, S. K. (2000) Biochemistry 39, 10695-10701] has strengthened the assignment of an arginine (Arg402) as the proton donor in fumarate reduction. Here we describe the crystallographic and kinetic analyses of the R402A, R402K, and R402Y mutant forms of the Shewanella enzyme. The crystal structure of the R402A mutant (2.0 A resolution) shows it to be virtually identical to the wild-type enzyme, apart from the fact that a water molecule occupies the position previously taken by part of the guanidine group of R402. Although structurally similar to the wild-type enzyme, the R402A mutant is inactive under all the conditions that were studied. This implies that a water molecule, in this position in the active site, cannot function as the proton donor for fumarate reduction. In contrast to the R402A mutation, both the R402K and R402Y mutant enzymes are active. Although this activity was at a very low level (at pH 7.2 some 10(4)-fold lower than that for the wild type), it does imply that both lysine and tyrosine can fulfill the role of an active site proton donor, albeit very poorly. The crystal structures of the R402K and R402Y mutant enzymes (2.0 A resolution) show that distances from the lysine and tyrosine side chains to the nearest carbon atom of fumarate are approximately 3.5 A, clearly permitting proton transfer. The combined results from mutagenesis, crystallographic, and kinetic studies provide formidable evidence that R402 acts as both a Lewis acid (stabilizing the build-up of negative charge upon hydride transfer from FAD to fumarate) and a Brønsted acid (donating the proton to the substrate to complete the formation of succinate).

Arginine↗
PubMed2001

Poststroke dementia: incidence and relationship to prestroke cognitive decline.

OBJECTIVE: To evaluate the 3-year incidence of poststroke dementia (PSD) and the influence of prestroke cognitive decline. METHODS: The authors evaluated prestroke cognitive functions in 202 consecutive stroke patients > or =40 years old using the Informant Questionnaire on Cognitive Decline in the Elderly (IQCODE), with a cut-off of 104 for the diagnosis of dementia. Six months and then annually after stroke, dementia was reassessed. The diagnosis of dementia was based on the International Classification of Diseases, 10th revision criteria in survivors who underwent a visit with a neurologist, or on the IQCODE score obtained by telephone contact with the family in survivors who did not. Statistics were performed using life-table methods. RESULTS: Thirty-three patients were excluded because of prestroke dementia. In the 169 remaining patients, the cumulative proportion of patients with dementia was 28.5% at the end of the follow-up period, with most of PSD occurring during the first 6 months. Using multivariate analysis, independent predictors of PSD were aging, preexisting cognitive decline, severity of deficit at admission, diabetes mellitus, and silent infarcts. Leukoaraiosis was an independent predictor of PSD when prestroke cognitive decline was not taken into account. The presumed etiology of dementia was vascular dementia (VaD) in two-thirds of patients and AD in one-third. CONCLUSIONS: The risk of PSD is high, and increased in patients with prestroke cognitive decline, with about one-third of patients meeting the criteria for AD and two-thirds meeting the criteria for VaD. These results confirm that, in stroke patients, an underlying degenerative pathology may play a role in the development of PSD.

Adult↗
PubMed2001

Tinzaparin in acute ischaemic stroke (TAIST): a randomised aspirin-controlled trial.

BACKGROUND: Low-molecular-weight heparins and heparinoids are superior to unfractionated heparin in the prevention and treatment of venous thromboembolism, but their safety and efficacy in acute ischaemic stroke are inadequately defined. METHODS: This randomised, double-blind, aspirin-controlled trial tested the safety and efficacy of treatment with high-dose tinzaparin (175 anti-Xa IU/kg daily; 487 patients), medium-dose tinzaparin (100 anti-Xa IU/kg daily; 508 patients), or aspirin (300 mg daily; 491 patients) started within 48 h of acute ischaemic stroke and given for up to 10 days. Primary intracerebral haemorrhage was excluded by computed tomography. Outcome was assessed, with treatment allocation concealed, by the modified Rankin scale at 6 months (independence [scores 0-2] vs dependence or death [scores 3-6]). FINDINGS: Of 1486 randomised patients, two did not receive treatment and 46 were lost to follow-up. The proportions independent at 6 months were similar in the groups assigned high-dose tinzaparin (194/468 [41.5%]), medium-dose tinzaparin (206/486 [42.4%]), or aspirin (205/482 [42.5%]). There was no difference in effect in any predefined subgroup, including patients with presumed cardioembolic stroke. Other outcome measures were similar between the treatment groups (disability, case-fatality, and neurological deterioration rates). During the in-hospital treatment period no patient assigned high-dose tinzaparin developed a symptomatic deep-vein thrombosis compared with nine assigned aspirin. Conversely, seven patients assigned high-dose tinzaparin developed symptomatic intracerebral haemorrhage compared with one in the aspirin group. INTERPRETATION: Treatment with tinzaparin, at high or medium dose, within 48 h of acute ischaemic stroke did not improve functional outcome compared with aspirin. Although high-dose tinzaparin was superior in preventing deep-vein thrombosis, it was associated with a higher rate of symptomatic intracranial haemorrhage.

