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Biomedical subjects

J S Mann

Publications and source records attributed to J S Mann.

At least 37 records · Page 2Linked to original sources
PubMed1994

Contrast-enhanced magnetic resonance imaging estimation of altered capillary permeability in experimental mammary carcinomas after X-irradiation.

RATIONALE AND OBJECTIVES: Dynamic magnetic resonance imaging (MRI) enhanced with a macromolecular contrast medium, albumin-(Gd-DTPA)35, was used to detect changes in microvascular characteristics in R3230 mammary adenocarcinomas induced by x-irradiation. METHODS: Tumors were implanted in either flank in nine rats. One of the tumors was exposed to single-dose x-irradiation (30 Gy) 3 days before MRI. The contralateral control tumor was shielded from irradiation. RESULTS: Capillary permeability to macromolecular contrast medium in irradiated tumors was elevated significantly (P < .05) compared to the control nonirradiated tumors. The mean estimated permeability surface area product for the irradiated tumors increased more than three-fold; 0.511 +/- .046 mL hr-1 cm-3 compared with 0.121 +/- .011 mL hr-1 cm-3 for the nonirradiated tumors. This radiation-induced increase in permeability was corroborated using a macromolecular Evans blue-protein complex measured in the same tumors using an invasive spectrophotometric technique. CONCLUSIONS: Dynamic MRI-enhanced with macromolecular contrast medium permits noninvasive quantitative estimates of capillary permeability in tumors, with and without x-irradiation. Because the transendothelial permeability for macromolecular solutes likely influences tumoral accumulation of macromolecular chemotherapeutic agents, this noninvasive technique may prove to be clinically useful in tailoring tumor treatment programs which combine radiation and chemotherapy.

Adenocarcinoma↗
PubMed1993

Quantification of tissue plasma volume in the rat by contrast-enhanced magnetic resonance imaging.

Magnetic resonance imaging enhanced with a macromolecular contrast medium (MMCM), albumin-Gd-DTPA, was used to estimate the plasma volume in vivo in the myocardium, lung, liver, and skeletal muscle of 10 normal rats. The plasma volumes of the same tissues in a parallel group of six rats were estimated in vitro by a conventional radioisotopic technique (111In-transferrin). Plasma volumes of myocardium, lung, liver, and skeletal muscle estimated by the MR technique (microliter plasma cc-1 of tissue) were 101, 109, 163, and 11.0, respectively, while plasma volumes measured by the 111In-transferrin radioisotope technique (mg plasma g-1 of tissue) were 78.6, 215, 143, and 11.2, respectively. Assuming a ratio of densities of aerated lung to blood of 0.45 and of other tissues to blood of 1.0, correlation between the methods was excellent (R2 = 0.99) indicating that MR imaging enhanced with MMCM permits reliable in vivo estimation of tissue plasma volume in the rat.

Albumins↗
PubMed1993

Role of protein synthesis, prostaglandins, and estrogen in rat ovarian metalloproteinase inhibitor production.

Matrix metalloproteinases and their inhibitors regulate follicular connective tissue remodeling associated with ovulation. We examined the control of metalloproteinase inhibitor activity and gene expression by various treatments in cultured rat granulosa cells and intact whole ovaries. Cells were isolated from preovulatory follicles of immature eCG-primed rats and cultured with various treatments for 24 h. Metalloproteinase inhibitor activity was measured in the media. The addition of LH or the phorbol ester 12-O-tetradecanoylphorbol 13-acetate (TPA) increased inhibitor activity 2.5- and 2.6-fold above that in control cultures, respectively. Cycloheximide treatment blocked basal and LH- and TPA-stimulated inhibitor activity, suggesting that the increase in granulosa cell inhibitor activity resulted from de novo protein synthesis. Indomethacin, a prostaglandin synthase inhibitor, had no effect on basal or LH-induced granulosa cell inhibitor activity. Addition of the antiestrogen tamoxifen citrate or an aromatase inhibitor, 10-propargylestr-4-ene-3,17-dione, did not affect basal or LH-stimulated inhibitor activity, implying that estrogen is not involved in the signal transduction pathway leading to increased inhibitor activity. Northern analysis demonstrated the presence of mRNA for a tissue-derived metalloproteinase inhibitor, TIMP-1, which increased with LH stimulation, in rat granulosa cells. Similarly, an hCG stimulus increased TIMP-1 mRNA in periovulatory ovaries to the highest levels prior to ovulation. Neither cycloheximide nor indomethacin altered hCG-stimulated TIMP mRNA levels in periovulatory ovaries. The present study demonstrates that the LH- and TPA-induced increase in inhibitor activity resulted from de novo protein synthesis; however, de novo protein synthesis does not appear necessary for the increase in TIMP mRNA.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1993

Stability of gadolinium complexes in vitro and in vivo.

