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We report a case of drug-induced pneumonitis associated with the herbal medications Sho-saiko-to and Ouren-gedoku-to. A 62-year-old man experienced fever and dry cough after using Ouren-gedoku-to for 2 months. He was admitted to our hospital because a subsequent 5-day course of Sho-saiko-to for suspected bronchitis aggravated these symptoms and caused exertional dyspnea. Chest X-ray films revealed a ground-glass appearance in both lower lung fields. Cessation of these medications improved the patient's clinical and X-ray findings. Bronchoalveolar lavage showed an increase in lymphocytes with a decreased CD 4/CD 8 ratio. While drug-induced lymphocyte stimulation tests gave negative results, challenge tests for Ouren-gedoku-to and Sho-saiko-to were both positive. A diagnosis of drug-induced pneumonitis was made. Our findings suggested the involvement of Ougon, the only common ingredient in the two medications.

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A 51-year-old man who had been working for 10 years with polyurethane paint containing isocyanate (MDI) was admitted to our hospital with complaints of fever and exertional dyspnea. Fine crackles were heard in both bases, and the patient had clubbed fingers. A chest X-ray film and computed tomograms of the lungs revealed patchy infiltrative shadows in both lung fields and subpleural honeycombing associated with irregular linear areas. Examination of bronchoalveolar lavage fluid showed increased T lymphocytes and a decreased CD 4/8 ratio. Specimens obtained by transbronchial lung biopsy revealed lymphoplasmacytic infiltration into the thickened alveolar walls, macrophage accumulation, and micro-epithelioid cell granulomas in the alveolar sacs. Hypersensitivity pneumonitis was suspected although the causative antigen was not identified because the results of short-term environmental provocation tests were negative in the patient's home and workplace. After discharge, the patient continued working as a paint sprayer. His acute symptoms recurred 1 month after exposure to isocyanate. Similar episodes occurred on two separate occasions. In addition, the patient tested positive for antibody to MDI-HSA in bronchoalveolar fluid. From the above observations, the patient was given a diagnosis of chronic hypersensitivity pneumonitis due to isocyanate (MDI). This condition is extremely rare. Furthermore, it is interesting that acute symptoms recurred 1 month after environmental exposure to the causative antigen.

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A 64-year-old woman had been feeding more than 60 pigeons in a coop in her back yard for 35 years. Diffuse reticulonodular shadows were found on a chest radiograph obtained as part of an annual check-up eight years before admission to the hospital. She was given a tentative diagnosis of idiopathic pulmonary fibrosis and was observed. She was admitted to our hospital because she noticed dry coughing and shortness of breath. A chest CT scan revealed segmentally distributed honeycombing and bronchi-bronchioloectasis. Tests for IgA and IgG antibodies to extracts of pigeon droppings in serum samples and in samples of bronchoalveolar lavage fluid were strongly positive, as were tests for lymphocyte blastogenic responses to samples of pigeon serum Examination of lung-biopsy specimens obtained by video-assisted thoracoscopic surgery revealed bronchiolitis, alveolitis, and honeycombing in a centrilobular distribution. The patient was given a diagnosis of pigeon-breeder's disease. Chronic hypersensitivity pneumonitis without acute episodes might be misdiagnosed as idiopathic interstitial pneumonia or bronchiectasis, as happened in this case. The possibility of chronic hypersensitivity pneumonitis should be considered when patients are suspected to have pulmonary fibrosis. It is important to obtain the detailed information on past or current avian contact, working history, and the home environment.

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We describe a case of recurrent histiocytic necrotizing lymphadenitis (HNL) with aseptic meningitis. The patient was a 46-year-old male and a carrier of human T lymphotropic virus type I (HTLV-I). The patient had a past medical history of at least three relapses of HNL. In addition, his sister, who was also an HTLV-I carrier, had recurrent clinical episodes consistent with those of HNL, suggesting familial HNL occurrence. This observation suggests the possibility that HTLV-I infection is relevant to the pathogenesis of HNL.