Aged↗
PubMed2001

[Therapeutic aspects of cerebral ischemia].

ACUTE STROKE: At the acute stage of cerebral ischemia, the treatment consists of:--general non-specific rules, such as treating a vital emergency, keeping biological parameters within normal limits and preventing complications;--admission in a stroke unit, to decrease mortality without increasing dependence or recurrence risks;--intravenous administration of rt-PA within 3 hours of stroke onset in eligible patients;--in patients who are not eligible for rt-PA, aspirin (160 to 300 mg) to reduce early recurrence and death, even in atrial fibrillation;--decompressive surgery in patients with raised intracranial pressure. SECONDARY PROPHYLAXIS: Secondary prevention consists of:--treatment of risk factors for stroke;--aspirin (75 to 325 mg), or clopidogrel, or the association aspirin-dipyridamole in high-risk subjects without cardiopathy, or warfarin in patients with high-risk cardiopathies;--carotid surgery in patients selected by clinical and imaging criteria.

Acute Disease↗
PubMed2001

Silent infarcts in stroke patients: patient characteristics and effect on 2-year outcome.

Although silent infarcts (SIs) are frequent in stroke patients, their clinical significance remains controversial, and their effect on stroke outcome remains unclear. This study evaluated the prevalence of SI on computed tomography, associated factors, and the effect on outcome in stroke patients. We studied 202 consecutive patients admitted for acute ischaemic or haemorrhagic stroke with clinical deficits lasting more than 24 h. Survivors were followed up for 24 months; no patient was lost to follow-up. Patients with Rankin scores of 2 or lower were considered separately. New vascular events were also recorded. Computed tomography showed that one-fourth of patients (52/202) had at least one SI; these were located in deep hemispheric areas in 46 patients, superficial hemispheric areas in 5, and the posterior fossa in 7. Logistic regression analysis showed the factors independently associated with SI to be severe leukoaraiosis (OR 1.71, 95% CI 1.26-2.31) and small-vessel occlusion as presumed cause of the index stroke (OR 2.66, 95% CI 1.22-5.79). SI did not affect vital or functional outcome or the occurrence of new vascular events within 2 years after stroke. Whether they affect cognitive outcome remains under evaluation over a longer follow-up period.

Adult↗
PubMed2001

Acute myelopathies: Clinical, laboratory and outcome profiles in 79 cases.

The main aetiologies of acute myelopathy (AM) are: multiple sclerosis, systemic disease (SD), spinal cord infarct (SCI), parainfectious myelopathy (PIM) and delayed radiation myelopathy (DRM). Although a large amount of data have been published for each individual aetiology, comparison studies are scarce. The aim of this study was to assess the various aetiological and outcome profiles of AM. We studied 79 cases: 34 (43%) in multiple sclerosis; 13 (16.5%) in SD; 11 (14%) in SCI; five (6%) in PIM; and three (4%) in DRM. Myelopathies were of unknown origin in 13 (16.5%) patients. We evaluated clinical, spinal cord and brain MRI, CSF and evoked potentials data at admission, MRI outcome at 6 months and clinical outcome at 12 months. A statistical comparison of clinical, laboratory and outcome data was only performed between multiple sclerosis, SD and SCI patients due to the small number of cases in the other groups. A motor deficit was more frequent in SD and SCI than in multiple sclerosis where initial symptoms were predominantly sensory (P < 0.001). Spinal cord MRI showed lateral or posterior lesions of less than two vertebral levels in multiple sclerosis, in contrast to SD and SCI, where lesions involved more vertebral levels and were centromedullar (P < 0.001). Brain MRI was most frequently abnormal in multiple sclerosis (68%), but was also abnormal in 31% of SD patients (P < 0.05). Oligoclonal bands in CSF were more frequent in multiple sclerosis than in SD (P < 0.001) and were never found in SCI. Clinical outcome at 12 months was good in 88% of multiple sclerosis cases, and poor or fair in 91% of SCI and 77% of SD. Aetiologies of AM may be differentiated on the basis of clinical, spinal cord and brain MRI, CSF and outcome data, and allow a probable diagnosis to be made in previously undetermined cases. These findings may have therapeutic implications for cases with a questionable diagnosis.

Acute Disease↗
PubMed2001

Crystallization and preliminary X-ray analysis of the recombinant dihaem cytochrome c (NapB) from Haemophilus influenzae.

The napB gene of the pathogenic bacterium Haemophilus influenzae encodes a dihaem cytochrome c, the small subunit of a heterodimeric periplasmic nitrate reductase (Nap). Recombinant NapB was overproduced in Escherichia coli, purified to near-homogeneity and crystallized using the hanging-drop method. Thin quadrilateral plates were grown under various conditions but proved to be unsuitable for X-ray analysis. However, a single crystal was grown using 1.75 M ammonium sulfate in 0.1 M sodium acetate pH 5.5, from which a native data set could be collected to 1.8 A resolution using synchrotron radiation. Using the same conditions, further crystals were obtained by microseeding. The space group was determined to be P42(1)2, with unit-cell parameters a = 77.55, b = 77.55, c = 28.64 A and an unusually low solvent content of 16.5%, assuming there to be one molecule of NapB in the asymmetric unit. Analysis of the dissolved crystals indicated that partial proteolysis of the protein had occurred. Taking the molecular mass of the crystallized form ( approximately 8500 Da) into account, the solvent content was estimated to be 53%, with a V(M) value of 2.64 A(3) Da(-1).

