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Biomedical subjects

J M Stevens

Publications and source records attributed to J M Stevens.

At least 37 records · Page 2Linked to original sources
PubMed2001

How broad is the phenotype of Hallervorden-Spatz disease?

Magnetic resonance imaging (MRI) has enabled ante mortem diagnosis of Hallervorden Spatz disease (HSD). Childhood-onset cases are the most common type and usually present with progressive dystonia and dementia. The duration of illness is 15 to 20 years, leading to death. Presentation in adulthood and infancy have also been reported, however again the progression is usually inexorable. We present a 30-year-old woman who developed cognitive and motor developmental delay from the age of 8 months. There was further cognitive decline in her late teenage years with seizures and then more recent motor decline with dystonia. The imaging appearance was of iron deposition in the globus pallidus and substantia nigra leading to a diagnosis of HSD. The increased availability of MRI has allowed more cases of HSD to be diagnosed in life but as our case illustrates classification of the disease may need to be further examined.

Adult↗
PubMed2001

PAX6 haploinsufficiency causes cerebral malformation and olfactory dysfunction in humans.

PAX6 is widely expressed in the central nervous system. Heterozygous PAX6 mutations in human aniridia cause defects that would seem to be confined to the eye. Magnetic resonance imaging (MRI) and smell testing reveal the absence or hypoplasia of the anterior commissure and reduced olfaction in a large proportion of aniridia cases, which shows that PAX6 haploinsuffiency causes more widespread human neuro developmental anomalies.

Adult↗
PubMed2001

Patterns of brain computed tomography infarction and carotid plaque echogenicity.

PURPOSE: It was suggested that in the absence of cardioembolism the discrete subcortical and cortical infarctions on brain computed tomography (CT) are most likely associated with carotid atheroma, whereas the hemodynamic infarctions, diffuse widespread white matter lesions, lacunae and basal ganglia infarctions are most likely associated with other pathologic conditions. The aim of this study was to determine the ultrasonic characteristics of carotid plaques and the degree of stenosis that were associated with the different brain CT infarction patterns and normal CT (pattern A, discrete subcortical and cortical infarctions; pattern B, hemodynamic infarctions, diffuse widespread white matter lesions, lacunae and basal ganglia infarctions). METHODS: Four hundred nineteen carotid plaques (315 patients), producing 50% to 99% stenosis on duplex scanning, were studied. These plaques were imaged on duplex scanning, captured, digitized, and normalized (standardized) in a computer. Subsequently, their gray scale median (GSM) was evaluated to distinguish quantitatively the hypoechoic (low GSM) from the hyperechoic (high GSM) plaques. The brain CT infarction patterns of A, B, or normal CT on the ipsilateral hemisphere were noted. RESULTS: The pattern A brain CT infarction was associated with carotid plaques having median GSM of 11 and median degree of stenosis of 80%, as contrasted with pattern B (median GSM, 28.5; median degree of stenosis, 75%) or normal CT (median GSM, 22; median degree of stenosis, 75%) (Kruskal-Wallis test, P <.001 for the GSM and P =.002 for the degree of stenosis). In the logistic regression analysis only the GSM and not the degree of stenosis distinguished the plaques associated with the three CT patterns. CONCLUSIONS: The pattern A brain CT infarction was associated with hypoechoic plaques suggesting an involvement of extracranial carotid artery embolization, whereas the pattern B was associated with hyperechoic plaques suggesting an involvement of other mechanisms (hemodynamic, intracranial small and large vessel disease).

Adult↗
PubMed2001

New inhibitors of iron-containing nitrile hydratases.

