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Biomedical subjects

L A Brown

Publications and source records attributed to L A Brown.

At least 19 recordsLinked to original sources
PubMed1995

Decreased contractile responses to isoproterenol in isolated cardiac myocytes from aging guinea-pigs.

We have characterized the age-related changes of contractility and beta-adrenoceptor function in isolated cardiac myocytes from guinea-pigs. We used either adult animals from 2 to 14 weeks of age, where body weight increases linearly with age, or senescent ones aged between 53-65 weeks. There was some indication of a decrease in contractility in maximum Ca2+ with age, with significant differences between a young (< or = 4 weeks, weight < 400 g) and aged (> or = 8 weeks, weight > 600 g) group in contraction amplitude expressed as percentage shortening (but not when expressed as micron change in length) or contraction and relaxation velocities. This decline was continued into senescence, and ANOVA showed a significant difference between the three groups for contraction amplitude (percentage shortening, 12.2 +/- 0.9%, young, n = 31; 9.5 +/- 0.6%, n = 28 aged; 6.7 +/- 0.8%, n = 6, senescent; P = 0.005), and contraction or relaxation velocities (P < 0.001). There was a more pronounced decline in maximum response to isoproterenol with age. ANOVA for the maximum isoproterenol response for the three divisions showed significant differences for percentage shortening (11.8 +/- 0.7%, n = 30, young; 7.9 +/- 0.5%, n-28, aged and 5.5 +/- 1.1%, n = 6, senescent; P < 0.001), velocities of contraction (P < 0.001) and relaxation (P < 0.001), and normalized velocities of contraction (P < 0.001) and relaxation (P < 0.01) at maximum isoproterenol, as well as in ISO EC50 (P < 0.001) and isoproterenol/Ca2+ ratio (P < 0.02). A general decrease in contractility of the myocyte occurs as the animal ages, with maximum contraction amplitude being reduced and velocity of contraction and relaxation slowed. The effect was more pronounced for beta-adrenoceptor stimulation than for high Ca2+, suggesting a specific lesion in the adenylate cyclase related pathway. Much of the change occurred between the young adult (< or = 4 weeks) and the aged adult (> or = 8 weeks), although the trend was continued in senescent animals (> 52 weeks).

Adrenergic beta-Agonists↗
PubMed1995

Pulmonary alveolar proteinosis in SCID mice.

Pulmonary alveolar proteinosis (PAP) is an uncommon disorder of unknown origin in which the alveoli are filled with lipoproteinaceous material, including surfactant. We have characterized a spontaneously occurring lesion in the lungs of CB.17 scid/scid mice which resembles PAP in humans. Lungs from 45 severe combined immunodeficient (SCID) mice were evaluated by light and electron microscopy and immunohistochemistry. Lung lavage fluid was evaluated biochemically and for the presence of surfactant protein A (SP-A) and B (SP-B) by enzyme-linked immunosorbent assay and Western blot. Light microscopy showed varying amounts of a homogeneous to granular proteinaceous material in alveolar spaces. This material was eosinophilic by hematoxylin and eosin stain and was periodic acid-Schiff (PAS) positive. Ultrastructurally, the material was predominantly homogeneous with areas of a lamellated pattern that resembled surfactant. Biochemical analysis revealed 2.7- and 3.6-fold increases in the surfactant-associated phospholipids phosphatidylcholine and disaturated phosphatidylcholine respectively, when affected SCID mice were compared with control mice. Immunohistochemical staining of lung tissue and Western blot and enzyme-linked immunosorbent assay of lavage fluid showed marked increases in SP-A and SP-B in comparison with controls. These results suggest that SCID mice have a defect in surfactant homeostasis that resembles PAP in humans and may serve as an animal model in further elucidating the pathogenesis of this disease.

Animals↗
PubMed1995

Selective increase in endothelin-1 and endothelin A receptor subtype in the hypertrophied myocardium of the aorto-venacaval fistula rat.

