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Biomedical subjects

A Cook

Publications and source records attributed to A Cook.

At least 37 records · Page 2Linked to original sources
PubMed1990

Evidence for allosteric variants of wild-type p53, a tumour suppressor protein.

A tumour suppressor function for p53 is indicated in human lung cancer and in carcinoma of the colorectum. Loss of suppressor function, by mutation of the p53 gene, is associated with activation of p53 as an oncogene. The suppressor (wild type) and oncogenic (mutant) forms of the murine p53 protein are distinguishable at the molecular level by reactivity with anti-p53 monoclonal antibodies. For example, activated mutant p53 fails to react with PAb246 (p53-246 degrees). We now demonstrate that wild type p53 mRNA can be expressed either as p53-246+ or p53-246 degrees. We propose that p53-246 degrees may represent an allosteric variant of wild type p53 compatible with positive growth control. Thus, for wild type p53 the variants p53-246+ and p53-246 degrees may reflect suppressor and activator functions of p53 in the normal control of cell proliferation. For human p53 we present evidence that the epitope recognised by PAb1620 is analogous to that for PAb246 on murine p53. Thus the epitope for PAb1620 may prove to be of use as a marker for wild type human p53 with anti-oncogenic function.

Animals↗
PubMed1990

Morphological evaluation of atrioventricular septal defects by magnetic resonance imaging.

Twelve patients aged between 2 weeks and 22 months (median 6 weeks) with atrioventricular septal defects were examined with a 1.5 T, whole body, magnetic resonance imaging system. Ten patients had a common atrioventricular orifice (complete defect) while two patients had separate right and left valve orifices (partial defect). Associated cardiac malformations included the tetralogy of Fallot in two, isomerism of the right atrial appendages and pulmonary atresia in two, and right isomerism and double outlet right ventricle in one. All had previously been examined by cross sectional echocardiography. Eight subsequently had angiography and six underwent surgical correction. There was one operative death and three other deaths. Three of these patients underwent postmortem examinations. Small children and infants were scanned inside a 32 cm diameter head coil. Multiple electrocardiographically gated sections 5 mm thick, separated by 0.5 mm, were acquired using a spin echo sequence with echo time of 30 ms. A combination of standard and oblique imaging planes was used. Magnetic resonance imaging was more accurate than echocardiography in predicting the size of the ventricular component of the defect. It was also better than either echocardiography and angiography in identifying the presence of ventricular hypoplasia. All these findings were confirmed by surgical or postmortem examinations or both. Magnetic resonance imaging is capable of providing detailed morphological information in children with atrioventricular septal defects which is likely to be of value in their management.

Abnormalities, Multiple↗
PubMed1990

Incidence of fractures in a geographically defined population.

STUDY OBJECTIVE: The aim was to describe the population based age and sex specific incidence of fractures at different sites in a large English health district. DESIGN: Recording of fractures was accomplished by a specially constructed outpatient index and by record linkage to hospital inpatient information, for the three years surrounding the 1981 census. SETTING: The fracture index was held by the Department of Community Health in Leicester using data from the fracture clinic at the central large district general hospital, supplemented by hospital inpatient data from Trent Region and the two adjoining regions. PARTICIPANTS: The denominator population was the Leicestershire Health Authority resident population. In the three years, 12,711 fractures amongst males and 10,565 amongst females were recorded. MEASUREMENTS AND MAIN RESULTS: The overall estimated annual incidence of fractures was 100 per 10,000 population for males and 81 per 10,000 population for females. Below the age of 55 years all fractures showed a higher incidence amongst males but amongst the over 55s, there was a consistent fall in the male:female incidence ratio with some sites showing a striking female preponderance. The results also show an apparent age specific temporal increase in incidence at certain fracture sites compared with earlier British data, but fracture incidence figures still suggest lower rates in this country than in North America and some Scandinavian countries. CONCLUSIONS: These findings provide population based incidence data on a major public health problem and are consistent with the major determinants of osteoporosis and increase in falls in postmenopausal women. The temporal and geographical variation in fracture incidence remain to be explained.

Age Factors↗
PubMed1989

Controlled trial of haem arginate in acute hepatic porphyria.