There is growing evidence in the literature emphasizing the significance of the post-translational modification of cysteine thiols to sulfenic acids (SOH), which have been found in a number of proteins. Crystallographic and mass spectrometric evidence has shown the presence of this group in an inactive form of the industrially important enzyme nitrile hydratase (NHase). This oxidized cysteine is unique in that it forms part of the coordination sphere of the low-spin iron III at the active site of the enzyme. The presence of this unstable sulfenic group in the active form of NHase is the subject of some controversy. To try to detect this function in NHase, we have studied the inhibitory effect on nitrile hydration of reagents known to react with sulfenic acids. Two NHases were studied, namely, Rhodococcus rhodochrous R312 NHase and Comamonas testosteroni NI1 NHase, and the reagents used were meta-chlorocarbonyldicyano-phenylhydrazone (m-ClCP), 7-chloro-4-nitrobenzo-2-oxa-1,3-diazole (NBD-Cl), and 2-nitro-5-thiocyanato-benzoic acid (NTBA). Following this approach we report three novel inhibitors of NHases. In addition, we report thiocyanate reagents that can be used to monitor NHase activity spectroscopically.

4-Chloro-7-nitrobenzofurazan↗
PubMed2001

Neurology in ancient faces.

BACKGROUND: Clinical paleoneurology is almost non-existent, but recognition of neurological diseases in ancient people might be possible by scrutinising portraits apparently representing people as they appeared in life. METHODS: About 200 mummy portraits painted in colour at the beginning of the first millennium were examined. Thirty two skulls excavated at Hawara in the Fayum (northern Egypt), where most of the portraits were found were measured, and nine caliper measures on each side of the skulls were taken. The right/left ratios were statistically analyzed by analysis of variance (ANOVA). One skull was subjected to 3D CT scanning and transilluminated. RESULTS: Two patients were found with progressive facial hemiatrophy (Parry-Romberg syndrome), three with deviations of the visual axes (tropia) and one with oval pupils (corectopia). CONCLUSIONS: Clinical paleoneurology is possible in the absence of a living nervous system. The patients probably had focal epilepsy, hemiplegic migraine, and autonomic nervous system dysfunction.

Facial Asymmetry↗
PubMed2001

Paroxysmal alternating skew deviation and nystagmus after partial destruction of the uvula.

A patient with suspected brain stem glioma involving the area of the left vestibular nuclei and cerebellar peduncle, developed paroxysmal alternating skew deviation and direction changing nystagmus after biopsy of the inferior cerebellar vermis resulting in destruction of the uvula. Between attacks she had right over left skew deviation with asymptomatic right beating horizontal nystagmus. Slow phases of the resting nystagmus showed increasing velocity, similar to congenital nystagmus. At intervals of 40-50 seconds, paroxysmal reversal of her skew deviation occurred, accompanied by violent left beating horizontal torsional nystagmus lasting 10-12 seconds and causing severe oscillopsia. It is proposed that this complex paroxysmal eye movement disorder results from (1) a lesion in the left vestibular nuclei causing right over left skew and right beating resting nystagmus and (2) a disruption of cerebellar inhibition of vestibular nuclei, causing alternating activity in the vestibular system with intermittent reversal of the skew deviation and paroxysmal nystagmus towards the side of the lesion.

Adult↗
PubMed2001

Patterns of temporal lobe atrophy in semantic dementia and Alzheimer's disease.

Volumetric magnetic resonance imaging analyses of 30 subjects were undertaken to quantify the global and temporal lobe atrophy in semantic dementia and Alzheimer's disease. Three groups of 10 subjects were studied: semantic dementia patients, Alzheimer's disease patients, and control subjects. The temporal lobe structures measured were the amygdala, hippocampus, entorhinal cortex, parahippocampal gyrus, fusiform gyrus, and superior, middle, and inferior temporal gyri. Semantic dementia and Alzheimer's disease groups did not differ significantly on global atrophy measures. In semantic dementia, there was asymmetrical temporal lobe atrophy, with greater left-sided damage. There was an anteroposterior gradient in the distribution of temporal lobe atrophy, with more marked atrophy anteriorly. All left anterior temporal lobe structures were affected in semantic dementia, with the entorhinal cortex, amygdala, middle and inferior temporal gyri, and fusiform gyrus the most severely damaged. Asymmetrical, predominantly anterior hippocampal atrophy was also present. In Alzheimer's disease, there was symmetrical atrophy of the entorhinal cortex, hippocampus, and amygdala, with no evidence of an anteroposterior gradient in the distribution of temporal lobe or hippocampal atrophy. These data demonstrate that there is a marked difference in the distribution of temporal lobe atrophy in semantic dementia and Alzheimer's disease. In addition, the pattern of atrophy in semantic dementia suggests that semantic memory is subserved by anterior temporal lobe structures, within which the middle and inferior temporal gyri may play a key role.