OBJECTIVE: At present little is known about the factors that regulate the expression of the endothelins and their receptors in cardiac tissue in vivo. The aim of this study was to investigate changes in expression of the endothelins (ET-1, ET-2, and ET-3) and their receptors (ETAR and ETBR) in the hypertrophied heart of the aortovenocaval (AV) fistula rat. METHODS: Reverse transcription-polymerase chain reaction (RT-PCR) was used to quantify cardiac mRNA expression of the endothelins and their receptors during the development of cardiac hypertrophy, while radioligand binding was employed to quantify the amount of [125I]-ET-1 binding to cardiac membranes. Tissue and plasma concentrations of ET-1 were measured by radioimmunoassay. RESULTS: In control sham operated animals, ET-1 mRNA was approximately fivefold greater in atria than in ventricles (P < 0.05), but there were no atrioventricular differences in ET-2 or ET-3 mRNA. In the AV fistula rats there was a prompt three- to fourfold increase in ET-1 mRNA in atria and a progressive five- to sevenfold rise in ventricles during cardiac hypertrophy. There were no changes in ET-2 or ET-3 transcript prevalences, except for a late rise (35 d) in ET-2 mRNA levels in left ventricle. Consistent with ET-1 mRNA measurements, immunoreactive endothelin levels were increased by 7 d in atria, but not in ventricles. In control rat hearts, ETAR mRNA levels were similar in atria and ventricles, but the prevalence of ETBR was approximately sevenfold greater in the former. ETAR mRNA prevalence increased with hypertrophy in all chambers, while ETBR transcript levels were raised only in the right ventricle. There was no significant difference in [125I]-ET-1 binding between atrial samples from 35 d control and 35 d AV fistula rats, suggesting rapid turnover of endothelin receptors balanced by increased transcription from the ETAR gene. CONCLUSIONS: During cardiac hypertrophy in AV fistula rats there is increased activity of the endothelin system mediated principally by ET-1 and the ETAR subtype.

Animals↗
PubMed1994

Glutathione protects signal transduction in type II cells under oxidant stress.

Brief exposure of type II cells to 100 microM t-butyl hydroperoxide (tBOOH) inhibits agonist-induced surfactant secretion and second messenger generation presumably through the oxidation of membrane lipids. Since glutathione (GSH) reduces lipid peroxides and protects type II cells from oxidant injury as determined by crude indicators, then GSH should also protect signal transduction. In the current study, tBOOH inhibited ATP-induced adenosine 3',5'-cyclic monophosphate and inositol trisphosphate generation and surfactant secretion. Stimulation of surfactant secretion by forskolin or phorbol acetate was also inhibited by tBOOH. Pretreatment with GSH (1 mM) blocked the tBOOH inhibition. This protection occurred in the presence of gamma-glutamyl transferase and gamma-glutamylcysteine synthetase inhibitors and suggested GSH was transported as an intact molecule. GSH protection was blocked by gamma-L-glutamyl-L-glutamate, an agent that blocks GSH transport. Protection of surfactant secretion and signal transduction was also provided by the constitutive amino acids but not if GSH synthesis was blocked. In the cultured type II cell model, GSH transport and synthesis protected signal transduction and, subsequently, surfactant secretion against oxidant injury.

1-Methyl-3-isobutylxanthine↗
PubMed1994

Prostate-specific antigen screening for prostate cancer: no reduction in Gleason scores.

Skepticism regarding prostate-specific antigen (PSA) screening arises from the possibility that screening procedures increase the yield of diagnosed prostate cancers occurring in an indolent form that does not require treatment. If PSA screening serves only to increase the yield of clinically trivial prostate cancer, one would expect a drop in the average Gleason score of prostate cancers detected with PSA screening compared with prostate cancers detected before the advent of PSA screening. In a 3-yr study of newly diagnosed prostate cancer, there was almost a 7-fold increase in PSA screening tests ordered between 1989 and 1992 and a greater than 2-fold increase in the number of newly diagnosed prostate cancers. In the same time period, the average Gleason scores of newly diagnosed prostate cancer increased slightly (from 6.2 to 6.5). In this study there was no prognostic difference (as predicted by Gleason score) between prostate cancers in populations whose cancers were diagnosed before and after the increased use of PSA as a screening tool.

