Synthetic study on novel immunosuppressant KF20444.

The two new synthetic routes to 6,7-dihydro-10-fluoro-3-(2-fluorophenyl)-5H- benzo[6,7]cyclohepta[1,2-b]-quinoline-8-carboxylic acid (1), a novel immunosuppressant KF20444, are described. The seven-membered ring construction from 2-[4-(2-fluorophenyl)phenyl]-3-(2-carboxyethyl)-4-chloromethyl-6-fluoroquinoline (17c) was achieved by intramolecular Friedel-Crafts reaction under acidic conditions as the key step. Subsequently, the oxidation of 4-chloromethyl group followed by reduction of carbonyl group on the seven-membered ring afforded 1. This route provides a new method for the synthesis of 1.

Role of airway nitric oxide on the regulation of pulmonary circulation by carbon dioxide.

The effects of hypercapnia (CO(2)) confined to either the alveolar space or the intravascular perfusate on exhaled nitric oxide (NO), perfusate NO metabolites (NOx), and pulmonary arterial pressure (Ppa) were examined during normoxia and progressive 20-min hypoxia in isolated blood- and buffer-perfused rabbit lungs. In blood-perfused lungs, when alveolar CO(2) concentration was increased from 0 to 12%, exhaled NO decreased, whereas Ppa increased. Increments of intravascular CO(2) levels increased Ppa without changes in exhaled NO. In buffer-perfused lungs, alveolar CO(2) increased Ppa with reductions in both exhaled NO from 93.8 to 61.7 (SE) nl/min (P < 0.01) and perfusate NOx from 4.8 to 1.8 nmol/min (P < 0.01). In contrast, intravascular CO(2) did not affect either exhaled NO or Ppa despite a tendency for perfusate NOx to decline. Progressive hypoxia elevated Ppa by 28% from baseline with a reduction in exhaled NO during normocapnia. Alveolar hypercapnia enhanced hypoxic Ppa response up to 50% with a further decline in exhaled NO. Hypercapnia did not alter the apparent K(m) for O(2), whereas it significantly decreased the V(max) from 66.7 to 55.6 nl/min. These results suggest that alveolar CO(2) inhibits epithelial NO synthase activity noncompetitively and that the suppressed NO production by hypercapnia augments hypoxic pulmonary vasoconstriction, resulting in improved ventilation-perfusion matching.

[A case of isolated tricuspid regurgitation caused by a dilated tricuspid annulus treated by ring annuloplasty].

Isolated tricuspid regurgitation is rare. A 64-year-old man was admitted to our hospital with a complaining of shortness of breath and edema of lower extremities. Chest X-ray showed remarkable cardiomegaly (cardiothoracic ratio, 73%). Echocardiogram demonstrated severe tricuspid regurgitation and dilated right atrium. At operation, the tricuspid annulus was severely dilated about 7 cm in diameter, and all leaflets of tricuspid valve were intact. Prosthetic ring annuloplasty with a 32 mm Carpentier-Edwards ring was performed. Postoperative course was uneventful. Four weeks after operation he was discharged from the hospital and he is now leading a normal life. Careful follow up for long time is essential in this case.

Flow-mediated release of nitric oxide in isolated, perfused rabbit lungs.

The effects of changing perfusate flow on lung nitric oxide (NO) production and pulmonary arterial pressure (Ppa) were tested during normoxia and hypoxia and after N(G)-monomethyl-L-arginine (L-NMMA) treatment during normoxia in both blood- and buffer-perfused rabbit lungs. Exhaled NO (eNO) was unaltered by changing perfusate flow in blood-perfused lungs. In buffer-perfused lungs, bolus injections of ACh into the pulmonary artery evoked a transient increase in eNO from 67 +/- 3 (SE) to 83 +/- 7 parts/billion with decrease in Ppa, whereas perfusate NO metabolites (pNOx) remained unchanged. Stepwise increments in flow from 25 to 150 ml/min caused corresponding stepwise elevations in eNO production (46 +/- 2 to 73 +/- 3 nl/min) without changes in pNOx during normoxia. Despite a reduction in the baseline level of eNO, flow-dependent increases in eNO were still observed during hypoxia. L-NMMA caused declines in both eNO and pNOx with a rise in Ppa. Pulmonary vascular conductance progressively increased with increasing flow during normoxia and hypoxia. However, L-NMMA blocked the flow-dependent increase in conductance over the range of 50-150 ml/min of flow. In the more physiological conditions of blood perfusion, eNO does not reflect endothelial NO production. However, from the buffer perfusion study, we suggest that endothelial NO production secondary to increasing flow, may contribute to capillary recruitment and/or shear stress-induced vasodilation.

