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Biomedical subjects

R E Howell

Publications and source records attributed to R E Howell.

At least 37 records · Page 2Linked to original sources
PubMed1991

Hamster cheek-pouch testing of dental soft polymers.

The hamster cheek pouch provides a suitable model system for the mucous-membrane irritation testing of dental materials. Poor retention of materials or difficulties in histopathological interpretation caused by surgical artifacts have been reported in published techniques. We describe a new "pouch-in-pouch" technique for mucous membrane irritation tests. The retention rate of polymer discs was 97% and 87% at 14 and 35 days, respectively. Clear differentiation was obtained between the tissue reaction to the test materials and the surgical procedure. Polymer discs containing dibutyltin diacetate (DBTD) or dibutyl phthalate (DBP) as plasticizer resulted in epithelial changes, including epithelial atypia, early papillomas, and areas resembling dysplasia. The potentially pre-malignant nature of these changes requires further investigation.

Animals↗
PubMed1990

Mechanism for the emetic side effect of xanthine bronchodilators.

The usefulness of xanthine bronchodilators in the treatment of asthma is often limited by the side effects of nausea and vomiting. We investigated the mechanism of emesis induced by xanthines, by examining the roles of phosphodiesterase (PDE) inhibition and adenosine antagonism. Theophylline, enprofylline, 8-phenyltheophylline and isobutylmethylxanthine (IBMX), as well as vehicle, were given to ferrets at doses ranging from 0.1 to 150 mg/kg i.p. The potencies of these compounds in producing emetic responses were ranked IBMX greater than enprofylline greater than theophylline greater than 8-phenyltheophylline. These results correlate well with the relative potencies of the compounds as nonselective PDE inhibitors but do not correlate with their relative potencies as adenosine A1 or A2 receptor antagonists. The emetic responses also correlate well with the previously reported potencies of these xanthines as bronchodilators in guinea pigs. We conclude that the emetic side effect of xanthine bronchodilators results from the inhibition of one or more forms of PDE rather than from adenosine antagonism.

1-Methyl-3-isobutylxanthine↗
PubMed1990

A transforming Kirsten ras oncogene in an oral squamous carcinoma.

This investigation has employed the NIH 3T3 cell transfection assay in an effort to detect transforming genes in DNA from squamous carcinomas of the head and neck. Of 11 tumor DNAs tested, 1 DNA sample from a gingival squamous carcinoma was able to produce primary and secondary transformants containing the human K-ras oncogene. This is the first report of an activated ras oncogene derived from a carcinoma of the head and neck. Head and neck cancers may possess activated ras oncogenes more often than is indicated by this study because of the relative inefficiency of transfection assays in detecting large transforming genes such as K-ras.

Animals↗
PubMed1990

Angiotensin-converting enzyme kinetics in an endothelial cell column.

The kinetics of saturable endothelial metabolic functions have been assessed in vivo by transient (indicator-dilution) measurements and in culture by steady-state measurements, but comparisons between the two are difficult. Therefore, we used indicator-dilution methods to assess the kinetics of angiotensin-converting enzyme (ACE) activity in cultured endothelium. Bovine fetal aortic endothelial cells were grown to confluence on microcarrier beads. Cell-covered beads were poured into polypropylene columns and perfused with serum-free culture medium. Six injections, containing [3H]benzol-Phe-Ala-Pro [( 3H]BPAP, an ACE substrate) and varying amounts of unlabeled BPAP, were applied to each column and effluent was collected in serial samples. The apparent kinetics of BPAP metabolism were determined by four models used previously to determine pulmonary endothelial ACE kinetics in vivo, the most useful model incorporating transit time heterogeneity. The Km averaged 5 microM, which is close to values determined previously in vivo and in vitro. The Amax (Vmax.reaction volume) and Amax/Km averaged 6 nmol/min and 1.5 ml/min, respectively, which are lower than estimates in vivo. In conclusion, we have developed a new method for investigating saturable metabolic activity in cultured endothelium, which after further exploration should also enable better comparisons of endothelial metabolic functions in vivo and in culture.

Animals↗
PubMed1990

Multiple mechanisms of xanthine actions on airway reactivity.