Biopsy, Needle↗
PubMed1992

Fine needle aspiration for the diagnosis and management of granulomatous disease.

Fine needle aspiration is a quick, minimally invasive and cost-effective technique for the diagnosis of granulomatous disease. Cytological diagnosis can often be specific, with the help of special stains and microbiological culture of aspirated material, particularly in the case of tuberculosis, the most common infective granulomatous disease in this country. At a fine needle aspiration clinic many cases of granulomatous disease, some from unusual sites, have been diagnosed and the use of more invasive investigations has been avoided. The problems involved in cytological diagnosis are discussed using seven cases as examples.

Adolescent↗
PubMed1992

Cost effectiveness of a fine needle aspiration clinic.

The resource implications of a Fine Needle Aspiration (FNA) Clinic at Northampton General Hospital have been evaluated over a 12 month period using a patient management questionnaire. A total of 490 cases from which fine needle aspirates were taken from superficial sites have been assessed (breast 381, thyroid 46, lymph node 44, salivary gland 9, soft tissue 10). Total resource savings (135,544 pounds) exceeded the expenses of the FNA clinic (27,290 pounds). Potential cost savings per case were the greatest for thyroid aspirates. The FNA clinic where the pathologist takes, stains and reports optimally prepared specimens, provides a high quality and accurate service on which clinicians can confidently base clinical management decisions. Unnecessary investigations and operations are avoided, allowing scant resources to be released for other procedures.

Ambulatory Care Facilities↗
PubMed1992

The effect of pertussis toxin on beta-adrenoceptor responses in isolated cardiac myocytes from noradrenaline-treated guinea-pigs and patients with cardiac failure.

1. A decreased responsiveness to the positive inotropic effects of beta-adrenoceptor agonists is a characteristic of human heart failure. We have investigated the involvement of inhibitory guanine nucleotide binding proteins (G-proteins) in this process using pertussis toxin treatment of isolated cardiac myocytes. 2. Myocytes isolated from failing human myocardium had a reduced maximum contractile response to isoprenaline relative to that for maximally stimulating concentrations of calcium, giving an isoprenaline/calcium ratio of 0.71 +/- 0.06 (n = 7 patients). This was significantly lower than in myocytes from non-failing myocardium, where the isoprenaline/calcium ratio was 1.16 +/- 0.07 (n = 6, P less than 0.001). Responses to high calcium were unchanged. 3. Myocytes were treated with pertussis toxin for 3-5 h at 35 degrees C. Successful inactivation of inhibitory G-proteins by pertussis toxin treatment was indicated by a loss of responsiveness to 10 microM adenosine (in the presence of submaximal isoprenaline). 4. Following pertussis toxin treatment of the myocytes from failing human heart the isoprenaline/calcium ratio increased to 1.43 +/- 0.27 (n = 7, P less than 0.05). Pertussis toxin treatment had no effect upon the maximum calcium contraction. The isoprenaline/calcium ratio in myocytes from non-failing human ventricle was not affected by the toxin treatment (n = 3). These observations support the hypothesis that increased inhibitory G-protein levels or activities contribute to beta-adrenoceptor desensitization in human heart failure. 5. beta-Adrenoceptor desensitization in human heart failure is thought to be secondary to raised noradrenaline levels in these patients. Experiments were repeated on myocytes isolated from hearts of guinea-pigs which had been chronically infused with noradrenaline. The isoprenaline/calcium ratio of these myocytes was reduced below that of myocytes from sham-operated animals (0.65 0.04, n = 6 compared with 0.88 +/- 0.02, n = 7, P<0.001).6. Pertussis toxin treatment (2 h at 35 degrees C) increased the isoprenaline/calcium ratio to 1.02 0.02 (n = 6,P<0.01) in myocytes from noradrenaline-treated guinea-pigs. This effect of pertussis toxin treatment was not seen in myocytes from sham-operated guinea-pig hearts.7. Incubation at 35 degrees C for similar periods in the absence of pertussis toxin also restored the isoprenaline/calcium ratio towards normal in the myocytes from both failing human and noradrenaline-treated guinea-pig hearts, although the effect was significantly smaller than that produced by the toxin. Myocytes kept at room temperature (22 degrees C) showed no such evidence of resensitization over periods up to 6h.8. These observations are consistent with the hypothesis that raised catecholamine levels result in increased inhibitory G-protein levels and functional P-adrenoceptor desensitization in heart failure.