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We studied the short-term effects and complications of the use of a dental device (prosthetic mandibular advancement: PMA) in 72 patients with obstructive sleep apnea syndrome (OSAS), and the compliance of these patients with this treatment. In 61 (84.5%) of the 72 patients, the apnea index decreased by more than 50%. The lowest SaO2 and symptom scores also improved significantly. The severity of OSAS was not related to the percent reduction in apnea index. Complications of PMA use were observed in 22 patients (30.6%), but no severe adverse effects were observed. Sixty-two of the 72 patients continued using the PMA throughout the entire study period (overall compliance rate, 86.1%). In addition, the long-term compliance rate (more than 5 years) was 61.5%. We conclude that the effects of PMA in patients with OSAS are clinically significant, that there are no severe complications, and that compliance with treatment is good.

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There is no well established therapeutic protocol for advanced thymic carcinoma, although chemotherapy and irradiation can apparently be used to control the malignancy. Here we report a case of advanced thymic carcinoma successfully controlled by combination of treatment with systemic chemotherapy and irradiation. A 79-year-old man was admitted to the Hiratsuka Kyosai Hospital with complaints of productive cough and dyspnea. Chest roentgenogram and computerized tomography on admission revealed a tumorous lesion in the anterior mediastinum and on accumulation of left pleural and pericardial effusion fluid. The tumor was diagnosed as a thymic squamous cell carcinoma, after percutaneous needle biopsy. Because of extension to the left pleura and cardiac sac, the tumor was considered to be unresectable and systemic chemotherapy (CDDP + VDS + MMC) was begun. After drainage of the pericardial effusion fluid, intrapericardial injection of MMC was also done. The anterior mediastinum was irradiated. The patient has been doing well, with regression of the thymic tumor for 48 months after irradiation. This case provides important information that can be used to establish an effective therapeutic regimen for advanced thymic carcinoma.

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Adamantinoma is a rare bone tumor, most of which originates in the long bone. Here, we present a case of adamantinoma of the rib with liver metastasis. The patient, a 69-year-old man, complained of dull chest pain for over 6 months. Chest X-ray and CT film revealed osteolytic mass of the right 7th rib. Under the clinical diagnosis of hepatic tumor with rib metastasis, resection of the rib and partial hepatectomy were performed. Pathologically, the bone tumor was diagnosed as primary adamantinoma and the liver tumor was its metastasis. The patient has been well without adjuvant chemotherapy for 5 years after the operation.

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We previously demonstrated disruptions of the pulmonary capillary endothelium and alveolar epithelium at transmural pressures (Ptm) of 52.5 cmH2O in rabbit by electron microscopy. In the present study, we determined the characteristics of the alveolar edema fluid in this condition by carrying out bronchoalveolar lavage after blood perfusion for 10 min at Ptm of 12.5 (low), 32.5 (intermediate), and 52.5 cmH2O (high). At low Ptm, where our previous studies showed no ultrastructural changes, the volume of alveolar fluid obtained by urea dilution was very small, and the concentrations of proteins, cells, and leukotriene B4 (LTB4) in the bronchoalveolar lavage fluid (BALF) were low. However, at high Ptm the volume of alveolar fluid and the concentrations of total protein and cells in the BALF were greatly increased. The amount of LTB4 in the BALF also increased substantially from 6.0 to 49.5 micrograms (P < 0.001). Intermediate changes were seen at intermediate Ptm. We concluded that exposing pulmonary capillaries to high Ptm results in a high-permeability form of edema. In addition, the presence of LTB4 suggests that chemical mediators are released, possibly as the result of exposure of the reactive capillary endothelial basement membrane, as demonstrated by electron microscopy.