A case of a chronic traumatic thoracic aneurysm 11 years after injury.

A 28-year-old male, who was involved in an automobile accident 11 years previously, was diagnosed as having a chronic traumatic thoracic aneurysm. An enhanced computed tomographic scanning (CT) and three-dimensional CT demonstrated that a thoracic aortic aneurysm of 50 mm in the maximal axis was located at the aortic isthmus and dilated posteriorly. He underwent thoracic aorta graft replacement using Femoro-femoral partial bypass. The surgery was successful and the postoperative course was uneventful.

[A case of pulmonary Mycobacterium avium infection with a rapid-growing solitary node].

A 72-year-old man was admitted to our hospital because of an abnormal shadow on his chest radiograph. Computed tomography revealed a 3 cm solitary nodular opacity in the right S1. Bronchofiberscopy could neither give any specific histological findings nor bacteriological findings. This nodular shadow increased in size to 1.5 times that in the first chest radiograph. In addition, since there was no abnormal finding in the chest radiograph one year before, we performed partial pulmonary resection by video-assisted thoracoscopic surgery, taking into consideration the possibility that the solitary node was malignant. The pathological findings of the resected specimen were an epitheloid cell granuloma with Langhans giant cell and caseous necrosis. We could not detect any acid-fast bacilli or malignant cells. After surgery, M. avium was detected in a 6-week culture of the resected specimen. We treated the patient with RFP, EB and CAM for 6 months. Outpatient follow-up revealed no relapse.

Detection of Photofrin Fluorescence From Malignant and Premalignant Lesions in the Bronchus using a Full-color Endoscopic Fluorescence Imaging System.

STUDY OBJECTIVES: To detect invisible lung cancer and to determine field of laser radiation during PDT we developed a full-color fluorescence fiberscopic system. We tested the efficacy of this system in patients with various bronchial malignancies.System design: A fiber-optic endoscope was attached to a camera box containing a color ICCD camera which can detect from 400 to 700nm fluorescence in full-color. Light of average wavelength 405 nm was selected and radiated through the light channel of the fiberscope from a 300W Xenon lamp. PATIENTS AND METHODS: We examined nine consecutive patients with bronchial malignancy admitted in our hospital to receive PDT. Sixteen lesions in these nine patients were observed with white light and excitation light and the results were compared. Histological examinations were done by taking biopsy specimens and samples for pathological and cytological examination. After the diagnosis was confirmed, 2.0 mg/kg Photofrin was injected. Forty eight hours after the administration of Photofrin, observation of the bronchial wall was made using a full-color endoscopic fluorescence imaging system just before PDT. RESULTS: Bright red fluorescence from Photofrin was Observed in 14/14 bronchial malignancies: 3 squamous cell carcinoma, 9 squamous cell carcinoma in situ, 1 metastatic breast cancer and 1 metastatic islet cell tumor. Bright red fluorescence was also detected in 2/2 squamous dysplasia. Green autofluorescence was observed in the normal part of the bronchus. CONCLUSIONS: RESULTS of the present study suggest that the full-color endoscopic fluorescence imaging system can be used to detect malignant and premalignant lesions as red fluorescence against green autofluorescence with Photofrin administration, and this system has the potential to detect absence of autofluorescence in cancerous lesions.

[Three cases of Mycobacterium avium lung disease in an iron foundry].

We report three cases of M. avium lung disease, all occurring in the same iron foundry over a 5-year period. Case 1: A 38-year-old man was admitted to our hospital because of abnormal chest x-ray shadows observed during a routine checkup. M. avium complex was isolated from the sputum and a CT scan showed multiple nodular shadows with cavities. Case 2: A 63-year-old man presented with dyspnea. Chest CT showed nodular shadows in both upper lobes. M. avium complex was isolated from his sputum. Case 3: A 62-year-old man was hospitalized for treatment of diabetes mellitus. A nodular cavitary shadow* OK?* in the right upper lobe was observed in the radiograph. CT scanning demonstrated a nodular shadow with thick pleural indentation. M. avium was isolated from the sputum and gastric juices. There were similarities in the radiographic findings in all cases: nodular shadows with cavities in the upper lung fields. These findings differed from those in another M. avium infection in the lung which occurred in a middle-aged woman. We suspected inhalation of an aerosol contaminated by M. avium complex. There have hitherto been no reports of group infections in healthy persons. We suspected the same environmental source for the infection.

