Biomedical subjects
J G Martin
Publications and source records attributed to J G Martin.
Morphometric changes during the early airway response to allergen challenge in the rat.
The purpose of this study was to determine the relative contributions of airway wall edema and smooth muscle contraction to the early response (ER) of allergic bronchoconstriction. Brown Norway rats, 6 to 7 wk old, were sensitized with ovalbumin (OA). Anesthetized rats were challenged with either OA or saline 2 wk later. Pulmonary resistance (RL) was measured every minute until either it increased to 150% of the baseline, defined as a significant ER, or until 15 min elapsed. Eight OA-challenged test rats with a significant ER and eight saline-challenged control rats were used for morphometric studies. The lungs were quick-frozen with liquid nitrogen, processed with freeze substitution, and sagittal sections (5 microns) were stained with hematoxylin and eosin. The airway lumen subtended by the epithelial basement membrane (LuB) and cross sectional airway wall area (AW) of all airways were measured by camera lucida and digitization. The LuB and AW of each airway was standardized for size by dividing by the ideal airway lumen (LuBideal), which was calculated from the length of basement membrane, assuming a perfect circle in the unconstricted state. The cumulative frequency distribution of the LuB/LuBideal for the airways from test rats was shifted to the left compared with the control rats (p less than 0.01), indicating airway narrowing after challenge. Airway narrowing increased as a function of airway size. Cumulative frequency distributions of AW/LuBideal showed that there was a significant increase in the wall thickness of only the small airways of test animals.(ABSTRACT TRUNCATED AT 250 WORDS)
Identification of adenylate cyclase-coupled histamine H2 receptors in guinea pig tracheal smooth muscle cells in culture and the effect of dexamethasone.
Histamine acts on airway contractile elements through at least two different receptor subtypes: H1, which mediates Ca(2+)-dependent contraction, and H2, which stimulates cyclic adenosine monophosphate (cAMP) synthesis and possibly relaxation. The aim of this study was to determine the relative contribution of the different receptor subtypes to histamine-stimulated cAMP production by guinea pig tracheal smooth muscle (GPTSM) cells in primary culture. Histamine and N-alpha-methylhistamine induced concentration-dependent cAMP synthesis; these effects were entirely blocked by 10(-4) M cimetidine, an H2-receptor antagonist, whereas 10(-6) M thioperamide, a selective H3 blocker, was ineffective. The H3 agonist, R-(alpha)-methylhistamine, did not stimulate cAMP synthesis. Triprolidine, an H1 antagonist, did not modify histamine (10(-5) M)-stimulated cAMP synthesis. Histamine (10(-5) M) doubled [Ca2+]i in GPTSM. A 24-h pretreatment of GPTSM cells with 10(-6) M dexamethasone enhanced cAMP synthesized in response to 10(-5) M histamine and to 5 x 10(-6) M forskolin but did not significantly alter either the affinity or the binding capacity for [3H]-tiotidine, an H2-receptor antagonist. These results indicate that GPTSM cells in culture express H2 but not H3 receptors, which are linked to adenylate cyclase; their functional expression does not seem to be modulated by the concurrent activation of H1 receptors, whose presence in GPTSM is evidenced by a histamine-stimulated increase in [Ca2+]i. The most likely site of action of dexamethasone in enhancing histamine-stimulated cAMP synthesis is at the level of adenylate cyclase since the steroid had no effect on the H2 receptor itself.
Feeding studies in rats with mineral hydrocarbon food grade white oils.
