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Biomedical subjects

J A Henry

Publications and source records attributed to J A Henry.

At least 19 recordsLinked to original sources
PubMed1996

Retinoblastoma protein in human breast carcinoma: immunohistochemical study using a new monoclonal antibody effective on routinely processed tissues.

Cyclic phosphorylation/dephosphorylation of the retinoblastoma gene product (pRB) has been found to play a central role in the progression of the normal cell cycle, through modulation of the activity of the E2F family of transcription factors. Mutations of the retinoblastoma gene have been described in a wide variety of human malignancies including carcinomas of the breast. The present investigation reports the production and application of a new monoclonal antibody in an immunohistochemical study of pRB expression in 233 primary breast carcinomas, allowing an assessment of the contribution made by this tumour suppressor gene to tumour development and progression. Overall, there was loss of pRB expression in 21 per cent of breast tumours. Although high-grade tumours were found to lack detectable pRB more frequently than low-grade tumours, the difference did not prove statistically significant. In addition, pRB immunostaining was not related significantly to relapse or survival. No significant correlations were observed between apparent loss of pRB and tumour size, parity, patient lymph-node status, p53, c-erbB-2, c-jun, EGFR or steroid hormone receptor expression. Preliminary findings, however, did suggest a relationship between pRB expression and response to endocrine therapy.

Adult↗
PubMed1996

Membrane action of chloramphenicol measured by protozoan motility inhibition.

The mechanism of the grey baby syndrome produced by chloramphenicol overdose is poorly understood. The present study assessed the membrane toxicity of this agent by means of its depressant effect on excitable tissues. The inhibition by drugs of protozoan motility was used as a toxicity endpoint, measured by the swimming speed of Tetrahymena pyriformis using an image analysis system. The n-octanol/water partition coefficient at pH 7.4, 37 degrees C was determined as a measure of the hydrophobicity of the drugs. Chloramphenicol dose-dependently depressed the motility of the test organism with an IC50 value (the concentration reducing the mean swimming speed to 50% of control) of 2.95 +/- 0.25 mM, in contrast to a significantly weaker effect of its succinate salt with an IC50 of 28.2 +/- 1.93 mM. Thiamphenicol, a drug with similar properties to chloramphenicol, produced little effect on protozoan motility. Several other antibiotics either in free or salt forms were also ineffective. A series of agents known to possess membrane stabilising action also tested for comparison showed that chloramphenicol possesses the ability to reduce protozoan motility. Measurement of the n-octanol/water partition coefficient revealed a value for chloramphenicol of 11.9 +/- 0.66. This property was correlated with protozoan immobilising potency among a series of heterogeneous compounds, suggesting that the mechanism involved a hydrophobic interaction with the excitable membrane. These results show that chloramphenicol has a depressant effect on protozoan motility comparable to agents with known toxicity effects on cell membranes. This suggests that chloramphenicol has the potential to cause membrane-mediated toxic effects, a mode of action that may underlie its acute toxicity to excitable tissues.

1-Octanol↗
PubMed1996

p53 protein as a prognostic indicator in breast carcinoma: a comparison of four antibodies for immunohistochemistry.

We examined the reactivity of four p53-specific monoclonal antibodies--PAb 1801, p53-BP-12, D07 and CM1--on sections of formalin-fixed tissue collected from 245 breast carcinomas. Immunodetection of p53 varied between 37.6% and 46.6%. The greatest variation was observed among lobular carcinomas and low-grade tumors in which immunodetection varied between 8.3% and 27.3%. In contrast, immunodetection of p53 in invasive ductal carcinomas was subject to a lower degree of variability with between 40.6% and 49.7% of these tumours proving to be positive. In general, we found antibodies PAb 1801 and DO7 to be the most effective in immunolocalising p53. Immunodetection of p53 with each of the four antibodies was found to correlate strongly with tumour grade. In survival analysis, the results gained using antibody PAb 1801 proved to be of greatest statistical significance and to provide the strongest index of prognosis. A significant relationship was observed between immunodetection of p53 with each of the four antibodies and poor responsiveness to endocrine therapy. In addition, relationships were also observed between p53 immunostaining and tumour oestrogen receptor (ER) status as well as c-jun expression. We observed no correlation between abnormalities of the p53 and the Rb gene products or between elevated c-erbB-2 or epidermal growth factor receptor (EGFR) expression and immunodetection of p53.

Adult↗
PubMed1996

Electrocardiographic changes in patients receiving neuroleptic medication.

