Pulmonary gas exchange in life-long nonsmoking patients with diabetes mellitus.

In a companion paper, we have found that the alveolar epithelial basal lamina, endothelial basal lamina and both fused were significantly thicker in 6 autopsied diabetics than in 6 control subjects. The purpose of the present work was to assess whether these lesions have detrimental effects on gas exchange. We investigated 20 life-long nonsmoking subjects: 10 healthy subjects and 10 insulin-dependent diabetics. All of them had one to four diabetic complications of the following organs: kidney, retina, nerves or arteries. Their pulmonary gas exchange and their transfer factor were measured at rest and during two levels of submaximal exercise. Spirometric data, specific airway conductance, transfer factor, transfer coefficient, oxygen consumption and arterial blood gases were normal and almost identical in both groups. In conclusion, the thickening of lung basal laminae has no detrimental effect on pulmonary gas exchange in insulin-dependent diabetics with peripheral complications.

Hypoxic hepatitis caused by acute exacerbation of chronic respiratory failure: a case-controlled, hemodynamic study of 17 consecutive cases.

Out of a prospective series of 142 consecutive episodes of hypoxic (ischemic) hepatitis (HH), we identified 17 episodes associated with an acute exacerbation of chronic respiratory failure (CRF) without left cardiac failure. In the aim to evaluate the role of arterial hypoxemia in the pathogenesis of HH associated with respiratory failure, these 17 episodes of HH (study group) were hemodynamically compared with a control group of 17 episodes of HH associated with congestive heart failure (CHF) (control group 1) and a group of 16 episodes of acute respiratory failure (ARF) not complicated by HH (control group 2). Arterial hypoxemia was significantly more severe in the study group (arterial blood tension in O2 [PaO2], 34 mm Hg) than in control group 1 (PaO2, 70 mm Hg; P <.0001) and control group 2 (PaO2, 45.5 mm Hg; P =.002). The role of arterial hypoxemia, however, appeared weakened by comparable degrees of systemic hypotension and liver passive congestion in episodes of HH associated with CRF and episodes of HH associated with CHF. Finally, the causative role of arterial hypoxemia emerged from hemodynamic measurements of cardiac index (CI), systemic vascular resistances (SVR), and oxygen transport: systemic hypotension in HH associated with CHF (control group 1) was the result of a fall in CI (median, 2. 33 L/min. m2; range, 1.21-3.14 L/min. m2) associated with high SVR (median, 2,492 dyn. s/cm5. m2; range, 1,382-4,053 dyn. s/cm5. m2), whereas in HH associated with respiratory failure (study group), systemic hypotension was the result of a fall in SVR (median, 1,053 dyn. s/cm5. m2; range, 646-3,148 dyn. s/cm5. m2), resulting in high CI (median, 4.23 L/min. m2; range, 1.9-5.32 L/min. m2) (P =.0087 and. 0038 for cardiac index and SVR, respectively). Moreover, measurements of oxygen transport in patients with HH associated with respiratory failure showed low values of O2 delivery (DO2) (median, 376 mL/min. m2; range, 253-427 mL/min. m2) as a result of extreme arterial hypoxemia despite high CI. In conclusion, these hemodynamic results and additional measurements of hepatic blood flow (HBF) by the method of galactose clearance at a low concentration suggest that in the setting of HH associated with respiratory failure, the liver is not "ischemic," despite hypotension, but rather "hypoxic" as a result of the combination of severe arterial hypoxemia and elevated central venous pressure (CVP).

Biomarker assessments in asbestos-exposed workers as indicators for selective prevention of mesothelioma or bronchogenic carcinoma: rationale and practical implementations.