Gd(III) toxicity is such that, for in vivo use, the ion must be incorporated into stable, ionically bound complexes with organic chelating agents. Although metal-chelate-based contrast agents have been demonstrated safe in phase I-III studies, their potential toxicities must be considered, particularly in the development of new contrast media. The potential for adverse effects is thought to arise from in vivo dissociation into constituent metal ion and ligand. Release of Gd(III) from ligand may also be facilitated by endogenous metals [e.g., Zn(II)] that compete with Gd(III) for ligand-binding sites. In vivo complex stability toward dissociation depends on several closely balanced characteristics of the metal and ligand that maintain metal-chelate integrity during residence in the body. Among design strategies explored to minimize the potential for in vivo Gd(III) release are the use of ligands that: form Gd(III) complexes with high thermodynamic stabilities; have binding selectivity for Gd(III) over endogenous metal ions; incorporate rigid cyclic structures and form Gd(III) complexes with greater kinetic stabilities than their open-chain homologs; or incorporate slight excess ligand to "scavenge" loosely bound or free endogenous metal ions that might otherwise compete with Gd(III) for ligand binding.

Animals↗
PubMed1992

Gelatinase and proteoglycanase activity during the periovulatory period in the rat.

Gelatinase and proteoglycanase are metalloproteinases that govern extracellular matrix remodeling. In the present study, immature rats were primed with eCG (20 IU) and hCG (10 IU). Ovarian gelatinase and proteoglycanase activity were determined at the time of hCG administration (0 h) as well as 4, 8, and 12 h later. Gelatinase and proteoglycanase were extracted by homogenization in Triton and by heating (i.e., heat extraction). An aliquot of the heat extract was reduced and alkylated to destroy metalloproteinase inhibitors. Heat extracts not reduced and alkylated showed low levels of gelatinase and proteoglycanase activity that did not change at the different time points. However, with reduction and alkylation, gelatinolysis increased approximately 4-fold (p less than 0.05) at 4 h, 8 h, and 12 h after hCG priming. Proteoglycanase activity increased approximately 2-fold (p less than 0.05) between 0 and 8 h and declined at 12 h after hCG. The ovarian gelatinolytic activity was due to a metalloproteinase as demonstrated by the inhibition of enzyme activity by phenanthroline and EDTA (97.1 +/- 0.7% and 97.4 +/- 0.6% inhibition respectively). Proteoglycanase activity was not inhibited by phenanthroline (11.5 +/- 3.5%), suggesting that the enzyme activity was not specifically a metal-dependent enzyme. Gelatin gel zymography of the ovarian extracts demonstrated four predominant and distinct gelatin-degrading enzymes of 78, 72, 66, and 62 kDa, similar to the size of gelatinase. The present findings demonstrate a periovulatory increase in ovarian gelatinolytic and proteglycanase activity that may play a pivotal role in connective tissue remodeling associated with ovulation.

Animals↗
PubMed1992

Survey of outpatient sputum cytology: influence of written instructions on sample quality and who benefits from investigation.

