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Biomedical subjects

A M Thompson

Publications and source records attributed to A M Thompson.

At least 55 records · Page 3Linked to original sources
PubMed1999

Abnormal depth perception from motion parallax in amblyopic observers.

Many similarities exist between the perception of depth from binocular stereopsis and that from motion parallax. Moreover, Rogers (1984, cited in, Howard, I. P., & Rogers, B. J. (1995). Binocular vision and stereopsis. Oxford Claridon, New York.) suggests a relationship between an observer's ability to use disparity information and motion parallax information in a depth perception task. To more closely investigate this relationship, depth perception was studied in normal observers and amblyopic observers with poor stereo vision. As expected, amblyopic observers performed much worse than normal observers on depth discriminations requiring use of binocular disparity. However, amblyopic observers also performed much worse than normal observers on depth discriminations based on motion parallax. This result provides supporting evidence for a psychoanatomical link between the perception of depth from motion and the perception of depth from binocular disparity.

Amblyopia↗
PubMed1999

Completion of the journey of care: Scottish Audit of Surgical Mortality (SASM).

The ideal must be to audit all deaths as part of routine surgical and anaesthetic practice. We have examined the level of compliance of surgeons and anaesthetists participating in the Scottish Audit of Surgical Mortality (SASM) for the audit's first three years. The audit has achieved more than 92% compliance, unchanged over a three year period. As a consequence it can be regarded as a truly routine part of surgical and anaesthetic practice within Scotland.

Data Collection↗
PubMed1998

Neurodegenerative changes in the guinea pig brainstem after intratympanic injection of gentamicin.

Gentamicin (4%) was injected intratympanically into the middle ear of guinea pigs and the effects on the brainstem evaluated 28 days later by immunohistochemistry with an antibody against glial fibrillary acidic protein to detect astrocytes, and by cytochrome oxidase staining to detect metabolic activity. Astrocytes were observed in the cochlear nucleus indicating the possible presence of anterograde degeneration. Deficiencies in the intensity of cytochrome oxidase staining up to the level of the superior olivary complex indicated the presence of abnormal metabolic activity. Both of these observations support the conclusion that a single intratympanic injection of gentamicin may lead to neuronal degeneration along the central auditory pathway.

Animals↗
PubMed1998

Serotoninergic innervation of stapedial and tensor tympani motoneurons.

Retrograde tracing and neurotransmitter immunohistochemistry were combined to determine whether serotonin neurons innervated stapedial and tensor tympani motoneurons. With high-power light microscopy, putative axo-somatic and axo-dendritic contacts were observed between serotonin-positive endings and both stapedial and tensor tympani motoneurons, indicating that serotonin neurons terminate on brainstem motoneurons innervating the middle-ear muscles. With this connection, the serotonin system may directly modulate middle-ear muscle activity.

Immunohistochemistry↗
PubMed1998

Consortium study on 1280 breast carcinomas: allelic loss on chromosome 17 targets subregions associated with family history and clinical parameters.

The pattern of loss of heterozygosity (LOH) on chromosome 17 in human breast cancer is complicated and shows many different regions of loss. In an attempt to narrow down the relevant regions of LOH on chromosome 17, we have studied the deletion pattern and its association with clinical parameters in 1280 breast carcinoma-venous blood lymphocyte pairs. In total, 42 different chromosome 17 loci were investigated, and between 25 and 625 cases were analyzed at each locus. The frequency of LOH observed on the p arm was much higher than that observed on the q arm. The opposite effect was observed in 52 ovarian cancer cases investigated, with less LOH on 17p than on 17q. Patterns of loss consistent with interstitial and terminal deletions, as well as loss of either the p or q arm or monosomy 17 were observed. To determine whether loss at particular loci may be associated with biological features of breast tumors, clinical data including age of onset, family history of breast cancer, tumor histopathology, tumor size, estrogen receptor (ER) status, and occurrence of lymph node or distant metastases were collected for each case. Overall, large-sized, ER-negative, lymph node-positive ductal tumors showed the highest frequencies of LOH, with ER-negative and ductal tumors showing LOH for markers along the majority of the chromosome. Eight regions of chromosome 17 appear to be associated with human breast cancer, two on 17p and six on 17q. These regions were not necessarily in the areas exhibiting the highest frequencies of LOH but were defined by interstitial and terminal deletions in multiple independent cases. Seven of these regions showed statistically significant differences in LOH associated with clinical parameters. These data strongly suggest that loci on chromosome 17 may determine aspects of tumor presentation and disease behavior in human breast cancer and pinpoint candidate tumor suppressor gene loci.

