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Biomedical subjects

J M Stevens

Publications and source records attributed to J M Stevens.

At least 19 recordsLinked to original sources
PubMed2000

Electrostatic interactions affecting the active site of class sigma glutathione S-transferase.

We have shown previously that the solvent-induced equilibrium unfolding mechanism of class Sigma glutathione S-transferase (GST) is strongly affected by ionic strength [Stevens, Hornby, Armstrong and Dirr (1998) Biochemistry 37, 15534-15541]. The protein is dimeric and has a hydrophilic subunit interface. Here we show that ionic strength alone has significant effects on the conformation of the protein, in particular at the active site. With the use of NaCl at up to 2 M under equilibrium conditions, the protein lost 60% of its catalytic activity and the single tryptophan residue per subunit became partly exposed. The effect was independent of protein concentration, eliminating the dissociation of the dimer as a possibility for the conformational changes. This was confirmed by size-exclusion HPLC. There was no significant change in the secondary structure of the protein according to far-UV CD data. Manual-mixing and stopped-flow kinetics experiments showed a slow single-exponential salt-induced change in protein fluorescence. For equilibrium and kinetics experiments, the addition of an active-site ligand (S-hexylglutathione) completely protected the protein from the ionic-strength-induced conformational changes. This suggests that the change occurs at or near the active site. Possible structural reasons for these novel effects are proposed, such as the flexibility of the alpha-helix 2 region as well as the hydrophilic subunit interface, highlighting the importance of electrostatic interactions in maintaining the structure of the active site of this GST.

Binding Sites↗
PubMed2000

Generalised cerebral atrophy following temporal lobectomy for intractable epilepsy associated with mesial temporal sclerosis.

Studies of post-operative imaging data have mainly concentrated on brain atrophy following radiotherapy and/or chemotherapy. We have investigated the effect of conventional surgery on the unresected brain tissue based on the comparison of magnetic resonance images acquired pre- and post-operatively in 13 subjects with a history of mesio-temporal epilepsy. The pre- and post-operative scans were co-registered prior to volumetric analysis. The total brain volume (TBV) was calculated by semi-automated segmentation, and the total volume loss was the difference between the post-operative and pre-operative TBV. The total volume of resection was determined by manual delineation in the post-operative scan. The atrophy volume in the post-operative scan was calculated as the difference between the total volume loss and the resection volume. In 6 cases, there was generalised cerebral atrophy of the order 4-5% of the total brain volume. In addition to the automated volumetric technique, the images were assessed by two expert neuroradiologists. There was complete correspondence between their assessment and the automated technique. The causes and significance of this phenomenon are unknown but it requires further investigation as it may be related to seizure control and neuropsychological changes following epilepsy surgery.

Adolescent↗
PubMed2000

Alzheimer's disease due to an intronic presenilin-1 (PSEN1 intron 4) mutation: A clinicopathological study.

We describe 21 affected individuals from a kindred with early-onset autosomal dominant familial Alzheimer's disease caused by an intronic presenilin-1 mutation (in intron 4). Mean age at onset of symptoms was 37.4 years [95% confidence interval (CI): 36.6-38.2 years], mean age at death was 44.7 years (95% CI: 43.1-46.3 years) and mean duration of illness was 7.3 years (95% CI: 5.9-8.7 years). Myoclonus and seizures were prominent features of this pedigree. In the four cases for whom neuropsychometric data were available, verbal memory impairment preceded visual memory deficits; naming was relatively preserved until late in the disease. One of these four cases underwent serial volumetric MRI scans demonstrating in vivo brain tissue loss of 3.9% (38.9 ml, annualized rate of atrophy: 1. 7%) over 22 months of follow-up. The four individuals who had necropsies demonstrated the neuropathological hallmarks of Alzheimer's disease. Apolipoprotein E (APOE) status was assessed in five individuals: the case with the youngest age at onset at 33 years of age was found to be homozygous epsilon4/epsilon4, > 1 SD below the mean age of onset for those of known APOE genotype (36.4 +/- 2.3 years, mean +/- SD), and > 2 SDs below the mean age of onset for the pedigree as a whole (37.4 +/- 1.7 years, mean +/- SD). APOE genotype may therefore modulate age at onset in this pedigree.

Adult↗
PubMed2000

Bilateral periventricular and subcortical heterotopia in a man with refractory epilepsy.

PURPOSE: To report a novel malformation in a male subject with refractory partial seizures. METHODS: Magnetic resonance imaging (MRI) and data reformatting in a subject referred for management of partial seizures. RESULTS: The patient had four distinct partial seizure types, without learning disability. MRI demonstrated the novel association of bilateral laminar subcortical heterotopia, bilateral temporal periventricular heterotopia, and hippocampal malformation. CONCLUSIONS: This previously unreported complex bilateral neocortical and archicortical malformation in a male patient cannot be explained by known genetic causes of heterotopia, raising the possibility of a novel gene involved in brain formation.

