Prevention of haematomas after auricular injuries.
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Ear Deformities, Acquired↗
Biomedical subjects
R J Martin
Publications and source records attributed to R J Martin.
Substance P and its receptor neurokinin 1 expression in asthmatic airways.
BACKGROUND: Neural mechanisms have been suggested to contribute to the pathogenesis of chronic asthma. The expression of neuropeptides such as substance P may be regulated by infectious pathogens, including Mycoplasma species. In contrast to substance P, the substance P receptor neurokinin 1 has not been examined at the protein level in asthmatic airways. OBJECTIVE: This study evaluated substance P and neurokinin 1 protein expression and mucus content in endobronchial biopsy specimens from normal control subjects and asthmatic subjects. Detection of Mycoplasma pneumoniae was performed in both biopsy and bronchoalveolar lavage specimens. METHODS: Biopsy specimens were collected from 10 normal control subjects and 18 asthmatic subjects before and after a 6-week treatment with a macrolide antibiotic (n = 11) or placebo (n = 7) and were stained for substance P, neurokinin 1, and mucus. M pneumoniae was evaluated by PCR. RESULTS: At baseline, compared with normal control subjects, asthmatic subjects demonstrated increased expression of substance P and neurokinin 1 and mucus content in the airway epithelium. Epithelial mucus content correlated with epithelial substance P expression (r (s) = 0.45, P =.04) and FEV(1) percent predicted (r (s) = -0.51, P =.019). After antibiotic treatment, both epithelial substance P and neurokinin 1 expression were significantly reduced in asthmatic subjects. M pneumoniae was found in 8 of 18 asthmatic subjects. Asthmatic subjects with M pneumoniae, compared with those without M pneumoniae, showed higher baseline epithelial neurokinin 1 expression, which was significantly reduced after antibiotic treatment (P =.02). CONCLUSION: Our data suggest that abnormalities in neural mechanisms may exist in the epithelium of asthmatic airways, and M pneumoniae is possibly involved in this process. Antibiotic intervention may be effective in the treatment of asthma partly through the downregulation of the neurogenic process.
Adult↗
Efficacy and safety overview of a new inhaled corticosteroid, QVAR (hydrofluoroalkane-beclomethasone extrafine inhalation aerosol), in asthma.
Chlorofluorocarbon (CFC)-containing inhalers are gradually being phased out and replaced with hydrofluoroalkane (HFA)-based alternatives. The reformulation provided the opportunity to improve the inhalation technology and physical characteristics of corticosteroid formulations. QVAR contains HFA-beclomethasone dipropionate (HFA-BDP) with the steroid in solution rather than suspension, which, in combination with improved inhaler technology, produces an extrafine aerosol with a mass median aerodynamic diameter of 1.1 microm (smaller than the 3.5-4.0 microm found with CFC-BDP). It was predicted and demonstrated that the smaller particle size of QVAR would be deposited in the lung to a greater extent than that found with CFC-BDP, particularly in the small airway, a major site of inflammation. Increased lung deposition of QVAR permits a reduction in dosage relative to CFC-BDP. Clinical evidence confirms that adult and elderly patients required approximately half the dose of QVAR to achieve the same degree of asthma control as with CFC-BDP. In long-term assessments, patients taking CFC-BDP could be switched to QVAR at half the daily dose without exacerbation of their asthma symptoms. QVAR was associated with a low overall incidence of side effects and, at the maximum recommended dose of 640 microg/d, caused no more adrenal suppression than 672 microg/d CFC-BDP.
Administration, Inhalation↗
Regulation of metabolism and body fat mass by leptin.