Regulation of pulmonary circulation by alveolar oxygen tension via airway nitric oxide.

The effects of airway (AH) and vascular hypoxia (VH) on the production of nitric oxide (NO; VNO) were tested in isolated buffer-perfused (BFL) and blood-perfused rabbit lungs (BLL). To produce AH and/or VH, the lung was ventilated with 1% O(2) gas, and/or the perfusate was deoxygenated by a membrane oxygenator located on the inlet limb to the pulmonary artery. We measured exhaled NO (VNO), accumulation of perfusate NOx, and pulmonary arterial pressure (Ppa) during AH (inspired O(2) fraction = 0.01) and/or VH (venous PO(2) = 26 Torr). In BFL, a pure AH without VH caused decreases in VNO and NOx accumulation with a rise in Ppa. However, neither VNO, NOx accumulation, nor Ppa changed during VH. Similarly, in BLL, only AH reduced VNO, although NOx accumulation was not measurable because of Hb. When alveolar PO(2) was gradually reduced from 152 to 0 Torr for 20 min, AH reduced VNO curvilinearly from 73.9 +/- 8 to 25.6 +/- 8 nl/min in BFL and from 26.0 +/- 2 to 5. 2 +/- 1 nl/min in BLL. This plot was analogous to that of a substrate-velocity curve for an enzyme obeying Michaelis-Menten kinetics. The apparent Michaelis-Menten constant for O(2) was calculated to be 23.2 microM for BLL and 24.1 microM for BFL. These results indicate that the VNO in the airway epithelia is dependent on the level of inspired O(2) fraction, leading to the tentative conclusion that epithelial NO synthase is O(2) sensitive over the physiological range of alveolar PO(2) and controls pulmonary circulation.

[A case of mediastinal myelolipoma].

Myelolipoma is a benign tumor composed of mature adipose tissue and hematopoietic tissue. It was mainly found in the adrenal grand, but there have been reports of extra-adrenal locations. Only 7 cases of mediastinal myelolipoma have been reported ever. We have experienced a case of mediastinal myelolipoma surgically resected from a 55-year-old-man. He has visited our department because of chest pain. Chest X-ray showed typical pneumothorax, but abnormal mediastinal shadow was remarked. Chest CT showed a well circumscribed mass with fat and soft-tissue attenuation in posterior mediastinum. Lung bullectomy and mediastinal tumor resection under VATS was performed. A blue-red tumor 4 cm in diameter was resected en bloc. Pathological examination showed its composition of mature adipose tissue and hematopoietic tissue. Diagnosis was extra-adrenal myelolipoma. No recurrent nor abnormality was found in 8 months since surgery.

[Matured mediastinal teratoma with a giant cyst resembling pleural effusion on X-ray films].

A 23-year-old man complaining of right-sided chest pain was admitted to our hospital for further examination of an abnormal shadow on chest X-ray films. Initially, we suspected the abnormal shadow was that of a pleural effusion in the right thorax. Computed tomographic scans disclosed a tumor in the anterior mediastinum, adjacent to the abnormal shadow. After closer examination, particularly by fluoroscopy on catheterization, we recognized that the abnormal shadow was a giant cyst, and that it connected with a solid mass. There were no abnormal laboratory data on admission. An examination of fluid specimens from the giant cyst revealed high levels of the tumor markers SCC antigen, CEA, and CA 19-9. These findings together suggested that the solid mass with giant cyst might be a mediastinal teratoma. The tumor was completely resectable without serious complications. The giant cyst contained 1,200 ml of fluid, and occupied half the volume of the right thoracic cavity. Pathological examination disclosed that the resected mediastinal tumor was a matured teratoma. Although matured teratoma are often composed of cysts, those that radiologically resemble pleural effusion, as in this case, were considered uncommon.