In the first part of this study we have shown how the serum levels of four selected tumour markers, namely tissue polypeptide antigen (TPA), carcino-embryonic antigen (CEA), hyaluronic acid (HA) and ferritin, display patterns characteristic of mesothelioma (M) or bronchogenic carcinoma (BC) in asbestos-exposed workers, and we hypothesize that the differences in marker patterns correspond to differences in carcinogenesis mechanisms. In a preliminary study, we found these specific marker patterns in 5/19 exposed workers of whom only one demonstrated any radiological signs of disease. Thus these specific marker patterns may be early events, occurring long (possibly years) before the classical radiological signs of exposure to asbestos. Accordingly they afford an optimal opportunity for prevention which should be adapted to the carcinogenesis mechanism as it is revealed by the marker pattern; it is aimed at antagonizing free radical carcinogenesis in all persons with TPA levels in excess of 100 U/l or Ferritin in excess of 400 ng/ml, and at inhibiting chemical carcinogenesis in those having elevated CEA levels (over 3 ng/ml). The mechanisms involved in these inhibitory processes are described and discussed, as well as the practical implementations that proceed from them. A prevention trial is now being started among 300 active and retired workers of an asbestos-cement works in northern France; the design of the study is presented. This prevention programme should be maintained over many years and holds a strong potential for reducing the untoward effects of exposure to asbestos.

Biomarker assessments in asbestos-exposed workers as indicators for selective prevention of mesothelioma or bronchogenic carcinoma: rationale and practical implementations.

Asbestos-associated malignancies are one of the major industrial hazards of recent decades and will continue to be so until beyond the end of the century. It has been estimated that, in the United States alone, there will be 131,200 cancer deaths as a result of asbestos exposure. At present the early lesions are detected radiologically, by which time intervention is no longer effective. The aim of this study was to test the value of a battery of serum biomarkers in the early detection of malignancy and in distinguishing between the early stages of mesothelioma and bronchogenic carcinoma. Many of the biomarkers had no discriminating value but on the basis of four such markers (namely TPA, CEA, HA and ferritin) it has been possible to distinguish between the late stages of the two malignancies and asbestosis. The results are discussed in terms of their possible application to the detection of early pre-malignant lesions in a screened population of asbestos-exposed persons, with the aim of attempting to prevent cancer death in such early detected cases.

Muscarinic receptor subtypes in lung. Clinical implications.

Several subtypes of muscarinic receptors have been identified in airways and lung parenchyma of different species, including humans. M1 receptors may be present in parasympathetic ganglia where they appear to facilitate ganglionic neurotransmission. M2 receptors seem to be located on cholinergic nerve endings where they function as "autoreceptors," inhibiting acetylcholine release. M3 receptors appear to be located on effector cells, smooth muscle, and mucus secreting glands. Experimental data in support of this view are presented and discrepant data are discussed.

A muscarinic agonist inhibits reflex bronchoconstriction in normal but not in asthmatic subjects.

Muscarinic receptors of the M2 subtype, which inhibit acetylcholine release from cholinergic nerves (autoreceptors), have been described in animal and human bronchi in vitro. We investigated whether these receptors may be involved in feedback inhibition of cholinergic reflex bronchoconstriction induced by sulfur dioxide (SO2) in seven nonasthmatic atopic subjects and in six mild asthmatic subjects. In a control experiment, total respiratory resistance (Rrs) was increased by 30 +/- 5% in nonasthmatic and by 60 +/- 18% in asthmatic subjects. In nonasthmatic subjects, pilocarpine, an agonist of muscarinic M2-autoreceptors, increased Rrs by 15 +/- 5% and addition of SO2 increased Rrs to 21 +/- 5% above base line, which was not significantly greater than after pilocarpine alone. Histamine gave a comparable bronchoconstriction (25 +/- 3% increase in Rrs) and SO2 further increased Rrs to 39 +/- 6% above base line (P less than 0.05). Thus pilocarpine appears to inhibit SO2-induced bronchoconstriction in nonasthmatic subjects, and this effect is not explained by an increase in airway tone. In asthmatic subjects, pretreatment with pilocarpine increased Rrs by 31 +/- 8% and SO2 further increased Rrs to 88 +/- 17% above base line. SO2 alone gave a 60 +/- 18% increase in Rrs. Our results suggest that feedback inhibitory muscarinic receptors may be present on cholinergic nerves in normal airways and that there may be a dysfunction of this feedback mechanism in asthmatic airways. This might be contributory to exaggerated cholinergic reflex bronchoconstriction in asthma.

