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Biomedical subjects

A Dean

Publications and source records attributed to A Dean.

At least 37 records · Page 2Linked to original sources
PubMed1999

Structural and functional cross-talk between a distant enhancer and the epsilon-globin gene promoter shows interdependence of the two elements in chromatin.

We investigated the requirements for enhancer-promoter communication by using the human beta-globin locus control region (LCR) DNase I-hypersensitive site 2 (HS2) enhancer and the epsilon-globin gene in chromatinized minichromosomes in erythroid cells. Activation of globin genes during development is accompanied by localized alterations of chromatin structure, and CACCC binding factors and GATA-1, which interact with both globin promoters and the LCR, are believed to be critical for globin gene transcription activation. We found that an HS2 element mutated in its GATA motif failed to remodel the epsilon-globin promoter or activate transcription yet HS2 nuclease accessibility did not change. Accessibility and transcription were reduced at promoters with mutated GATA-1 or CACCC sites. Strikingly, these mutations also resulted in reduced accessibility at HS2. In the absence of a globin gene, HS2 is similarly resistant to nuclease digestion. In contrast to observations in Saccharomyces cerevisiae, HS2-dependent promoter remodeling was diminished when we mutated the TATA box, crippling transcription. This mutation also reduced HS2 accessibility. The results indicate that the epsilon-globin promoter and HS2 interact both structurally and functionally and that both upstream activators and the basal transcription apparatus contribute to the interaction. Further, at least in this instance, transcription activation and promoter remodeling by a distant enhancer are not separable.

Binding Sites↗
PubMed1999

The relationship of magnetic source imaging to ictal electrocorticography in a neuronavigational workspace.

Magnetic source imaging (MSI) registers magnetoencephalographic (MEG) activity to a three-dimensional MRI volume. State-of-the-art MSI allows concurrent whole head coverage, but is practically restricted to interictal recording. However, the purpose of the presurgical evaluation of epileptic patients, in which MSI is playing an increasing role, is the elucidation of the ictal epileptogenic focus. The manner in which interictal MSI activity relates to the ictal focus has not yet been adequately examined. To facilitate this analysis, we are developing techniques to precisely coregister MSI to the ictal onset zone as defined by extraoperative intracranial grid/strip monitoring. The neuronavigational workspace is a convenient area in which to precisely coregister these (and other) imaging and physiological data sets.

Cerebral Cortex↗
PubMed1998

A clinicopathological study of autism.

A neuropathological study of autism was established and brain tissue examined from six mentally handicapped subjects with autism. Clinical and educational records were obtained and standardized diagnostic interviews conducted with the parents of cases not seen before death. Four of the six brains were megalencephalic, and areas of cortical abnormality were identified in four cases. There were also developmental abnormalities of the brainstem, particularly of the inferior olives. Purkinje cell number was reduced in all the adult cases, and this reduction was sometimes accompanied by gliosis. The findings do not support previous claims of localized neurodevelopmental abnormalities. They do point to the likely involvement of the cerebral cortex in autism.

Adult↗
PubMed1998

Rasmussen's encephalitis: neuroimaging findings in 21 patients with a closer look at the basal ganglia.

Rasmussen's encephalitis usually presents in childhood. The clinical picture in Rasmussen's disease is protean, and the findings from direct brain imaging help to explain the variations seen in this syndrome. The role and involvement of the basal ganglia in this condition is clarified by comparing the changes seen on computerised tomography and magnetic resonance imaging with the clinical details of 21 patients described in this retrospective study.

Adolescent↗
PubMed1998

The vasopressin precursor is not processed in the hypothalamus of Wolfram syndrome patients with diabetes insipidus: evidence for the involvement of PC2 and 7B2.

Wolfram syndrome (WS) is characterized by optic atrophy, insulin-dependent diabetes mellitus, vasopressin (VP)-sensitive diabetes insipidus, and neurosensory hearing loss. Here we report a disturbance in VP precursor processing in the supraoptic and paraventricular nuclei of WS patients. In these patients with diabetes insipidus we could hardly detect any cellular immunoreactivity for processed VP in the supraoptic and paraventricular nuclei. On the other hand, in the paraventricular nucleus a considerable number of cells immunoreactive for the VP precursor were present. In addition, the proprotein convertase PC2 and the molecular chaperone 7B2 were absent. As expression of PC2 and 7B2 was detected in the nearby nucleus basalis of Meynert of one WS patient and in the anterior lobe of the other WS patient, the absence of the two proteins in the paraventricular nucleus was not due to mutations in their genes. These results indicate that in WS patients with diabetes insipidus, not only does VP neuron loss occur in the supraoptic nucleus, but there is also a defect in VP precursor processing.

Adult↗
PubMed1997

Fibrinolytic inhibitors for cancer-associated bleeding problems.

This pilot study of 16 patients explored the use of two fibrinolytic inhibitors, tranexamic acid and aminocaproic acid, for the suppression of tumor-associated hemorrhage. The effects of such bleeding include anemia requiring transfusion, practical difficulties with dressings, and psychological morbidity from constant reminder of poor physical health. Cessation of bleeding occurred in 14 of the 16 patients treated. The average time until significant improvement in bleeding was just 2 days and the average time for complete cessation was 4 days. We conclude that fibrinolytic inhibitors are potentially useful agents in palliative care.

Adult↗
PubMed1997

Eosinophilic ulcer of the oral mucosa: report of a recurrent case on the tongue.