Aged↗
PubMed2001

Carotid plaque echogenicity and types of silent CT-brain infarcts. Is there an association in patients with asymptomatic carotid stenosis?

BACKGROUND: The aim of this study was to identify the differences in echogenicity and the degree of stenosis of asymptomatic carotid plaques associated with different types of ipsilateral silent CT-brain infarcts. METHODS: Some 273 asymptomatic carotid plaques (218 patients) causing 50 to 99% stenosis were studied with high-resolution ultrasound. B-mode images were digitised and normalised by assigning certain grey values to blood and adventitia. The grey scale median (GSM) of the plaque in the normalised image was used to quantify echogenicity. Every patient had a CT-brain scan which an independent neuroradiologist read. The presence of 1) non-lacunar and 2) lacunar silent CT-brain infarcts ipsilateral to the carotid plaque was noted. RESULTS: The mean GSM of plaques associated with non-lacunar silent CT-brain infarcts was 19.6, of plaques associated with lacunar infarcts was 35.5 and of those associated with no infarcts was 32 (p=0.008, ANOVA). The mean degree of stenosis was 79%, 72% and 73% respectively (p = 0.1, ANOVA). Plaque echogenicity (p = 0.007) and not the degree of stenosis (p = 0.07) predicted the presence of non-lacunar silent CT-brain infarcts (logistic regression). CONCLUSIONS: Carotid bifurcation plaques, which are associated with non-lacunar silent CT-brain infarcts, are significantly more hypoechoic than those associated with lacunar or no infarcts. Plaques associated with lacunar silent infarcts and no infarcts have the same echogenicity and degree of stenosis. These findings suggest an embologenic mechanism of non-lacunar silent CT-brain infarcts that may have prognostic implications in patients with asymptomatic carotid stenosis. Prospective studies of asymptomatic carotid stenosis should assess the significance of 1) plaque echogenicity and 2) the presence of different types of silent CT-brain infarcts and atheroembolic stroke.

Adult↗
PubMed2001

Brain CT infarction in patients with carotid atheroma. Does it predict a future event?

BACKGROUND: The aim of the present study was to investigate the predictive value for subsequent stroke of different patterns of brain CT infarction in patients with carotid atheroma. METHODS: Prospective study on 138 patients, with 138 carotid plaques, having, on presentation, a greater than 50 percent stenosis on duplex scanning and associated with an ipsilateral (to the plaque) amaurosis fugax (AF), hemispheric transient ischaemic attack (HTIA) or which were asymptomatic. This carotid artery defined the side of interest. All patients had a brain CT scan on presentation and subsequently were followed for a period of 1-5 years (mean 3.14). The baseline CT neurovascular findings on the side of interest were classified as pattern A (discrete subcortical and cortical infarctions), pattern B (haemodynamic infarctions, widespread white matter lesions, basal ganglia infarctions and lacunae) and normal CT. RESULTS: On follow-up, 5/27 (18.5 percent) of patients with pattern A, 4/38 (10.5 percent) with pattern B and 3/73 (4.1 percent) with normal CT appearance developed stroke in the hemisphere of interest (Cox regression: p=0.02). CONCLUSIONS: Pattern A confers an unfavourable prognosis in patients with carotid atheroma who are either asymptomatic or presented with amaurosis fugax or hemispheric transient ischaemic attacks.

Adult↗
PubMed2000

Equilibrium folding of dimeric class mu glutathione transferases involves a stable monomeric intermediate.

