Nobuaki Shigematsu

CLINICOPATHOLOGICAL STUDY ON FATAL MYOCARDIAL SARCOIDOSIS

Presented here was an outline of fatal myocardial sarcoidosis in Japan based on 42 autopsy cases. The incidence, clinical features, pathological findings (particularly the distribution of sarcoid lesions in various organs, and gross as well as histological patterns have been reviewed. The ratio of fatal myocardial sarcoidosis to the total number of sarcoidosis deaths is higher than that of other countries and it appears characteristic of Japanese sarcoidosis that the disease occurs here predominantly after the fourth decade in females. Only 12% of myocardial sarcoidosis cases are diagnosed exactly. Conduction disturbances and dysrhythmias due to myocardial damage are its most common manifestations. The modes of presentation or cardiac death are sudden death, 16 cases (41%); congestive heart failure, 9 cases (23.1%); Adams-Stokes syndrome, except sudden death, 7 cases (17.9%); death due to dysrhythmia, 6 cases (15.4%); and 2 pacemaker deaths among the application of pacemakers, 7 cases. As for the ECG findings, A-V block and bundle-branch block was observed in most cases and ectopic beats were also frequently observed. The difficulty in exact diagnosis of myocardial sarcoidosis appears to be due to the frequency of lack of manifestation of systemic sarcoidosis as well as insidious cardiac involvement. The gross findings on myocardial lesions showed 3 patterns and each of the localized patterns corresponded to the histological extension. The conglomerate-band-like pattern corresponded to expansive invasion, the dendrite pattern to interstitial extension. The histological findings on the myocardial lesions were classified into four types: 1) exudative type, 2) granuloma type, 3) combined type of granuloma and fibrosis, 4) fibrotic type. Two extreme cases showed the exudative and fibrotic type, respectively, and were discussed.

A possible role of airway epithelium in modulating hyperresponsiveness

1 In order to examine the role of airway epithelium in the responsiveness of smooth muscle in man, we measured the contractile responses to acetylcholine (ACh), histamine, and prostaglandin F2α (PGF2α) and the relaxation response to isoprenaline (Isop), in 48 bronchi obtained from 10 patients who received surgery. Responses were measured in the presence and absence of the epithelium. 2 Removal of epithelium (by rubbing the mucosa gently with forceps) significantly increased the contractile responses evoked by ACh, histamine and PGF2α. 3 In contrast, removal of epithelium did not alter the relaxation response to Isop. 4 To clarify the mechanism underlying this epithelial inhibitory effect on smooth muscle contraction, we measured the contractile responses of dog trachea with the epithelium removed to increasing concentrations of ACh. After measuring the control response, we added about 0.1 g of the chopped epithelium in the organ chamber, and measured the response again. 5 After adding airway epithelium and incubating with tracheal strips, the contractile response of tracheal strips decreased significantly as compared to the control response. 6 These results show that airway epithelium possesses the ability to decrease the smooth muscle contraction to ACh, histamine and PGF2α in man and dogs. 7 The mechanism of this inhibitory effect of the airway epithelium is not explained by a change in mechanical property of the airway nor the change in diffusion of these drugs to the smooth muscle across the epithelium. Thus, these results suggest that airway epithelium may have an important role in modulating smooth muscle tone, possibly by inactivation of these mediators, or by releasing an epithelium‐derived relaxing factor.

Respiratory involvement and immune status in yusho patients.

Clinical and experimental studies on respiratory involvement and alterations in immune status were carried out. Respiratory distress occurring in these patients has improved gradually for 14 years but still remains. Copious expectoration at an early stage of the disease may be related to the fact that a number of discrete polychlorinated biphenyls (PCBs) are distributed throughout the lung parenchyma. For accumulation in the bronchial mucosa, structural requirements and specific dose dependence of PCBs have been clearly shown; however, pathological and physiological studies have indicated that respiratory involvement in yusho is mainly small airway disease that may be caused by involvement of cellular component (Clara cells) in bronchioles and/or associated infection. Respiratory distress is often exacerbated by viral or bacterial infection. Changes in the immune status in PCB and polychlorinated dibenzofuran (PCDF) poisoning are as follows: IgA and IgM in the serum are decreased at an early stage of the disease and then return to normal; suppression of cellular immunity was reported in Taiwanese patients and some may remain in the later stages of the disease, as shown in our patients. PCDFs now appear to be the main causal agents in yusho. Rats given PCDFs showed necrosis of the Clara cells in bronchioles and marked thymus atrophy, while few such changes were noted in rats given PCBs. Therefore, further examination is needed for the difference of the toxic effects between two compounds. ImagesFIGURE 1.FIGURE 2.FIGURE 3.FIGURE 4. AFIGURE 4. BFIGURE 4. C

