Biomedical subjects

P Macpherson

Publications and source records attributed to P Macpherson.

At least 19 recordsLinked to original sources

PubMed1996

Processing of O6-methylguanine by mismatch correction in human cell extracts.

Human cell extracts perform an aberrant form of DNA synthesis on methylated plasmids [1], which represents processing of O6-methylguanine (O6-meG). Here, we show that extracts of colorectal carcinoma cells with defects in the mismatch repair proteins that normally correct replication errors do not carry out this synthesis. hMSH2-defective LoVo cell extracts (hMSH for human MutS homologue) performed O6-meG-dependent DNA synthesis only after the addition of the purified hMutS alpha mismatch recognition complex. Processing of O6-meG by mismatch correction requires PCNA and therefore probably DNA polymerase delta and/or epsilon. Mismatch repair-defective cells withstand O6-meG in their DNA [2], making them tolerant to methylating agents. Methylation-tolerant HeLaMR clones, with a mutator phenotype and a defect in either mismatch recognition or correction in vitro, also performed little O6-meG-dependent DNA synthesis. Assays of pairwise combinations of tolerant and colorectal carcinoma cell extracts identified hMLH1 as the missing mismatch repair function in a group of tolerant clones. The absence of processing by extracts of methylation-tolerant cells provides the first biochemical evidence that lethality of DNA O6-meG derives from its interaction with mismatch repair.

Cell Extracts↗

PubMed1996

hMSH2-independent DNA mismatch recognition by human proteins.

Two distinct mismatch binding activities are detected using bandshift assays with human cell extracts and DNA with mispairs at defined positions. One requires hMSH2 protein and is absent from extracts of LoVo cells, which contain a partial deletion of the hMSH2 gene. The second activity is independent of hMSH2 and is present at normal levels in LoVo and three other cell lines, which are defective in in vitro hMSH2-dependent binding. The two mismatch recognition activities are distinguished by their sensitivity to polycations and can be resolved by chromatography on MonoQ. hMSH2-independent activity has been purified extensively from wild-type cells and from a cell line deficient in hMSH2-dependent binding. The purified material preferentially recognizes A-C, some pyrimidine-pyrimidine mismatches, and certain slipped mispaired structures. Binding exhibits some sequence preferences. The similar properties of the two mismatch binding activities suggest that they both contribute to mismatch repair.

Adenocarcinoma↗

PubMed1994

The design and construction of a medical simulation model.

This paper describes the design, construction and validation of a probabilistic simulation model of patients who present with abdominal pain. The model incorporates text-book medical knowledge, clinical judgment, and statistics collected from real cases. The knowledge representation combines techniques of Bayesian network modelling with ideas of logistic discrimination. The model is shown to generate convincing, realistic cases; large numbers of artificial cases with no missing observations can be generated quickly. This should make the model a useful tool for investigating factors which limit achievable computer accuracy in the diagnosis of abdominal pain.

Abdominal Pain↗

PubMed1994

Surfactant proteins A (SP-A) and D (SP-D): levels in human amniotic fluid and localization in the fetal membranes.

Surfactant proteins A (SP-A) and D (SP-D) are major proteins, in the lung, which are composed of collagenous and globular domains. They show an overall similarity to the serum complement protein Clq, which is involved in the initiation of antibody-dependent defence mechanisms. Both SP-A and SP-D were detected, immunochemically, in amniotic fluid as early as 26 weeks gestation and, as expected, SP-A levels rose sharply from 32 weeks towards term. By contrast, SP-D levels in the same samples rose only moderately. Immunochemistry of paraffin sections of fetal membranes, revealed the presence of both SP-A and SP-D in the amniotic epithelium and chorio-decidual layers. SP-A and SP-D are both lectins and therefore they may play a role in the antibody-independent recognition and clearance of pathogens in the amniotic fluid.

Amniotic Fluid↗

PubMed1994

Diffuse brain swelling after head injury: more often malignant in adults than children?