Adult↗
PubMed2000

High yield criteria for emergency cranial computed tomography in adult patients with no history of head injury.

OBJECTIVES: A recent American study identified clinical factors which effectively predicted those patients who would have significant findings on cranial computed tomography. It was proposed to apply these criteria in a UK setting and to determine whether modifications could be made to improve their efficiency. METHODS: A prospective observational study was conducted over a four month period including all non-trauma adult patients referred from the accident and emergency (A&E) department for urgent cranial computed tomography. Presenting symptoms and signs were analysed for ability to predict clinically significant computed tomography findings, namely: acute infarct, malignancy, acute hydrocephalus, intracranial haemorrhage, or intracranial infection. RESULTS: Sixty two patients were included; 22 (35%) had significant findings on computed tomography. Applying the original criteria (any of: age 60 years or older, focal neurology, headache with nausea or vomiting, altered mental status) to the study population showed that no clinically significant tomograms would have been omitted but only 11% fewer performed. Modifying the criteria by removing "age 60 years or older" and replacing "altered mental status" with a Glasgow coma score <14, still ensured 100% sensitivity and would have resulted in 19% fewer scans being performed. CONCLUSION: Simple clinical criteria can be usefully applied to patients presenting to an A&E department in this country to target patients most likely to have clinically significant findings on urgent cranial computed tomography.

Adult↗
PubMed1999

Disproportion in the distribution of gray and white matter: neuropsychological correlates.

OBJECTIVE: To examine the relationship between measures of disproportion in the regional distribution of gray and white matter and preoperative neuropsychological function in temporal lobe epilepsy patients with proved hippocampal sclerosis (HS). BACKGROUND: Subtle cerebral structural disruption, not evident on routine inspection of high-resolution MRI, is associated with poor surgical outcome in patients with histologically proved HS. Preoperative global memory dysfunction is also associated with poor postoperative seizure control. The authors hypothesize that patients with HS and abnormal regional distributions of gray and white matter would show more diffuse neuropsychological deficits preoperatively than patients with isolated HS alone. METHODS: A total of 28 adults with lateralized temporal lobe epilepsy and hippocampal volume loss measured on MRI were assessed preoperatively on neuropsychological tests of general intellect and the learning and recall of both verbal and nonverbal material. Quantitative MRI analysis of the regional distribution of gray and white matter was performed. Chi-square analyses were used to examine the relation between the presence or absence of cerebral abnormalities and preoperative performance on the neuropsychological tests. RESULTS: A total of 15 of 28 patients had extrahippocampal abnormalities on quantitative MRI analysis. Thirteen patients had global memory impairment. Bilateral memory deficits were significantly associated with both the presence of cerebral abnormalities (p < 0.02) and poor postoperative seizure control (p < 0.05). CONCLUSIONS: Disproportion in the regional distribution of gray and white matter in patients with HS may form the structural basis of global memory disturbance in a distinct group of patients with temporal lobe epilepsy.

Adult↗
PubMed1999

Hippocampal layers on high resolution magnetic resonance images: real or imaginary?

To evaluate whether the lines occasionally detected on clinical magnetic resonance (MR) images are genuine hippocampal layers, a formalin fixed hippocampal specimen was scanned using T2 weighted sequences at 7 Tesla (voxel dimensions 0.064 x 0.064 x 1 mm) and at 1.5 Tesla (voxel dimensions: 0.156 x 0.156 x 1 mm) and compared with the results of histological examination. In addition, a healthy volunteer was scanned with a T2 weighted sequence at 1.5 Tesla (voxel dimensions: 0.469 x 0.469 x 2 mm). On 7 Tesla images hippocampal layers and the granule cell layer of the dentate were visible. On 1.5 Tesla images of the specimen, the hippocampal layers were again identified, but the granule cell layer of the dentate was not detectable. On 1.5 Tesla images of the hippocampus in vivo, 3 layers could be distinguished in the hippocampus on some slices. These mainly represented the alveus, pyramidal cell layer and stratum radiatum. A dark line consisting of a few pixels possibly represented the dentate gyrus. Our results show that the lines occasionally detected on clinical MR images are likely to be real hippocampal layers. However, the resolution currently used in clinical imaging (typically 0.469 x 0.469 x 2 mm or lower) is not sufficient for the detection of all hippocampal layers. For the reliable detection of all hippocampal layers on MR images an increase by a factor of approximately 20 would be necessary.