This investigation compared the effects of feeding rats diets containing food grade white oil processed by either conventional oleum treatment or the more modern method of catalytic hydrogenation. In two separate experiments, male or female Fischer-344 rats were given free access for 90 days to diets containing 0, 10, 100, 500, 5,000, 10,000, or 20,000 ppm of either oleum-treated white oil (OTWO) or hydrotreated white oil (HTWO). There were no mortalities and no adverse clinical signs associated with feeding either white oil. Treatment-related effects evidenced by hematological, clinical chemical, and pathological changes were generally dose-related and more marked in female than in male rats, and the OTWO caused a greater pathological response than the HTWO. Tissue residues of saturated hydrocarbons were up to 5.2 times higher in female rats than in males. Rats fed 5,000 ppm or more of either white oil showed dose-related alterations in several hematological and clinical chemistry variates associated mainly with hepatic damage or functional alteration. At necropsy, mesenteric lymph nodes were enlarged, and increases in weight of liver, kidney, and spleen were significant. Microscopic changes were characterized by multifocal lipogranulomata in mesenteric lymph node and liver. No changes were observed in rats fed OTWO or HTWO for 90 days at dietary concentrations of 10 or 100 ppm, equivalent to a minimum intake of 0.65 and 6.4 mg/kg/day, respectively. Differences in degree of pathological response associated with each oil may have been due to their differences in specification rather than processing method.
Aorticopulmonary paraganglioma. A case report with immunohistochemical studies and literature review.
We present a case of nonfunctioning aorticopulmonary paraganglioma in a 41-year-old man. The mediastinal tumor was accidentally discovered on a chest roentgenogram performed for an unrelated minor chest trauma. Complete resection of the tumor was done and followed by postoperative radiotherapy. Two years after surgery, the patient is well and asymptomatic.
The role of the transcerebellar view in the detection of fetal central nervous system anomaly.
The current resolution of antenatal ultrasonography permits the sonologist to visualize and critically evaluate the cerebellum and cisterna magna. Abnormalities in the size and shape of these structures will assist the sonologist in the detection of the majority of central nervous system malformations.
A randomized clinical trial of negative pressure ventilation in severe chronic obstructive pulmonary disease: design and methods.
This report documents the design and methods of a randomized clinical trial designed to test the effectiveness of home negative pressure ventilation in patients with severe chronic obstructive pulmonary disease. Active negative pressure ventilation was compared with a sham version of the treatment after a pre-trial assessment had indicated the feasibility of the latter. Over 1200 patients in the metropolitan Montreal area were screened. Of these, 348 patients were recruited to enter a 4-week stabilization period, and 184 were subsequently randomized to receive either active or sham negative pressure ventilation. A 5-day in-hospital period was used to train patients in ventilator use and obtain baseline measures of exercise capacity, lung function, respiratory symptoms, and quality of life. Home ventilation treatment took place during a following 12-week period. Respirator use was recorded both from patient logs and from concealed meters installed in the units. Patients received four home visits by physiotherapists during the 12-week period and returned for follow-up to the hospital 4 and 12 weeks post-discharge for reassessment.
Epithelium modulates the potency of vasoactive intestinal peptide in the guinea pig.
The purpose of the study was to evaluate the importance of the epithelium in determining the potency of exogenous vasoactive intestinal peptide (VIP) in inhibiting responses of isolated guinea pig trachea to vagal stimulation. Isolated innervated tracheal preparations (n = 56) were mounted in glass organ baths in Krebs-Henseleit (K-H) solution at 37 degrees C and gassed with 95% O2-5% CO2. The inside of the trachea was separately perfused with K-H solution at 1 ml/min. The vagal nerve trunks were stimulated (20 V, 1-ms pulses, 10-s trains) at low (0.5 Hz) and high frequency (15 Hz) alternately, and the contractile responses were measured as increases in intratracheal pressures. VIP (10(-8)-10(-7) M) inhibited responses to both high- and low-frequency stimulation. VIP was more potent in inhibiting contractions when administered to the outside than the inside surface of the trachea, and disruptionon of the epithelium abolished this difference. The endopeptidase inhibitors phosphoramidon and thiorphan (5 x 10(-6) M) potentiated the action of VIP. These data indicate that the epithelium reduces the efficacy of VIP. We suggest that the epithelium is a site of degradation of VIP by endopeptidase and may also be a diffusion barrier.
Morphometry of the airways during late responses to antigen challenge in the rat.