The precise aetiology of sudden death in patients receiving neuroleptic medication is uncertain, but cardiac arrhythmias are a possible cause. We investigated the link between neuroleptic medication and electrocardiographic changes predictive of malignant cardiac arrhythmias. Electrocardiographs were performed on 111 patients receiving neuroleptic medication and on 42 unmedicated controls. Prolonged QTc intervals were more common in the patient sample, but QTc dispersion was not significantly increased. QTc interval prolongation was more likely in patients on doses above 2000 mg chlorpromazine equivalents daily (odds ratio 4.28, P < 0.02). Neuroleptic medication, especially at high doses, is associated with ECG changes that may herald more serious cardiac problems.

Adult↗
PubMed1995

Determination of the prognostic value of cyclin D1 overexpression in breast cancer.

Cyclin D1 plays a critical role in the timing of the initiation of DNA synthesis in the normal cell cycle of mammalian cells. Deregulated expression of this protein has been seen in a variety of tumours either as a result of gene amplification or chromosomal translocation, in breast cancer and B cell malignancies respectively. In order to determine the role this putative oncoprotein plays in breast cancer, we have applied a new monoclonal antibody, recently produced in our laboratory, in an immunohistochemical study of 93 primary breast carcinomas. We show that approximately 28% of the cases displayed enhanced expression of the cyclin D1 protein. Furthermore, either cyclin D1, cyclin D3, or both, were expressed in 69% of cases, suggesting that overexpression of any one member of this family may relieve cancer cells of their mitogenic stimulatory requirement. In addition, we show that those patients whose breast cancers co-express cyclin D1 with either epidermal growth factor receptor (EGFR) or the retinoblastoma protein (pRB) have a significantly poorer prognosis in comparison to those expressing cyclin D1 alone. Our observations indicate that, in a subset of breast cancers, aberrant cyclin D1 expression is a contributory factor to tumorigenesis and in association with EGFR or pRB expression, identify those tumours which may require more aggressive therapy.

Animals↗
PubMed1995

Relative mortality from overdose of antidepressants.

OBJECTIVE: To compare the fatal toxicities of antidepressant drugs in 1987-92. DESIGN: Retrospective epidemiological review of prescription data of the Department of Health, Scottish Office Home and Health Department, and Welsh Health Common Services Authority (excluding data from most private general practices and most hospitals), and mortality data from the Office of Population Censuses and Surveys and General Register Office in Scotland. SETTING: General practice, England, Scotland, and Wales. MAIN OUTCOME MEASURES: Deaths per million prescriptions and deaths per defined daily dose. RESULTS: 81.6% (1310/1606) of deaths from antidepressant overdose were due to two drugs, amitriptyline and dothiepin. The overall average of deaths per million prescriptions was 30.1. The overall rate for tricyclic drugs was 34.14 (95% confidence interval 32.47 to 38.86; P < 0.001), monoamine oxidase inhibitors 13.48 (6.93 to 22.19; P < 0.001), atypical drugs 6.19 (4.04 to 8.80; P < 0.001), and selective serotonin reuptake inhibitors 2.02 (0.64 to 4.17; P < 0.001). The numbers of deaths per million prescriptions of amoxapine, dothiepin, and amitriptyline were significantly higher than expected, while nine drugs had a significantly lower number of deaths per million prescriptions than expected. Analysis of deaths per defined daily dose showed a similar pattern. CONCLUSIONS: Safety in overdose should be considered in risk-benefit and cost-benefit considerations of antidepressants. A switch in prescribing, from drugs with a high number of deaths per million prescriptions to drugs with a low number, could reduce the numbers of deaths from overdose. Although this form of suicide prevention can be implemented easily and immediately, its introduction needs to be considered against the higher costs of some of the newer drugs.

Amitriptyline↗
PubMed1995

Prevention of drug absorption in simulated theophylline overdose.

1. The effects of emesis, gastric lavage and oral activated charcoal on theophylline absorption were compared in healthy volunteers. 2. One of four regimes (ipecacuanha-induced emesis, gastric lavage, oral activated charcoal and no treatment) was randomly chosen one hour after a simulated overdose with sustained-release theophylline on four separate occasions in twelve healthy volunteers. 3. Syrup of ipecacuanha produced emesis in all twelve volunteers but only seven vomited any tablets. Gastric lavage yielded tablets in only one volunteer. 4. The mean systemic availabilities (areas under the concentration-time curves relative to control) of theophylline for ipecacuanha-induced emesis, gastric lavage and charcoal, were 107.1%, 101.1% and 16.9%, respectively. 5. Oral activated charcoal was thus highly effective, while gastric lavage and emesis were ineffective in preventing theophylline absorption. Activated charcoal is potentially the most effective first-line treatment for acute overdosage with sustained-release theophylline tablets.

Administration, Oral↗
PubMed1995

High-frequency toneburst-evoked ABR latency-intensity functions in sensorineural hearing-impaired humans.

