Search PubMed⌕ Search

Biomedical subjects

R J Martin

Publications and source records attributed to R J Martin.

At least 181 records · Page 10Linked to original sources
PubMed1995

Dysregulation of interleukin 4, interleukin 5, and interferon gamma gene expression in steroid-resistant asthma.

In steroid-resistant (SR) asthma, there is a lack of clinical responsiveness to oral prednisone. Previous studies indicate that this may be explained by the effect of the combination of interleukin 2 (IL-2) and IL-4 on glucocorticoid receptor binding affinity. By contrast, steroid-sensitive (SS) asthmatics respond well to glucocorticoids, and this is accompanied by a decrease in the numbers of bronchoalveolar lavage (BAL) messenger RNA+ (mRNA+) cells expressing IL-4 and IL-5, and an increase in interferon gamma (IFN-gamma) transcripts. In the present study, we hypothesized that SR asthma is associated with alterations in T helper types 1/2 (Th2/Th1)-type cytokine gene expression. BAL was performed in six SR asthmatics and six SS asthmatics, before and after a 1-wk course of 40 mg daily prednisone. mRNA+ cells for IL-2, IL-4, IL-5, and IFN-gamma was measured by in situ hybridization using 35S-labeled RNA probes. Before prednisone therapy, there were significantly greater numbers of BAL cells (per 1,000) expressing IL-2 mRNA (p < 0.01) and IL-4 mRNA (p < 0.05) in SR asthmatics as compared with SS asthmatics, but no differences between the two groups in the numbers of BAL cells expressing IFN-gamma or IL-5 mRNA expression were observed. After a 1-wk course of prednisone, IL-2 expression was not altered in either group. However, SS asthmatics had a significant decrease in the numbers of BAL cells expressing mRNA for IL-4 (p < 0.01) and IL-5 (p < 0.001), and a rise in the numbers of IFN-gamma mRNA+ cells (p < 0.01). In contrast, after prednisone treatment, SR asthmatics had no significant change in either the number of BAL cells expressing mRNA for IL-4 or IL-5. Of note, there was an unexpected decrease in the numbers of IFN-gamma mRNA+ cells (p = 0.05). Our current findings indicate that SR asthma is associated with a dysregulation of the expression of the genes encoding for Th2/Th1 cytokines in airway cells and is compatible with the concept that a combination of IL-2 and IL-4 induce glucocorticoid (GR) binding affinity and T cell responsiveness to glucocorticoids.

Adult↗
PubMed1995

Carotid bodies and ventilatory response to hypoxia in aminophylline-treated piglets.

Peripheral chemoreceptors may be immature in neonatal animals, exhibiting maturational changes in the perinatal period. Even though methylxanthines are respiratory stimulants, many premature neonates do not respond to them. Thus, we hypothesized that carotid body activity is necessary for aminophylline to reverse hypoxia-induced respiratory depression. We exposed 16 anesthetized newborn piglets (age 2-7 days) to hypoxia (inhalation of 12% oxygen) for 5 min. Aminophylline (15 mg/kg iv) was administered either prior to (11 piglets) or following (5 piglets) carotid body denervation (CBD). Before CBD, hypoxia elicited transient initial increases in tidal volume (from 79 +/- 4 to 99 +/- 1% of maximum, mean +/- SE), minute ventilation (from 64 +/- 5 to 93 +/- 4%), and peak phrenic electroneurogram (from 63 +/- 8 to 91 +/- 6%, all P < 0.05). This was followed by a decrease in tidal volume, minute ventilation and phrenic electroneurogram (all P < 0.05). Prior to CBD, aminophylline pretreatment prevented the decrease in all the measures of respiratory output during late hypoxia. After CBD, hypoxia induced an initial and sustained depression of ventilation (tidal volume from 100 to 33 +/- 14%; frequency from 94 +/- 4 to 42 +/- 17%; minute ventilation from 100 to 32 +/- 14%, all P < 0.05) and phrenic electroneurogram (peak phrenic from 100 to 47 +/- 18%; minute phrenic from 85 +/- 6 to 55 +/- 21%, both P < 0.05). Administration of aminophylline after CBD did not prevent the profound respiratory depression elicited by hypoxia in the chemodenervated piglets.(ABSTRACT TRUNCATED AT 250 WORDS)

Aminophylline↗
PubMed1995

A Cl channel in Ascaris suum selectivity conducts dicarboxylic anion product of glucose fermentation and suggests a role in removal of waste organic anions.