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During exercise (especially in hypoxia), the alveolar-arterial O2 tension difference increases. This impairment of pulmonary gas exchange is caused partly by diffusion disequilibrium, but it has also been shown that an exercise-induced increase in ventilation-perfusion (VA/Q) inequality develops. Possible explanations of increased VA/Q mismatch include nonuniform pulmonary vasoconstriction, reduced gas mixing in the large airways, airway obstruction, and the development of interstitial pulmonary edema. To directly determine whether the latter develops in high-intensity short-term exercise, we exercised pigs on a motor-driven treadmill at the highest speed that they could sustain for 6-7 min. Heart rate reached 274 +/- 5 min-1 in the exercised group, confirming that the pigs reached a near-maximal level of exercise. While running, the pigs were killed by an intravenous overdose of pentobarbital. Postmortem, the lungs were immediately removed, drained of blood, weighed, and then airway fixed with 10% formaldehyde. Four tissue blocks of the right lung of each pig were taken from the ventral and dorsal areas of the upper and lower lobes, respectively. They were stained with hematoxylin and eosin and prepared for histological examination by light microscopy. There was no difference in the lung-to-body weight ratio between exercised pigs (7.72 +/- 0.87 g/kg) and a nonexercised control group (7.70 +/- 0.68 g/kg). However, we found a significantly higher percentage of pulmonary arteries with perivascular edema in exercised (33.8 +/- 3.4%) than in nonexercised pigs (20.0 +/- 4.0%; P < 0.02). Thus, perivascular edema (and thus possibly also parenchymal interstitial edema) can occur during short-term heavy exercise.(ABSTRACT TRUNCATED AT 250 WORDS)

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Maximum oxygen uptake (VO2max) is affected by hemoglobin concentration ([Hb]). Whether this is simply due to altered convection of O2 into the muscle microcirculation or also to [Hb]-dependent diffusive transport of O2 out of the muscle capillary is unknown in humans. To examine this, seven healthy volunteers performed four maximal cycle exercise bouts at sea level immediately after 8 wk at altitude (3,801 m, barometric pressure 485 Torr), a sojourn designed to increase [Hb]. The first two bouts were at ambient [Hb] of 15.9 +/- 0.7 g/100 ml breathing 21 or 12% O2 in random order. [Hb] was then decreased to a prealtitude level of 13.8 +/- 0.6 g/100 ml by venesection and isovolemic replacement with 5% albumin in 0.9% saline, and the exercise bouts were repeated. At whole body VO2max, PO2, PCO2, pH, and O2 saturation were measured in radial arterial and femoral venous blood. Femoral venous thermodilution blood flow was determined for calculation of leg VO2. Mean muscle capillary PO2 and muscle diffusing capacity (DO2) were computed by Bohr integration between measured arterial and femoral venous PO2. Averaged over both fractional concentrations of inspired O2, leg VO2 at maximum decreased by 17.7 +/- 4.3% as [Hb] was lowered while leg O2 delivery decreased by 17.5 +/- 2.6% and DO2 decreased by 10.7 +/- 2.7% (all P < 0.05). The relative contributions of decreases in leg O2 delivery and DO2 to the decrease in VO2max were computed to be 64 and 36%, respectively. These findings suggest that [Hb] is an important determinant of O2 diffusion rates into working muscle in humans. Possible mechanisms include 1) dependence of DO2 on intracapillary red blood cell spacing, 2) changes in the total rate of dissociation of O2 from [Hb], and 3) increased red blood cell flow heterogeneity as [Hb] is reduced.

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We previously showed that when the pulmonary capillaries in anesthetized rabbits are exposed to a transmural pressure (Ptm) of approximately 40 mmHg, stress failure of the walls occurs with disruption of the capillary endothelium, alveolar epithelium, or sometimes all layers. The present study was designed to determine whether some of the ultrastructural changes are rapidly reversible when the capillary pressure is reduced. To test this, the Ptm was raised to 52.5 cmH2O for 1 min of blood perfusion and then reduced to 12.5 cmH2O for 3 min of saline-dextran perfusion, followed by intravascular fixation at the same pressure. In another group of animals, the pressure was elevated for 1 min of blood and 3 min of saline-dextran before being reduced. The results were compared with previous studies in which the capillary pressures were maintained elevated at 52.5 cmH2O during the entire procedure. Control studies were also done at sustained low pressures. The results showed that the number of endothelial and epithelial breaks per millimeter and the total fraction area of the breaks were reduced when the pressure was lowered. For example, the number of endothelial breaks per millimeter decreased from 7.1 +/- 2.1 to 2.4 +/- 0.7, and the number of epithelial breaks per millimeter fell from 11.4 +/- 3.7 to 3.4 +/- 0.7. There was evidence that the breaks that closed were those that were initially small and were associated with an intact basement membrane. The results suggest that cells can move along their underlying matrix by rapid disengagement and reattachment of cell adhesion molecules, causing breaks to open or close within minutes.(ABSTRACT TRUNCATED AT 250 WORDS)