The conformational stabilities of two homodimeric class mu glutathione transferases (GSTM1-1 and GSTM2-2) were studied by urea- and guanidinium chloride-induced denaturation. Unfolding is reversible and structural changes were followed with far-ultraviolet circular dichroism, tryptophan fluorescence, enzyme activity, chemical cross-linking, and size-exclusion chromatography. Disruption of secondary structure occurs as a monophasic transition and is independent of protein concentration. Changes in tertiary structure occur as two transitions; the first is protein concentration dependent, while the second is weakly dependent (GSTM1-1) or independent (GSTM2-2). The second transition corresponds with the secondary structure transition. Loss in catalytic activity occurs as two transitions for GSTM1-1 and as one transition for GSTM2-2. These transitions are dependent upon protein concentration. The first deactivation transition coincides with the first tertiary structure transition. Dimer dissociation occurs prior to disruption of secondary structure. The data suggest that the equilibrium unfolding/refolding of the class mu glutathione transferases M1-1 and M2-2 proceed via a three-state process: N(2) <--> 2I <--> 2U. Although GSTM1-1 and GSTM2-2 are homologous (78% identity/94% homology), their N(2) tertiary structures are not identical. Dissociation of the GSTM1-1 dimer to structured monomers (I) occurs at lower denaturant concentrations than for GSTM2-2. The monomeric intermediate for GSTM1-1 is, however, more stable than the intermediate for GSTM2-2. The intermediates are catalytically inactive and display nativelike secondary structure. Guanidinium chloride-induced denaturation yields monomeric intermediates, which have a more loosely packed tertiary structure displaying enhanced solvent exposure of its tryptophans and enhanced ANS binding. The three-state model for the class mu enzymes is in contrast to the equilibrium two-state models previously proposed for representatives of classes alpha/pi/Sj26 GSTs. Class mu subunits appear to be intrinsically more stable than those of the other GST classes.

Anilino Naphthalenesulfonates↗
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

Comparison of PathVysion and INFORM fluorescence in situ hybridization kits for assessment of HER-2/neu status in breast carcinoma.

BACKGROUND: Fluorescence in situ hybridization is advocated for precise assessment of HER-2/neu status in breast carcinoma; however, few objective data compare available kits for clinical laboratories contemplating development of the test. METHODS AND RESULTS: Thirty breast carcinomas were analyzed for HER-2/neu amplification with the PathVysion kit (Vysis, Downers Grove, IL) and INFORM kit (Ventana Medical Systems, Tucson, AZ). Each kit was evaluated for morphology, background staining, technical and interpretation time, and cost. PathVysion detected amplification in seven of 30 cases (23.3%); INFORM detected six of 30 cases (20%). A greater percentage of PathVysion cases showed good morphology and lower background staining than INFORM. Technical and interpretation times, as well as cost, were less with PathVysion than INFORM. CONCLUSION: PathVysion is superior to INFORM because it produces better morphology and less background staining and is faster and less expensive than the INFORM kit. It also includes a chromosome 17 probe that serves as an internal control and enables correction for chromosome 17 aneuploidy.

Breast Neoplasms↗
PubMed2000

HER-2/neu assessment in breast cancer by immunohistochemistry and fluorescence in situ hybridization: comparison of results and correlation with survival.

BACKGROUND: HER-2/neu immunohistochemistry (IHC) and fluorescence in situ hybridization (FISH) results guide breast cancer therapy; however, few studies compared the results and no published studies have correlated them with patient outcome. METHODS AND RESULTS: We compared results, cost, and turnaround time in 117 archival, invasive breast carcinomas and compared 50-month survival in 65 of these cases using commercial HER-2/neu IHC and FISH assays. Twenty-one of 112 FISH (19%) and 33 of 117 IHC cases (28%) were positive. Concordance was high overall (88%; 98 of 112 cases) and in IHC 3+ cases (88%; 14 of 16 cases) but low in IHC 2+ cases (35%; six of 17 cases). Survival correlated with IHC results in 3+ cases (P =.02) and FISH cases with signal ratio greater than 4.0 (P =.03), but not in IHC 2+ cases (P=.7). Cost and turnaround time were greater for FISH. CONCLUSION: IHC is appropriate for initial HER-2/neu assessment; however, patients with tumors scored less than 3+, particularly those interpreted as 2+, would benefit from FISH to more accurately assess HER-2/neu status and avoid inaccurate prognostication and inappropriate treatment.

Breast Neoplasms↗
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↗