Effect of metyrapone pretreatment on adrenocorticotropin secretion induced by corticotropin-releasing hormone in normal subjects and patients with Cushing's disease.

To examine the influence of endogenous cortisol on the ACTH response to CRH, we compared ACTH secretion during CRH tests before and after metyrapone administration in 9 normal subjects and 12 patients with Cushing's disease. The administration of 4.5 g metyrapone (750 mg, orally, every 4 h) resulted in a decrease in basal (pre-CRH) plasma cortisol levels and an increase in basal plasma ACTH levels in both normal subjects and Cushing's patients. The pretreatment with metyrapone significantly blunted the increase in plasma cortisol levels and markedly enhanced ACTH secretion after iv injection of 100 micrograms human CRH. The peak ACTH levels during CRH test before and after metyrapone administration were 8 +/- 1 and 58 +/- 8 pmol/L, respectively, in normal subjects (P less than 0.01) and 26 +/- 5 and 50 +/- 11 pmol/L, respectively, in Cushing's patients (P less than 0.05). Although the basal and peak ACTH levels as well as delta ACTH (peak ACTH - basal ACTH) during the CRH test before metyrapone administration were significantly higher in Cushing's disease patients than in normal subjects (P less than 0.01), no such difference was observed between the 2 groups after metyrapone administration. The results clearly indicate that the endogenous cortisol levels greatly influence the ACTH response to CRH, and that the CRH test as commonly performed does not allow a correct evaluation of potential responsiveness of normal pituitaries and Cushing's adenomas to CRH.

Cellular and intracellular localization of epsilon-subspecies of protein kinase C in the rat brain; presynaptic localization of the epsilon-subspecies.

The cellular and intracellular localization of the epsilon-subspecies of protein kinase C (PKC) in the rat brain was demonstrated by immunocytochemistry using specific antibodies against epsilon-PKC. The epsilon-PKC-specific immunoreactivity was most abundant in the hippocampal formation, olfactory tubercle and Calleja's islands, was moderate in the cerebral cortex, anterior olfactory nuclei, accumbens nucleus, lateral septal nuclei and caudate-putamen and low in the thalamus and medulla. The epsilon-PKC-immunoreactivity was scanty in the perikarya, except for the pyramidal cells of CA3 region of the hippocampus and the immunoreactivity was mainly present in neuropils and nerve fibers. The distribution of epsilon-PKC immunoreactive neurons was consistent with that obtained by in situ hybridization histochemistry. Electron microscopic observations of the hippocampus revealed that the epsilon-PKC is predominantly present in the cytoplasm of axon and nerve terminals and that this enzyme is associated with mitochondrial membrane and vesicles. These results suggested that epsilon-PKC is probably involved in presynaptic functions in CNS, perhaps even neurotransmitter release.

Increased levels of lipid peroxides in aged rat brain as revealed by direct assay of peroxide values.

Lipid peroxide concentrations in brain tissues of young and aged rats were determined by a direct method for measuring peroxide values. Three different brain regions were analyzed for lipid peroxides. The peroxide levels increased in all three regions of aged as compared to those of young rats, while lipid peroxides in plasma appeared to be stable along with age. Lipid peroxides in cerebrum and cerebellum increased 1.6-2.0 times in aged brains compared with young ones, and about 3-fold in the brain stem. Increased levels of lipid peroxides in aged brains seem not merely due to increased pools of precursor polyene fatty acids, but rather due to altered protection systems for lipid peroxidase formation.

Angiotensin-converting enzyme inhibitors and probucol suppress the time-dependent increase in urinary Type IV collagen excretion of Type II diabetes mellitus patients with early diabetic nephropathy.