The permeability of organic anions (produced anaerobic fermentation of glucose) through a non-selective membrane Cl channel was examined. Single channel recording techniques were used to study the permeabilities of the anions: oxalate, succinate, oxaloacetate, malate, lactate and pyruvate in Ascaris muscle cell membranes. All of the anions, except malate, were found to be conducted through the channel. The relative permeability of most anions could be predicted from the component structure of the anions. The failure of the channel to conduct malate prevents an energy drain on the cell. These studies further the hypothesis that a Cl channel functions to transport waste organic anions across the cell membrane. This mechanism does not require specific exchange carriers for the anions. Channels with properties like the nonselective anion channels of Ascaris, are suitable for transport of carboxylic anions through cell membranes, down a concentration or potential gradient.

Action Potentials↗
PubMed1995

Chronobiology and chronotherapy in medicine.

There is a fascinating and exceedingly important area of medicine that most of us have not been exposed to at any level of our medical training. This relatively new area is termed chronobiology; that is, how time-related events shape our daily biologic responses and apply to any aspect of medicine with regard to altering pathophysiology and treatment response. For example, normally occurring circadian (daily cycles, approximately 24 hours) events, such as nadirs in epinephrine and cortisol levels that occur in the body around 10 PM to 4 AM and elevated histamine and other mediator levels that occur between midnight and 4 AM, play a major role in the worsening of asthma during the night. In fact, this nocturnal exacerbation occurs in the majority of asthmatic patients. Because all biologic functions, including those of cells, organs, and the entire body, have circadian, ultradian (less than 22 hours), or infradian (greater than 26 hours) rhythms, understanding the pathophysiology and treatment of disease needs to be viewed with these changes in mind. Biologic rhythms are ingrained, and although they can be changed over time by changing the wake-sleep cycle, these alterations occur over days. However, sleep itself can adversely affect the pathophysiology of disease. The non-light/dark influence of biologic rhythms was first described in 1729 by the French astronomer Jean-Jacques de Mairan. Previously, it was presumed that the small red flowers of the plant Kalanchoe bloss feldiuna opened in the day because of the sunlight and closed at night because of the darkness. When de Mairan placed the plant in total darkness, the opening and closing of the flowers still occurred on its intrinsic circadian basis. It is intriguing to think about how the time of day governs the pathophysiology of disease. On awakening in the morning, heart rate and blood pressure briskly increase, as do platelet aggregability and other clotting factors. This can be linked to the acrophase (peak event) of heart attacks. During the afternoon we hit our best mental and physical performance, which explains why most of us state that "I am not a morning person." Even the tolerance for alcohol varies over the 24-hour cycle, with best tolerance around 5 pm (i.e. "Doctor, I only have a couple of highballs before dinner"). Thus, all biologic functions, from those of the cell, the tissue, the organs, and the entire body, run on a cycle of altering activity and function.(ABSTRACT TRUNCATED AT 400 WORDS)

Arthritis↗
PubMed1995

Vulnerability of respiratory control in healthy preterm infants placed supine.