Adult↗
PubMed1992

Glutathione protection in alveolar type II cells from fetal and neonatal rabbits.

Previous studies have demonstrated a correlation between intracellular glutathione (GSH) pools and sensitivity to oxidative injury. In the present study, we demonstrated that de novo GSH synthesis or GSH uptake could increase intracellular GSH by 7- and 19-fold, respectively, in type II cells from neonatal rabbits. This suggested that the rate of GSH uptake was against a concentration gradient and greater than the synthetic rate. This increased intracellular GSH was associated with protection from oxidant injury by paraquat or 80% O2. A relationship between GSH uptake and protection was further supported by blockage of both processes by gamma-L-glutamyl-L-glutamate, a GSH analogue. With a greater oxidative burden, both de novo synthesis and GSH uptake were required to maintain protection. Although the transport rate was only 6% of that for neonatal cells, cells from fetal animals transported GSH and were protected from oxidative injury. From these results we conclude there was a causal relationship between GSH transport and protection from oxidative injury in type II cells from neonatal and fetal animals.

Amino Acids↗
PubMed1992

Stimulation of phosphatidylcholine hydrolysis in type II alveolar epithelial cells.

The effects of phorbol 12-myristate 13-acetate (TPA) or ATP on phosphatidylcholine (PC) hydrolysis were investigated in cultured type II pneumocytes prelabeled with [3H]choline or 1-O-[3H]octadecyl-sn-glycero-3-phosphocholine ([3H]lyso-PAF). In cells prelabeled with [3H]choline, TPA or ATP stimulated an increase in [3H]choline, [3H]phosphocholine, and [3H]glycerophosphocholine. The formation of these choline metabolites was associated with a concomitant loss of [3H]PC but not from disaturated PC or phosphatidylinositol. In cells prelabeled with [3H]lyso-PAF, the formation of [3H]phosphatidic acid (PA) and then [3H]1,2-DG was stimulated by TPA or ATP and was associated with a loss of 3H from PC but not from disaturated PC or phosphatidylinositol. There was a concentration-dependent formation of [3H]1,2-DG and [3H]PA in response to ATP. Downregulation of protein kinase C with TPA abolished the stimulation of PC hydrolysis. In addition to the generation of metabolites indicative of phospholipase C and/or D activity, [3H]lyso-PC, a product of phospholipase A2, was also generated in response to TPA. These findings suggest an important role for PC breakdown in signal transduction in type II pneumocytes.

Adenosine Triphosphate↗
PubMed1992

Concordance between clinician and patient assessment of physical and mental health status.

The degree of concordance between clinicians' and patients' assessment of the patient's physical and mental functioning was examined in 166 consecutive eligible outpatients with rheumatoid arthritis (RA) using 4-category ordinal scales. The weighted kappa statistic was 0.39 for physical functioning and 0.30 for mental functioning, both indicating a fair degree of concordance. This disagreement differed in magnitude and direction depending on the level of disability present. We conclude that clinicians and their patients with RA often disagree in their assessment of the degree of physical and mental impairment that the patient experiences. These disagreements demonstrate the need for formal assessments of outcome and should be recognized and resolved when managing individual patients.