Xanthines are effective in the treatment of asthma, but the mechanism of action remains unclear. Pulmonary effects of seven xanthines, exhibiting a range of potencies as cyclic nucleotide phosphodiesterase (PDE) inhibitors and as adenosine antagonists, were investigated in anesthetized and ventilated guinea pigs. The bronchodilator effects of xanthines, determined from reversal of bronchoconstriction induced by aerosols of histamine and carbachol, correlated with their relative potencies as cyclic AMP-PDE inhibitors. The hypotensive effects of xanthines at bronchodilator doses were also consistent with PDE inhibition. Prophylactic effects of xanthines against bronchoconstriction induced by an aerosol of ovalbumin in sensitized guinea pigs, or by aerosols of leukotriene D4 and platelet-activating factor (PAF) in normal guinea pigs, occurred by a mechanism unrelated to bronchodilation and could not be readily attributed to PDE inhibition or adenosine A1/A2 receptor antagonism. There was a close association between inhibition of the responses to antigen and leukotriene D4, suggesting a common mechanism of action, but these effects gave a different profile from inhibition of the response to PAF. In addition, PAF-induced hypotension was unaffected in animals in which PAF-induced bronchoconstriction was inhibited, suggesting a mechanism other than PAF receptor antagonism. These results indicate that the bronchodilator, antiallergic and anti-inflammatory effects of xanthines occur through multiple molecular mechanisms of action, including at least one unknown mechanism. Furthermore, 8-phenyltheophylline produces these prophylactic effects at a dose that does not produce the cardiovascular or emetic side effects associated with xanthines, thereby exhibiting unique characteristics of potential therapeutic importance.

2',3'-Cyclic-Nucleotide Phosphodiesterases↗
PubMed1989

Loss of Harvey ras heterozygosity in oral squamous carcinoma.

This investigation of oral squamous carcinoma in five individuals revealed that four of the patients were constitutionally heterozygous at the c-Ha-ras-1 locus and that the tumour from one patient had lost that heterozygosity. The loss of c-Ha-ras-1 alleles provides a useful marker for detecting deletions of genetic material located on the short arm of chromosome 11 (11p) and has been found in association with a number of malignant tumours but has not been previously described in carcinoma of the head and neck. The repeated association of 11p deletions with malignancies has led to the postulation of a recessive cancer gene or tumour suppressor gene at this location involved in carcinogenesis and tumour progression. This study indicates that such a mechanism may contribute to the development of oral squamous carcinoma.

Carcinoma, Squamous Cell↗
PubMed1989

Chromatographic demonstration of reversible changes in endothelial permeability.

This report describes a new in vitro method for measuring the diffusional permeability of an endothelial monolayer and its use in investigating the modulation of permeability by various agents, e.g., isoproterenol, propranolol, dibutyryl adenosine 3',5'-cyclic monophosphate (cAMP), and cytochalasin D. To determine permeability, tracers of different molecular weights were applied simultaneously on a chromatography column containing confluent endothelial cells cultured on porous microcarrier beads. The Sangren-Sheppard model was used to determine the permeability of the endothelial monolayer from the tracer elution profiles. For six radiolabeled tracers the mean (+/- SD) permeabilities (cm/s x 10(-5)) in order of increasing tracer molecular weight were [3H]water, 82.0 +/- 28.8; [14C]urea, 49.5 +/- 9.5; [14C]mannitol, 13.3 +/- 4.7; [14C]-sucrose, 14.1 +/- 2.5; [3H]polyethylene glycol (900 mol wt), 4.80 +/- 1.61; and [3H]polyethylene glycol (4,000 mol wt), 1.97 +/- 1.01. These permeabilities deviate less from in vivo values than those obtained in other in vitro systems and are 10 times higher than in vivo estimates. The values were reproducible for up to the 4 h tested. Modulation of endothelial monolayer permeability was studied in a separate series of experiments. The beta-adrenergic agonist isoproterenol (10(-6) M) decreased the permeability to mannitol by 36% and to polyethylene glycol (900 mol wt) by 49%; in both instances the decrease in permeability was reversed by propranolol. Propranolol alone had no effect. Dibutyryl cAMP (10(-3) M) decreased the permeability to mannitol by 40% and to polyethylene glycol by 47%; permeability returned to base line when dibutyryl cAMP was removed. Cytochalasin D (1 microgram/ml) increased permeability by 350% for mannitol and 380% for polyethylene glycol; the permeability change was reversed after removal of cytochalasin D. The results indicate that cell-column chromatography is a powerful method that can be used to characterize the permeability of endothelial monolayers and to investigate permeability changes produced by various agents.

Animals↗
PubMed1989

Pulmonary extraction of propranolol in normal and oxygen-toxic sheep.

To help define the mechanisms involved in the handling of propranolol by normal and injured lungs, we studied the pulmonary extraction of [3H]propranolol in 23 unanesthetized sheep. Extraction of propranolol by normal lungs during a single circulation was characterized by 1) subsequent back-diffusion and pulmonary retention of the drug, 2) no evidence of saturable uptake or binding, 3) no effect of isoproterenol or imipramine, and 4) no effect of increasing cardiac output by treadmill exercise. In lungs damaged by oxygen toxicity, [3H]propranolol extraction decreased progressively to 63% of base line, paralleling progressive arterial hypoxemia and hypercapnia. In contrast, [14C]serotonin extraction remained unchanged from base line. Our results suggest that in normal unanesthetized sheep, pulmonary extraction of propranolol occurs primarily by passive diffusion that is flow-limited. Also, lung injury induced by oxygen toxicity in sheep reduces the pulmonary extraction of propranolol. Indeed, in oxygen toxicity, the depressed extraction of propranolol is a more sensitive marker of lung injury than is serotonin extraction.