Adult↗
PubMed1999

Presurgical evaluation of patients with epilepsy and normal MRI: role of scalp video-EEG telemetry.

When considering surgery for intractable partial seizures, even with high resolution MRI, some patients do not show structural abnormalities. The aim was to consider whether these patients were likely to proceed to surgical treatment after scalp video-EEG telemetry. All patients undergoing presurgical evaluation at the National Hospital for Neurology and Neurosurgery between 1995 and 1997 were reviewed and 40 were identified without definite MRI abnormalities. None of 40 disclosed a well localised epileptogenic zone concordant with other tests that would have allowed the patient to proceed directly to surgery. In five of the 40, evaluation led to a hypothesis that could be tested by intracranial studies; three proceeded to surgery. It is suggested that high quality MRI is performed first when surgical evaluation is undertaken and if negative the patient carefully counselled before proceeding with any investigations, as successful resective surgery is an unlikely outcome in such MRI negative cases.

Adolescent↗
PubMed1999

Supratentorial cavernous haemangiomas and epilepsy: a review of the literature and case series.

OBJECTIVES: To characterise the clinical features and response to treatment of supratentorial cavernomas associated with epilepsy. METHODS: A systematic review of the literature was carried out and a retrospective case series of patients with cavernoma diagnosed by MRI and/or histology was compiled. Patient selection biases in the literature review were reduced as far as possible by selection of unbiased publications. RESULTS: In the literature, cavernomas were relatively less common in the frontal lobes. There were multiple cavernomas in 23% of cases. The main clinical manifestations were seizures (79%) and haemorrhage (16%). The annual haemorrhage rate was 0.7%. The outcome after excision was good with improvement in seizures in 92% of patients. In the case series the surgical outcome was less favourable, reflecting inclusion of a higher proportion of patients with intractable epilepsy. In both the literature review and the case series, outcome was poorer in cases with a longer duration of seizures at the time of surgery. CONCLUSIONS: The good surgical results, particularly in cases treated earlier, and the significant cumulative haemorrhage rate, suggest that excision is the optimum treatment. However, these factors have not been examined prospectively and, despite the availability of several retrospective studies, the optimum treatment, particularly for non-intractable cases, will only be determined by a prospective study.

Adolescent↗
PubMed1999

Cortical dysplasia with angiodysgenesis and chronic inflammation in multifocal partial epilepsy.

A 25-year-old man with a long history of temporal lobe epilepsy developed right occipital lobe seizures and a progressive right homonymous hemianopia. MRI showed diffuse enhancement of the left temporoparieto-occipital white matter and cortical thickening of the left medial temporal lobe. The resected temporal lobe revealed cortical dysplasia and angiodysplasia with foci of more recent ischemic necrosis and chronic inflammation as an explanation for the clinical deterioration.

Adolescent↗
PubMed1998

Class sigma glutathione transferase unfolds via a dimeric and a monomeric intermediate: impact of subunit interface on conformational stability in the superfamily.

Solvent-induced equilibrium unfolding of a homodimeric class sigma glutathione transferase (GSTS1-1, EC 2.5.1.18) was characterized by tryptophan fluorescence, anisotropy, enzyme activity, 8-anilino-1-naphthalenesulfonate (ANS) binding, and circular dichroism. Urea induces a triphasic unfolding transition with evidence for two well-populated thermodynamically stable intermediate states of GSTS1-1. The first unfolding transition is protein concentration independent and involves a change in the subunit tertiary structure yielding a partially active dimeric intermediate (i.e., N2 left and right arrow I2). This is followed by a protein concentration dependent step in which I2 dissociates into compact inactive monomers (M) displaying enhanced hydrophobicity. The third unfolding transition, which is protein concentration independent, involves the complete unfolding of the monomeric state. Increasing NaCl concentrations destabilize N2 and appear to shift the equilibrium toward I2 whereas the stability of the monomeric intermediate M is enhanced. The binding of substrate or product analogue (i.e., glutathione or S-hexylglutathione) to the protein's active site stabilizes the native dimeric state (N2), causing the first two unfolding transitions to shift toward higher urea concentrations. The stability of M was not affected. The data implicate a region at/near the active site in domain I (most likely alpha-helix 2) as being highly unstable/flexible which undergoes local unfolding, resulting initially in I2 formation followed by a disruption in quaternary structure to a monomeric intermediate. The unfolding/refolding pathway is compared with those observed for other cytosolic GSTs and discussed in light of the different structural features at the subunit interfaces, as well as the evolutionary selection of this GST as a lens crystallin.

Animals↗
PubMed1998

Fast fluid-attenuated inversion-recovery imaging: first experience with a 3D version in epilepsy.

