Biomedical subjects

R A Lewis

Publications and source records attributed to R A Lewis.

At least 271 records · Page 15Linked to original sources

PubMed1985

Mapping X-linked ophthalmic diseases: II. Linkage relationship of X-linked retinitis pigmentosa to X chromosomal short arm markers.

X-linked retinitis pigmentosa (XLRP) is a series of hereditary dystrophic diseases of the retina that occur in three clinically distinguishable variants: the classic form (McK31360), a type known as choroidoretinal dystrophy (McK30330), and a variant with golden-metallic or "tapetal" reflex in the heterozygote (McK30320). Controversy exists as to whether these phenotypic differences are due to clinical variability in disease expression, heterogeneity in disease alleles at a single locus, or a multiplicity of loci for XLRP. We have studied a single large kindred segregating for XLRP with the metallic fundus reflex in the heterozygote with restriction fragment length polymorphisms (RFLPs) from the short arm of the human X chromosome, and found measurable linkage to DXS7 (theta = 12.5 cMorgans at LOD = 2.5), the same RFLP previously shown by others to be tightly linked to the other forms of XLRP at theta = 3 cM. Although these estimates appeared to be different, each fell just within the 95% probability interval of the other and, therefore, were insufficient to prove or disprove that the metallic sheen form of XLRP is allelic with other forms of XLRP. Additional RFLPs at the DXS43 and the ornithine transcarbamoylase loci provided three-point crosses for determining the relative positions of DXS7 and XLRP, and supported an order that placed this form of XLRP distal to DXS7 on the Xp. Until the question of genetic heterogeneity is resolved, careful phenotypic characterization of the clinical type of XLRP present in families being used for linkage analyses is advisable.

Adolescent↗

PubMed1985

Fractional deposition from a jet nebulizer: how it differs from a metered dose inhaler.

The fractional deposition from an Inspiron 'Mini-Neb' jet nebulizer was assessed in six normal and two asthmatic subjects using technetium-99m-labelled millimicrospheres of human serum albumin suspended in saline. Sixty-six per cent of activity was retained in the apparatus tubing, 20% exhaled, 2% deposited in the mouth and 12% was retained in the lungs. The nebulizer fractional deposition therefore differs from the findings reported for a metered dose inhaler (Newman et al. 1981; Spiro et al. 1984), where 80-85% of particles leaving the cannister deposits in the mouth, and only 5-10% in the apparatus. The lung fraction from a nebulizer is, however, similar to the 9-11% from an MDI.

Adult↗

PubMed1985

Arachidonic acid derivatives as mediators of asthma.

Arachidonic acid metabolites generated by the cyclooxygenase pathway and by the various lipoxygenase pathways are produced by both resident pulmonary cells and infiltrating cells from the vascular compartment. The various proinflammatory biologic activities of these naturally occurring compounds include bronchoconstriction, increased vascular permeability, alterations in vasomotor tone, enhanced mucus secretion, and granulocyte adherence and chemotaxis. The leukotrienes derived from the 5-lipoxygenase pathway are particularly potent as mediators of inflammation, requiring only nanomolar concentrations for the evocation of their effects. Thus, although a variety of potent cyclooxygenase inhibitors are currently available for anti-inflammatory therapy, therapeutic modalities for the downregulation of leukotriene biosynthesis or efficacy would be highly desirable. Current concepts about the enzymatic cascade in leukotriene generation, the prospects for dietary modification as an adjunct to pharmacotherapeutic intervention, and the implications of specific receptors in leukotriene-mediated events are therefore considered.

Anti-Inflammatory Agents↗

PubMed1985

Exercise-induced anaphylaxis: a serious form of physical allergy associated with mast cell degranulation.