Eosinophilic ulcer of the oral mucosa (EUOM) is an uncommon lesion that usually affects the tongue. The lesion is benign and self-limiting, develops rapidly and usually disappears after several weeks without treatment. Microscopically, it contains a diffuse polymorphous cell infiltrate composed mainly of eosinophils. The cause of EUOM is unknown, but the condition has been attributed to trauma. We now describe a case of EUOM on the lateral surface of the tongue with recurrence on its dorsal surface 3 years later. The occurrence of multiple lesions, whether at the same time or subsequently as reported here, makes a purely traumatic origin rather unlikely and suggests that there may be a predisposition of some patients to develop EUOM. Eosinophilic ulcer of the oral mucosa (EUOM) is an uncommon lesion that is very rarely reported in the dermatological literature. It usually affects the tongue and presents clinically as an ulcer with elevated and indurated borders. Recognition is important because it often mimicks tongue cancer; however, the lesion is benign and self-limiting, develops rapidly and usually disappears after several weeks without treatment. Usually the ulcer occurs in a single episode, but the possibility of recurrence at other sites has been poorly emphasized.

Adult↗
PubMed1996

Training in the management of critical obstetric problems: trainee's view.

This paper evaluates the content of the training and the educational methods used in teaching how to handle critical obstetric problems. Structural training, description of aims and objectives and educational counselling encourage the acquisition, assessment and application of knowledge and skills. Educational counselling combined with continuous assessment can compensate for structural changes in the health service and improve and retain good clinical practise.

Emergency Medicine↗
PubMed1996

Combining Laue diffraction and molecular dynamics to study enzyme intermediates.

Two separate techniques, Laue diffraction and computational molecular dynamics (MD) simulations, have been independently developed to allow the visualization and assessment of transient structural states. Recent studies on isocitrate dehydrogenase show that computational MD simulations of an enzymatic Michaelis complex are consistent with difference Fourier electron density maps of the same structure from a Laue experiment. The use of independent MD studies during crystallographic refinement has allowed us to assign with confidence a number of additional contacts and features important for hydride transfer. We find that unrestrained independent MD simulations provides a very useful method of cross-validation for highly mobile atoms in regions of experimental density that are poorly defined. Likewise, information from Laue difference maps provides information about substrate conformation and interactions that greatly facilitate MD simulations.

Computer Simulation↗
PubMed1996

Essential role of NF-E2 in remodeling of chromatin structure and transcriptional activation of the epsilon-globin gene in vivo by 5' hypersensitive site 2 of the beta-globin locus control region.

Much of our understanding of the process by which enhancers activate transcription has been gained from transient-transfection studies in which the DNA is not assembled with histones and other chromatin proteins as it is in the cell nucleus. To study the activation of a mammalian gene in a natural chromatin context in vivo, we constructed a minichromosome containing the human epsilon-globin gene and portions of the beta-globin locus control region (LCR). The minichromosomes replicate and are maintained at stable copy number in human erythroid cells. Expression of the minichromosomal epsilon-globin gene requires the presence of beta-globin LCR elements in cis, as is the case for the chromosomal gene. We determined the chromatin structure of the epsilon-globin gene in both the active and inactive states. The transcriptionally inactive locus is covered by an array of positioned nucleosomes extending over 1,400 bp. In minichromosomes with a (mu)LCR or DNase I-hypersensitive site 2 (HS2) which actively transcribe the epsilon-globin gene, the nucleosome at the promoter is altered or disrupted while positioning of nucleosomes in the rest of the locus is retained. All or virtually all minichromosomes are simultaneously hypersensitive to DNase I both at the promoter and at HS2. Transcriptional activation and promoter remodeling, as well as formation of the HS2 structure itself, depended on the presence of the NF-E2 binding motif in HS2. The nucleosome at the promoter which is altered upon activation is positioned over the transcriptional elements of the epsilon-globin gene, i.e., the TATA, CCAAT, and CACCC elements, and the GATA-1 site at -165. The simple availability of erythroid transcription factors that recognize these motifs is insufficient to allow expression. As in the chromosomal globin locus, regulation also occurs at the level of chromatin structure. These observations are consistent with the idea that one role of the beta-globin LCR is to maintain promoters free of nucleosomes. The restricted structural change observed upon transcriptional activation may indicate that the LCR need only make a specific contact with the proximal gene promoter to activate transcription.

Animals↗
PubMed1995

Alcohol in Hebridean culture: 16th-20th century.

This paper sets out to document certain cultural antecedents to alcohol use in a British community. In order to demonstrate the extent to which patterns of alcohol consumption arise within broader social and cultural contexts, drinking practices on the Western Isles of Scotland are examined in light of specific social, economic and religious changes which have taken place between the 16th and 20th centuries. This paper thus seeks to argue that drinking practices are historical in that they arise within the context of the social and material conditions of a given epoch.

Alcoholic Beverages↗
PubMed1994

Neocortical cholinergic activities differentiate Lewy body dementia from classical Alzheimer's disease.

Activity of the enzyme which synthesizes acetylcholine, choline acetyltransferase, was estimated in the neocortex of three series of control and demented cases. Clinically demented cases were divided into those with the classical neuropathological features of Alzheimer's disease (numerous neocortical plaques and tangles) and those with Lewy bodies in the brain stem and cortex (together with plaques and variable neurofibrillary pathology). In the Lewy body cases neocortical choline acetyltransferase was consistently lower than in the classical Alzheimer-type cases. Two of the Lewy body cases with extremely low cholinergic activity were responders in therapeutic trials of the cholinesterase inhibitor, tacrine, and the combined data suggest that cholinergic therapy may be particularly relevant to patients with Lewy body type dementia.

Alzheimer Disease↗