We developed a 3D version of fast fluid-attenuated inversion-recovery imaging (FLAIR) which provides images with a slice thickness of 1.5 mm. We present our initial experience with 3D fast FLAIR in patients with epilepsy. We compared 3D fast FLAIR (slice thickness 1.5 mm), 2D fast FLAIR (slice thickness 5 mm) and a 3D spoiled GRASS (IRSPGR) sequence (slice thickness 1.5 mm) in 10 patients with lesional epilepsy (head injury 1, hippocampal sclerosis 2, low-grade glioma 2, dysembryoplastic neuroepithelial tumour 2, polymicrogyria 1, perinatal infarct 1 and presumed thrombosed aneurysm 1). Both 2D and 3D fast FLAIR sequences yielded higher conspicuity for lesions than the T1-weighted IRSPGR sequence, except in the patient with polymicrogyria. The extent of the lesion, in particular that of low-grade tumours, was best assessed on 3D fast FLAIR images. 3D fast FLAIR may be a useful additional tool especially for imaging low-grade tumours.

Artifacts↗
PubMed1998

Image contrast and hippocampal volumetric measurements.

The objective was to assess the influence of image contrast on the repeatability of hippocampal measurements. We compared measurements on spoiled GRASS (SPGR) three-dimensional acquisition with measurements on inversion pulse prepared spoiled GRASS (IRSPGR) three-dimensional acquisition. IRSPGR images had a higher grey matter-white matter contrast than SPGR images. Repeated measurements of hippocampi of 13 subjects were performed on both SPGR and IRSPGR images and the standard deviation of the differences of repeated measurements calculated. SD was 239 mm3 for SPGR and 134 mm3 for IRSPGR. Our data suggest that higher image contrast improves the repeatability of hippocampal measurements.

Hippocampus↗
PubMed1998

Longitudinal quantitative hippocampal magnetic resonance imaging study of adults with newly diagnosed partial seizures: one-year follow-up results.

PURPOSE: We wished to establish whether hippocampal changes occur in 1 year in adults with newly diagnosed partial seizures and, if so, to identify possible causes and mechanisms. METHODS: Thirty-six adult patients with newly diagnosed partial seizures underwent a magnetic resonance imaging (MRI) scan of the brain including hippocampal volume and T2 relaxation time (HCT2) measurement and had a follow-up quantitative MRI scan approximately 1 year after the baseline MRI scan. RESULTS: At baseline, 4 patients (11%) had hippocampal sclerosis (HS), 4 (11%) had abnormalities other than HS, and 28 had a normal MRI scan (78%). Twenty-three patients (64%) had recurrent seizures in the period between the two MRI scans. One of the 4 patients with HS, who had daily seizures, had significantly increased HCT2 values on follow-up, possibly reflecting progressive hippocampal damage. None of the 32 patients with MRI findings other than HS at baseline progressed to HS on follow-up. However, 2 of the 32 patients had significant hippocampal changes, probably related to resolution of inflammatory swelling or edema after seizures were controlled. CONCLUSIONS: Subtle changes in hippocampi can occur in 1 year in adults with newly diagnosed partial seizures, which could be due to resolution of edema after seizure control or to hippocampal changes associated with frequent and daily seizures. Follow-up of the studied cohort for several years will be required to settle the question of whether progressive hippocampal damage occurs in temporal lobe epilepsy (TLE).

Adolescent↗
PubMed1997

Correlation of widespread preoperative magnetic resonance imaging changes with unsuccessful surgery for hippocampal sclerosis.

Despite meticulous preoperative assessment, about 30% of patients with refractory partial epilepsy due to hippocampal sclerosis fail to become seizure free after appropriate temporal lobe surgery. Perioperative complications, hippocampal remnants, and bitemporal disease do not account for all failures; extrahippocampal epileptogenic tissue must persist in some patients. Such dual pathology is detected on routine visual inspection of magnetic resonance images in about 15% of patients with hippocampal sclerosis, but most such patients are excluded from surgery. We postulated that some patients have occult extrahippocampal cerebral structural abnormalities (i.e., subtle dual pathology) and that the presence of these abnormalities would be associated with a poor surgical outcome. Quantitative postprocessing of preoperative magnetic resonance images from 27 patients subsequently proved to have hippocampal sclerosis demonstrated extrahippocampal structural abnormalities in 14, 10 of whom did not become seizure free, while 11 of 13 patients without such changes did become seizure free (chi2, p < 0.005). Such structural information may supplement clinical decision making in some patients being evaluated for epilepsy surgery and help to explain the biological basis of poor outcome from such surgery.

Adolescent↗