The relative stability of body weight over the long term and under a variety of environmental conditions that alter short-term energy intake and expenditure provides strong evidence for the regulation of body energy content. The lipostatic theory of energy balance regulation proposed 40 years ago that circulating factors, generated in proportion to body fat stores, acted as signals to the brain, eliciting changes in energy intake and expenditure. The discovery of leptin and its receptors has now provided a molecular basis for this theory. Leptin functions as much more than an adipocyte-derived signal of lipid stores, however. Although suppression of food intake is an important centrally mediated effect of leptin, considerable evidence indicates that leptin also functions both directly and indirectly, via the brain, to orchestrate complex metabolic changes in a number of organs and tissues, altering nutrient flux to favor energy expenditure over energy storage.
Adipocytes↗
Insulin-like growth factor I mediates high-fat diet-induced adipogenesis in Osborne-Mendel rats.
To determine if high-fat (HF) diet-induced changes in adipose tissue cellularity are associated with the presence of paracrine growth factor(s) that alter preadipocyte proliferation, Osborne-Mendel rats were fed either a HF (76% energy) or a low-fat (LF, 12% energy) diet for 85 days. HF-fed rats had greater (P < 0.05) fat pad size, total fat cell number, number of small (30-70 microm) and large (80-140 microm) adipocytes, and percentage of 100- to 140-microm adipocytes compared with LF-fed rats. Preadipocytes in primary cell culture treated with inguinal adipose tissue conditioned medium (ATCM) prepared from HF-fed rats had greater (P < 0.05) proliferation compared with cultures treated with ATCM from LF-fed rats. Proliferative capacity of ATCM prepared from HF-fed rats was attenuated after the stripping of the medium of insulin-like growth factor I using an immunomagnetic bead separation system. These data are consistent with the concept that insulin-like growth factor I is involved in the paracrine regulation of adipogenesis.
Adipose Tissue↗
Role of endogenous nitric oxide in hyperoxia-induced airway hyperreactivity in maturing rats.
We sought to define the effects of maturation and hyperoxic stress on nitric oxide (NO)-induced modulation of bronchopulmonary responses to stimulation of vagal preganglionic nerve fibers. Experiments were performed on decerebrate, paralyzed, and ventilated rat pups at 6-7 days (n = 21) and 13-15 days of age (n = 23) breathing room air and on rat pups 13-15 days of age (n = 19) after exposure to hyperoxia (>/=95% inspired O(2) fraction for 4-6 days). Total lung resistance (RL) and lung elastance (EL) were measured by body plethysmograph. Vagal stimulation and release of acetylcholine caused a frequency-dependent increase in RL and EL in all animals. The RL response was significantly potentiated in normoxic animals by prior blockade of nitric oxide synthase (NOS) (P < 0.05). Hyperoxic exposure increased responses of RL to vagal stimulation (P < 0.05); however, after hyperoxic exposure, the potentiation of contractile responses by NOS blockade was abolished. The response of EL was potentiated by NOS blockade in the 13- to 15-day-old animals after both normoxic and hyperoxic exposure (P < 0.01). Morphometry revealed no effect of hyperoxic exposure on airway smooth muscle thickness. We conclude that NO released by stimulation of vagal preganglionic fibers modulates bronchopulmonary contractile responses to endogenously released acetylcholine in rat pups. Loss of this modulatory effect of NO could contribute to airway hyperreactivity after prolonged hyperoxic exposure, as may occur in bronchopulmonary dysplasia.
Aging↗
Alterations in fetal adipose tissue leptin expression correlate with the development of adipose tissue.