Exercise-induced anaphylaxis (EIA) is a unique and an increasingly recognized syndrome consisting of premonitory symptoms and signs of generalized body warmth, pruritus, and erythema, which progresses on continued exertion to confluent urticaria, laryngeal edema with stridor or hoarseness, and gastrointestinal colic and frequently culminates in vascular collapse. Previous studies of five individuals with this condition have demonstrated significant elevations of serum histamine concurrent with the early clinical manifestations after experimental exercise. To assess relevant morphologic alterations in the skin of these patients, cutaneous mast cells were examined by light and transmission electron microscopy before and during the initial erythema elicited by exertion. The marked alterations observed in mast cells immediately after exercise consisted of (1) loss of electron density and internal substructure of granules, (2) fusion of granule membranes with those of adjacent granules and with mast cell membranes creating conduits to the extracellular space, and (3) an apparent decrease in the number of intact granules per cell. Biopsy specimens obtained before exercise from patients with EIA and from two normal individuals who served as control subjects were identical, and the control subjects had normal mast cell morphology after exercise. Serum histamine levels were significantly elevated in patients with EIA after exercise at the time of biopsy, whereas control subjects had normal levels. These observations provide evidence that EIA is a distinct form of physical allergy associated with mast cell degranulation similar in morphology to that of human pulmonary mast cell IgE-Fc-dependent activation secretion. Characterization of this disorder is important because its prevalence may be underestimated, and its clinical consequences, which may include some morbidity, are not fully known.

Adult↗

PubMed1985

Brown oculocutaneous albinism. Clinical, ophthalmological, and biochemical characterization.

The clinical, ophthalmological, and biochemical characteristics of a 28-year-old black woman with brown oculocutaneous albinism were determined. Hair color was medium brown and skin color was light brown, and a faint tan developed with sun exposure. The irides were light brown in the central one-third, blue-gray in the peripheral two-thirds, and showed punctate and radial translucency. Visual acuity was 20/60 in the right eye and 20/100 in the left eye. There was a moderate pendular nystagmus, and previous surgeries had corrected an exotropia. The foveal reflex was muted, and the retinal pigment was reduced. Hairbulb tyrosinase activity was 1.75 pmoles/120 min/hairbulb, hairbulb glutathione content 0.83 nmoles/hairbulb, and urine excretion of 5-S-cysteinyldopa 174.9 ng/mg creatinine. Electron microscopy of hairbulb and skin melanocytes showed arrested melanosomal development. These findings suggest that there is a partial block in the distal eumelanin pathway in this form of albinism. The ophthalmological characteristics of six additional cases of this form of albinism are also presented.

Adult↗

PubMed1985

Quantitative office perimetry.

This study presents a preliminary comparison of six commercially-available automated threshold static parameters, consisting of three projection perimeters (Humphrey Field Analyzer, Squid, and Octopus 500) and three light-emitting diode (LED) perimeters (Dicon 2000, Fieldmaster 50, and Digilab 350). Eighteen individuals were included in the study: 6 normal observers (31-58 years old), six patients with glaucomatous field loss in both eyes (55-70 years old), and six patients with neuro-ophthalmologic or retinal visual field abnormalities in both eyes (12-61 years old). Three aspects of quantitative testing were evaluated: (1) the patients' and normal observers' acceptance and subjective impressions of the test procedure; (2) the technician's ease of operating the device and related tasks; and (3) practitioner-oriented considerations such as test-retest reliability, comparability of test results and testing time. Our results showed that no device was clearly superior to the others in all respects. Patients were most favorably impressed with the Octopus 500, Squid, and the Fieldmaster 50, while technician impressions were most favorable to the Humphrey Field Analyzer and the Squid. The projection perimeters (Humphrey Field Analyzer, Squid, and Octopus 500) were the easiest to perform cross-comparisons of test results, although there was considerable variation in the clarity of data interpretation from one case to another. Test-retest reliability and the time of testing varied among the six automated perimeters.

Adolescent↗

PubMed1985

Mapping X-linked ophthalmic diseases. Provisional assignment of the locus for choroideremia to Xq13-q24.