Adult↗
PubMed1998

Heterogeneous projections of the cat posteroventral cochlear nucleus.

The anterograde tracer Phaseolus vulgaris-leucoagglutinin was used to identify the projections of the posteroventral cochlear nucleus in cats. After labeling predominately cells of the core and multipolar regions, varicose fibers were observed in a variety of auditory nuclei. Ipsilaterally, most varicose fibers were located in periolivary regions situated lateral to the medial superior olive of the superior olivary complex. Contralaterally, the majority of labeled fibers were located in the ventral nucleus of the trapezoid body and the ventral nucleus of the lateral lemniscus. Labeled varicose fibers were also observed in regions not commonly identified as receiving input from the posteroventral cochlear nucleus. These regions included bilaterally the principal nuclei of the superior olivary complex, some periolivary regions, and the sagulum, as well as the ipsilateral intermediate and dorsal nucleus of the lateral lemniscus, inferior colliculus, and lateral pontine nucleus. Both similarities and differences were observed in the projections of the core and multipolar regions. With the exception of calyceal-type endings in the contralateral ventral nucleus of the lateral lemniscus, the varicose fibers in all regions, including the contralateral medial nucleus of the trapezoid body, were beaded, en passant type terminal varicosities.

Animals↗
PubMed1998

An immunochemical analysis of mdm2 expression in human breast cancer and the identification of a growth-regulated cross-reacting species p170.

mdm2 is a 491 amino acid nuclear protein which is involved in complex interactions with important cell-cycle and stress-response regulators including p53, Rb and E2F. Recent data implicate mdm2 in the regulation of both p53 activity and level, and burgeoning data suggest that mdm2 may be involved in human epithelial tumourigenesis, including breast cancer. In this study the expression of mdm2 protein has been investigated in a series of 54 human breast carcinomas using immunoblotting methods. Overexpression of the predominant p90 mdm2 isoform is common in breast cancer (54 per cent) and this is not frequently a consequence of gene amplification. There is no relationship between p90 expression and either p53 protein expression or p53 mutational status. Additional mdm2 immunoreactive species of differing mobilities are identifiable, greatly complicating the analysis. For example, a p170 form is seen in many breast cancer samples (44 per cent) using 2A10 but is not identified by 3G5. This 2A10 immunoreactive species, which is almost certainly not an mdm2 isoform, is a growth-regulated protein, being undetectable in resting peripheral blood lymphocytes and rising to high levels after PHA stimulation. In contrast to mdm2 (p90), p170 is not induced by DNA damage caused by UV light. p170 is identifiable in mdm2 null cells by immunoblotting and is detected as a nuclear protein. While mdm2 immunostaining studies are increasing, this report highlights the complexity of mdm2 analysis in vivo and emphasizes the need to correlate immunohistological and biochemical assays since, in some mdm2 (p90) negative tumours, nuclear immunoreactivity may be identified as a consequence of cross-reacting species such as p170.

Adenocarcinoma↗
PubMed1998

Uncut Collis-Nissen fundoplication: learning curve and long-term results.