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We previously showed that when pulmonary capillaries in anesthetized rabbits are exposed to a transmural pressure (Ptm) of approximately 40 mmHg, stress failure of the walls occurs with disruption of the capillary endothelium, alveolar epithelium, or sometimes all layers. The present study was designed to test whether stress failure occurred more frequently at high than at low lung volumes for the same Ptm. Lungs of anesthetized rabbits were inflated to a transpulmonary pressure of 20 cmH2O, perfused with autologous blood at 32.5 or 2.5 cmH2O Ptm, and fixed by intravascular perfusion. Samples were examined by both transmission and scanning electron microscopy. The results were compared with those of a previous study in which the lung was inflated to a transpulmonary pressure of 5 cmH2O. There was a large increase in the frequency of stress failure of the capillary walls at the higher lung volume. For example, at 32.5 cmH2O Ptm, the number of endothelial breaks per millimeter cell lining was 7.1 +/- 2.2 at the high lung volume compared with 0.7 +/- 0.4 at the low lung volume. The corresponding values for epithelium were 8.5 +/- 1.6 and 0.9 +/- 0.6. Both differences were significant (P less than 0.05). At 52.5 cmH2O Ptm, the results for endothelium were 20.7 +/- 7.6 (high volume) and 7.1 +/- 2.1 (low volume), and the corresponding results for epithelium were 32.8 +/- 11.9 and 11.4 +/- 3.7. At 32.5 cmH2O Ptm, the thickness of the blood-gas barrier was greater at the higher lung volume, consistent with the development of more interstitial edema. Ballooning of the epithelium caused by accumulation of edema fluid between the epithelial cell and its basement membrane was seen at 32.5 and 52.5 cmH2O Ptm. At high lung volume, the breaks tended to be narrower and fewer were oriented perpendicular to the axis of the pulmonary capillaries than at low lung volumes. Transmission and scanning electron microscopy measurements agreed well. Our findings provide a physiological mechanism for other studies showing increased capillary permeability at high states of lung inflation.

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A 38-year-old male with pulmonary emphysema due to severely reduced serum alpha-1-antitrypsin (AAT) level (14.5 mg/dl) was found to have an inherited new AAT deficient variant Siiyama. Chest roentgenogram and CT scanning revealed advanced emphysema, and severe obstructive ventilatory impairment was observed. During the 4-year follow-up period, the annual rate of decline of FEV 1.0 showed approximately 10-fold greater than the normal decline in FEV 1.0 (-380 ml/yr). Treatment with tamoxifen in order to raise the serum AAT level only resulted in an insufficient increase. Augmentation therapy of human AAT should be considered in the future.

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Ventilation-perfusion (VA/Q) inequality has been shown to increase with exercise. Potential mechanisms for this increase include nonuniform pulmonary vasoconstriction, ventilatory time constant inequality, reduced large airway gas mixing, and development of interstitial pulmonary edema. We hypothesized that persistence of VA/Q mismatch after ventilation and cardiac output subside during recovery would be consistent with edema; however, rapid resolution would suggest mechanisms related to changes in ventilation and blood flow per se. Thirteen healthy males performed near-maximal cycle ergometry at an inspiratory PO2 of 91 Torr (because hypoxia accentuates VA/Q mismatch on exercise). Cardiorespiratory variables and inert gas elimination patterns were measured at rest, during exercise, and between 2 and 30 min of recovery. Two profiles of VA/Q distribution behavior emerged during heavy exercise: in group 1 an increase in VA/Q mismatch (log SDQ of 0.35 +/- 0.02 at rest and 0.44 +/- 0.02 at exercise; P less than 0.05, n = 7) and in group 2 no change in VA/Q mismatch (n = 6). There were no differences in anthropometric data, work rate, O2 uptake, or ventilation during heavy exercise between groups. Group 1 demonstrated significantly greater VA/Q inequality, lower vital capacity, and higher forced expiratory flow at 25-75% of forced vital capacity for the first 20 min during recovery than group 2. Cardiac index was higher in group 1 both during heavy exercise and 4 and 6 min postexercise. However, both ventilation and cardiac output returned toward baseline values more rapidly than did VA/Q relationships. Arterial pH was lower in group 1 during exercise and recovery. We conclude that greater VA/Q inequality in group 1 and its persistence during recovery are consistent with the hypothesis that edema occurs and contributes to the increase in VA/Q inequality during exercise. This is supported by observation of greater blood flows and acidosis and, presumably therefore, higher pulmonary vascular pressures in such subjects.