Choroideremia (McK 30310), an X-linked hereditary retinal dystrophy, causes nyctalopia, progressive visual field loss, and ultimately central blindness in affected males in early adulthood. We have used restriction fragment length polymorphisms from the X-chromosome to localize the region of the mutation for choroideremia in three families with this disorder. One polymorphic marker, DXYS1, located within Xq13-q21, shows no recombination with choroideremia at a LOD score of 5.78. Thus choroideremia maps within 9 centiMorgans of DXYS1 at 90% probability. Another marker, DXS11, located at Xq24-q26, shows no recombination with choroideremia but at a smaller LOD score of 1.54. These results suggest that the locus for choroideremia is distal to DXYS1 and between the two markers in the region Xq13-q24. This information may be useful for antenatal diagnosis, isolation of the mutant gene, and development of a rational therapy for the disorder.

Adult↗

PubMed1985

Foveomacular vitelliform dystrophy, adult type. A clinicopathologic study including electron microscopic observations.

Foveomacular vitelliform dystrophy, adult type (FVDAT), is a dystrophy of the retinal pigment epithelium (RPE) characterized in part by autosomal dominant inheritance, midlife onset, mild visual loss, and various patterns of foveal yellow deposits located at the level of the pigment epithelium. Detailed pathologic studies of two postmortem eyes from a 61-year-old woman with documented FVDAT disclosed striking abnormalities involving mainly the foveal RPE and overlying photoreceptors. By light microscopy, marked focal atrophy of the pigment epithelial cells in the foveolar area was bordered by hypertrophic RPE. Interposed between the atrophic RPE and Bruch's membrane were scattered eosinophilic, fusiform collagenous plaques. The sensory retina overlying the deranged RPE displayed marked atrophy of the outer nuclear layer with loss of photoreceptor inner and outer segments. Pigment-laden macrophages containing periodic acid-Schiff-positive material had migrated into the atrophic, outer sensory retina. Ultraviolet fluorescent microscopy demonstrated massive accumulation of lipofuscin pigment within the macular RPE as well as within macrophages in the atrophic outer retina. By scanning electron microscopy, a confluent area of flattened, atrophic retinal pigment epithelial cells was rimmed by taller, hypertrophic RPE cells. By transmission electron microscopy, the pigment epithelial cells contained myriad lipofuscin granules. Bruch's membrane and the intercapillary pillars were slightly thickened and the choriocapillaris was patent. The possible interrelationships between FVDAT and the other pattern dystrophies of the RPE are discussed.

Female↗

PubMed1985

Isolation and characterization of leukotriene C4 synthetase of rat basophilic leukemia cells.

When leukotriene (LT) A4 was incubated with subcellular fractions of sonicated rat basophilic leukemia (RBL) cells in the presence of glutathione, the enzyme producing LTC4, designated LTC4 synthetase, was found in the 105,000 X g pellet (microsomes) with a 3-fold enrichment in specific activity over that of the sonicate. The identification of the reaction product as LTC4 was confirmed by its identical retention time on reverse-phase HPLC to that of synthetic LTC4, the incorporation of [3H]glutathione into the product, its reactivity in a radioimmunoassay, and its UV absorption spectrum. In contrast, glutathione S-transferase activity, measured spectrophotometrically with 1-chloro-2,4-dinitrobenzene, was detected predominantly in the 105,000 X g supernatant (89%) and also in the microsomes (7%). The microsomal glutathione S-transferase and LTC4 synthetase were solubilized with 0.4% Triton X-102 and separated by DEAE-Sephacel chromatography; the former appeared in the effluent and the latter in the eluate after the addition of 0.16 M NaCl to the equilibration buffer. Solubilized, microsomal glutathione S-transferase was inhibited by S-hexylglutathione with an IC50 of 36 microM and was stable at 40 degrees C for 5 min, whereas LTC4 synthetase was only slightly inhibited (IC50, 2.3 mM) by S-hexylglutathione and retained no activity after incubation at 40 degrees C for 5 min. The partially purified LTC4 synthetase showed a specific activity of 1.34 +/- 0.51 nmol of LTC4 per 10 min per mg of protein (mean +/- SD, n = 9), representing a 10-fold purification from the sonicate and catalyzed the dose- and time-dependent production of LTC4 from LTA4 and glutathione. The apparent Km values for LTA4 and glutathione were estimated by Lineweaver-Burk plots to be 5-10 microM and 3-6 mM, respectively. These results indicate that the conjugation of LTA4 with glutathione to form LTC4 is catalyzed by a unique microsomal enzyme.