BACKGROUND: Between September 1985 and July 1990, the first 100 consecutive patients (50 female and 50 male) undergoing primary uncut Collis-Nissen fundoplication performed by one surgeon were reviewed. METHODS: Median age was 62 years and ranged from 19 to 89 years. Indications for repair included gastroesophageal reflux in 56 patients, obstructive symptoms in 34, and a combination of both in 10. An upper gastrointestinal endoscopy was performed in 99 patients; all were abnormal. Esophagitis was documented in 53 patients, large diaphragmatic hernia in 36, stenosis in 18, "Cameron's erosions" in 17, Barrett's disease in 13, and other findings in 9 patients. An abnormal upper gastrointestinal series was demonstrated in 96 of 97 patients evaluated. Motility studies were performed in 95 patients, and 11 had abnormal peristalsis. All procedures were performed through a left thoracotomy. RESULTS: Complications occurred in 23 patients and included respiratory failure in 6, atrial fibrillation in 3, atelectasis in 3, pneumonia in 2, myocardial infarction in 2, and chylothorax, severe dysphagia, early breakdown of repair, cardiac tamponade, hematuria, spinal headache, and intraoperative perforation by dilator in 1 each. There were 2 postoperative deaths, both cardiac in origin. Median hospitalization was 8 days (range, 6 to 76 days). The first 25 patients had 10 complications (40%) and 2 deaths (8%). The remaining 75 patients had 13 complications (17%) and no deaths (mortality, p = 0.06; morbidity, p = 0.03). Follow-up was complete in all patients for a median of 100 months (range, 3 to 138 months). Eighty-six of the 98 operative survivors are currently alive. At last follow-up, excellent functional results were observed in 58 patients (59%), good in 24 (25%), fair in 8 (8%), poor in 7 (7%), and unknown in 1 (1%). CONCLUSION: We conclude that the uncut Collis-Nissen fundoplication provides good to excellent long-term results in 84% of patients. Operative mortality and morbidity is acceptable but is associated with a learning curve.

Adult↗
PubMed1998

Effects of para-chlorophenylalanine (pCPA) on the bush baby auditory brainstem response.

Click-evoked auditory brainstem responses were recorded in a prosimian primate, the bush baby (Otolemur garnettii), before and after depletion of serotonin (by systemic injection of para-chlorophenylalanine; pCPA) and up to 20 days after discontinuing pCPA injections (during the recovery of serotonin). Biphasic 100 micros clicks were presented at five repetition rates (13.2, 33.2, 53.2, 73.2, and 93.2 clicks/s; RATE) and sound pressure levels (SPL) were varied in 10 dB steps from 120-60 dB SPL peak equivalent. Absolute latencies of vertex-positive peaks I, III, IV, and V were measured from click onset. The latencies from each wave were statistically analyzed with a two-way analysis of variance using either RATE or SPL (but not both) and TIME AFTER pCPA as independent variables. Prior to pCPA, brainstem response latencies increased as a function of both decreasing SPL and increasing RATE. After pCPA, these normal increases in wave latency increased even more, particularly in response to high click rates. After pCPA was discontinued, measurements taken at weekly intervals indicated that latencies decreased after 1 week, increased to the highest values recorded after 2 weeks, and returned to normal after 3 weeks. These dynamic changes were interpreted to be the result of postsynaptic receptor up-regulation during the 10 days of continuous pCPA administration. These results suggest that serotonin plays an important role in sensory processing at the cellular level and, tonically, facilitates the auditory brainstem response to sound.

Animals↗
PubMed1998

Allelic imbalance at chromosome 17p13.3 (YNZ22) in breast cancer is independent of p53 mutation or p53 overexpression and is associated with poor prognosis at medium-term follow-up.