Crystallization↗
PubMed2001

Identification of a small tetraheme cytochrome c and a flavocytochrome c as two of the principal soluble cytochromes c in Shewanella oneidensis strain MR1.

Two abundant, low-redox-potential cytochromes c were purified from the facultative anaerobe Shewanella oneidensis strain MR1 grown anaerobically with fumarate. The small cytochrome was completely sequenced, and the genes coding for both proteins were cloned and sequenced. The small cytochrome c contains 91 residues and four heme binding sites. It is most similar to the cytochromes c from Shewanella frigidimarina (formerly Shewanella putrefaciens) NCIMB400 and the unclassified bacterial strain H1R (64 and 55% identity, respectively). The amount of the small tetraheme cytochrome is regulated by anaerobiosis, but not by fumarate. The larger of the two low-potential cytochromes contains tetraheme and flavin domains and is regulated by anaerobiosis and by fumarate and thus most nearly corresponds to the flavocytochrome c-fumarate reductase previously characterized from S. frigidimarina to which it is 59% identical. However, the genetic context of the cytochrome genes is not the same for the two Shewanella species, and they are not located in multicistronic operons. The small cytochrome c and the cytochrome domain of the flavocytochrome c are also homologous, showing 34% identity. Structural comparison shows that the Shewanella tetraheme cytochromes are not related to the Desulfovibrio cytochromes c(3) but define a new folding motif for small multiheme cytochromes c.

Amino Acid Sequence↗
PubMed2001

Atherothrombosis: a major health burden.

Atherosclerosis involves structural change to the intima and media of medium- and large-sized arteries. Although an atherosclerotic plaque may remain clinically silent, it is prone to disruption, leading to local platelet activation and aggregation. Therefore, the major complication of atherosclerosis is thrombosis, with local occlusion or distal embolism - a generalized disease process known as atherothrombosis. The three main clinical manifestations of atherothrombosis are coronary heart disease (myocardial infarction and angina), peripheral arterial disease and cerebral ischaemia. Atherothrombosis is a leading cause of mortality, and stroke is the leading cause of disability in adults, the second most important cause of dementia and the third most common cause of death in Western countries. Ischaemic stroke accounts for 80% of strokes and atherothrombosis accounts for approximately 20% of all strokes. Criteria for atherothrombotic stroke are evidence of a 50% (or greater) stenosis of a cervical artery and exclusion of other potential causes. The incidence of cerebrovascular events is 2,900 per million inhabitants per year, consisting of 500 transient ischaemic attacks and 2,400 strokes, of which 75% are first-ever stroke. The prevalence of stroke in the same population is 12,000, of which 800 patients (7%) per year have recurrences. The risk of ipsilateral stroke is 5% per year and the risk of a cardiac event is higher at 7%. Besides optimal management of risk factors for atherothrombosis and carotid surgery, antiplatelet therapy is the cornerstone of vascular prevention. In secondary prevention, antiplatelet agents are effective in reducing the risk of further ischaemic events in patients with atherothrombosis. Clopidogrel, a newly licensed ADP receptor antagonist, is the only antiplatelet agent to have demonstrated its superiority versus aspirin for the reduction of major ischaemic events (myocardial infarction, ischaemic stroke, vascular death) in patients whose initial manifestation of atherothrombosis was one of the three main clinical manifestations of the disease (recent ischaemic stroke, myocardial infarction, established peripheral arterial disease).

Arteries↗
PubMed2001

Relationship between leuko-araiosis and blood pressure variability in the elderly.

Although leuko-araiosis is a common finding on computed tomographic (CT) scans of the brain, its pathogenesis remains uncertain. To investigate the association between blood pressure (BP) disturbances and leuko-araiosis, we retrospectively reviewed CT scans and 24-hour ambulatory blood pressure monitorings of 79 elderly patients (57 women and 22 men; mean age: 83.3 +/- 6.4 years). Of the 79 patients, 50 were demented (30 had Alzheimer's disease and 18 vascular dementia) and 29 were not demented. The leuko-araiosis score (LA score) was determined by using Rezek's scale. To evaluate short-term variation of BP, we determined (1) the variability of systolic and diastolic BPs (SBP, DBP; within-subject standard deviation of all readings over a 24-hour period), (2) the coefficient of variability (variability of BP/mean BP) and (3) the maximal variation of BP (difference between the maximum and minimum 24-hour BPs). Higher LA scores were associated with higher SBPs in 24-hour, diurnal and nocturnal periods, higher maximal variation of SBP, greater variability of SBP during 24-hour, diurnal and nocturnal periods and greater coefficient of variability of SBP during sleep. Our study suggests that elevations and short-term variations of SBP may contribute to the pathogenesis of white matter lesions in elderly persons.

Aged↗