OBJECTIVE: We tested the hypothesis that healthy preterm infants have attenuated ventilatory responses to hypercapnia, associated with a decreased rib cage contribution to ventilation, in the supine versus prone position. STUDY DESIGN: We elicited hypercapnic ventilatory responses from 19 healthy preterm infants (postconceptional age 35 +/- 1 weeks) who were being prepared for hospital discharge. The O2 saturation was continuously monitored. Before and during CO2 rebreathing, ventilation was measured with a nasal mask pneumotachygraph and was derived from chest wall motion as determined by respiratory inductance plethysmograph. This measuring method allowed us to compare both ventilation and the percentage rib cage contribution to ventilation between supine and prone positions. Statistical analysis employed analysis of variance with repeated measures. RESULTS: The supine position was associated with a higher respiratory rate (p < 0.02) and lower O2 saturation (p < 0.007) than the prone position. The increase in ventilation in response to hypercapnia was lower in the supine than in the prone position. This was statistically significant for the respiratory inductance plethysmograph (p < 0.008) but not the pneumotachygraph (p = 0.077), and was associated with a smaller rib cage contribution to ventilation in the supine than in the prone position (p < 0.0001). CONCLUSION: Respiratory control may be vulnerable when healthy preterm infants are placed supine. Widespread avoidance of the prone position may not be appropriate for such patients.

Carbon Dioxide↗
PubMed1995

Chronotherapy of asthma with inhaled steroids: the effect of dosage timing on drug efficacy.

BACKGROUND: Studies in asthma with systemic corticosteroids given at 3:00 PM have shown a superior therapeutic benefit compared with dosing at other time points. OBJECTIVE: The study was designed to compare beneficial and systemic effects of 800 micrograms of inhaled triamcinolone once daily at 3:00 PM (QD group) versus 200 micrograms conventional four times a day dosing (QID group). METHODS: Efficacy outcome measures included forced expiratory volume in 1 second (FEV1), peak expiratory flow rates, bronchial responsiveness, and use of beta-agonist. Systemic effects were blood eosinophil and cortisol levels, 24-hour urinary cortisol, and evaluation for oral candidiasis and dysphonia. RESULTS: The baseline FEV1 was comparable in the two groups: QD = 67% +/- 2% and QID = 66% +/- 2% of predicted value. After 4 weeks of treatment, FEV1 increased similarly in the QD group to 77% +/- 4% and in the QID group to 74% +/- 4% of predicted value. Likewise, the improvement in morning and evening peak expiratory flow rates was not significantly different between the groups. Both QD and QID groups experienced comparable daily decrements in beta-agonist use. The systemic responses to the two regimens as assessed by eosinophil count, morning serum cortisol, and 24-hour urinary cortisol were also comparable. CONCLUSIONS: The single daily administration of inhaled triamcinolone at 3:00 PM has no increased systemic effects and produces similar improvement in efficacy variables. A dosing strategy based on once daily dosing should increase compliance of inhaled steroid use in the clinical setting.

Administration, Inhalation↗
PubMed1995

Oxantel-activated single channel currents in the muscle membrane of Ascaris suum.

The patch clamp technique was used to investigate the action of the anthelmintic drug, oxantel, on nicotinic acetylcholine receptor (nAChR) currents recorded from vesicles of the somatic muscle cells of the nematode parasite Ascaris suum. The amplitudes of the currents were analysed at different membrane potentials to determine the single channel conductance. Also the open and closed durations were measured to determine the kinetic properties of the activated channel. Oxantel activated single nAChR currents throughout a concentration range 10-100 microM, these currents were not observed with oxantel-free pipette solutions. The mean open time of the activated channels at a membrane potential of -75 mV and a concentration of 10 microM was 1.34 ms. At higher concentrations the open times were shorter and voltage sensitive, decreasing in duration on hyperpolarization, thus suggesting open channel block. The kinetics were analysed using a simple channel block model. The forward block rate, K + B, increased with increasing oxantel concentration but showed little increase as the membrane was hyperpolarized. K + B was 2.41 x 10(7) M-1 s-1 at -50 mV and 2.64 x 10(7) M-1 s-1 at -100 mV. The unblocking rate constant, K-B, did exhibit voltage sensitivity being 443.6 s-1 at -50 mV and 86.8 s-1 at -100 mV. Thus the blocking dissociation constant KB (= K-B/K + B) was 18.5 microM at -50 mV and 3.3 microM at -100 mV. The simple channel block scheme was found to be insufficient to explain fully the observations made; reasons for this are discussed.