Molecular and immunohistochemical studies of genetic events on chromosome 17p were prospectively compared with conventional clinical and pathological parameters and disease behaviour at a minimum of 72 months follow-up. In a series of 91 patients with primary operable breast cancer, 37 out of 91 (41%) patients had disease relapse and 23 out of 91 (25%) had died during the follow-up period. Allelic imbalance at the YNZ22 locus (17p13.3), demonstrated in 33 out of 63 (52%) informative patients, was significantly associated with disease recurrence (P < 0.01, 2 d.f. Cox analysis) and showed a trend towards impaired survival (P = 0.08, 2 d.f. Cox analysis) after a mean follow-up of 84 months for survivors. By contrast, p53 mutation (in 10 out of 60, 17% of cancers), p53 allelic imbalance (in 23 out of 56, 41% informative patients), p53 mRNA expression (in 47 out of 87, 54% patients), p53 mRNA overexpression (in 24 out of 87, 28%) or p53 protein expression (detected in 25/76, 32%) were not associated with disease behaviour. There was no significant association between allelic imbalance at YNZ22 and any abnormality of p53 DNA, RNA or protein. Allelic imbalance at 17p13.3 (YNZ22) serves as a marker of poor prognosis in breast cancer. As yet unidentified genes on 17p13.3, distinct from and telomeric to p53, are therefore likely to be of clinical importance in breast cancer.

Adult↗
PubMed1998

PS2 mRNA expression adds prognostic information to node status for 6-year survival in breast cancer.

Expression of pS2, an oestrogen-regulated gene, has been associated with a good short-term prognosis and response to endocrine therapy. The aim of this study was to determine whether expression of mRNA for the pS2 gene in breast cancer could contribute useful information on disease behaviour and survival at medium-term follow-up. Northern blotting was used to detect pS2 messenger ribonucleic acid (mRNA) in the primary tumour tissue from each of 90 patients with breast cancer. Axillary node status was established by sampling or clearance, oestrogen receptor concentration by enzyme immunosorbant assay and follow-up was continued for at least 6 years or until death. At 83 months mean follow-up, 29 of 90 (32%) patients had recurrent disease and, of these, 18 (20%) had died from breast cancer. pS2 mRNA expression, present in 26 of 90 (29%) cancers, was associated with freedom from disease recurrence (P = 0.026) and was significantly associated with survival at a minimum of 6 years follow-up (P < 0.001). Pathological node status and tumour size were also significantly associated with disease recurrence (P < 0.001 and P = 0.002 respectively) and inversely with survival (P < 0.001 and P < 0.001 respectively). After multiple Cox regression analysis, pS2 expression was still a significant predictor of recurrence (but not survival) after adjusting for node status and tumour size; oestrogen receptor was an independent predictor of survival. The combination of node status and pS2 expression discriminated patients with particularly good prognosis (node negative, pS2 positive: no mortality at 6 years) or poor prognosis (node positive, pS2 negative; 41% mortality at 6 years). Evaluation of pS2 expression in breast cancer at diagnosis may provide additional useful prognostic information to conventional staging.

Breast Neoplasms↗
PubMed1998

The effects of a novel sulphidopeptide leukotriene antagonist, BAY x7195, against elicited bronchoconstriction in the anaesthetized guinea-pig.

1. The novel leukotriene antagonist Bay x7195, has been evaluated against bronchoconstriction induced by leukotriene D4 (LTD4), the thromboxane A2 (TXA2) mimetic U46619, histamine and antigen, in the guinea-pig in vivo by use of a modified Konzett-Rössler preparation. 2. LTD4, given intravenously (i.v.) at 1 or 3 microg kg(-1) in the presence of indomethacin and sotalol, caused a 50-70% maximal bronchoconstriction in most animals. 3. BAY x7195, given i.v., orally (p.o.), by aerosol or dry powder insufflation, in lactose, reduced LTD4-induced bronchoconstriction dose-dependently. The approximate ID50 values were 83 microg kg(-1), 3 mg kg(-1), 0.0003% w/v for 20 breaths and 20 microg respectively. 4. The action of BAY x7195 (10 mg kg(-1), p.o.) was long lasting, causing significant inhibition of the LTD4-induced response (88% reduction) 8 h after dosing. 5. When given intravenously, in the presence of selected antagonists, BAY x7195 caused a dose-related reduction in the antigen-induced response, with an approximate ID50 of 2 mg kg(-1). 6. At 3 mg kg(-1), i.v., a dose which abolished the response to LTD4, BAY x7195 had no effect on U46619- or histamine-induced bronchoconstriction. 7. BAY x7195 is a potent, selective and long acting antagonist of LTD4-induced bronchoconstriction, in an anaesthetized, ventilated guinea-pig model. It is therefore worthy of clinical evaluation in diseases believed to involve the sulphidopeptide leukotrienes, such as asthma.