Capsaicin-induced bronchodilation in mild asthmatic subjects: possible role of nonadrenergic inhibitory system.

We investigated whether stimulation of vagal afferent nerve fibers with inhaled capsaicin could induce a nonadrenergic inhibitory reflex in nine mild asthmatic subjects. Changes in total respiratory resistance (Rrs) were measured with a forced oscillation technique. First we induced a rise of 71 +/- 15% in Rrs (P less than 0.001) after leukotriene D4 aerosol. Subsequent inhalation of capsaicin (2 nmol) caused no significant change in mean Rrs of -1.1 +/- 8.2%. After the muscarinic receptor antagonist ipratropium bromide (120 micrograms) was inhaled, leukotriene D4 increased Rrs by 103 +/- 9% (P less than 0.001). Capsaicin subsequently caused bronchodilation in all subjects (Rrs = -22.3 +/- 2.7%, P less than 0.001). Ethanol-saline (diluent) alone caused a nonsignificant fall in Rrs (-9.9 +/- 4.7%) but a deep breath and coughing resulted in bronchodilation (-16.9 +/- 6.1%, P less than 0.05 and -11.6 +/- 2.9%, P less than 0.01, respectively). As observed in normal subjects, capsaicin may initiate an inhibitory reflex, presumably of nonadrenergic origin. This reflex could not be distinguished from that caused by coughing or by deep inhalation. A defect in nonadrenergic mechanisms, at least in mild asthma, seems unlikely.

The role of pirenzepine-sensitive (M1) muscarinic receptors in vagally mediated bronchoconstriction in humans.

In a double-blind randomized study, we compared the effects of the M1-selective muscarinic receptor antagonists pirenzepine and the nonselective antagonist ipratropium bromide on bronchoconstriction induced by inhaled sulfur dioxide (SO2) and methacholine in atopic volunteers. Both inhaled pirenzepine (70 micrograms) and ipratropium bromide (7 micrograms) significantly inhibited vagally mediated bronchoconstriction by SO2 to the same extent (p less than 0.02). However, at this dose, pirenzepine had no effect on methacholine-induced bronchoconstriction, whereas ipratropium bromide gave significant protection (p less than 0.02). This indicates that vagally mediated bronchoconstriction in humans can be inhibited by blockade of pirenzepine-sensitive (M1) muscarinic receptors probably present on a different site from muscarinic receptors at the neuromuscular junction and presumably localized to parasympathetic ganglia. Pirenzepine may be useful in investigating ganglionic function and could be beneficial therapeutically in airway disease.

Muscarinic receptor subtypes mediating vasodilation in the pulmonary artery.

Binding studies in several species have demonstrated a high proportion of M1 muscarinic receptors in the lung but their localization is uncertain. Using [3H]quinuclidinyl benzylate we have confirmed that binding sites with high affinity for pirenzepine account for 50% of muscarinic receptors in the rat lung. Our functional studies using the muscarinic antagonists 4-diphenylacetoxy-N-methylpiperidine (4-DAMP), methoctramine and pirenzepine have demonstrated that the muscarinic receptor on the rat pulmonary artery endothelium which mediates vasodilation is of the M3 subtype and cannot account for the high proportion of M1 receptors identified in lung homogenates.

Ketotifen inhibits the cutaneous but not the airway responses to platelet-activating factor in man.