Control pig fetuses and fetuses hypophysectomized (hypox) at 70 days of gestation were treated with hormones on day 90. At 105 days of gestation, subcutaneous adipose tissue was prepared for morphological studies, leptin Northern blot and Western blot analysis. Fetal ontogeny studies showed that leptin mRNA in adipose tissue increased with morphological development, and the highest level of leptin mRNA was observed in 105-day fetal pigs. In hypox fetuses, levels of leptin mRNA were similar to those in controls. Treatment with either hydrocortisone (HC) or thyroxine (T(4)) resulted in a slight increase in leptin mRNA levels in hypox fetuses but not in intact fetuses. Supplementation with both HC and T(4) markedly stimulated leptin mRNA expression in both hypox and intact fetuses. Morphological data showed that hypox slightly enhanced lipid accretion and treatment of hypox fetuses with HC and T(4) increased lipid accretion to a greater degree than did either HC or T(4) alone. However, serum leptin levels were not influenced by age, hypox or hormone treatment. Leptin protein expression was not detected in adipose tissue of hypox or intact fetuses regardless of hormone treatment. Leptin protein was detected in adipose tissue of 7-day-old pigs and placenta. As compared to 7-day postnatal adipose tissue, placenta showed a higher level of leptin protein expression. Leptin mRNA expression in fetal adipose tissue was not correlated with body weight and organ weight. The expression of long-form leptin receptor mRNA was detected in fetal adipose tissue. Our results indicate that adipose tissue leptin may not be the main source of serum leptin in the fetus and may not be involved in general prenatal growth and development. But adipose tissue leptin may act as an autocrine or paracrine factor in the development of fetal adipose tissue.
Adipose Tissue↗
Airway-parenchyma uncoupling in nocturnal asthma.
Airway flow resistance is well known to be dependent upon lung volume. The rise in lung volume that occurs in asthma is therefore thought to be an important mechanism that defends airway patency. The purpose of the current study was to investigate the interdependence or mechanical coupling between airways and lung parenchyma during the inflammatory processes that occur in the patient with nocturnal asthma. Five patients with documented nocturnal asthma were studied in both a vertical and a horizontal body plethysmograph. Lung volume was altered with continuous negative pressure as applied to the chest wall with a poncho cuirass in different postures and during sleep. We found during the awake phase that an increase in lung volume decreased lower pulmonary resistance (Rlp); however, within 30 min of sleep onset, functional residual capacity (FRC) fell and Rlp rose more than would be expected for the fall in FRC. Restoring FRC to presleep values either at an early (half-hour) or a late (3-h) time point did not cause Rlp to significantly fall. A second phase of the study showed that the loss of Rlp dependence on lung volume was not due to the assumption of the supine posture. Indirect measurements of lung compliance were consistent with a stiffening of the lung. We conclude that with sleep there is an immediate uncoupling of the parenchyma to the airway, resulting in a loss of interdependence that persists throughout sleep and may contribute to the morbidity and mortality associated with nocturnal asthma.
Adult↗
The effect of polymorphisms of the beta(2)-adrenergic receptor on the response to regular use of albuterol in asthma.
Inhaled beta-adrenergic agonists are the most commonly used medications for the treatment of asthma although there is evidence that regular use may produce adverse effects in some patients. Polymorphisms of the beta(2)-adrenergic receptor (beta(2)-AR) can affect regulation of the receptor. Smaller studies examining the effects of such polymorphisms on the response to beta-agonist therapy have produced inconsistent results. We examined whether polymorphisms at codon 16 (beta(2)-AR-16) and codon 27 (beta(2)-AR-27) of the beta(2)-AR might affect the response to regular versus as-needed use of albuterol by genotyping the 190 asthmatics who had participated in a trial examining the effects of regular versus as needed albuterol use. During the 16-wk treatment period there was a small decline in morning peak expiratory flow in patients homozygous for arginine at B(2)-AR-16 (Arg/Arg) who used albuterol regularly. This effect was magnified during a 4-wk run out period, during which all patients returned to using as-needed albuterol, so that by the end of the study Arg Arg patients who had regularly used albuterol had a morning peak expiratory flow 30. 5 +/- 12.1 L/min lower (p = 0.012) than Arg/Arg patients who had used albuterol on an as needed basis. There was no decline in peak flow with regular use of albuterol in patients who were homozygous for glycine at beta(2)-AR-16. Evening peak expiratory flow also declined in the Arg/Arg patients who used albuterol regularly but not in those who used albuterol on an as-needed basis. No significant differences in outcomes between regular and as-needed treatment were associated with polymorphisms at position 27 of the beta(2)-AR. No other differences in asthma outcomes that we investigated occurred in relation to these beta(2)-AR polymorphisms. Polymorphisms of the beta(2)-AR may influence airway responses to regular inhaled beta-agonist treatment.