Animals↗
PubMed1988

CEA immunoreactivity in odontogenic tumors and keratocysts.

Forty-five oral tumors and cysts were stained immunohistochemically for the presence of carcinoembryonic antigen (CEA). CEA, or a CEA-like antigen that is not nonspecific cross-reacting antigen (NCA), was demonstrated in the majority of aggressive or malignant tumors showing squamous differentiation, including cases of ameloblastoma, odontogenic carcinoma, and squamous carcinoma. CEA immunoreactivity was also found in cases of odontogenic keratocyst and focally in squamous odontogenic tumors but was not found in any of the ameloblastic fibromas, myxofibromas, odontogenic adenomatoid tumors, malignant melanomas, or apical cysts.

Carcinoembryonic Antigen↗
PubMed1988

Characterization of beta-adrenergic receptors in cultured human and bovine endothelial cells.

We used radioligand binding methods to characterize beta-adrenergic receptors on endothelial cells cultured from adult human iliac vein (HIVE) and bovine fetal aorta (BFAE). For comparison, we also studied the well-characterized C6 glioma cell line (C6). Both human and bovine endothelial cells showed specific saturable binding of [125I]iodopindolol. There was no difference in the binding affinity (KD) of iodopindolol to membranes from the three cell types. However, the beta-receptor density (Bmax) was greater on HIVE cells and BFAE cells than on C6 cells. Displacement of ligand from HIVE and BFAE cells by zinterol or from BFAE cells by ICI 89,406 was consistent with binding to the beta 2-subtype. In contrast, displacement of ligand from C6 cells by zinterol or ICI 89,406 was consistent with binding to both beta 1- and beta 2-subtypes. Exposing BFAE cells in culture to 10 microM isoproterenol for 6 h resulted in a 55% decrease in Bmax without a change in KD. We conclude that 1) human and bovine endothelial cells in culture contain a substantial population of beta-adrenergic receptors, which are predominantly of the beta 2-subtype, and 2) endothelial beta-receptors exhibit downregulation by beta-agonists in culture.

Animals↗
PubMed1988

Pulmonary angiotensin-converting enzyme activity in the oxygen-toxic sheep.

Despite the potential utility of endothelial metabolic substrates for the early clinical detection of acute lung injury, the relationship between lung capillary injury and pulmonary endothelial metabolic function remains incompletely understood. Previous studies have shown that lung capillaries are damaged by oxygen toxicity in the sheep; however, metabolic functions of the pulmonary endothelium have not been examined in this otherwise well-characterized animal model of lung injury. Therefore, we studied the activity of pulmonary endothelial angiotensin-converting enzyme (ACE) in five unanesthetized adult sheep that breathed 100% O2 via tracheostomy for 3 days and in four other sheep that breathed compressed air. In contrast to the sheep that breathed air, the sheep that breathed O2 developed substantial arterial hypoxemia and hypercapnia, an increased alveolar-to-arterial O2 gradient and a slight respiratory acidosis. Morphological examination of lungs from sheep that breathed O2 revealed a multifocal distribution of injury, including interstitial edema, capillary endothelial damage, and alveolar epithelial damage. Indicator-dilution methods were used to assess first-pass pulmonary metabolism of the ACE substrate [3H]Benzoyl-Phe-Ala-Pro (BPAP) and the apparent kinetics (KM and Vmax) of ACE activity. Pulmonary metabolism of BPAP exhibited saturability, was reduced by an ACE inhibitor (enalaprit), and did not result from the activity of circulating plasma ACE. There was no difference between the 2 groups of sheep in the percent metabolism of either 0.1 mumol BPAP/kg or 1.0 mumol BPAP/kg or in the KM of BPAP metabolism. In both groups, the Vmax and Vmax/KM decreased as a result of reductions in cardiac output and volume distribution.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1987

Extranodal oral lymphoma. Part II. Relationships between clinical features and the Lukes-Collins classification of 34 cases.