[Assessment of beta-methyl lodophenyl pentadecanoic acid myocardial scintigraphy in patients with chronic pulmonary diseases].

The purpose of this study was to determine whether impaired fatty acid metabolism occurs in the right ventricle of patients with chronic pulmonary diseases (TB sequelae, TB seq.; 8, and chronic pulmonary emphysema. CPE; 14). 123I-BMIPP myocardial scintigraphy was performed on 22 subjects. The RV-BMIPP index (ratio of radioactivity in the right ventricle to that in the upper mediastinum), LV-BMIPP index (ratio of radioactivity in the left ventricle to that in the upper mediastinum), and RVc/LVc (ratio of radioactivity in the right ventricle to that in the left ventricle) were calculated to compare the distribution of radioactivity in the right and left ventricles. We also examined the correlations between these parameters and parameters of blood gas analysis and pulmonary hemodynamics. The RV-BMIPP index. LV-BMIPP index, and RVc/LVc were elevated in the TB seq. and CPE patient groups compared to the control group. The RV-BMIPP and LV-BMIPP indices demonstrated significant, negative correlations with PaO2; also a significant positive correlation was observed between the RV-BMIPP index and mean pulmonary arterial pressure. On the other hand, no significant correlation was found between the LV-BMIPP index and mean pulmonary arterial pressure. In the arm-stretching test under right heart catheterization, the RV-BMIPP and LV-BMIPP indices demonstrated significant, positive correlations with the cardiac index during exercise. These results suggest that hypoxemia accelerates fatty acid metabolism in the myocardium, and that local pressure overloading accelerates fatty acid metabolism in the right ventricle. Anomalies of fatty acid metabolism in the right ventricle may appear in patients with chronic pulmonary disease, and could be an adaptation to hypoxemia and overload, not an impairment.

[Pulmonary function and the pathogenesis of obstructive sleep apnea syndrome].

We studied the relationships between results of pulmonary-function tests and sleep-induced respiratory disorders in men with obstructive sleep apnea syndrome (OSAS). Pulmonary-function tests were done in 23 men with OSAS and in 9 men without OSAS who were matched for age and body mass index. Tests were done both in sitting and in supine positions. For both positions, results of pulmonary-function tests did not differ between the OSAS and the non-OSAS groups. In both groups, %TLC, %FRC, PaO2, and V25/Ht were lower while supine than while sitting, and CC/FRC was higher. In both positions, CC/FRC was significantly and positively correlated with apnea index and with 4% desaturation time. Body mass index was not correlated with apnea index or with 4% desaturation time. These findings suggest that low lung volume and peripheral airway closure contribute to sleep-induced respiratory disorders in men with OSAS, regardless of the body mass index.

Crohn's disease associated with growth hormone secretory dysfunction.

A 10-year-old boy presented in 1989 with repeated episodes of vomiting, abdominal distension and severe growth retardation. Endocrinologic examination indicated growth hormone (GH) secretory dysfunction. Administration of recombinant human GH (rhGH) led to growth, but the patient discontinued treatment. He was readmitted to our hospital in 1993, at the age of 16. His stature was very short. Laboratory findings suggested malnutrition. Radiologic examination revealed regional stenosis and a cobblestone appearance of the intestine. The histologic diagnosis was compatible with Crohn's disease. Administration of prednisolone alleviated gastrointestinal symptoms with the improvement of GH secretory function.

[A case of chronic type farmer's lung which led to severe pulmonary fibrosis and spontaneous pneumothorax].

We present a case of chronic type farmer's lung which showed progressive pulmonary fibrosis and spontaneous pneumothorax 12 years after the first admission. A 56-year-old woman was diagnosed as having farmer's lung in 1981. After the first hospitalization, her chest roentgenogram showed regression with steroid therapy. After that, she sometimes worked at a dairy farm and required rehospitalization three times for recurrence. In April 1993, she was readmitted complaining of sudden chest pain and dyspnea after cough. Her chest roentgenogram on admission showed spontaneous pneumothorax. After treatment, her chest roentgenogram revealed severe pulmonary fibrosis and loss of lung volume.

Plasma levels of corticotropin-releasing hormone in hypothalamic-pituitary-adrenal disorders and chronic renal failure.