BACKGROUND: A multicenter prospective clinical trial was carried out in 9 National Hospitals in Japan to elucidate the time-dependent change in urinary Type IV collagen excretion rate of Type II diabetes mellitus (DM) patients, and to investigate whether an angiotensin-converting enzyme inhibitor (ACE-I) or probucol is effective in preventing progression of renal involvement of diabetics by evaluating urinary Type IV collagen excretion. METHODS: Normo- and microalbuminuric patients with Type II DM were recruited. Patients were assigned to either the control (n = 88), ACE-I (n = 43) or probucol (n = 37) group and treated for 24 months. Besides albumin excretion rate (AER), urinary Type IV collagen excretion rate was also measured. RESULTS: Although, AER, urinary N-acetyl-beta-D-glucosaminidase and beta2-microglobulin excretion rates in the control group did not vary over 24 months, urinary Type IV collagen excretion rate in the control group increased time-dependently (p < 0.01 vs baseline at 18 months and p < 0.005 vs baseline at 24 months). In the ACE-I and probucol groups, time-dependent increases in urinary Type IV collagen excretion rates were not observed. In the ACE-I group, the urinary Type IV collagen excretion rate was significantly lower than that in the control group at 24 months (p < 0.05). In the probucol group, the urinary Type IV collagen excretion rate was significantly lower than that in the control group at 6 months (p < 0.05). In the ACE-I group, AER decreased significantly compared with baseline at 18 months (p < 0.05) and at 24 months (p < 0.005). CONCLUSIONS: ACE-I has a beneficial effect and probucol may have a beneficial effect in preventing the progression of early diabetic nephropathy. Measurement of the urinary Type IV collagen excretion rate in combination with AER would be useful for the management of early renal involvement in Type II DM.

First sporadic cases of non-pneumonic legionellosis, Pontiac fever in Japan.

Pontiac fever has rarely been found in sporadic cases. Here, we report the first sporadic cases of non-pneumonic legionellosis, Pontiac fever in Japan. Case 1. A 53-year-old man with spinocerebellar degeneration was presented to our hospital. He had an acute onset of high fever and consciousness disturbance. A chest X-ray film on admission was normal, but transient bilateral pleural effusions were revealed on hospital day 14. Case 2. A 77-year-old woman with gastric ulcer was presented to our hospital. She had an acute onset of high fever. A chest X-ray film on admission was normal, but transient bilateral pleural effusions were revealed on hospital day 7. High fever, resistant to beta-lactam antibiotics, continued in both cases. Both had serologic confirmation of legionellosis by indirect fluorescent antibody assay for Legionella pneumophila without seroconversion for Mycoplasma pneumoniae, and Chlamydia pneumoniae, and had a good prognosis. Both were thought to be sporadic community-acquired cases rather than epidemics.

[Clinical study of aztreonam on respiratory tract infections caused by gram-negative pathogens].

Aztreonam (E-0734, AZT) was administered to pneumonia and chronic respiratory tract infections. The results were as follows: AZT was administered to 29 patients. Twenty-six cases were evaluable and 3 cases were excluded from evaluation of efficacy because 1 was Gram-positive infection, 2 were unclear symptom of infection. Pneumonia was 4 cases. Chronic respiratory tract infections were 22 cases. Clinical efficacy was judged as follows; excellent in 7 cases, good in 10 cases, fair in 5 cases and poor in 4 cases, then the efficacy rate was 65.4%. Efficacy rate in pneumonia, acute aggravation of diffuse panbronchiolitis and bronchiectasis with infection was 50%, 67% and 83%, respectively. Bacteriological response was judged on 21 cases with eradication rate was 66.7%. Bacteriological response classified by pathogen was as follows: All 6 isolates of H. influenzae, 2 in 6 isolates of P. aeruginosa, 4 in 5 isolates of H. parainfluenzae and all 3 isolates of K. pneumoniae were cleared. Total eradicated rate was 74.1%. Eruption was observed in 1 case as side effect. Abnormal laboratory findings were observed in 4 cases. Elevation of GOT and GPT was in 3 cases. Increase of eosinophil and basophil was in 1 case. AZT was considered to be a useful antibiotic for the treatment of respiratory tract infections, especially chronic respiratory tract infections, caused by Gram-negative pathogens.