Thirty-four cases of extranodal oral lymphoma were classified according to the Lukes-Collins system on the basis of morphology and immunoperoxidase staining, and these findings were correlated with the clinical features of each case. Vestibule and gingiva, mandible, palatal soft tissue, and maxilla were, respectively, the most common locations for all the tumors, and the most frequently stated signs and symptoms were swelling, pain, paresthesia, anesthesia, ulceration, and discoloration. Eighty percent of the lymphomas were composed of transformed follicular center cells or postfollicular cells. Patients with lymphomas composed of nontransformed follicular center cells had a greater mean age than those with tumors of transformed follicular center cells or postfollicular cells, and a trend of decreasing age with increasing B cell transformation of the tumor type was seen. Within each Lukes-Collins category, the percentage of tumors that presented with bone involvement increased as the tumor category advanced in B cell transformation. Follow-up information indicated that the prognosis was poorest with postfollicular lymphomas, intermediate with transformed follicular center cell lymphomas, and best with nontransformed follicular center cell lymphomas.

Adult↗
PubMed1986

Extranodal oral lymphoma. Part I. A morphologic and immunoperoxidase study of 34 cases.

Thirty-four cases of oral lymphoma were classified by the Lukes-Collins system on the basis of morphology and immunoperoxidase staining. Ninety-seven percent of these were morphologically identified as B-cell neoplasms: 6% SCFCC, 9% LCFCC, 26% SNCFCC, 24% LNCFCC, 12% IBS, and 18% malignant plasma cell proliferations. Monoclonal immunoperoxidase staining for cytoplasmic immunoglobulin was positive in 41% of the cases overall, but 100% of the cases of immunoblastic sarcoma and malignant plasma cell lesions stained positively.

B-Lymphocytes↗
PubMed1986

Human cervical and hamster oral epithelial neoplasia--colposcopic similarities.

Epithelial dysplasias and squamous carcinomas were experimentally produced in the cheek pouches of Syrian hamsters. These lesions were observed and photographed in the living animals with the aid of a stereoscopic microscope at magnifications of 20 and 40 times. Very apparent similarities were noted in the vascular patterns and epithelial configurations between the hamster oral dysplasias and carcinomas and the corresponding lesions seen in published cases of cervical intraepithlial neoplasia and invasive squamous carcinoma. It is speculated that these similarities reflect common factors in the interaction between neoplastic squamous epithelium and its blood supply. These findings are important in understanding the biology of cervical neoplasia and may be useful in the diagnosis and management of human oral neoplasia.

Animals↗
PubMed1986

Three phase contractile response of rabbit pulmonary artery to norepinephrine: influence of ruthenium red and calcium.

We recorded isometric contractile force of rabbit pulmonary artery after application of norepinephrine (50 microM), plotted semilogarithmic graphs of force development over time, and calculated rates of force development. The normal contractile response contained three phases: an initial fast, a short intermediate and a final slow. Correlation coefficients for each phase and differences between rates of force development of each phase were significant (P less than 0.05). Ruthenium red (1 mM) removed only the slow phase and significantly reduced the rates of the fast and intermediate phases. A calcium-free solution removed both the slow and intermediate phases and significantly reduced the rate of the fast phase.

Animals↗
PubMed1986

Effects of repetitive stimulation by norepinephrine, histamine or potassium chloride on contractile responses of pulmonary vascular smooth muscle.

We examined consecutive contractile responses of isolated rabbit pulmonary arteries during repeated exposures to either norepinephrine, histamine or KC1, with washout and relaxation between trials. For each agonist, EC50 values remained constant during consecutive determinations, but the maximum force increased after the first determination. A maximum concentration of norepinephrine or histamine produced a biphasic contraction: the fast phase increased subsequent to the first determination and was retained in a calcium-free medium, while the slow phase was unaltered during consecutive determinations and was absent in a calcium-free medium. We conclude that in the rabbit pulmonary artery: the initial contractile response is a useful control for studies of sensitivity but not of maximum activity; there may be a nonspecific increase in the availability of intracellular calcium after the initial contraction and relaxation, and desensitization or tachyphylaxis to these agonists does not occur.

Animals↗
PubMed1986

Influence of magnesium on norepinephrine-and histamine-induced contractions of pulmonary vascular smooth muscle.

We examined the effects of magnesium on contractile responses of the rabbit pulmonary artery. The contractile force was determined, after applications of norepinephrine or histamine, in a normal or Ca++-free solution containing 0 mM Mg++ or 1.2 mM Mg++. In a normal solution, Mg++ increased the EC50 value for histamine, but did not alter the EC50 value for norepinephrine or the maximum force induced by norepinephrine or histamine. Contractile responses to norepinephrine and histamine were equally reduced by a Ca++-free, Mg++-free solution, and were further reduced by a Ca++-free solution containing Mg++, but with a greater reduction in the response to histamine than in the response to norepinephrine. The results indicate that in the pulmonary artery, Mg++ alters the sensitivity to histamine but not to norepinephrine, and may differentially inhibit bound Ca++ release by norepinephrine and histamine.

Animals↗