To quantitate the structural changes in the airways that contribute to the late bronchial response (LR) to antigen challenge we killed six Brown-Norway rats, sensitized to ovalbumin (OA) and challenged by aerosol, during the LR and compared the dimensions of the intraparenchymal airways with those of six control animals. Lungs were rapidly frozen with liquid nitrogen and fixed in Carnoy's solution. Paraffin sections were stained with hematoxylin-phloxine-saffron. At the time of the LR (382 +/- 39 min after OA challenge), RL increased from the baseline value (0.067 +/- 0.034 cm H2O.ml-1.s) by 0.107 +/- 0.03 cm H2O.ml-1.s (p less than 0.05). RL did not change significantly in the control rats. The lumen size and the wall area of all membranous airways were measured and were corrected for airway size by dividing by the basement membrane length squared (BM2). There was no increase in airway wall area in OA-challenged animals. However, the lumen of large airways (BM: 2.0 to 2.99 mm) was significantly less for the OA-challenged animals (0.039 +/- 0.0055 mm2) than for the control animals (0.058 +/- 0.0063 mm2; p less than 0.05). In six additional rats, the distribution of mast cells (MC) in the bronchial tree was determined. Tissues were fixed with Carnoy's solution and stained with a modified May-Grunwald-Giemsa stain. There were significantly more MC in the large airways than in medial or small airways. We conclude that smooth muscle constriction of large airways and not airway wall edema accounts for the LR in the rat. The distribution of the mast cells corresponds closely to the site of bronchoconstriction.
Lymphokine-induced airway hyperresponsiveness in the rat.
We evaluated the potential role of the lymphocyte in chronic airway inflammation and responsiveness by repeated administration to rats of interleukin-2 (IL-2), the principal lymphokine responsible for lymphocyte proliferation. Lewis rats (mean weight, 184 +/- 2 g) received either 120,000 units of IL-2 (n = 10) or vehicle (n = 7) subcutaneously twice a day for 4.5 days. Animals were anesthetized with urethane and intubated for measurements of pulmonary resistance (RL) and airway responsiveness to aerosol methacholine (MCh). Lung lavage was performed, the animals were exsanguinated, and the lungs were fixed in 10% formalin. Histologic edema and the extent of infiltration of the bronchi, pulmonary veins, and arteries by cells was scored blindly. IL-2 increased airway responsiveness to MCh; the concentrations of MCh causing a doubling of RL were 0.14 versus 1.39 mg/ml (geometric mean) for the IL-2 and vehicle group, respectively (p = 0.001). IL-2 significantly increased total cellular return and the percentage of lymphocytes, neutrophils, and eosinophils in lavage. IL-2 caused edema and a mixed cellular infiltration of the bronchovascular tree. Lymphocytes predominated around the airways and veins. A correlation (r = 0.50) was present between airway responsiveness and airway inflammation but not with edema or vascular infiltration. Release of IL-2 by lymphocytes in the airways may be an important mediator of airway hyperresponsiveness.
Acute effects of interleukin-2 on lung mechanics and airway responsiveness in rats.
We studied the acute effects of interleukin-2 (IL-2), the principal lymphokine responsible for lymphocyte proliferation, on lung mechanics and airway responsiveness to methacholine (MCh) in rats. Lewis (n = 12) and Fisher 344 (n = 13) rats were anesthetized and intubated, and intravenous and intra-arterial lines were inserted. IL-2 (750,000 U/kg) was infused intravenously over 2 to 4 min into seven Lewis and seven Fisher rats, and vehicle alone was administered to five Lewis and six Fisher rats. Blood pressure, heart rate, respiratory frequency (f), tidal volume (VT), minute ventilation (VE), and lung resistance (RL) were measured before and every 5 min for 45 min after the infusion of IL-2. Lung compliance was measured before and 30 min after IL-2. Bronchial provocation testing with MCh was performed 45 min after the infusion of IL-2. Subsequently, the animals were exsanguinated, and the lungs were removed for histologic examination. Infused IL-2 did not alter heart rate or blood pressure, VT, f, VE, and RL increased significantly by 15 min (p less than 0.05), but they returned to baseline by 45 min. Lung compliance decreased significantly in both rat strains. IL-2 increased airway responsiveness only in Lewis rats; the concentration of MCh that caused a doubling of RL (EC200RL) was 0.6 mg/ml and 4.3 mg/ml (p = 0.003) in IL-2-treated and control rats, respectively. The airway responsiveness did not change significantly in Fisher rats; EC200RL was 0.13 and 0.35 mg/ml for IL-2-treated and control rats, respectively (p = 0.09).(ABSTRACT TRUNCATED AT 250 WORDS)
Structural changes in the airways of sensitized brown Norway rats after antigen challenge.