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In a recent study by Tsukimoto et al. (J. Appl. Physiol. 68: 2488-2493, 1990), CO2 inhalation appeared to reduce the size of the high ventilation-perfusion ratio (VA/Q) mode commonly observed in anesthetized mechanically air-ventilated dogs. In that study, large tidal volumes (VT) were used during CO2 inhalation to preserve normocapnia. To separate the influences of CO2 and high VT on the VA/Q distribution in the present study, we examined the effect of inspired CO2 on the high VA/Q mode using eight mechanically ventilated dogs (4 given CO2, 4 controls). The VA/Q distribution was measured first with normal VT and then with increased VT. In the CO2 group at high VT, data were collected before, during, and after CO2 inhalation. With normal VT, there was no difference in the size of the high VA/Q mode between groups [10.5 +/- 3.5% (SE) of ventilation in the CO2 group, 11.8 +/- 5.2% in the control group]. Unexpectedly, the size of the high VA/Q mode decreased similarly in both groups over time, independently of the inspired PCO2, at a rate similar to the fall in cardiac output over time. The reduction in the high VA/Q mode together with a simultaneous increase in alveolar dead space (estimated by the difference between inert gas dead space and Fowler dead space) suggests that poorly perfused high VA/Q areas became unperfused over time. A possible mechanism is that elevated alveolar pressure and decreased cardiac output eliminate blood flow from corner vessels in nondependent high VA/Q regions.

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Water immersion can cause airways closure during tidal breathing, and his may result in areas of low ventilation-perfusion (VA/Q) ratios (VA/Q less than or equal to 0.1) and/or shunt and, ultimately, hypoxemia. We studied this in 12 normal males: 6 young (Y; aged 20-29 yr) with closing volume (CV) less than expiratory reserve volume (ERV), and six older (O; aged 40-54 yr) with CV greater than ERV during seated head-out immersion. Arterial and expired inert gas concentrations and dye-dilution cardiac output (Q) were measured before and at 2, 5, 10, 15, and 20 min in 35 degrees C water. During immersion, Y showed increases in expired minute ventilation (VE; 8.3-10.3 l/min), Q (6.1-8.2 l/min), and arterial PO2 (PaO2; 91-98 Torr; P less than or equal to 0.05). However, O2 uptake (VO2), shunt, amount of low-VA/Q areas (% of Q), and the log standard deviation of the perfusion distribution (log SDQ) were unchanged. During immersion, O showed increases in shunt (0.6-1.8% of Q), VE (8.5-11.4 l/min), and VO2 (0.31-0.40 l/min) but showed no change in low-VA/Q areas, log SDQ, Q, or PaO2. Throughout, O showed more VA/Q inequality (greater log SDQ) than Y (O, 0.69 vs. Y, 0.47).(ABSTRACT TRUNCATED AT 250 WORDS)