Animals↗

PubMed1985

Mechanism of the negative inotropic action of leukotrienes C4 and D4 on isolated rat heart.

Leukotrienes C4 and D4 (LTC4 and LTD4), possible mediators of cardiac dysfunction during inflammatory injury, may depress cardiac function by reducing coronary flow or by exerting a negative effect directly on the myocardium. We used an isovolumic rat heart preparation perfused at constant pressure and measured left ventricular developed pressure (mmHg), coronary flow (ml.min-1), oxygen extraction, and myocardial oxygen consumption and delivery (mumol O2.[gramme dry weight]-1.min-1) during infusion of five doses of angiotensin II, LTC4, LTD4 (approximately 10 to approximately 300 pmol.min-1), and noradrenaline (400 to 2000 pmol.min-1), or perfusion with medium which contained calcium at half-concentration. LTC4 and LTD4 were equipotent with angiotensin. At low effective doses, increased oxygen extraction offset the decrease in oxygen delivery, maintaining a stable level of oxygen consumption and left ventricular developed pressure. At the highest doses, angiotensin, LTC4 and LTD4 reduced coronary flow from 21 to 15, 21 to 13, and 21 to 13 ml.min-1, respectively. And, despite greater oxygen extraction of 59%, 58% and 65% for angiotensin, LTC4 and LTD4, left ventricular developed pressure fell from a baseline of 120 mmHg to 113, 106 and 92, respectively. In contrast, low calcium perfusion reduced left ventricular developed pressure (126 to 92) and oxygen extraction (46 to 30%) without changing coronary flow or oxygen delivery. These results suggest that LTC4 and LTD4 are potent coronary vasoconstricting agents which depress cardiac function by limiting oxygen delivery.

Angiotensin II↗

PubMed1985

Pharmacologic regulation of mediator generation and release from the murine bone marrow derived mast cell.

Mucosal mast cells constitute the subclass of IgE-FcR-bearing cells for which the murine bone marrow derived mast cell (BMMC) is an in vitro model. BMMC can be induced by an IgE-dependent mechanism to biosynthesize prostaglandin D2, several 5-lipoxygenase products, and an alkyl-ether phospholipid metabolite, as well as to degranulate. By introduction of selective enzyme inhibitors, it was determined that the bioavailability of each mediator class occurred without regulatory effects on the others. Additionally, since BMMC divide in culture, cell responsiveness for secretion of each mediator class was shown to be independent of the state of proliferation by employing three different nontoxic inhibitors of cell division.

Animals↗

PubMed1985

Unique features of human basophilic granulocytes developed in in vitro culture.

Human basophilic granulocytes were obtained in suspension culture of mononuclear cells from umbilical cord blood. Precursors of basophils in the cord blood are nonadherent cells and bear neither surface Ig nor T cell marker. Cultured basophils contain chondroitin-4-sulfate proteoglycan, 1.74 micrograms histamine per 10(6) cells in average, and bear 120,000-380,000 IgE receptors per cell. The IgE receptor molecule has a molecular weight of approximately 64,000 daltons. Human, rat and mouse IgE bind to the receptors with comparable high affinity and passively sensitize the cells for mediator release. Challenge of sensitized basophils with anti-IgE resulted in stimulation of phospholipid methylation, 45Ca uptake, release of both histamine and free arachidonic acid, and enhancement of phosphatidylinositol (PI) turnover. Evidence was obtained that the activation of membrane-associated proteolytic enzyme and methyltransferases is involved in subsequent IgE-mediated biochemical cascades such as PI turnover, Ca2+ uptake and mediator release.