Administration, Oral↗
PubMed1998

The p53 tumour suppressor gene.

BACKGROUND: Abnormalities of the p53 tumour suppressor gene are thought to be central to the development of a high proportion of human tumours. This article reviews current understanding of its function and potential clinical significance. METHODS: Material was identified from previous review articles, references cited in original papers, a Medline search of the literature over the 12 months to January 1998, and by scanning the latest issues of relevant journals. RESULTS AND CONCLUSION: p53 is considered to be a stress response gene, its product (the p53 protein) acting to induce cell cycle arrest or apoptosis in response to DNA damage, thereby maintaining genetic stability in the organism. These functions are executed by a complex and incompletely understood series of steps known as the 'p53 pathway', part of which involves induction of the expression of a number of other genes. As p53 is the most commonly mutated gene in human cancer, it has attracted a great deal of interest as a prognostic factor, diagnostic tool and therapeutic target. However, despite many promising studies, its potential in practical cancer management has still to be realized.

Apoptosis↗
PubMed1997

Tyrosine kinase inhibitors. 13. Structure-activity relationships for soluble 7-substituted 4-[(3-bromophenyl)amino]pyrido[4,3-d]pyrimidines designed as inhibitors of the tyrosine kinase activity of the epidermal growth factor receptor.

The general class of 4-(phenylamino)quinazolines are potent (some members with IC50 values << 1 nM) and selective inhibitors of the tyrosine kinase activity of the epidermal growth factor receptor (EGFR), via competitive binding at the ATP site of the enzyme, but many of the early analogues had poor aqueous solubility (<< 1 mM). A series of 7-substituted 4-[(3-bromophenyl)-amino]pyrido[4,3-d]pyrimidines, together with selected (3-methylphenyl)amino analogues, were prepared by reaction of the analogous 7-fluoro derivatives with appropriate amine nucleophiles in 2-BuOH or aqueous 1-PrOH. All of the compounds were evaluated for their ability to inhibit the tyrosine-phosphorylating action of EGF-stimulated full-length EGFR enzyme. Selected analogues were also evaluated for their inhibition of autophosphorylation of the EGF receptor in A431 human epidermoid carcinoma cells in culture and against A431 tumor xenografts in mice. Analogues bearing a wide variety of polyol, cationic, and anionic solubilizing substituents retained activity, but the most effective in terms of both increased aqueous solubility (> 40 mM) and retention of overall inhibitory activity (IC50's of 0.5-10 nM against isolated enzyme and 8-40 nM for inhibition of EGFR autophosphorylation in A431 cells) were weakly basic amine derivatives. These results are broadly consistent with a proposed model for the binding of these compounds to EGFR, in which the 6- and 7-positions of the pyridopyrimidine ring are in a largely hydrophobic binding region of considerable steric freedom, at the entrance of the adenine binding cleft. The most active cationic analogues have a weakly basic side chain where the amine moiety is three or more carbon atoms away from the nucleus. Two of the compounds (bearing weakly basic morpholinopropyl and strongly basic (dimethylamino)butyl solubilizing groups) produced in vivo tumor growth delays of 13-21 days against advanced stage A431 epidermoid xenografts in nude mice, when administered i.p. twice per day on days 7-21 posttumor implant. Treated tumors did not increase in size during therapy and resumed growth at the termination of therapy, indicating an apparent cytostatic effect for these compounds under these treatment conditions. The data suggest that continuous long-term therapy with these compounds may result in substantial tumor growth inhibition.