Plasma levels of corticotropin-releasing hormone (CRH) were measured in hypothalamic-pituitary-adrenal disorders and chronic renal failure to investigate the clinical significance of plasma CRH. The mean plasma CRH level in normal subjects (N = 26) was 1.64 +/- 0.43 pmol/l (normal range 0.77-2.5 pmol/l). Four of six patients with hypothalamic disorders receiving hydrocortisone supplementation had a low plasma CRH level. Two of six patients with Sheehan's syndrome had a low plasma CRH level whereas one patient had a high plasma CRH level. Two patients with Cushing's syndrome had a low plasma CRH level whereas two patients with Cushing's disease had a normal plasma CRH level. Six of 19 patients receiving prednisolone therapy had a low plasma CRH level. The mean plasma CRH level in this group was 0.97 +/- 0.34 pmol/l, which is significantly lower than that in the normal group. In this group, significant correlation was seen between plasma CRH and adrenocorticotropin levels. Eleven of 21 patients with chronic renal failure undergoing hemodialysis had a high plasma CRH level. Just after hemodialysis the plasma CRH levels decreased in 15 of 20 patients, while plasma adrenocorticotropin and cortisol levels increased in 13 of 19 patients and in 15 of 20 patients, respectively. Immunoreactive CRH in plasma measured both before and after hemodialysis eluted similarly on reversed-phase high-performance liquid chromatography. These results suggest that the plasma CRH level is at least partially suppressed by a chronically elevated plasma glucocorticoid level and that CRH in plasma is partially removed by hemodialysis.

Cerebrospinal fluid corticotropin-releasing hormone and ACTH, and peripherally circulating choline-containing phospholipid in senile dementia.

Cerebrospinal fluid (CSF) levels of corticotropin-releasing hormone (CRH) and ACTH, plasma levels of ACTH and cortisol, and serum levels of phospholipid and its fractions were determined in samples taken simultaneously from patients with senile dementia of the Alzheimer type (SDAT), multi-infarct dementia (MID) or dementia following a cerebrovascular accident (CVD), and the borderline-to-normal control subjects. CRH levels in CSF were significantly reduced in patients with SDAT and CVD but not with MID compared to the borderline-to-normal controls. ACTH levels in CSF were significantly reduced in SDAT compared to MID. The levels of circulating lecithin (phosphatidyl-choline) were depressed in a similar fashion to the levels of CRH in CSF in the SDAT patients and the group of severe dementia. Dementia and its severity did not affect the morning plasma levels of ACTH and cortisol. CSF CRH was positively correlated with CSF ACTH, while CSF ACTH was negatively correlated with plasma cortisol. No significant correlations were found between serum lecithin and CSF CRH or ACTH. These findings suggest that: 1) abnormalities in the extrahypothalamic CRH system play a role in the pathophysiology of senile dementia, which may not be specific to SDAT; 2) the CRH system and the ACTH system correlate with each other within the brain; 3) CSF ACTH is subject to the feedback inhibition by circulating cortisol; and 4) in the SDAT patients and the severe dementia group CSF CRH and serum lecithin are reduced probably via independent mechanisms.

[Hyperresponsiveness of TSH and prolactin and impaired responsiveness of GH in Japanese patients with isolated ACTH deficiency].