The purpose of this study was to quantitate the structural changes in the airways of sensitized rats after repeated challenge with aerosolized antigen and to examine the relationship between these changes and alterations in responsiveness to methacholine (MCh). We studied 28 Brown Norway rats that were actively sensitized to ovalbumin (OA). Responsiveness to aerosolized MCh was quantitated as the concentration of MCh required to double pulmonary resistance (EC200 RL). The EC200 RL was determined before and 1 and 5 days after three inhalational challenges with OA (n = 17) or saline (n = 11) at 5-day intervals (on Days 14, 19, and 24 after sensitization). Responsiveness to MCh increased after OA; EC200 RL fell from 1.71 to 0.71 mg/ml at 1 day (p less than 0.01) and 0.87 mg/ml at 5 days (p less than 0.02) after OA but did not change after saline challenge. Formalin-fixed lungs from a sample of OA-challenged (n = 12) and saline-challenged (n = 6) animals were paraffin embedded, and 5-microns sections were stained with hematoxylin-phloxin-saffron. Cross-sectional areas of the airway wall and smooth muscle (ASM) were determined for all intrapulmonary membranous airways. There was an approximately twofold increase in the quantity of airway smooth muscle in airways of OA-challenged animals compared with saline-challenged control animals. Airway wall area did not change significantly. There was a correlation (r = 0.618, p less than 0.05) between the quantity of ASM in large airways (basement membrane length 2.00 to 2.99 mm) and change in responsiveness to MCh.
Strain-related differences in airway smooth muscle and airway responsiveness in the rat.
The purpose of this study was to evaluate the possible role of the quantity of airway smooth muscle (AWSM) as a determinant of differences in responsiveness between inbred rat strains. To do this, we studied several batches of 8- to 10-wk-old Lewis and Fisher 344 rats. Animals were anesthetized intraperitoneally with pentobarbital (30 mg/kg) and xylazine (7 mg/kg). The peak value of pulmonary resistance (RL) was measured after progressively doubling concentrations of inhaled aerosolized methacholine (MCh). The MCh concentration required to double RL (EC200RL) was calculated as an index of airway responsiveness. Fisher rats were significantly more responsive than Lewis, and the interstrain variability in responsiveness was significantly greater than the intrastrain variability. Additional animals from the less responsive Lewis strain (n = 8) and the more responsive F344 strain (n = 11) were killed immediately after measurement of responsiveness, and AWSM was quantitated as a fraction of total lung tissue using a point-counting technique. F344 rats were again significantly more responsive than Lewis rats (EC200RL geometric mean: 0.72 versus 2.16 mg/ml, p less than 0.005). F344 rats also had significantly more AWSM than did Lewis rats (3.22 +/- 0.176 versus 2.48 +/- 0.185%, mean +/- SE, p less than 0.001). We conclude that highly inbred Fisher rat strains characteristically exhibit a degree of airways responsiveness greater than that of the Lewis strain and that the quantity of AWSM may be an important determinant of interstrain differences.
Ovarian pregnancy resulting in a surviving neonate. Ultrasound findings.
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Unusual presentations of fetal teratoma.
Teratomas are the most common congenital neoplasm. Fetal intracranial teratomas generally are large solid/cystic tumors that often completely replace normal brain tissue. Mediastinal teratomas are uncommon and rarely result in nonimmune hydrops fetalis. We describe two unusual presentations of fetal teratoma. The first is a fetus with massive hydrocephalus and marked facial deformities that were caused by a small intracranial teratoma. The second is a fetus with a mediastinal teratoma associated with non-immune hydrops fetalis. In both cases, compression by the mass resulted in lethal sequelae.