Animals↗
PubMed1995

Rats treated with somatotropin select diets higher in protein.

It was previously shown that somatotropin (STH) increases growth rate, improves food efficiency and stimulates protein accretion. In rats, STH also increases food intake. This study examined the effect of exogenous STH on rats' selection of diets varying in protein content. It was hypothesized that the increase in food intake in response to STH is driven by an increased protein requirement. Rats were allowed to select between two diets varying in casein (5 and 30%) or given a diet of a single casein level (20%). In each diet group, rats were treated with 0 or 4 mg of porcine STH/d. Rats treated with STH showed greater food intake (20%) and protein accretion (125%), regardless of diet. However, the greater food intake in rats allowed to select was due to greater consumption of the high protein diet. Diet selecting, STH-treated rats consumed 75% more of the 30% casein diet than did the saline-treated controls, while consuming a similar amount of 5% casein diet. Total protein intake (g/d) was 22 and 53% greater in rats injected with STH consuming the 20% casein diet and selection diets, respectively. The results indicate that rats injected with somatotropin select a diet greater in protein when compared with those not receiving somatotropin. It is suggested that the STH-induced increase in protein accretion results in a greater demand for essential amino acids. The mechanism whereby animals are able to monitor this greater need is not clear.

Animals↗
PubMed1995

Effect of somatotropin and feed restriction on body composition and adipose metabolism in obese Zucker rats.

The objective of the present study was to determine whether exogenous somatotropin (STH) administration in conjunction with feed restriction could alter the composition of gain in the obese rat. Five-week-old female lean and obese Zucker rats were assigned to the following treatments for 6 wk: ad libitum fed (AL), restricted (approximately 75% of AL lean), and restricted with STH (2 mg STH/day). Growth rate was decreased in restricted groups and was normalized to that of the AL lean group in restricted rats treated with STH. In lean rats, restriction decreased protein accretion. Restriction plus STH treatment decreased lipid accretion but increased protein accretion and body weight gain compared with the AL lean group. As expected, feed restriction reduced body size in obese rats, but carcass lipid was maintained at 44%, a level similar to that of the AL obese rats. Lipid accretion rate was decreased with restriction in obese rats and was further reduced, to a level similar to that of the lean group, in the obese rats that were restricted and treated with STH. Protein accretion was decreased in the restricted obese group but was normalized in those treated with STH to a level similar to that in the AL lean group. Basal rates of lipolysis in isolated adipocytes were not affected by STH. However, STH treatment normalized the responsiveness of cells from the obese rats to stimulation of lipolysis by isoproterenol. The results demonstrate that a combination of caloric restriction and STH was effective in normalizing body weight and composition of gain in the obese Zucker rat.

Adipose Tissue↗
PubMed1995

Dissociation between food intake, diet composition, and metabolism in parabiotic partners of obese rats.

When one member of a parabiosed pair of rats is overfed, its ad libitum-fed partner loses body fat in the absence of a statistically significant decrease in food intake. Three experiments investigated the relationships between food intake, metabolism, and body composition in this model. In vivo measurement of lipogenesis confirmed that loss of fat is associated with decreased fat deposition. When partners of overfed rats were compared with food-restricted single rats, proportional changes in body composition and metabolism were similar for the two treatments, although there was no significant change in the food intake of parabiotic rats, whereas restricted rats received only 60% of the intake of their controls. The final experiment demonstrated that changes in body composition of partners of overfed rats were independent of dietary composition. These results suggest that, when a rat is made obese by overfeeding, a circulatory factor is released that inhibits fat deposition and disrupts regulatory mechanisms that normally stimulate food intake during a period of negative energy balance.

Adipose Tissue↗
PubMed1995

Central effects of endothelin on respiratory output during development.