Antibodies, Anti-Idiotypic↗

PubMed1985

Identification and characterization of leukotriene C4 receptors in isolated rat renal glomeruli.

The immediate reduction of renal blood flow and glomerular filtration rate in response to intravenous infusion of leukotriene C4 in the rat prompted an analysis of isolated rat renal glomeruli for the presence of specific receptors for leukotriene C4. Specific binding of [3H]leukotriene C4 to glomeruli increased in a time-dependent manner, reached equilibrium after 60 minutes of incubation at 4 degrees C, and was 80% reversible upon addition of excess unlabeled leukotriene C4 at equilibrium. Specific binding of [3H]leukotriene C4 to glomeruli increased in a dose-dependent manner, approaching saturation at concentrations of 40-60 nM. Inhibition of binding of [3H]leukotriene C4 with increasing concentrations of unlabeled leukotriene C4 was dose dependent. The equilibrium dissociation constant for [3H]leukotriene C4 binding to glomeruli, calculated from saturation and competitive binding-inhibition studies, was 25 +/- 7 nM and 35 +/- 16 nM (mean +/- SEM), respectively, and glomerular leukotriene C4 receptor density was 8.5 +/- 1.5 and 9.0 +/- 3.0 pmol/mg protein, respectively. The other natural vasoactive sulfidopeptide leukotrienes, leukotriene D4 and leukotriene E4, the chemotactic agent, leukotriene B4, and the sulfidopeptide leukotriene antagonist, FPL 55712, competed for the receptor at concentrations 2-3 orders of magnitude higher than the homoligand, leukotriene C4. The binding and specificity characteristics of the glomerular leukotriene C4 receptor are similar to those previously reported for the DDT1 nonvascular smooth muscle cell line derived from hamster vas deferens, for guinea pig ileum smooth muscle, and for a subcellular fraction of rat lung homogenate, and represent the first characterization of such a receptor in a vascular tissue.

Animals↗

PubMed1985

Airway and cardiovascular responses to inhaled prostacyclin in normal and asthmatic subjects.

Prostacyclin (PGI2) is one of several prostanoids released after antigen challenge of human lung fragments. To define its activity on human airways, we studied the effect of inhaled PGI2 in 10 normal and 8 asthmatic subjects. In random order, PGI2, 1 mg/ml, its hydrolysis product, 6-oxo-PGF1 alpha, 1 mg/ml, and glycine vehicle were given on separate occasions by nebulizer. Measurements of specific airway conductance (SGaw), blood pressure (BP), heart rate (HR), plasma 6-oxo-PGF1 alpha, and cyclic AMP levels were made at frequent intervals for as long as 45 min after nebulization. Prostacyclin and 6-oxo-PGF1 alpha caused cough and retrosternal discomfort. None of the drugs had any significant effect on SGaw in either the normal or asthmatic subjects, though 2 asthmatics showed consistent bronchodilatation with prostacyclin. Prostacyclin caused a marked fall in diastolic blood pressure (mean 20 +/- 3 mmHg) and increase in heart rate (29 +/- 3 beats X min-1) with a small late fall in systolic blood pressure (8 +/- 2 mmHg). This was associated with a 12- to 15-fold increase in plasma 6-oxo-PGF1 alpha levels maximal at 1 min, and in normal subjects only, a later twofold increase in plasma levels of cyclic AMP maximal at 5 min. Thus, inhaled PGI2 at concentrations that had pronounced cardiovascular activity produced no consistent effect on airway caliber in normal or asthmatic subjects.

6-Ketoprostaglandin F1 alpha↗

PubMed1985

The effects of a fish-oil-enriched diet on pulmonary mechanics during anaphylaxis.