Respiratory involvement in polychlorinated biphenyls poisoning

Abstract Clinical, laboratory, and pathological findings on respiratory involvement in polychlorinated biphenyl (PCB) poisoning were studied in 401 patients and their pathological changes were produced in rats given PCBs orally. Respiratory symptoms included expectoration in 40% of the 289 nonsmoking patients with PCB poisoning and mild wheezing in 2%. The incidence and severity of the respiratory symptoms correlated well with the concentration of PCBs in the blood and sputa. Chest roentgenographic findings, pulmonary function tests, and pathological findings revealed bronchiolitis in many, and pneumonia or atelectasis in about one-tenth of the patients with reticulo-linear shadows. Peribronchiolar changes may be primarily due to either PCB poisoning or associated infection. Respiratory distress was often exacerbated by viral or bacterial infection persisting for more than a half year in about half of the patients examined. The IgA and IgM levels in the serum decreased considerably within 2 years after the onset of the disease and definite decreases in IgA levels may correlate well with the bacterial infection. PCBs found in sputa may have been present in association with lipid in type II cells of the lung (or with excretion from bronchial cells) and may have been phagocytosed in alveolar macrophages and may change their phagocytic function.

Reverse effect of gram-positive bacteria vs. gram-negative bacteria on adjuvant-induced arthritis in germfree rats

Germfree (GF) F344 rats developed severe adjuvant‐induced arthritis with a 100% incidence after a single intradermal injection of heat‐killed Mycobacterium bovis (BCG). Specific pathogene‐free (SPF) rats developed less severe arthritis with a lower incidence. The rats colonized with Escherichia coli or Bacteroides developed mild disease comparable to that in SPF rats. The rats colonized with Bifidobacterium, Propionibacterium acnes, Lactobacillus casei, L. fermentum, L. murini, and L. acidophilus developed more severe disease than that in GF rats. Furthermore, the rats colonized with a mixture of E. coli and the above lactobacilli developed very mild disease similar to that in SPF rats. These results suggest that (1) gram‐negative bacteria, such as E. coli and Bacteroides, may suppress the disease, possibly through their lipopolysaccharides, and may be responsible for the lower susceptibility of SPF rats; (2) gram‐positive bacteria, such as Bifidobacterium, P. acnes, and lactobacilli, may enhance the disease, possibly through their peptidoglycans; and (3) E. coli may play a dominant role in modulating the development of adjuvant‐induced arthritis.

The changing pattern of lung cancer by histological type — a review of 1151 cases from a university hospital in Japan, 1970–1989

We have analysed the frequency distribution and incidence rates for each histological type of newly diagnosed lung cancer in 1151 cases seen from 1970 through 1989 at Kyushu University, Japan. The incidence of adenocarcinoma has increased significantly since 1970. The proportion of adenocarcinoma increased from 26% to 45% in males (P<0.0001) and from 45% to 69% in females (P=0.0002). In addition, the proportion of subtypes of adenocarcinoma, classified in an electron microscopic study, underwent marked changes during the period 1982–1985; thus, e.g. 71% of all adenocarcinomas were classified as being of the bronchiolo-alveolar type. The smoking rates were similar during the period for patients with adenocarcinoma, suggesting that some etiological factors other than smoking may account for the increased incidence of adenocarcinoma. Further analysis, especially respecting dietary or ecological factors, is necessary.