Both endothelin-1 protein and endothelin-1 specific binding sites have been identified in areas of the medulla oblongata involved in respiratory control. We examined whether endothelin acting centrally affects respiratory output during early postnatal life. We initially examined the effect of intracisternally administrated endothelin on respiratory output in 10 2- to 18-day-old piglets. Endothelin-1 administration at 50 nmol to 1 mumol caused respiratory inhibition. We subsequently examined whether this response is mediated through chemosensitive areas of the ventral medulla. Endothelin-1 was microinjected into specific ventral or dorsal medullary regions in 31 14- to 22-day-old piglets. Microinjection of endothelin-1 (10 fmol to 0.1 pmol) just above the hypoglossal roots, lateral to the pyramids, and within 1 mm from the surface (n = 24) attenuated respiratory output, and complete apnea occurred with 1 pmol in all animals. However, microinjection of endothelin-1 3 mm below the ventral surface (n = 5) and into the dorsal medulla (n = 3) had no inhibitory effect. Comparable doses of angiotensin II (n = 5) and norepinephrine (n = 5) microinjected into the endothelin-1 sensitive area also did not influence respiratory output. These effects of endothelin-1 were not altered by prior endothelin-B receptor blockade (IRL-1038) but could be reversed by endothelin-A receptor blockade (BQ-610). These results suggest that endothelin-1 release may cause ventilatory depression mediated through endothelin-A receptors located in the chemosensitive areas of the ventrolateral medulla.

Animals↗
PubMed1995

Neurochemical control of tissue resistance in piglets.

Lung resistance may be influenced by chemoreceptor activity and modulated by inspiratory neural output; however, it is unknown whether the contractile elements of lung tissue participate in these changes during early development. In anesthetized paralyzed open-chest piglets, we measured phrenic electroneurogram, lung resistance (RL), and tissue resistance utilizing alveolar capsules to partition the hypercapnic and hypoxic responses of RL into tissue (Rti) and airway resistance (Raw) components. Inhalation of 7% CO2 significantly increased RL (7.4 +/- 0.5 to 11.3 +/- 0.6 cmH2O.l-1.s), Rti (5.2 +/- 0.5 to 6.9 +/- 0.5 cmH2O.l-1.s), and Raw (2.2 +/- 0.2 to 4.4 +/- 0.4 cmH2O.l-1.s). Inhalation of 12% O2 caused more modest increases in RL, Rti, and Raw. Oscillations in tracheal and alveolar pressures appeared in synchrony with phrenic activity in response to both chemoreceptor stimuli. Cholinergic blockade eliminated these oscillations and significantly reduced the hypercapnic and hypoxic responses of RL, Rti, and Raw. These data demonstrate for the first time that hypercapnia and hypoxia elicit a cholinergically mediated increase in Rti which, just like the airway component of RL, is modulated by inspiratory neural output and is present during early development. Such coordination in neural function throughout the respiratory system may serve to optimize gas exchange during early postnatal life.

Airway Resistance↗
PubMed1995

Effect of 5-lipoxygenase inhibition on bronchoconstriction and airway inflammation in nocturnal asthma.

To investigate the contribution of leukotrienes (LTs) to inflammation and bronchoconstriction in nocturnal asthma, we performed a randomized trial in 12 asthmatic patients and 6 normal control subjects. This study involved pulmonary function testing, methacholine challenge, bronchoscopy for cell counts, LT and thromboxane (TX) levels in bronchoalveolar lavage (BAL) fluid, and collection of urine for LTs at 4:00 P.M. and 4:00 A.M. At 4:00 P.M. BAL fluid LTB4 and sulfidopeptide LT levels in asthmatic and control subjects were not statistically different. At 4:00 A.M. alone, LTB4 and cysteinyl LT levels increased to become significantly greater in asthmatic than in control subjects, LTB4 levels correlating significantly (r = -0.66, p < 0.0001) with nocturnal fall in FEV1. Nocturnal asthmatic urinary LTE4 levels were also significantly higher than those of control subjects. The 4:00 A.M. testing was repeated during treatment with a 5-lipoxygenase inhibitor, zileuton. In asthmatic subjects, zileuton decreased BAL fluid LTB4 (p = 0.01) and urinary LTE4 (p = 0.01) while showing a trend for improving nocturnal FEV1 (p = 0.086). These decreases in LTB4 levels and improvement in FVE1 were associated with significant reductions in 4 A.M. BAL fluid and blood eosinophil percentages on zileuton compared with placebo administration. These findings demonstrate the importance of LTs in both the inflammation and the physiology of nocturnal asthma.