Behavior of morphometric indices in pancreatic elastase-induced emphysema in rats.
Two morphometric indices, the destructive index (DI), a measure of alveolar wall destruction, and the proportion of destroyed alveolar attachments to the airways (AA), have been proposed as measures of early lung destruction in human smokers. The aim of this study was to compare DI and AA to the usual measure of airspace enlargement--the mean linear intercept (Lm)--in experimental emphysema. Porcine pancreatic elastase was administered intratracheally to 2 groups of Brown Norway rats (high-dose, n = 8, 1 IU/g body weight; low-dose, n = 4, 0.7 IU/g; control, n = 7). Total lung capacity (TLC), functional residual capacity (FRC) and pressure-volume curves were measured 3 weeks after administration of elastase. Lung elasticity was assessed by chord compliance (Cst). Administration of high-dose, but not low-dose, elastase led to significant increases in FRC and TLC. Cst significantly increased after high-dose elastase compared to controls (p less than 0.01). Lm increased after both low-dose and high-dose elastase compared to controls (p less than 0.01); DI and AA were increased only after high-dose elastase. Significant correlations were found between each morphometric index and Cst; the highest correlation was with AA. Behavior of the morphometric indices in this model differed from that reported in human smokers: Lm was a more sensitive measure of destruction than DI, reflecting a process marked by predominance of airspace enlargement over alveolar septal breaks. These differences from human smokers may result from a differing underlying pathogenesis of lung destruction.
The effects of vasoactive intestinal polypeptide on cholinergic neurotransmission in an isolated innervated guinea pig tracheal preparation.
To explore the possibility that VIP modulates cholinergic neurotransmission in the airways, we studied the effects of exogenous VIP on contractile responses of an isolated innervated guinea pig tracheal preparation to vagal nerve stimulation (NS), electrical field stimulation (EFS) and exogenous acetylcholine (ACh). VIP (2.5 x 10(-8), 2.5 x 10(-7) M) caused concentration-dependent reductions in responses to NS and EFS. Low frequency stimulations (1 Hz) were significantly more inhibited than higher frequencies (5 and 20 Hz). VIP inhibited NS significantly more than EFS at 1 and 5 but not 20 Hz. In contrast, VIP (2.5 x 10(-7) M) did not significantly reduce responses to ACh (3 x 10(-7), 10(-6), and 3 x 10(-6) M). The neutral endopeptidase inhibitor phosphoramidon (5 x 10(-6) M) enhanced responses of NS to VIP but did not affect responses to NS in the absence of VIP. We conclude that in the isolated guinea pig tracheal preparation, VIP can modulate cholinergic neurotransmission by actions that are predominantly on post-ganglionic nerves but it has also a small additional effect on ganglionic transmission.
A theoretical study of the effect of airway smooth muscle orientation on bronchoconstriction.
If airway smooth muscle shortened in vivo to the extent that it does in vitro, then maximal bronchoconstriction would result in complete closure of virtually all airways. The fact that this does not happen indicates the existence of inhibitory mechanisms preventing maximal muscle shortening. There are many factors potentially limiting shortening in vivo. In this study we investigated one of these factors, the orientation of the smooth muscle around the airway wall. The airway was modeled as a cylinder of given wall thickness around which the muscle was wound as a spiral. The longitudinal and circumferential elasticities of the airway were embodied in a 2 x 2 matrix of elastic coefficients. We investigated smooth muscle shortening under three conditions: 1) a longitudinally stiff airway, 2) a circumferentially stiff airway, and 3) a longitudinally and circumferentially compressible airway. In case 1, for a given degree of smooth muscle shortening, airway resistance increased markedly with increasing pitch of the smooth muscle spiral. On the other hand, the muscle tension required to elicit a given change in resistance also increased markedly with pitch. In case 2, the effect with increasing pitch was reversed. In case 3, resistance first increased and then decreased as spiral pitch increased. Similarly, the muscle tension required to elicit a given change in resistance first increased and then decreased with pitch. These results suggest that the orientation of the smooth muscle about the airway may be very important in determining airway responsiveness.