Two hundred and forty-one cases of isolated ACTH deficiency have been reported in Japan since 1969. Pituitary hormone responsiveness to stimulation tests before and after hydrocortisone supplementation was investigated in these cases. Plasma ACTH level showed no or little change in response to lysine vasopressin, metyrapone, CRF or insulin-induced hypoglycemia in 97.3-100% of the cases. Serum GH level changed little or not at all in response to GRF, insulin-induced hypoglycemia, glucagon, 1-dopa and arginine in 26.9, 29.3, 40.0, 50.0 and 56.1%, respectively. Serum TSH and prolactin (PRL) levels showed hyperresponse to TRH in 34.7 and 35.6%, respectively. After hydrocortisone therapy, GH secretion was more responsive than before therapy in 78.9% of the cases. After supplementation, TSH level was less responsive to TRH stimulation than before therapy in 59.3% of the cases. After hydrocortisone supplementation, TSH response to TRH decreased in 75% of ACTH-deficient patients without primary hypothyroidism but did not decrease in more than half of those with primary hypothyroidism. TSH response to TRH decreased after supplementation in 76.5% of the patients with TSH hyperresponsiveness before therapy, and increased after therapy in 66.7% of those with normal TSH responses before therapy. After supplementation, PRL response to TRH was less than that before therapy in 43.5% of ACTH--deficient patients, and greater than that before therapy in 30.4%. PRL response to TRH decreased after therapy in 66.7% of the patients with PRL hyperresponsiveness before therapy, and increased in 63.6% of those with normal PRL response before therapy. Primary hypothyroidism and Hashimoto's thyroiditis were complicated in 21.6 and 11.6%, respectively, of the 241 patients with isolated ACTH deficiency. In patients who had TSH hyperresponsiveness and/or high basal TSH levels and PRL hyperresponsiveness and/or high basal PRL levels, primary hypothyroidism was complicated in 58.4 and 42.3%, respectively. Hashimoto's thyroiditis was complicated in 29.8 and 20.5%, respectively, of these patients. Pituitary cell antibody (PCA) was detected in 36.6% of ACTH-deficient patients who were examined. Pituitary cell surface antibody (PCSA) to AtT-20 cells and GH3 cells was detected in 50.0 and 28.0% of the examined cases, respectively. The prevalence of PCA and PCSA did not differ between TSH-hyperresponsive patients and those with normal TSH basal levels and response, whereas PCA and PCSA were significantly more prevalent in PRL-hyperresponsive patients than in those with normal PRL levels and response. An empty sella was found in 30.2% of the examined case.(ABSTRACT TRUNCATED AT 400 WORDS)

The magnocellular arginine-vasopressin mRNA responds differently to food deprivation between the supraoptic and paraventricular nuclei of the hypothalamus in adrenalectomized rats with low corticosterone replacement.

We previously reported that food deprivation significantly decreased arginine-vasopressin (AVP) mRNA levels in the supraoptic (SON) and paraventricular (PVN) nuclei of the hypothalamus and also greatly stimulated the pituitary-adrenocortical system in rats. In this study, we deprived adrenalectomized rats with subcutaneously implanted low-dose corticosterone pellets (ADX + B) of food for 3 days to investigate the involvement of corticosteroid feedback regulation in the food deprivation-induced decrease in AVP mRNA in both the SON and the PVN. The plasma corticosterone levels in these animals were maintained at low levels constantly over 24 h. The ACTH concentration in the morning plasma was markedly increased in the food-deprived ADX + B rats as compared to the fed ADX + B rats. Food deprivation significantly decreased the corticotropin-releasing hormone (CRH) content in the median eminence and increased the CRH and AVP content in the neurointermediate lobe of the pituitary. Semiquantitative in situ hybridization histochemistry revealed that AVP mRNA levels were decreased in the SON but, inversely, increased in magnocellular as well as parvocellular subdivisions of the PVN following food deprivation. These results suggest that: (1) AVP mRNA responds differently to food deprivation between the SON and the PVN; (2) the glucocorticoid feedback can exert on AVP mRNA in the PVN but not in the SON in the food-deprived rats; and (3) food deprivation affects the neurohypophysial levels of CRH and AVP.

Food deprivation decreases vasopressin mRNA in the supraoptic and paraventricular nuclei of the hypothalamus in rats.

We examined the effect of food deprivation for three days on hypothalamic arginine vasopressin (AVP) mRNA in rats. Simultaneously the effect of water deprivation for the same period was examined as a model of dehydration. Levels of AVP mRNA in the supraoptic nucleus (SON) and the paraventricular nucleus (PVN) were determined by semiquantitative in situ hybridization histochemistry. Water deprivation increased AVP mRNA in both nuclei as previously reported. In contrast, food deprivation decreased AVP mRNA in these nuclei. The changes in AVP mRNA levels in the PVN were observed in the magnocellular subdivision of the nucleus. Plasma levels of ACTH and corticosterone were greatly increased in both treated groups of rats. Plasma AVP and osmolality levels were significantly elevated in water-deprived rats but not in food-deprived rats. These observations indicated that both food deprivation and water deprivation stimulated the pituitary-adrenal axis and that a reduction in AVP mRNA levels in food-deprived rats was caused by food deprivation but not by glucocorticoid feedback suppression nor by altered plasma osmolality.