Adolescent↗
PubMed1995

Genetic polymorphisms of the beta 2-adrenergic receptor in nocturnal and nonnocturnal asthma. Evidence that Gly16 correlates with the nocturnal phenotype.

Nocturnal asthma represents a unique subset of patients with asthma who experience worsening symptoms and airflow obstruction at night. The basis for this phenotype of asthma is not known, but beta 2-adrenergic receptors (beta 2AR) are known to downregulate overnight in nocturnal asthmatics but not normal subjects or nonnocturnal asthmatics. We have recently delineated three polymorphic loci within the coding block of the beta 2AR which alter amino acids at positions 16, 27, and 164 and impart specific biochemical and pharmacologic phenotypes to the receptor. In site-directed mutagenesis/recombinant expression studies we have found that glycine at position 16 (Gly16) imparts an accelerated agonist-promoted downregulation of beta 2AR as compared to arginine at this position (Arg16). We hypothesized that Gly16 might be overrepresented in nocturnal asthmatics and thus determined the beta 2AR genotypes of two well-defined asthmatic cohorts: 23 nocturnal asthmatics with 34 +/- 2% nocturnal depression of peak expiratory flow rates, and 22 nonnocturnal asthmatics with virtually no such depression (2.3 +/- 0.8%). The frequency of the Gly16 allele was 80.4% in the nocturnal group as compared to 52.2% in the nonnocturnal group, while the Arg16 allele was present in 19.6 and 47.8%, respectively. This overrepresentation of the Gly16 allele in nocturnal asthma was significant at P = 0.007 with an odds ratio of having nocturnal asthma and the Gly16 polymorphism being 3.8. Comparisons of the two cohorts as to homozygosity for Gly16, homozygosity for Arg16, or heterozygosity were also consistent with segregation of Gly16 with nocturnal asthma. There was no difference in the frequency of polymorphisms at loci 27 (Gln27 or Glu27) and 164 (Thr164 or Ile164) between the two groups. Thus the Gly16 polymorphism of the beta 2AR, which imparts an enhanced downregulation of receptor number, is overrepresented in nocturnal asthma and appears to be an important genetic factor in the expression of this asthmatic phenotype.

Alleles↗
PubMed1995

Methacholine challenge does not affect bronchoalveolar fluid cell number and many indices of cell function in asthma.

Methacholine (MCh) challenge testing is often incorporated into clinical studies prior to performing bronchoscopy as a measure of bronchial hyperresponsiveness (BHR). However, the effect of methacholine on many aspects of bronchoalveolar lavage (BAL) fluid cell count and function have not been fully evaluated. Ten patients with asthma, maintained on inhaled beta 2-agonists, were studied. Each subject underwent two bronchoscopies in a random order, one preceded by methacholine challenge within 30 min of the BAL. The investigators were blinded to the regimen. Several markers of BAL fluid cell number and function were studied: cell count and differential histamine, eosinophil products, including eosinophil cationic protein and Charcot-Leyden crystal protein, macrophage production of thromboxane B2 and leukotriene B4, neutrophil lysozyme and lactoferrin, and lymphocyte typing and activation markers measured via flow cytometry. No significant differences were noted in any of these markers of cell number or function which could be ascribed to methacholine challenge. Thus, methacholine challenge does not appear to affect these markers of cell number and function. These findings indicate that a methacholine challenge can be used as a measure of bronchial hyperresponsiveness within 30 min prior to bronchoscopy without altering bronchoalveolar lavage fluid characteristics.

Adult↗