A series of 118 patients with diffuse traumatic brain swelling was studied retrospectively in order to compare the clinical findings in children with those in adults, and to determine the occurrence of neurological deterioration and outcome. The computerized tomography (CT) picture of absent third ventricle and basal cisterns was used to identify the cases. Although this condition has been associated with children, we found the same number of children and adults (59 cases each). Secondary deterioration (decline in consciousness, the development of new focal neurological signs, or an increase in intracranial pressure) occurred in 40% of cases and was more common in adults than children. Features that were significantly associated with deterioration were the presence of prolonged coma (> 1 hour) after the injury, CT signs of diffuse axonal injury or subarachnoid hemorrhage, or a recorded episode of hypotension. A moderate or good recovery at 6 months was achieved by 70 patients (59%), but 45 patients had a poor outcome (severe disability in nine, vegetative state in three, and death in 33) and this was often a consequence of secondary deterioration. In three patients, the outcome was not known. The combination of a severe initial injury, secondary insult, and diffuse swelling is associated with a poor outlook, particularly in adults. The CT appearance of diffuse swelling may develop more readily in children because of the lack of cerebrospinal fluid available for displacement. In children, diffuse swelling may have a relatively benign course unless there is a severe primary injury or a secondary hypotensive insult.

Adolescent↗

PubMed1994

Case-based explanation for medical diagnostic programs, with an example from gynaecology.

One of the most accountable methods of providing machine assistance in medical diagnosis is to retrieve and display similar previously diagnosed cases from a database. In practice, however, classifying cases according to the diagnoses of their nearest neighbours is often significantly less accurate than other statistical classifiers. In this paper the transparency of the nearest neighbours method is combined with the accuracy of another statistical method. This is achieved by using the other statistical method to define a measure of similarity between the presentations of two cases. The diagnosis of abdominal pain of suspected gynaecological origin is used as a case study to evaluate this method. Bayes' theorem, with the usual assumption of conditional independence, is used to define a metric on cases. This new metric was found to correspond as well as Hamming distance to the clinical notion of "similarity" between cases, while significantly increasing accuracy to that of the Bayes' method itself.

Abdomen, Acute↗

PubMed1993

O6-methylguanine residues elicit DNA repair synthesis by human cell extracts.

We have investigated the processing of O6-methylguanine (O6-MeGua) in plasmid DNA by extracts of human cells defective in O6-MeGua-DNA methyltransferase. Cell extracts of HeLaMR cells performed viral T antigen-independent DNA synthesis on plasmids that had been treated with low concentrations of methylating agents. The in vitro DNA synthesis was non-semiconservative and depended on the presence of O6-MeGua in the substrate. The involvement of DNA polymerase delta or epsilon and proliferating cell nuclear antigen but not single-strand binding protein was indicated by partial fractionation, inhibitor, and antibody studies. Processing of O6-MeGua is not via the UV nucleotide excision repair pathway since additional component(s) are apparently required to perform repair synthesis on the methylated substrate. This is the first direct demonstration of DNA repair synthesis provoked by O6-MeGua in DNA. Since O6-MeGua is not excised from DNA by Mex- cells, it represents a novel type of processing of the methylated base that may be involved in its cytotoxicity.

Antibodies↗

PubMed1993

A probabilistic rule-based expert system.

This paper explores a medical expert system combining techniques of Bayesian network modelling with ideas of weighted inference rules. The weights of the individual rules can be estimated objectively from a training set of actual cases; and they can be used in a Monte Carlo stimulation to estimate objectively conditional probabilities of diagnosis given particular combinations of symptoms. The paper describes and evaluates a medical expert system built according to this design. The diagnostic accuracy of the program was found to be similar to that obtained through the usual application of Bayes theorem with the assumption of conditional independence of symptoms given disease, even though the Bayesian classifier has more than 70 times as many numerical parameters. The method may be promising in cases where small training sets do not permit accurate estimation of large numbers of parameters.

Abdominal Pain↗

PubMed1992

Indications for and accuracy of magnetic resonance imaging and computed tomography in orbital disease.