We studied the effect of ketotifen, an oral antiallergic and antihistaminic drug, on the airway and cutaneous responses to platelet-activating factor (PAF) in a double-blind, randomized, and crossover study in six normal subjects. Ketotifen (three doses of 2 mg taken during a 14-hour period before PAF) did not alter PAF-induced bronchoconstriction and did not prevent the accompanying flushing and coughing. The transient neutropenia (74.5 +/- 4.8% fall; p less than 0.001) and rebound neutrophilia (104 +/- 55% rise) induced by PAF were not affected by ketotifen. On the day placebo was received, airway responsiveness to methacholine increased after PAF exposure with the concentration needed to cause a 40% fall in baseline partial expiratory flow rate (PC40), decreasing from 69.2 mg/ml (geometric standard error of the mean, 2.69) to 23.3 mg/ml (2.34) on day 3 (p less than 0.001). Ketotifen had no effect, because on the day ketotifen was administered, mean PC40 also decreased from 52.7 mg/ml (2.5) to 21.5 mg/ml (2.14) (p less than 0.01). In the skin, ketotifen reduced the flare area (from 8.05 +/- 3.60 to 1.14 +/- 0.29 cm2; p less than 0.05) and the wheal volume (from 0.068 +/- 0.010 to 0.045 +/- 0.008 cc; p = 0.02) induced by intradermal PAF (200 ng). Cutaneous responses to histamine (1 microgram) were significantly inhibited. Thus, the bronchoconstriction and bronchial hyperresponsiveness induced by PAF are not inhibited by ketotifen. Ketotifen inhibits PAF-induced wheal and flare in the skin, which is probably histamine dependent. The airway effects of PAF are unlikely to be mediated by histamine release.

Prejunctional inhibitory muscarinic receptors on cholinergic nerves in human and guinea pig airways.

We have investigated whether prejunctional inhibitory muscarinic receptors ("autoreceptors") exist on cholinergic nerves in human airways in vitro and whether guinea pig trachea provides a good model for further pharmacological characterization of these receptors. Pilocarpine was used as a selective agonist and gallamine as a selective antagonist of these autoreceptors. Acetylcholine (ACh) release from postganglionic cholinergic nerves was elicited by electrical field stimulation (EFS) (40 V, 0.5 ms, 32 Hz). In human bronchi, pilocarpine inhibited the contractile response to EFS in a dose-related fashion; the dose inhibiting 50% of the control contraction was 2.2 +/- 0.4 x 10(-7) (SE) M (n = 22), and the inhibition was 96% at 3 x 10(-5) M. The inhibitory effects of pilocarpine were antagonized by gallamine in a dose-related fashion. The results were qualitatively the same in the guinea pig. Gallamine significantly enhanced the contractile response to EFS in the guinea pig, whereas pirenzepine failed to do so, which suggests that M2-receptors are involved. We conclude that prejunctional muscarinic receptors that inhibit ACh release are present on cholinergic nerves in human airways and that guinea pig trachea is a good model for further pharmacological characterization of these receptors, which appear to belong to the M2-subtype.

Nonadrenergic bronchodilator mechanisms in normal human subjects in vivo.

In seven normal subjects we investigated whether a nonadrenergic bronchodilator nervous system is demonstrable in humans in vivo. After inhalation of leukotriene D4 (LTD4), respiratory resistance (Rrs) increased by 115 +/- 11% (SE). Subsequent inhalation of 2 nmol of capsaicin induced coughing and a fall in Rrs of 22.1 +/- 2% (P less than 0.01). However, inhalation of the diluent of capsaicin, 10% saline-ethanol, decreased Rrs similarly. These bronchodilator responses were not altered by inhaled ipratropium bromide (120 micrograms) and oral propranolol (80 mg). After ipratropium and propranolol, voluntary coughing alone decreased Rrs by 25 +/- 3% (P less than 0.05). We next investigated whether these bronchodilator responses could be blocked by anesthesia of the airways with inhaled lidocaine. After inhalation of lidocaine and LTD4, capsaicin aerosol induced coughing and a transient increase in Rrs of 18 +/- 6% (P less than 0.05) but no bronchodilation. Inhalation of saline-ethanol (n = 4) and a deep inhalation (n = 6) decreased Rrs by 18 +/- 4% (P less than 0.05) and 34 +/- 3% (P less than 0.001), respectively. We conclude that in normal subjects a nonadrenergic, noncholinergic bronchodilator mechanism exists, which can be activated by inhalation of capsaicin and inhibited by local anesthesia.