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Electronmicroscopic appearances of pulmonary capillaries were studied in rabbit lungs perfused in situ when the capillary transmural pressure (Ptm) was systematically raised from 12.5 to 72.5 +/- 2.5 cmH2O. The animals were anesthetized and exsanguinated, and after the chest was opened, the pulmonary artery and left atrium were cannulated and attached to reservoirs. The lungs were perfused with autologous blood for 1 min, and this was followed by saline-dextran and then buffered glutaraldehyde to fix the lungs for electron microscopy. Normal appearances were seen at 12.5 cmH2O Ptm. At 52.5 and 72.5 cmH2O Ptm, striking discontinuities of the capillary endothelium and alveolar epithelium were seen. A few disruptions were seen at 32.5 cmH2O Ptm (mostly in one animal), but the number of breaks per millimeter cell lining increased markedly up to 72.5 cmH20 Ptm, where the mean frequency was 27.8 +/- 8.6 and 13.6 +/- 1.4 (SE) breaks/mm for endothelium and epithelium, respectively. In some instances, all layers of the blood-gas barrier were disrupted and erythrocytes could be seen moving into the alveolar spaces. In about half the endothelial and epithelial breaks, the basement membranes remained intact. The average break lengths for both endothelium and epithelium did not change significantly with pressure. The width of the blood-gas barrier increased at 52.5 and 72.5 cmH2O Ptm as a result of widening of the interstitium caused by edema. The cause of the disruptions is believed to be stress failure of the capillary wall. The results show that high capillary hydrostatic pressures cause major changes in the ultrastructure of the walls of the capillaries, leading to a high-permeability form of edema.

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In the mammalian lung, alveolar gas and blood are separated by an extremely thin membrane, despite the fact that mechanical failure could be catastrophic for gas exchange. We raised the pulmonary capillary pressure in anesthetized rabbits until stress failure occurred. At capillary transmural pressures greater than or equal to 40 mmHg, disruption of the capillary endothelium and alveolar epithelium was seen in some locations. The three principal forces acting on the capillary wall were analyzed. 1) Circumferential wall tension caused by the transmural pressure. This is approximately 25 dyn/cm (25 mN/m) at failure where the radius of curvature of the capillary is 5 microns. This tension is small, being comparable with the tension in the alveolar wall associated with lung elastic recoil. 2) Surface tension of the alveolar lining layer. This contributes support to the capillaries that bulge into the alveolar spaces at these high pressures. When protein leakage into the alveolar spaces occurs because of stress failure, the increase in surface tension caused by surfactant inhibition could be a powerful force preventing further failure. 3) Tension of the tissue elements in the alveolar wall associated with lung inflation. This may be negligible at normal lung volumes but considerable at high volumes. Whereas circumferential wall tension is low, capillary wall stress at failure is very high at approximately 8 x 10(5) dyn/cm2 (8 x 10(4) N/m2) where the thickness is only 0.3 microns. This is approximately the same as the wall stress of the normal aorta, which is predominantly composed of collagen and elastin. The strength of the thin part of the capillary wall is probably attributable to the collagen IV of the basement membranes. The safety factor is apparently small when the capillary pressure is raised during heavy exercise. Stress failure causes increased permeability with protein leakage, or frank hemorrhage, and probably has a role in several types of lung disease.

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Several previous studies have shown worsening ventilation-perfusion (VA/Q) relationships in humans during heavy exercise at sea level. However, the mechanism of this deterioration remains unclear because of the correlation with ventilatory and circulatory variables. Our hypothesis was that the decrease in the series dead space-to-tidal volume ratio during exercise might be partly responsible because mixing in the common dead space can reduce apparent inequality. We tested this notion in 10 resting anesthetized normocapnic dogs passively hyperventilated by increase tidal volume and a) inspired CO2 or b) external dead space. We predicted less apparent VA/Q inequality in condition b because of mixing in the added dead space. After base-line measurements, conditions a and b were randomly assigned, and after a second set of base-line measurements they were repeated in the reverse order in each dog. VA/Q inequality was measured by the multiple inert gas elimination technique. Comparison of conditions a and b demonstrated that additional external dead space improved (P less than 0.001) the blood flow distributions as hypothesized [log standard deviation of perfusion = 0.49 +/- 0.02 (SE) in condition b and 0.61 +/- 0.03 in condition a with respect to 0.52 +/- 0.03 at base line]. This study suggests that the increased tidal volume during exercise could uncover VA/Q inequality not evident at rest because of the higher ratio of common dead space to tidal volume at rest.

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