A double-blind study comparing placebo and haem arginate was conducted in 12 patients with acute intermittent porphyria. 2 days after admission in attack patients were randomised to receive intravenous haem arginate 3 mg/kg per 24 h for 4 days or placebo. 9 patients were readmitted with a further attack and were given the alternative treatment. Before randomisation the paired attacks were of similar severity with respect to urinary porphobilinogen (PBG) excretion and clinical manifestations. With haem arginate the median PBG excretion of the 9 patients with two attacks (normal range 0-16 mumol per 24 h) fell significantly from 332 mumol per 24 h (range 137-722) on admission to a median lowest level of 40 (range 22-105). On placebo, median PBG excretion was 382 (range 196-542) on admission, falling to 235 (range 128-427). Median duration of admission after the start of treatment was 11 days (range 2-28) for placebo and 8 days (3-26) for haem arginate. Median total analgesic requirement between the start of treatment and discharge was 8150 mg pethidine equivalents (range 0-17,650) with placebo versus 6425 (range 50-20,650) with haem arginate. Phlebitis occurred in 5 patients on haem arginate and in 2 on placebo. Haem arginate effectively reduces porphyrin precursor overproduction in the acute porphyric attack but this reduction is not accompanied by striking resolution of the clinical manifestations of the attack.

Acute Disease↗
PubMed1989

p53 is associated with a 35 kD protein in cells transformed by simian virus 40.

The p53 protein is functionally implicated in the normal control of cell proliferation and, abnormally, in cell transformation. p53 is believed to function via specific cellular target proteins and activated mutants of p53 are associated with proteins of the hsp/hsc 70 heat shock family. However, cellular target proteins of wild type p53 have not, as yet, been described. With the aim of detecting such targets we have screened for cellular protein(s) that co-precipitate with wt p53. We now describe a 35 kD protein co-precipitated with p53 from SV40-transformed cells (a similar protein is detectable in non-viral transformed cells). The 35 kD protein does not appear to be a degradation product of p53. In sequential immunoprecipitations the 35 kD protein was depleted in parallel with p53, with which it appeared to be physically associated. This was substantiated by dissociation experiments in which the 35 kD protein was dissociated under conditions that also dissociate p53 from SV40 large T antigen. Thus wt p53 appears to interact with a cellular protein of 35 kD, the identity of which is under investigation.

Antigens, Polyomavirus Transforming↗
PubMed1989

A review of the practice of fibreoptic endoscopic dilatation of oesophageal stricture.

Over a 5-year period 82 patients underwent 244 fibreoptic endoscopic dilatations for oesophageal stricture. A total of 55 patients had benign peptic oesophageal stricture caused by reflux oesophagitis. Two-thirds of these patients had good symptomatic relief with dilatation combined with medical treatment of reflux, whereas one-third had an unsatisfactory result. The practice of endoscopic dilatation in benign stricture proved to be safe and was cost-effective as the procedure was carried out under intravenous sedation on a day-care basis. Three patients underwent dilatation for achalasia with good results in two cases. There were 16 patients with malignant oesophageal stricture and, in this group, fibreoptic endoscopic dilatation had little role to play in relieving dysphagia and its practice was associated with a substantial morbidity and mortality. Dilatation of malignant strictures facilitated biopsy and was used prior to oesophageal intubation. The virtues of the Atkinson or Celestin tube put in with the Nottingham introducer are summarised. Eight patients developed anastomotic stricture after resection of carcinoma of the oesophagus and dilatation provided only very transient relief of dysphagia in this group. Most anastomotic strictures represented recurrent malignancy and the difficulty in gaining biopsy proof endoscopically is emphasised. We advocate the early use of a CT scan in this situation to make the diagnosis of recurrent malignancy so that, if appropriate, palliative treatment can be instituted while the patient's general condition is good enough to benefit from it.

Adolescent↗
PubMed1989

Pathogenesis of venous ulceration in relation to the calf muscle pump function.

Air plethysmography has been used to quantitate venous reflux by measuring the average filling rate of the veins (venous filling index; in milliliters per second) on standing from the supine position, the ejection fraction of the calf muscle pump as a result of one tip-toe movement, and the residual volume fraction after 10 tip-toe movements. Thirty normal limbs, 110 limbs with primary varicose veins, 34 limbs with reflux in the deep veins but without occlusion, and 31 limbs with deep venous occlusion, with or without reflux, have been studied. An increase in the incidence of ulceration occurred with increasing values of reflux and decreasing values of the calf muscle pump ejection fraction. A poor ejection fraction was the primary cause of venous ulceration in limbs with minimal reflux. A good ejection fraction, however, significantly reduced the incidence of ulceration in limbs with marked reflux (p less than 0.05). The residual volume fraction, which expresses the combined effect of venous reflux and ejection fraction with rhythmic exercise, showed a good correlation with the incidence of ulceration and the measurements of ambulatory venous pressure (r = 0.81). The air-plethysmographic measurements completely assess the calf muscle pump function and provide an accurate method to identify the predominant hemodynamic factor (ejection fraction, reflux, or both) responsible for the clinical picture of the patient.