The latency-intensity functions (LIFs) of ABRs elicited by high-frequency (8, 10, 12, and 14 kHz) toneburst stimuli were evaluated in 20 subjects with confirmed 'moderate' high-frequency sensorineural hearing loss. Wave V results from clicks and tonebursts revealed all intra- and intersession data to be reliable (p > 0.05). Linear regression curves were highly significant (p < or = 0.0001), indicating linear relationships for all stimuli analyzed. Comparisons between the linear regression curves from a previously reported normal-hearing subject group and this sensorineural hearing-impaired group showed no significant differences. This study demonstrated that tonebursts at 8, 10, and 12 kHz evoked ABRs which decreased in latency as a function of increasing intensity and that these LIFs were consistent and orderly (14 kHz was not determinable). These results will contribute information to facilitate the establishment of change criteria used to predict change in hearing during treatment with ototoxic medications.

Acoustic Stimulation↗
PubMed1995

Prevention of drug absorption in simulated theophylline overdose.

To assess the effectiveness of oral activated charcoal and catharsis in preventing theophylline absorption, 12 healthy subjects, aged 20-35 years, received 3 x 200 mg sustained-release theophylline tablets and 16 radio-opaque placebo tablets on six occasions. On each occasion, they received either no treatment (control) or one of five treatments. Treatments were a) oral activated charcoal (Carbomix): 50 g at 1 h, 25 g at 5 h and 9 h; b) sorbitol 70%: 150 mL at 1 h; c) activated charcoal: 50 g at 6 h, 25 g at 10 h and 14 h; d) sorbitol 70%: 150 mL at 6 h; e) charcoal commencing at 6 h plus sorbitol at 6 h (i.e. a combination of treatments c and d). Plasma theophylline concentrations were measured and all stools collected over 36 h to assess placebo tablet recovery by radiography. Charcoal administration at 1 h was 91.2% effective in preventing theophylline absorption and at 6 h was 57.3% effective, while combined charcoal and catharsis at 6 h was 63.3% effective. Sorbitol-induced catharsis at 1 h and 6 h did not reduce theophylline absorption despite greater tablet recovery. Oral activated charcoal may be the most effective treatment for sustained-release theophylline overdose, with maximum benefit when administered soon after an overdose, though later administration might still be of value. Sorbitol catharsis is of no benefit either alone or in combination with charcoal.

Administration, Oral↗
PubMed1995

Response to glucagon in imipramine overdose.

A 25-year-old woman, severely hypotensive following a massive imipramine overdose, had an immediate and sustained rise in blood pressure following intravenous glucagon (10 mg bolus followed by an infusion of 10 mg over 6 h). The QRS interval on the electrocardiogram shortened from 129 to 89 msec. Glucagon should be considered in hypotension following tricyclic antidepressant overdose; it may also be antiarrhythmic.

Adult↗
PubMed1994

Relationships between pharmacokinetics and nonpulmonary pharmacodynamic effects of theophylline.

Concentration-effect relationships between oral theophylline and its nonpulmonary pharmacodynamic effects were examined in a double-blind, randomized, two-way crossover study in which 10 healthy subjects received a single dose of 500 mg ordinary-release theophylline or placebo. Mean plasma theophylline concentrations rose to 16.1 mg.L-1 at 1 hour and 16.8 mg.L-1 at 2 hours. Maximum decreases in plasma potassium (0.33 mmol.L-1) and magnesium (0.039 mmol.L-1) and increases in supine (11.1 mm Hg) and standing (8.0 mm Hg) diastolic blood pressure and plasma total cholesterol (0.59 mmol.L-1) occurred after the achievement of peak plasma theophylline concentrations (negative hysteresis). This delay is consistent with the intracellularly mediated effects of theophylline and with compartmental shifts of electrolytes. Discrepancies between the pharmacokinetic profile and pharmacodynamic effects should be borne in mind when assessing the duration of action of a drug.

Adult↗
PubMed1994

Acute arsenic poisoning: absence of polyneuropathy after treatment with 2,3-dimercaptopropanesulphonate (DMPS).

Two men aged 19 and 21 years ingested 1 g and 4 g respectively from 3 kg of a white crystalline powder that they thought was a substance of abuse. It was later identified as almost pure arsenic trioxide. Both had nausea and vomiting and one developed acute renal failure. Each was treated with 2,3-dimercaptopropanesulphonate (DMPS), and made a full recovery with no evidence of prolonged renal or neurological impairment. The DMPS-arsenic complex is probably associated with lower penetration into the CNS and as a consequence treatment with DMPS may result in lower acute and chronic neurotoxicity than treatment with the currently standard recommended chelating agent dimercaprol (British Anti-Lewisite; BAL).

Acute Disease↗