OBJECTIVES: To evaluated quality of outpatient sputum cytology and whether written instructions to patients improve sample quality and to identify variables that predict satisfactory samples. DESIGN: Prospective randomised study. SETTING: Outpatient department of a district general hospital. PATIENTS: 224 patients recruited over 18 months whenever their clinicians requested sputum cytology, randomized to receive oral or oral and written advice. INTERVENTIONS: Oral advice from nurse on producing a sputum sample (114 patients); oral advice plus written instructions (110). MAIN MEASURES: Percentages of satisfactory sputum samples and of patients who produced more than one satisfactory sample; clinical or radiological features identified from subsequent review of patients' notes and radiographs associated with satisfactory samples; final diagnosis of bronchial cancer. RESULTS: 588 sputum samples were requested and 477 received. Patients in the group receiving additional written instructions produced 75(34%) satisfactory samples and 43(39%) of them one or more sets of satisfactory samples. Corresponding figures for the group receiving only oral advice (80(31%) and 46(40%) respectively)were not significantly different. Logistic regression showed that radiological evidence of collapse or consolidation (p<0.01) and hilar mass (p<0.05) were significant predictors of the production of satisfactory samples. Sputum cytology confirmed the diagnosis in only 9(17%) patients with bronchial carcinoma. CONCLUSIONS: The quality of outpatients' sputum samples was poor and was not improved by written instructions. Sputum cytology should be limited to patients with probable bronchial cancer unsuitable for surgery. IMPLICATIONS: Collection of samples and requests for sputum cytology should be reviewed in other hospitals.

Bronchial Neoplasms↗
PubMed1992

Multiple cystic pulmonary hamartomas.

A patient with multiple cystic hamartomas presented with a pneumothorax and later developed a cystic myxomatous vaginal polyp. This and three of the cysts were resected. She remains well 13 years later. Multiple cystic hamartomas are uncommon and may be misdiagnosed as pulmonary metastases.

Cysts↗
PubMed1991

Hormonal regulation of matrix metalloproteinase inhibitors in rat granulosa cells and ovaries.

Metalloproteinases, such as collagenase or gelatinase, and their associated inhibitors appear to control connective tissue remodeling during follicular rupture. We examined the regulation of metalloproteinase inhibitor activity by various treatments in cultured rat granulosa cells. Granulosa cells were harvested from immature PMSG-primed rats and cultured with LH, the phorbol ester 12-O-tetradecanoylphorbol 13-acetate (TPA), cAMP, or forskolin. Inhibitor activity was measured in the medium. Increasing concentrations of either LH (0.1-1000 ng/ml) or TPA (2.5-100 nM) resulted in a dose-dependent increase in metalloproteinase inhibitor activity (2.9- and 2.4-fold increases above control, respectively). There was also a time-dependent induction of inhibitor activity in cells incubated in the presence of LH (100 ng/ml) for 6, 12, 18, or 24 h. Forskolin (0.1 mM) or cAMP (1 mM) treatment increased inhibitor activity 2.8- and 1.6-fold above that in control cultures. LH and TPA treatment in combination resulted in an additive increase in inhibitor activity compared to LH or TPA treatment alone. This finding suggested that the granulosa cell inhibitor activity might be induced through separate intracellular pathways. The inhibitor present in conditioned medium was isolated by chromatographic separation on a Sepharose 6B mol wt exclusion column. The inhibitor present was approximately 28,000 mol wt, which is consistent with the size of tissue inhibitor of metalloproteinase (TIMP). In addition to the granulosa cell experiments, changes in ovarian mRNA levels for TIMP were determined. There was a preovulatory increase in TIMP mRNA from whole rat ovaries, with the highest levels detected 12 h after hCG administration. The present study establishes that metalloproteinase inhibitor activity from rat granulosa cells is induced through separate pathways: a LH-cAMP-dependent protein kinase-A pathway and a cAMP-independent protein kinase-C pathway. Furthermore, a TIMP-like protein is observed in granulosa cell-conditioned medium, while TIMP mRNA is present in rat ovaries and increases before ovulation, suggesting that the granulosa cell metalloproteinase inhibitor is TIMP. We propose that TIMP acts in part to control the site and extent of follicular connective tissue remodeling associated with ovulation.

Animals↗
PubMed1990

A single oral dose method for predicting steady state theophylline concentrations in clinical practice.