Adult↗
PubMed1988

Development of radioimmunoassays for free tetra-L-aspartyl-L-lysine trypsinogen activation peptides (TAP).

Tetra-L-aspartyl-L-lysine (D4K) containing trypsinogen activation peptides were synthesised on solid-phase supports. Synthetic D4K peptides were N-terminally haptenised and used to generate specific C-terminally directed anti-D4K antibodies. Affinity purification of antisera using Sepharose-immobilised synthetic D4K segregated two highly purified populations of anti-D4K antibodies, one eluting with EDTA recognising the calcium chelate and the other eluting with propionic acid recognising an alternative epitope on the anionic oligopeptide. Both specific anti-D4K antibodies were C-terminally directed and did not bind trypsinogen. Specific antisera and calcium-independent antibodies were used to develop and characterise solution and solid-phase immunoassays specific for free trypsinogen activation peptides (TAP assay), with a detection limit of 10(-11) M and between assay CV of 10.7% for the solution-phase system. The release of D4K peptides by enteropeptidase activation of trypsinogen and dog pancreatic secretion is demonstrated. TAP assays specifically indicate trypsinogen activation and may contribute to the recognition and understanding of disease states such as pancreatitis.

Amino Acid Sequence↗
PubMed1988

Food craving, mood and the menstrual cycle.

Seventy-six women, with a mean age of 35.7 years, who reported premenstrual craving for sweet foods in a retrospective questionnaire, were assessed prospectively with a pre- and post-menstrual eating questionnaire and daily ratings of craving, mood, irritability and breast tenderness over two menstrual cycles. In 72% of these women a perimenstrual pattern of food craving was confirmed. In 13% this craving was confined to the menstrual phase. There was no consistent association between food craving and mood change, either in timing or severity. Women with more severe mood change did not report more severe craving. There was also no association between food craving and cyclical breast tenderness. Perimenstrual food craving, therefore, appears to be a cyclical phenomenon in its own right, of uncertain aetiology and worthy of further study.

Adult↗
PubMed1988

Prostatectomy: patients' perception and long-term follow-up.

We have reviewed 500 consecutive prostatectomies with a follow-up period of between 5 and 8 years; 184 surviving patients were sent a questionnaire and patients with residual urinary symptoms were interviewed, examined and a flow rate was performed. The operative mortality rate was 0.5%. Patients who presented with retention of urine had a high mortality rate in the first 3 years after the operation. Thirty-six per cent of surviving patients with chronic retention and 24% of those who underwent elective prostatectomy had residual urinary symptoms at the time of the study. Of patients who were sexually active pre-operatively, 34% felt that the operation was responsible for a deterioration in their sex lives. The incidence of retrograde ejaculation was 93%. It was concluded that prostatectomy is a safe operation with good patient acceptability. Patients with symptoms of prostatism require careful evaluation before prostatectomy and sexually active patients should be warned of the risks of impotence and decreased satisfaction due to retrograde ejaculation.

Age Factors↗
PubMed1987

A new anti-p53 monoclonal antibody, previously reported to be directed against the large T antigen of simian virus 40.

The PAb1620 antibody belongs to a group of monoclonal antibodies reported to recognize nuclear large T antigen of simian virus 40 (SV40). In the case of PAb1620 there was some indication that the antibody reacted preferentially with large T when it was complexed with p53, the cellular transformation-related antigen. However, we found that PAb1620 does not appear to react with SV40 large T, either free or in complex with p53. In this paper we demonstrate that PAb1620 is, in fact, directed against the p53 protein and recognizes a conformation-dependent epitope. In addition, PAb1620 recognises human p53 from SV80 cells.

Antibodies, Monoclonal↗
PubMed1987

Evaluation of the nitrosamine hypothesis of gastric carcinogenesis in man.