Adolescent↗
Comparison of apnea identified by respiratory inductance plethysmography with that detected by end-tidal CO(2) or thermistor. The CHIME Study Group.
As part of the Collaborative Home Infant Monitoring Evaluation (CHIME) we compared apnea identified by a customized home monitor using respiratory inductance plethysmography (RIP) with simultaneously recorded polysomnography-acquired nasal end-tidal CO(2) (PET(CO(2))) and nasal/oral thermistor in 422 infants during overnight laboratory recordings to determine concordance between techniques, sources of disagreement, and capacity of RIP to detect obstructed breaths within an apnea. Among 233 episodes of apnea identified by at least one method as >/= 16 s, 120 were observed by the CHIME monitor, 219 by PET(CO(2)), and 163 by thermistor. The positive predictive value of the CHIME-identified apnea was 89.2% (95% CI 83, 95) and 73% (95% CI 65, 81) for PET(CO(2)) and thermistor, respectively. However, the sensitivity of the CHIME monitor in identifying events detected by the other methods was only approximately 50%. Among 87 apnea events identified by all three techniques, no two methods showed high agreement in measurement of apnea duration: RIP and PET(CO(2)) (ICC = 0.54), RIP and thermistor (ICC = 0.13), PET(CO(2)) and nasal thermistor (ICC = 0.41). Among the 179 breaths identified by RIP as obstructed, 79.9% were judged to be obstructed on the PET(CO(2)) and 80.4% were judged to be obstructed on the thermistor channel. Among 238 breaths identified on PET(CO(2)) as obstructed, 54.2% were determined to be obstructed by RIP. Among 204 breaths identified on thermistor as obstructed, 55. 4% were determined to be obstructed by RIP. Reasons for discrepancies in apnea detection among channels included body movement, partial airway obstruction, and obstructed breaths. Despite these limitations the CHIME monitor provides an opportunity to record physiological data previously unavailable in the home.
Apnea↗
Serum lidocaine concentrations in asthmatics undergoing research bronchoscopy.
STUDY OBJECTIVES: To determine how often serum lidocaine concentrations (SLC) fall into the potentially toxic range (> 5 mg/L) in asthmatics undergoing research bronchoscopy, and to determine whether subject or procedure characteristics are associated with higher SLC. DESIGN: Prospective, observational study. SETTING: Academic research center. PARTICIPANTS: Fifty-one volunteers with mild to moderate asthma enrolled in three separate bronchoscopy protocols to study airway inflammation in asthma. INTERVENTIONS: Lidocaine was administered topically to the upper airway and tracheobronchial tree to achieve local anesthesia for bronchoscopy. Venous blood was sampled during bronchoscopy, 30 min after upper airway anesthesia was completed (time 1), and 30 min after bronchoscopy was completed (time 2). MEASUREMENTS AND RESULTS: The mean total amount of lidocaine administered was 600 +/- 122 mg (8.2 +/- 2.0 mg/kg). No signs or symptoms of lidocaine toxicity were observed in any of the subjects. SLC ranged between 0.10 and 2.90 mg/L at time 1 and 0.50 and 3.20 mg/L at time 2. SLC was significantly correlated with the total amount of lidocaine (milligrams/kilogram) administered at both points (time 1, r = 0.33, p = 0.021; time 2, r = 0.33, p = 0.023). No statistically significant relationship was observed between SLC and subject age, sex, weight, baseline FEV(1), procedure length, or study protocol. No statistically significant relationship was found between subject FEV(1) and either total lidocaine dose or procedure length. CONCLUSIONS: An average total dose of 600 mg (8.2 mg/kg) of lidocaine appears to be safe in mild to moderate asthmatics undergoing research bronchoscopy.
Academic Medical Centers↗
CO2-induced c-fos expression in medullary neurons during early development.