All patients referred for orbital imaging to the neuroradiology department of the Institute of Neurological Sciences in Glasgow over a three year period were enrolled in the study and were scheduled to undergo both magnetic resonance imaging and computed tomography. A total of 101 of the 110 referred patients were deemed suitable for analysis. Details of key presenting symptoms, signs, and a pre-imaging diagnosis were recorded prospectively. A final diagnosis was obtained by histology in 65% of cases with an orbital abnormality, by a minimum of one year of clinical review in 19.5%, by response to antibiotic or steroid therapy in 8.5%, or by conclusive investigations such as carotid angiography in in 7% of patients, 29% of the patients had no detectable orbital disease despite a minimum one years' follow-up, and so were regarded as a "normal" group. The images were interpreted prospectively by separate masked observers. The diagnostic accuracies of the two techniques were compared to the final diagnosis. The two imaging methods were shown to be comparable in overall diagnostic accuracy, with a small and statistically non-significant advantage held by magnetic resonance imaging. Interpretation of the two investigations gave more accurate information in different types of disease.

Academies and Institutes↗

PubMed1991

The value of pre-operative embolisation of meningioma estimated subjectively and objectively.

In a personal series a comparison has been made of the subjective and objective assessments of benefit between a group of patients in whom preoperative embolisation for meningioma was performed and a group, referred during the same timescale, in whom embolisation was either not possible or not appropriate. Preoperative difficulty with bleeding was experienced in 25% of the embolisation group and in 62% of the non-embolised group. Blood replacement overall was less in the embolised patients. Surgical complications occurred in 21% of those embolised but in 54% of those in whom embolisation had not been performed. At follow-up the outcome was rated as good in 79% in the embolisation group as opposed to 58% in the non-embolised group. Preoperative embolisation was therefore beneficial.

Adult↗

PubMed1991

Supplementary CT temporal lobe cuts confer no worthwhile benefit.

The value of angled temporal lobe cuts as a supplement to conventional head computed tomography (CT) has been assessed by comparing the diagnostic yield of standard axial and specific temporal lobe images (TLCT) in 62 patients with temporal lobe epilepsy and 87 with Alzheimer-type senile dementia. Fewer than one patient in six had structural abnormality in the temporal lobe most readily demonstrated by axial CT. Five patients with epilepsy and ten with dementia had changes demonstrated only by TLCT, reported on by one or other of a pair of observers. However such changes were of dubious clinical relevance, or arose as a result of artefact. In one patient with epilepsy and underlying neoplasm, axial CT was positive and TLCT false-negative. The routine addition of temporal lobe cuts to a conventional axial examination confers no added benefit to justify the prolonged examination time and increased radiation dose to the lens of the eye.

Alzheimer Disease↗

PubMed1991

Gadolinium DTPA enhanced magnetic resonance imaging in acute head injury.

We studied the effect of contrast enhancement on magnetic resonance imaging (Gadolinium DTPA Magnetic Resonance) in 10 patients with a recent head injury. The use of contrast did not increase the number of traumatic lesions identified and we did not detect evidence of altered blood brain barrier permeability in any of the 7 patients, who had a total of 27 lesions, imaged between one and 4 days after injury. Enhancement was found in each of 3 patients imaged 6 or more days after injury. These findings suggest that traumatic cortical and intraparenchymal lesions are not associated with increased cerebrovascular permeability within the first 96 hours of a head injury.

Adult↗

PubMed1991

MRI in the management of suspected cervical spondylotic myelopathy.

One hundred and two patients with suspected cervical spondylotic myelopathy were prospectively investigated using MRI as the initial imaging technique. The aim was to discover if clinicians could manage patients with MRI alone, or if they would find a second investigation necessary. Eighty two patients were managed using MRI alone, 34 of whom were treated surgically. Twenty patients had a second investigation: a myelogram in 18 and a CT myelogram in two. This was performed in nine patients to exclude structural pathology in the thoracic or lumbar region (which was not examined with MRI), and in 11 to obtain more specific information about the cervical region. Only five of these 20 patients had surgical treatment. The diagnosis changed after the second investigation in four patients, but management was not influenced in any of these. MRI is a satisfactory alternative to myelography for most patients with suspected cervical spondylotic myelopathy.

Adult↗

PubMed1991

Fibrous dysplasia of the skull: disease activity in relation to age.