Patients who had undergone a Billroth II gastrectomy (PG) or had pernicious anaemia (PA) and healthy matched control subjects (MC) participated in 24-h studies in which bacteria, nitrite and N-nitroso compounds (NOC) were measured in gastric juice and N-nitrosoproline (NPRO) in urine. Consistent with the nitrosamine hypothesis, intragastric levels of bacteria and nitrite were positively related to intragastric pH, but, contrary to the hypothesis, NOC in gastric juice and NPRO in urine were negatively related to intragastric pH.

Anemia, Pernicious↗
PubMed1986

The cellular tumour antigen p53: evidence for transformation-related, immunological variants of p53.

The protein p53 is involved in the control of normal cell proliferation. However, when expressed abnormally, p53 also contributes to the process of cell transformation. The possibility that multifunctional forms of p53 exist was realised when two cell cycle dependent forms of the protein were identified in normal cells (lymphocytes: J. Milner, 1984, Nature (London) 310, 143-145). Interestingly these two forms of p53 in normal cells lack some of the epitopes recognised by monoclonal antibodies developed against p53 in transformed cells. This suggests that p53 may bear additional transformation-related epitopes in transformed cells. We have now investigated this possibility by screening a variety of cell lines for immunological variants of p53. The monoclonal antibodies PAb421, PAb122, RA3.2C2, PAb248, PAb200.47, and PAb246 were used. Our results indicate the existence of two immunologically distinct variants of p53 expressed in transformed cells. The two p53 variants are distinguished by the presence or absence of the epitope recognised by PAb246. A given cell line generally expressed a single immunological variant of p53. However, 3T6 cells expressed two subsets of p53 and appeared to modulate p53 synthesis in response to cell density.

Animals↗
PubMed1986

Regional assignment of Y-linked DNA probes by deletion mapping and their homology with X-chromosome and autosomal sequences.

A series of Y recombinants have been isolated from Y-specific DNA libraries and regionally located on the Y chromosome using a Y deletion panel constructed from individuals carrying structural abnormalities of the Y chromosome. Of twenty recombinants examined twelve have been assigned to Yp and eight to Yq. Five of the Yp recombinants map between Yp11.2 and Ypter and one can only be assigned to Yp. Of the former, four detect homologies on the X chromosome between Xq13 and Xq24 and the latter one between Xp22.3 and Xpter. The sixth recombinant detects autosomal homologous sequences. The six remaining Yp probes are located between Ycen and Yp11.2. One of these detects a homology on the X chromosome at Xq13-Xq24 and a series of autosomal sequences, two detect uniquely Y-specific sequences and three a complex pattern of autosomal homologies. The remaining eight recombinants have been assigned to three intervals on Yq. Of three recombinants located between Ycen and Yq11.21 two detect only Y sequences and one additional autosomal homologies. Two recombinants lie in the interval Yq11.21-Yq11-22, one of which detects only Y sequences and the other an Xp homology between Xp22.3 and Xpter. Finally, the three remaining Yq recombinants all detect autosomal homologies and are located between Yq11.22 and Yq12. The divergence between homologies on different chromosomes has been examined for three recombinants by washing Southern Blots at different levels of stringency. Additionally, Southern analysis of DNA from flow sorted chromosomes has been used to identify autosomes carrying homologies to two of the Y recombinants.

Chromosome Deletion↗
PubMed1986

Visualisation, by immunocytochemistry, of p53 at the plasma membrane of both nontransformed and SV40-transformed cells.

The cellular protein p53 normally functions in the control of cell proliferation; but, when expressed abnormally p53 also contributes towards the process of cell transformation. The functioning of p53 is thought to involve interaction with specific cellular targets and, in SV40- and other transformed cells, p53 is located in the nucleus: thus p53 may function via interacting with specific nuclear components. In addition, there is indirect evidence that in SV40-transformed cells p53 is also associated with the plasma membrane; however, this is not evident in cells stained by immunofluorescence. We have sought to obtain direct evidence for p53 at the plasma membrane by staining with a very sensitive immunocytochemical procedure. We have compared SV40-transformed BALB 3T3 cells with BALB 3T3, NIH 3T3, and NIH 3T3 transfected with v-mos provirus. The last cell line is tumorogenic. We found direct evidence for p53 at the plasma membrane for each cell line. In nontransformed and SV40-transformed cells the association of p53 with the plasma membrane was restricted to the period of mitosis. These results indicate that association of p53 with the plasma membrane is a normal, rather than a transformation-related phenomenon, and is temporally linked to the period of mitosis.

Animals↗