A single dose, single point method of predicting patients' oral maintenance theophylline dosage has been compared with a noninvasive method. Twenty patients with obstructive lung disease received an oral dose (6 mg kg-1) of micro-crystalline theophylline. The plasma theophylline concentration after 8-10 h was then used to calculate the optimum maintenance dose of sustained release aminophylline required to achieve steady state concentrations between 55 and 110 mumols l-1. The mean steady state plasma theophylline concentration for this dosage schedule was also predicted by a method using population average pharmacokinetic parameters (assumed clearance method). These predictions were then compared with observed concentration-time profiles at steady state. The mean difference between the observed values and those predicted from a morning test dose was -0.11 mumol l-1 (95% CI -7.0 to +7.2). A larger difference (-7.4 mumol l-1 95% CI -18.2 to +3.4) was found for the assumed clearance method. Since the confidence intervals contain zero, these differences are not significantly different from zero at the 5% level, although the morning test dose method allowed prediction of the whole concentration-time profile and was more precise. An evening test dose was also used in the study, but the mean difference between the observed values and those predicted from this method was larger at -24.8 mumol l-1 (95% CI -32.89 to -17.21) and was significantly different from zero. This study indicates that a morning test dose followed by a single blood sample can be used to establish maintenance theophylline therapy quickly and safely in selected patients.

Adult↗
PubMed1990

Childhood risk factors for ischaemic heart disease and stroke.

To explore the relation between environmental influences in early life and risk of cardiovascular disease in adulthood, case-control comparisons were made on 99 patients with acute myocardial infarction and 55 patients with recent hemisphere stroke. After allowance for smoking habits and current social class, risk of myocardial infarction was higher in subjects of lower social class at birth, smaller stature, and with a history of infant and especially perinatal death in a sibling. Stroke was also associated with infant or perinatal death in a sibling. Although none of these associations was statistically significant at a 5% level, they support other evidence that implicates the pre and early postnatal environment in the aetiology of cardiovascular disease.

Adult↗
PubMed1990

Alpha 2-macroglobulin and tissue inhibitor of metalloproteinases: collagenase inhibitors in human preovulatory ovaries.

Extensive remodeling of the follicular extracellular matrix occurs during the process of ovulation. This remodeling involves the breakdown of collagen, which is regulated, in part, by the action of the metalloproteinase collagenase and its associated inhibitors. In the present study, follicular metalloproteinase inhibitors were characterized to determine whether they were serum-borne or of ovarian origin, possibly a tissue-derived inhibitor known as tissue inhibitor of metalloproteinase (TIMP). Human follicular fluid and granulosa cells were obtained from preovulatory follicles of patients in an in vitro fertilization program. Chromatographic separation of follicular fluid on Sepharose 6B resulted in two peaks of inhibitory activity. The large molecular radius (Mr) inhibitor was similar in size to the serum-borne metalloproteinase inhibitor alpha 2-macroglobulin (i.e. Mr 700,000) whereas the small Mr inhibitor approximated the size of TIMP (i.e. Mr 29,000). Incubation of aliquots from either of the two peaks of inhibitor activity or an alpha 2-macroglobulin standard with an antibody to alpha 2-macroglobulin decreased the inhibitory activity in both the large Mr peak and the alpha 2-macroglobulin standard by 86.6 +/- 1.7% and 71.5 +/- 7.7% (n = 4, P less than 0.005), respectively, implying cross-reactivity with the alpha 2-macroglobulin antibody. The inhibitory activity in the small Mr peak, however, was unchanged. Northern analysis of total granulosa cell RNA demonstrated TIMP messenger RNA (mRNA) in all eight granulosa cell samples examined whereas alpha 2-macroglobulin mRNA was virtually undetectable. A positive correlation (r = 0.85, P less than 0.01) was observed between the levels of TIMP mRNA and the ratio of the follicular estradiol-progesterone concentration. However, inhibitor activity in the follicular fluid was not correlated with the levels of TIMP mRNA (r = 0.05). These findings confirm the presence of alpha 2-macroglobulin in follicular fluid and demonstrate that human preovulatory granulosa cells contain mRNA for TIMP, an inhibitor that regulates metalloproteinases such as collagenase, gelatinase, and proteoglycanase. Additionally, the expression of TIMP mRNA is steroid related and may be hormonally regulated. It is proposed that TIMP produced in the granulosa cell compartment in conjunction with alpha 2-macroglobulin from the serum may act to control the site and extent of ovarian connective tissue remodeling.

Antibodies↗
PubMed1986

Relationships between adenosine, cyclic nucleotides, and xanthines in asthma.