Eighteen of 19 patients with histologically confirmed fibrous dysplasia of the skull seen at the Institute of Neurological Sciences, Glasgow, in the past 20 years have been reviewed and recent radiographs obtained. Sex, age at presentation and at follow-up were recorded, in addition to the site, type and extent of cranial involvement. The findings have been related to disease activity and progression. In comparison with other reports we found the proportion of patients with activity in adulthood to be relatively high (37%). Overall, there was an equal sex distribution, but of seven patients presenting as adults, six were female as were six of seven patients with evidence of disease activity in adulthood.

Adolescent↗

PubMed1990

Coregulation of the human O6-methylguanine-DNA methyltransferase with two unrelated genes that are closely linked.

The loss of expression of the enzyme O6-methylguanine-DNA methyltransferase (the Mex- phenotype), which often results from cellular transformation, confers hypersensitivity to alkylating agents. We have observed two unrelated examples in which human cell lines have undergone a spontaneous alteration in their Mex phenotype during propagation in vitro. The change was reversible and was not the result of mutation. In both cases a loss of methyltransferase expression was accompanied by a simultaneous loss of expression of two metabolically unrelated enzymes: thymidine kinase and galactokinase. "Reversion" to methyltransferase expression was accompanied by simultaneous reexpression of both kinase activities. A third example of this coordinate gene regulation was seen with the Burkitt's lymphoma cell line Raji which expresses methyltransferase, thymidine kinase, and galactokinase at high levels. A thymidine kinase- Raji cell line derived by bromodeoxyuridine mutagenesis that is also Mex- was found to be galactokinase-. It appears that methyltransferase expression may in some instances be coordinately regulated with the tk and glk loci which are closely linked on human chromosome 17.

Adenosine Triphosphatases↗

PubMed1990

Gadolinium-DTPA enhanced magnetic resonance imaging in human head injury.

We used low field magnetic resonance imaging and Gadolinium-DTPA to study 10 recently head injured patients. On the pre-contrast images we identified 36 abnormalities in 9 of the 10 patients. After contrast enhancement was seen in 9 of these lesions in 3 patients imaged 5-6 days after injury. Altered blood brain barrier permeability to gadolinium was not seen in 6 patients studied within 4 days of trauma. We did not identify any lesions with gadolinium that were not present on the pre-contrast images. We do not think that the routine use of contrast in head injury is justified since clinically important lesions will be present on routine sequences. However the use of gadolinium may provide information about the nature and timing of the underlying pathophysiological changes. In human head injury cytotoxic oedema occurs early and vasogenic oedema does not occur until 5-6 days after injury.

Adult↗

PubMed1990

CT scanning and surgical treatment of 1551 head injured patients admitted to a regional neurosurgical unit.

Computed tomographic (CT) scans of 1551 recently head injured patients transferred to a regional neurosurgical unit (NSU) were reviewed. Some 90% of first scans were done outside normal working hours. More than a third of first scans were normal including a fifth of the patients who were in deep coma. Haematoma was found in 50%, contusion 28%, shearing injuries 13% and general swelling in 9%. In 22% the first scan led to urgent surgical evacuation of an intracranial haematoma. More than one scan was done in 41% of patients and more than two in 10%, making 2608 scans in all. Repeat scans were more often done when the first scan was abnormal. In only five of 554 patients (1%) whose first scan had been normal were contusions or haematomas seen on subsequent scans, and in none of these was surgery required. Of 997 patients whose first scan had been abnormal a new lesion (contusion, haematoma and/or infarction) was seen on a subsequent scan in 103 cases (10%). Surgery was required (for the first time), in 57 patients whose abnormal first scans had not indicated the necessity for surgery at that time. The implications of these and other findings for the scanning of recently head injured patients in general hospitals, as scanners become more widely available, are discussed in our accompanying paper on p. 88.

Brain Concussion↗

PubMed1990

Implications of scanning recently head injured patients in general hospitals.

Increasing availability of computed tomography (CT) in general hospitals makes it appropriate to scan certain categories of acutely head injured patients in these hospitals. Policies should be devised locally indicating which types of patient should be scanned there, and what circumstances require transfer to the neurosurgical unit (NSU). Consideration must be given to the implications for training, staffing and other CT scanner commitments. The paper discusses these issues in the light of a study of the CT scans and surgical treatment of 1551 patients admitted to an NSU over a five year period, and provides models for discussion.

Brain Injuries↗