Comparison of blood glucose profile and glycemic control in type 1 diabetic patients treated with Actrapid-Monotard or Actrapid Protaphane (NPH) human insulins.

The aim of this study is to compare the blood glucose profile and the glycemic control in Type 1 diabetic patients under two conventional semi-synthetic human insulin regimens (2 daily injections) combining regular (Actrapid) and intermediate acting insulins (Monotard or Protaphane). Actrapid-Monotard (scheme A) and Actrapid-Protaphane (scheme B) were administered during 3 months each, in a randomized order, to 18 outpatients. The glycemic control was evaluated by home glucose monitoring, as well as by the monthly measurements of HbA1. The total daily dose of insulin was comparable during each treatment period: 0.68 +/- 0.06 (scheme A) and 0.71 +/- 0.06 U/kg body wt. (scheme B) (mean +/- SEM). However, the total percentage of regular insulin was higher with Monotard than with Protaphane: 58 +/- 3 vs 48 +/- 5% in the morning (p less than 0.005) and 51 +/- 2 vs 46 +/- 3% in the evening (p less than 0.05). In C-peptide positive patients, the blood glucose values were comparable at all times with either insulin scheme. In contrast, in C-peptide negative patients, the blood glucose levels were higher in the afternoon with scheme B: 11.8 +/- 1 vs 8.6 +/- 1 mmol/l at 3 pm (p less than 0.02) and 12.2 +/- 1.3 vs 9.7 +/- 1.6 mmol/l at 6 pm (p less than 0.01). A slight but not significative increase of HbA1 was observed during the B period. In conclusion, an Actrapid-Protaphane scheme requires the use of a lower proportion of regular insulin than an Actrapid-Monotard treatment.(ABSTRACT TRUNCATED AT 250 WORDS)

Cerebrovascular circulation "steal" syndrome secondary to a voluminous retrotracheal goiter.

A case of recurrent transient ischaemic attacks in the brain resolved after removal of a voluminous retrotracheal goiter is presented. The presence of congenital atretic left vertebral artery, associated with impairment of left carotid artery blood flow by a very large inferior thyroid artery, probably caused the episodes to transient ischaemic attack.

Bronchodilating and density dependence effects of fenoterol, ipratropium bromide and Duovent in reversible chronic obstructive pulmonary disease.

The bronchodilating effect of Duovent (0.2 mg fenoterol +0.8 mg ipratropium bromide) was compared with that of each of its components at the same doses. Twenty patients were included in the trial. Maximum expiratory flow-volume curves with air and helium-oxygen, intrathoracic gas volume and airway conductance were used for assessing the bronchomotor tone before and 15, 30, 60, 240 and 360 min after drug administration. All the drugs showed a significant bronchodilating effect. No differences between Duovent and fenoterol or ipratropium bromide were observed except a slight but statistically significant greater decrease of ITGV with Duovent. When expressing the data as percentage variation of the initial values, Duovent induced a better effect than the other drugs. The evaluation of density dependence was highly disappointing, and no conclusion can be drawn.

Validity of air-helium DVmax measurements in trials of bronchodilators.

The authors studied the intraindividual variability of DVmax50 He-air in a large homogeneous group of 57 young healthy subjects. They found a 95% confidence interval for a true change between two repeated measurements of DVmax50 of +/- 28%. They compared the discriminant power of FEV1, Vmax50 and DVmax50 in 27 asthmatic young males and 12 normal controls, challenged on different days with fenoterol and ipratropium bromide aerosols given in random order under standardized conditions. FEV1 was not able to discriminate between the effect of the drugs in the normals or asthmatics. Vmax50 increased significantly more after fenoterol than after ipratropium in the asthmatics. DVmax50 was sometimes increased after fenoterol in the asthmatics but not by ipratropium in this group. These results suggest that sympathomimetics are more active on peripheral airways than the antimuscarinics.