Animals↗
PubMed1997

Tyrosine kinase inhibitors. 6. Structure-activity relationships among N- and 3-substituted 2,2'-diselenobis(1H-indoles) for inhibition of protein tyrosine kinases and comparative in vitro and in vivo studies against selected sulfur congeners.

A small series of 2,2'-diselenobis(1H-indoles) was synthesized as redox-modified congeners of our earlier reported 2,2'-dithiobis(1H-indole) series. Utilizing chemistry similar to that developed earlier for the disulfur series, compounds were made from 2-halogeno-3-indolecarboxylic acid precursors bearing various polar functionality at the C-3 position and small alkyl substituents at the N-1 position of the indole nucleus. Additional compounds were derived from (R)- or (S)-tryptophan via a novel application of diselenium dichloride as an electrophilic source of diselenium, and a much improved process to a 2,2'-dithiobis(1H-indole) congener was developed utilizing disulfur dichloride as a source of disulfur. Against isolated epidermal growth factor receptor (EGFr), platelet-derived growth factor receptor (PDGFr), and v-src tyrosine kinases, compounds in this series displayed broad inhibitory activity with IC50 = 0.9 to > 100 microM vs EGFr, 3.4 to > 50 microM vs PDGFr, and 0.4-6.7 microM vs v-src. In general, compounds derived from tryptophan displayed the greatest potency against EGFr and those from 2-halogeno-3-indolecarboxylic acids greater potency against PDGFr and v-src. Enzyme kinetics studies showed that both classes of compounds display primarily noncompetitive inhibition with respect to either ATP or peptide substrate. The sulfhydryl reducing agent dithiothreitol (DTT) caused a general decrease in inhibition of the EGFr and v-src tyrosine kinases by both the diselenium and disulfur series with the reversal of enzyme inhibition occurring less readily within the diselenium series. In whole cell studies, compounds of this class were growth inhibitory against Swiss 3T3 mouse fibroblasts with IC50 values from 0.5 to 19.5 microM, and the observed SAR was different from that of the 2,2'-dithiobis(1H-indoles). A comparative study in the same cell line on the effects of the 2,2'-diselenobis(1H-indole) derived from (R)-tryptophan vs its disulfur congener on growth factor mediated tyrosine phosphorylation showed that this compound significantly inhibited EGFr and PDGFr (in response to its ligand) autophosphorylation with complete suppression at 25 and 5 microM, respectively. Tyrosine phosphorylation of an 85 kDa protein typically phosphorylated in response to bFGF was also exquisitely sensitive to this compound, and it displayed inhibitory effects on DNA, RNA, and protein synthesis at submicromolar concentrations. The disulfur congener exhibited a qualitatively similar pattern; however, its potency was 10-fold less. This same diselenium/disulfur pair was evaluated in vivo against the B16 melanoma, colon carcinoma 26, and M5076 sarcoma murine tumors, and the A431 epidermoid, and C6 glioma human tumor xenografts. At maximum tolerated doses (1.8 and 5.0 mg/kg/injection, respectively), neither the diselenium nor disulfur congener was effective against the C6 glioma when administered intraperitoneally on a d1-9 schedule. Studies were also carried out against the A431 epidermoid xenograft to evaluate the same pair of compounds via continuous subcutaneous infusion from Alzet miniosmotic pumps. The maximum dose that could be administered daily was limited by compound solubility. Neither compound produced an antitumor effect in a 7-day continuous infusion study. In the 27-day study, the disulfur compound was inactive whereas the diselenium compound produced a 10.8-day growth delay without appreciable treatment related weight loss. The in vitro and in vivo findings offer a mechanistic rationale as to why the 2,2'-diselenobis(1H-indoles) are more potent inhibitors than their disulfur congeners.

3T3 Cells↗