In this study, we characterized the responses of brainstem neurons to hypercapnic loading at 5, 15, and 40 postnatal days, using c-fos gene encoded protein (Fos), as a marker of neuronal activity. At any of these studied ages exposure to 10% CO2 for 1 h produced a significant increase in the number of activated neurons within the ventral and the dorsal aspects of the brainstem. In the ventrolateral aspect of the medulla oblongata, Fos positive cells were observed within the ventrolateral medulla, extending from the pontomedullary border to the decussation of the pyramids. In the most rostral regions, within the retrotrapezoid field, the number of Fos positive cells was lower than in caudal ventral medullary regions at the levels of the area postrema and the caudal to it. No age related differences were observed in the number of neurons exhibiting CO2-induced Fos expression. Fos positive cells were additionally observed in the lateral paragigantocellular and gigantocellular reticular nuclei, in the medullary midline complex, in the raphe pallidus and in the raphe obscurus. The number of activated cells in the midline neurons was higher at 5 than at 40 days of age. In the dorsal aspect of the medulla oblongata Fos positive neurons were observed mainly within the caudal nucleus tractus solitarius (nTS). Postnatal age had no effect on the distribution and number of nTS cells activated by hypercapnic loading. These findings indicate that neurons activated by increases in CO2/H+ concentrations appear to be well developed from the first days of postnatal life in maturing rat pups.
Aging↗
CO2-induced prolongation of expiratory time during early development.
In these studies, we determined the contribution of central mechanisms and the role of GABA(A)-receptor signal transduction pathways in mediating hypercapnia-induced slowing of breathing frequency. Experiments were performed in decerebrate, vagotomized, paralyzed and mechanically ventilated piglets of 3-5 days and 2-3 weeks of age (n=19). Repeated exposure to progressive hyperoxic hypercapnia induced a reproducible increase in phrenic nerve activity, accompanied by a CO2 concentration-dependent increase in expiratory duration. No differences were observed in piglets with intact or cut carotid sinus nerves. Intravenous administration of bicuculline (2 mg/kg: n=7), a gamma-aminobutyric acid (GABA(A)) receptor antagonist, significantly reduced the CO2-induced prolongation of TE. These data demonstrate for the first time that in early postnatal life, hypercapnia induced increase in phrenic activity is associated with centrally mediated prolongation of expiratory duration. Furthermore. the results suggest that brainstem GABAergic mechanisms play an important role in CO2-induced prolongation of expiratory time during early development.
Animals↗
Bronchopulmonary dysplasia--no simple solution.
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Administration, Inhalation↗
Endocrine regulation of fetal adipose tissue metabolism in the pig: interaction of porcine growth hormone and thyroxine.
OBJECTIVE: This study tested the hypothesis that combined treatment of thyroxine (T4) and growth hormone (GH) could normalize cellular and metabolic aspects of adipose tissue development of hypophysectomized fetal pigs. RESEARCH METHODS AND PROCEDURES: On day 70 of gestation, pig fetuses were hypophysectomized by microcauterization or remained intact. Hypophysectomized fetuses remained untreated or were treated from day 90 to day 105 of gestation with T4, GH, or a combination of both hormones. RESULTS: Body weights were unaffected by hypophysectomy or hormone treatment. De novo lipogenesis in subcutaneous adipose tissue was increased 10-fold by hypophysectomy, consistent with our previous results. This increase was abolished by GH treatment in the hypophysectomized fetuses. In contrast, T4 treatment of the hypophysectomized fetuses resulted in a 12-fold further increase in adipose tissue lipogenesis, an effect that was negated by concomitant administration of GH. Lipolytic response to isoproterenol was decreased by hypophysectomy, unaffected by GH treatment, and restored to intact values by T4 or by T4+GH treatment in the hypophysectomized fetuses. DISCUSSION: In contrast to T4, GH does not influence serum insulin-like growth factor-I or adipose tissue lipolysis, but decreases lipogenesis in the fetal pig. However, replacing both T4 and GH normalized hypophysectomized fetuses to a greater extent than either GH or T4 alone. Thus, any influence of thyroid hormones on stimulating adipose tissue lipogenesis in the developing fetal pig may be normally counterregulated by pituitary-derived growth hormone.