Influences of salts on high-performance liquid chromatography of leukotrienes

The effects of concentrations and kinds of salts on the resolution of leukotrienes (LT) C4, D4, E4, and B4 were investigated by two kinds of reversed-phase high-performance liquid chromatography columns (muBondapak C18 and Novapak C18). When a mobile phase (acetonitrile/methanol/water) with a lower concentration of acetic acid (0.02-0.1%) at pH 5.6 was used, LTC4 and LTD4 were not eluted from the muBondapak column. On the Novapak column, LTC4 and LTD4 were eluted, but they were poorly resolved. When the concentration of acetic acid in the mobile phase was raised to 1.0% and adjusted to pH 5.6 with ammonium hydroxide or triethylamine, excellent resolution of LTs was obtained. Sodium hydroxide was, to some extent, useful for the pH adjustment of the mobile phase. Sodium chloride could not be substituted for acetic acid-ammonium hydroxide or -triethylamine salt. The resolution of LTC4, LTD4, and LTE4 was affected more strongly than that of LTB4 by changes of concentrations and kinds of salts. When the acetonitrile/methanol/water/acetic acid solvent system adjusted to pH 5.6 with triethylamine was applied to the analysis of the leukotrienes produced from rat peritoneal cells with stimulation of calcium ionophore A23187, de novo-synthesized LTC4, LTD4, LTB4, and isomers were clearly separated. This solvent system may be useful for the investigation of variations in the synthesis of subclasses of LTs with different stimuli and under different circumstances.

A possible role of a nonadrenergic inhibitory nervous system in airway hyperreactivity

To investigate a possible role of a nonadrenergic inhibitory nervous system in airway hyperreactivity, we measured changes in RL and CL caused by electrical stimulation of cervical vagus nerve during the infusion of 5-HT, after treatment with atropine and propranolol in 18 cats. RL decreased to 56 +/- 3% (mean +/- SE) and CL increased to 186 +/- 13% of the prestimulated values, respectively, after stimulation. Hexamethonium diminished these responses significantly. Airway reactivity to 5-HT was reduced by continuous electrical stimulation of cervical vagus nerve in cats pretreated with atropine and propranolol. Hexamethonium potentiated airway reactivity to 5-HT. These results suggest that a nonadrenergic inhibitory nervous system could play an important role in the control of the bronchomotor tone and contribute to airway hyperreactivity.

Effect of Endogenous Tachykinins on Neuro-Effector Transmission of Vagal Nerve in Guinea-Pig Tracheal Tissue

To elucidate the effect of endogenous tachykinins on neuro-effector transmission of vagal nerves, we performed in vitro experiments using guinea-pig tracheal smooth muscle. The subthreshold dose (the highest dose which did not induce any smooth muscle contraction) of capsaicin (10(-8) to 10(-7) M) increased the amplitudes of contractions evoked by electrical field stimulation (EFS) significantly, but not those by acetylcholine (ACh). The inhibitor of neutral endopeptidase, phosphoramidon (10(-7) to 10(-6) M), increased the contractions evoked by EFS significantly. The inhibitor of cholinesterase, physostigmine (10(-6) to 10(-5) M), induced smooth muscle contractions, but such contractions were inhibited by atropine, suggesting the spontaneous release of ACh from the vagal nerve terminals. The subthreshold dose of substance P or capsaicin increased the contractions evoked by physostigmine. These results indicated that endogenous tachykinins increase the spontaneous ACh release as well as the ACh release in response to vagal stimulation from the nerve terminals. Furthermore, it is suggested that the excitatory effects of the tachykinins on the vagal neuro-effector transmission may be modulated by neutral endopeptidase in the guinea pig.

Pulmonary Alveolar Proteinosis and Disseminated Atypical Mycobacteriosis in a Patient with Busulfan Lung

A 32‐year‐old Japanese man with chronic granulocytic leukemia died of respiratory failure. Autopsy revealed alveolar proteinosis and pulmonary fibrosis, complicated by disseminated atypical mycobacteriosis. Epithelial hyper‐plasia caused by busulfan therapy was probably responsible for the induction of excessive surfactant production, resulting in alveolar proteinosis, and the immunosuppres‐sive state due to chronic granulocytic leukemia was probably related to the induction of disseminated atypical mycobacteriosis. Acta Pathol Jpn 40: 63–66, 1990.