The pulmonary mechanical responses observed after antigen challenge in 2 groups of sensitized, mepyramine-treated, mechanically ventilated guinea pigs were compared: one group was fed a diet rich in fish oil and the other a control diet enriched with beef tallow. The lung tissue of animals fed a fish-oil-enriched diet for 9 to 10 wk incorporated eicosapentaenoic acid (EPA) and docosahexaenoic acid, which constituted 8 to 9% of the total fatty acid content, whereas these alternative fatty acids constituted less than 1% of total fatty acid content of the lung tissue of animals receiving a diet supplemented with beef tallow. With mepyramine pretreatment, animals receiving a fish oil diet exhibited a significantly greater decrease in dynamic compliance from 1.5 through 4.5 min after antigen challenge than did animals receiving a beef fat diet, whereas the decrements in pulmonary conductance were comparable. The combination of indomethacin and mepyramine markedly augmented the antigen-induced decrease in pulmonary mechanics in animals receiving a beef fat diet but not in those receiving a fish oil diet, such that the overall responses of the 2 groups were similar. These findings indicate that the fish oil diet and the indomethacin pretreatment of animals receiving the beef fat diet each facilitates the nonhistamine-mediated bronchoconstrictor response in pulmonary anaphylaxis.

Airway Resistance↗

PubMed1985

Leukotrienes and other lipid mediators of asthma.

It is now recognized that, in addition to the preformed mast cell granule mediators, newly generated lipid compounds are likely to be exceedingly important in the mediation of allergic asthma and other atopic diseases. That the initiating event in allergic diseases evokes a far more complex set of biochemical events than those that only lead directly to the release of histamine and other preformed mediators, and that the functional efficacies of the leukotrienes, PGD2, and PAF are significant for allergic pathobiology mandate that the latter compounds will necessarily be subject to efforts for future therapeutic intervention in allergic patient populations.

Animals↗

PubMed1985

A presumptive role for leukotrienes in obstructive airways diseases.

The likelihood that the leukotriene products derived from the 5-lipoxygenase pathway mediate aspects of obstructive airways diseases is strongly suggested by their documented capacities to effect airway spasmogenicity, airway hyperreactivity, tissue edema formation, mucus secretion, and tissue infiltration by leukocytes. That the various leukotriene components of SRS-A have unique receptors on responding tissues and are recoverable from airway surfaces in several inflammatory lung diseases and that several resident and infiltrating cell types have significant potential for leukotriene biosynthesis lend further support to their postulated pathobiologic roles. To fulfill Koch's postulates for proof of leukotrienes' etiologic role, it remains to be shown that inhibition of their biosynthesis or specific antagonism at their end-organ receptors can greatly ameliorate these disease states.

Animals↗

PubMed1985

Captopril versus enalapril maleate: a comparison of antihypertensive and hormonal effects.

The antihypertensive effects of captopril and enalapril maleate were studied over a 10-week period in 24 hypertensive patients randomized into captopril or enalapril treatment groups. Prestudy blood pressure was 171 +/- 4/109 +/- 1 mm Hg and after 4 weeks of hydrochlorothiazide 160 +/- 4/103 +/- 1 (p less than 0.05). With the addition of converting enzyme inhibitor to hydrochlorothiazide the blood pressure decreased at 3 h to 132 +/- 3/87 +/- 2 in the subjects. The diastolic blood pressure decreased acutely more with captopril (-24) than with enalapril (-17) (p less than 0.05). After 10 weeks of combined therapy the depressor response was maintained (134 +/- 3/83 +/- 1) and there was no difference between the diastolic blood pressure in the two groups treated with captopril and enalapril. Acute and chronic responses of plasma renin activity, plasma aldosterone, and converting enzyme to the angiotensin-converting enzyme inhibitor were determined. There was a significant correlation between the acute fall in diastolic blood pressure and rise in plasma renin activity in patients treated with captopril but not with enalapril. In conclusion, there is an acute depressor response with converting enzyme inhibition which is more pronounced with captopril than with enalapril and which correlates with an increase in plasma renin activity. With more prolonged treatment, the two drugs show equivalent efficacy in reducing blood pressure, inhibiting angiotensin-converting enzyme, reducing aldosterone, and stimulating plasma renin activity.

Adult↗