Adipose Tissue↗
Adipocyte development is dependent upon stem cell recruitment and proliferation of preadipocytes.
OBJECTIVES: The ability to acquire fat cells persists over the life spans of animals. It is unknown whether adipocyte acquisition is the result of preadipocyte proliferation or stem cell recruitment to become adipocytes. The purposes of these studies were 1) to characterize early differentiation of stromal vascular (S-V) cells to preadipocytes as it is influenced by insulin, dexamethasone (DEX), and insulin-like growth factor-I (IGF-I); and 2) to determine whether new fat cells arise from stem cell recruitment or preadipocyte proliferation. RESEARCH METHODS AND PROCEDURES: Freshly isolated S-V cells from rat inguinal adipose tissues were plated for 24 hours then exposed to serum-free medium. RESULTS: Approximately 15% of freshly plated S-V cells were preadipocytes as determined by a preadipocyte specific marker, AD3. Total cell number and proportion of preadipocytes were significantly greater with 100 nM insulin treatment than with 0, 0.1, or 1.0 nM, but IGF-I treatment at 10 nM resulted in preadipocyte development similar to that with 100 nM insulin treatment. The addition of 5 nM DEX to the 100 nM insulin treatment resulted in a 20% increase in preadipocyte number by day 2 when compared to either treatment alone. 5-Bromo-2'-deoxy-uridine treatment suppressed the increased proportion of preadipocytes from days 0-2 in non-insulin treated cells and prevented the increase typically observed with insulin. A mitosis inhibitor also significantly reduced the proportion of preadipocytes. DISCUSSION: These results show for the first time that S-V cells are recruited as preadipocytes and that proliferation of these preadipocytes and early differentiation occur simultaneously.
Adipocytes↗
Inhibition of methylprednisolone elimination in the presence of clarithromycin therapy.
BACKGROUND: Macrolide antibiotics have long been used as steroid-sparing agents in patients with severe steroid-dependent asthma. Their efficacy and their propensity to potentiate glucocorticoid adverse effects have been attributed in part to their ability to delay glucocorticoid clearance. OBJECTIVE: We sought to determine whether clarithromycin, a newer macrolide antibiotic, can alter the pharmacokinetic profile of oral glucocorticoids and thereby increase the risk of steroid-induced adverse effects. METHODS: An open-label study in a paired design (before and after treatment) was conducted in a hospital-based outpatient clinic. Participants were 6 adult patients (mean age, 30 years) with mild-to-moderate asthma. Prednisone (40 mg/1.73 m2) and methylprednisolone (40 mg/1.73 m2) were given as single randomized doses on consecutive study days before and on days 8 and 9 of a clarithromycin (500 mg twice daily) course. Twelve-hour pharmacokinetic profiles with measurement of plasma methylprednisolone and prednisolone levels were taken before and after clarithromycin therapy. RESULTS: Clarithromycin therapy resulted in a 65% reduction of methylprednisolone clearance and significantly higher mean plasma methylprednisolone concentrations compared with preclarithromycin concentrations but had no significant effect on prednisolone clearance or mean prednisolone plasma concentrations. CONCLUSIONS: Clinicians must be aware of potential drug interactions that could place patients at increased risk for steroid-induced adverse effects. Such an effect has been demonstrated between clarithromycin and methylprednisolone, two drugs that may be administered concomitantly in asthma. To avoid potential steroid-enhancing effects, prednisone should be substituted for methylprednisolone during prolonged courses of clarithromycin therapy.
Adult↗
Assessment of the AirWatch lung function monitoring system. Asthma Clinical Research Network (ACRN).
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Calibration↗