Adolescent↗
PubMed1991

Audit of diagnostic accuracy of FNA cytology specimens taken by the histopathologist in a symptomatic breast clinic.

One thousand and two patients with palpable breast lumps have had fine needle aspiration at a surgical symptomatic breast clinic where the pathologist takes, stains and immediately reports the aspiration cytology smears. High levels of complete sensitivity (95.7%) and specificity (100%) have been maintained with a combined complete sensitivity for aspiration cytodiagnosis, mammography and clinical assessment of 99.7%. Significant reductions of unnecessary biopsies and out-patient revisits have allowed major resource savings to be made. In view of the high degree of accuracy obtained by this approach to the investigation of palpable breast lesions, combined clinics with their benefits for the patient, both physical and psychological, should be encouraged.

Biopsy, Needle↗
PubMed1991

Fine needle aspiration cytology of the breast: factors affecting sensitivity.

At Northampton General Hospital a pathologist takes, stains and immediately reports aspirates at a fine needle aspiration clinic which is run in conjunction with a busy surgical breast clinic. The effect of various factors on the sensitivity of the technique have been quantified. Small tumour size, certain types of tumour and lesions difficult to palpate are causes of reduced sensitivity. Acellular samples had little effect on sensitivity. In this clinic trainee aspirators achieved good results early in their experience. After one year each had improved to the level of an experienced aspirator.

Biopsy, Needle↗
PubMed1991

High-grade T-cell lymphoma following treatment with cyclosporin A.

A 47-year-old man with persistent severe oropharyngeal ulceration developed a high-grade T-cell lymphoma soon after commencing treatment with cyclosporin A. Using Southern blotting to identify T-cell beta-chain gene rearrangements, evidence of clonal restriction was found both in blood and lymph node DNA samples. Two BamH1 rearranged bands were demonstrated in both samples. In the blood a 16 Kb band predominated, with a weaker 28 kb band. In the lymph node sample this pattern was reversed. The findings suggest that a bi-clonal population of T-lymphocytes or clonal evolution of an existing T-cell monoclone had developed, and that cyclosporin contributed to the emergence of a high-grade T-cell lymphoma.

Antigens, CD↗
PubMed1991

Influence of streptozotocin-induced diabetes on adenylate cyclase activity in cultured type II pneumocytes.

Previous studies with cultured type II pneumocytes from streptozotocin-induced diabetic rats demonstrated altered surfactant synthesis and secretion. The effects of the diabetic state were reversed by in vivo but not in vitro insulin treatment. In the current study, cultured type II pneumocytes from control and streptozotocin-induced diabetic rats were demonstrated to possess approximately 17,500 and 8,500 receptors per cell, respectively. High-affinity binding sites were determined to have a dissociation constant of 0.429 nM and 0.203 nM for control and diabetic cells, respectively. Functional capacity of the insulin receptors was determined by the initial rates of 2-deoxy-D-glucose uptake. Uptake was stimulated by insulin in a dose-dependent manner and was not significantly altered by the diabetic state. This would suggest that the insulin receptor was present and functioning in cells isolated from diabetic rats. Basal adenylate cyclase activity of type II cell homogenates from diabetic rats was shown to be 16% of that for controls. In addition, isoproterenol, guanosine 5'-triphosphate (GTP), and NaF were unable to stimulate adenylate cyclase activity. However, forskolin, which directly activates the catalytic subunit of adenylate cyclase, was able to increase the cellular content of cyclic adenosine monophosphate (cAMP) in this model. This would suggest that some step prior to adenylate cyclase but not the catalytic subunit was altered by the diabetic state. But forskolin was unable to restore surfactant secretion, suggesting that in addition to adenylate cyclase, other processes are affected by the diabetic state. The effects of the diabetic state on adenylate cyclase and surfactant secretion were reversed by in vivo but not in vitro insulin treatment.

Adenylyl Cyclases↗