Methylxanthines have been used for the treatment of asthma for more than 60 years, but their mechanism of action is poorly understood. Their ability to inhibit cyclic adenosine monophosphate phosphodiesterase has attracted much attention. However, this is clearly demonstrable only in high doses and is more likely to be related to toxicity. An alternative mechanism is antagonism of adenosine receptors in the lung. Adenosine has been shown to be released in asthma and cause bronchoconstriction in patients with asthma. Its effects are selectively inhibited by concentrations of theophylline that do not block histamine-induced bronchoconstriction. Neither phosphodiesterase inhibition nor adenosine receptor antagonism explains the action of enprofylline in asthma. Consequently, additional actions of methylxanthines are likely to contribute to their beneficial effects. They may include adrenaline release from the adrenal medulla, an effect on cell calcium distribution, inhibition of the generation of contractile prostaglandins, and an improvement of diaphragmatic contractility.

3',5'-Cyclic-AMP Phosphodiesterases↗
PubMed1986

Release of adenosine and its metabolites from activated human leucocytes.

Human leucocytes whose adenine nucleotide pool was prelabelled with [3H]adenine were investigated for their capacity to release adenosine and its metabolites and histamine when activated with the calcium ionophore A23187, anti-immunoglobulin E and the chemotactic peptide N-formyl-methionyl-leucyl-phenylalanine (f-MLP). Sixty-nine per cent of the 3H-label assimilated by the cells was incorporated into their adenine nucleotide pool in the ratio adenosine 5'-phosphate (AMP):adenosine 5'-pyrophosphate (ADP):adenosine 5'-triphosphate (ATP), 3:1:1. Spontaneous release of label from leucocytes plateaued at 5 min at 22.1 +/- 4.2% of the total radiolabel incorporated and mainly consisted of hypoxanthine, inosine and adenosine. Activation of cells with the calcium ionophore A23187 (1.0 mumol/l) caused a net increase in [3H]purine release above baseline of 27.9 +/- 4.6% accompanied by a net basophil histamine release of 46.6 +/- 9.4%. A23187 (1.0-3.0 mumol/l) caused a parallel concentration-dependent release of labelled purines and histamine. Purified mononuclear cells and granulocytes exhibited a similar ionophore-dependent capacity to release [3H]purines. The distribution of label did not significantly differ between supernatants of activated and non-activated cells. Preincubation of cells with dipyridamole (10 mumol/l) and erythro-9-(2-hydroxy-3)-nonyladenine (EHNA) (10 mumol/l) to inhibit uptake and catabolism of adenosine respectively, produced an increase in adenosine at the expense of hypoxanthine recovered from the supernatant of both ionophore-stimulated and resting cells. Activation of leucocytes with f-MLP (1.0 mumol/l) caused a net increase in release of basophil histamine, but was associated with only a transient net increase in release of [3H]purine in four of five experiments.(ABSTRACT TRUNCATED AT 250 WORDS)

Adenosine↗
PubMed1986

Effect of inhaled piriprost (U-60, 257) a novel leukotriene inhibitor, on allergen and exercise induced bronchoconstriction in asthma.

The leukotrienes, a group of oxidative metabolites of arachidonic acid, have potent pharmacological actions on human airways. We have investigated the effects of a leukotriene synthesis inhibitor, piriprost (U-60, 257) administered by inhalation on allergen and exercise induced bronchoconstriction in 12 subjects with allergic asthma. Subjects underwent diagnostic challenges with allergen and treadmill exercise to define the strengths of the stimuli required to reduce the FEV1 to about 25% of baseline (PS25). On separate study days subjects inhaled either piriprost 1 mg or vehicle placebo, followed 15 minutes later by the PS25 allergen or exercise. The FEV1 was measured at regular intervals before and after challenge up to 60 minutes. After allergen challenge in six subjects peak expiratory flow (PEF) was measured for the following 20 hours. When compared with placebo, inhalation of piriprost had no significant protective effect on the fall in FEV1 at any time point within 60 minutes of allergen or exercise challenge. In the four subjects with a documented late asthmatic reaction 2-12 hours after allergen challenge piriprost had no protective effect when compared with placebo. In the subjects who recorded PEF over 20 hours after allergen challenge there was no significant difference between piriprost and placebo. Piriprost was appreciably more irritant to the respiratory tract than was placebo. On the assumption that inhaled piriprost was bioavailable in the airways, this study casts doubt on any theory of a pivotal role for leukotrienes in the pathogenesis of acute exercise and allergen induced airway bronchoconstriction in asthma.

Administration, Inhalation↗