[A clinical study on lomefloxacin to find appropriate dose levels in the treatment of respiratory tract infections].

A comparative clinical study of lomefloxacin hydrochloride (LFLX) was performed to confirm the optimal dose of LFLX for treatment of respiratory tract infections. Daily dosages of LFLX, 400 mg (200 mg b.i.d.) and 600 mg (200 mg t.i.d.) were allocated by the randomization method. Treatment period was 7-14 days. Of a total of 136 cases, 14 cases were excluded from evaluation of clinical efficacy and 4 cases from evaluation of safety. There were no differences in the background factors of the patients between the 2 dosage groups. The clinical efficacy rates, judged by a committee, were 76.4% (42/55) for the 400 mg group and 74.6% (50/67) for the 600 mg group. No significant difference was observed between the 2 groups (P = 1.000). Incidences of adverse effects were 1.6% (1/64) for the 400 mg group and 2.9% (2/68) for the 600 mg group. Incidences of abnormal laboratory test values were 3.4% (2/58) for the 400 mg group and 1.6% (1/63) for the 600 mg group. No significant differences were found between the 2 groups. These adverse effects and abnormal laboratory test values improved with the cessation of the administration of the drug. From these results, a dose of 400 mg (200 mg b.i.d.) LFLX seems to be better than that of 600 mg (200 mg t.i.d.) LFLX in the treatment of respiratory tract infections.

[A case of miliary tuberculosis with skull tuberculosis].

A 47-year old woman was admitted to our hospital with complaints of headache and right occipital swelling. Brain CT scan showed right occipital bone defect with a sequestrum and soft tissue swelling. T1 weighted MRI enhanced by GD-DTPA revealed several nodules. A right occipital craniotomy was performed. Subcutaneous pus and a well-circumscribed yellowish, firm mass which existed under the bone defect was extirpated. Pathologically, this mass was considered to be a tuberculoma and intracranial nodules were suspected to be cerebral tuberculosis. Anti-tuberculous therapy was started. Since her admission fecal occult blood continued and endoscopic examination with biopsy revealed sigmoid colon cancer. Sigmoidectomy was performed and she has been well during 1 year post-operative follow up. Although tuberculous disease are decreasing in number in our country, we must take into account of the existence of skull tuberculosis.

[A case of pulmonary tuberculosis presenting with infected bulla].

A case of pulmonary tuberculosis manifested as infected bulla complicating with tuberculous pneumonia is reported. A 63-year-old male visited our hospital because of chest X-ray abnormality detected by his home doctor. He complained of pyrexia and productive cough. Chest X-ray showed large bulla with air-fluid level, associated with surrounding infiltration at right upper lobe. On the diagnosis of infected bulla empirical antibiotic therapy was started on out-patient basis and continued after admission, but chest X-ray findings worsened, although subjective symptoms were once relieved. Surgical intervention was recommended, but after short interval pulmonary infiltrates rapidly worsened and expanded to other lobes. Sputum was reexamined and Mycobacterium, later proved as Mycobacterium tuberculosis with DNA probe method, was detected in the sputum specimen. Anti-mycobacterial drugs were administered and subjective symptoms, laboratory, and chest X-ray findings improved. Infected bulla caused by Mycobacterium tuberculosis is rare, but when it is resistant to common empirical therapy, Mycobacterium tuberculosis should be considered as one of its causative agents.

[A case of generalized disseminated atypical mycobacteriosis caused by M. avium complex with a giant gravitation abscess].

A case of generalized disseminated atypical mycobacteriosis caused by M. avium complex (MAC) was reported. The case was a female of 52 years of age. She was admitted to our hospital due to high fever and polyarthralgia. Her chest X-ray and CT scan revealed infiltrative shadows in the right S2b and S4 segments, and multiple accumulation shadows were seen on osteoscintigraphy. Pus aspirated from a lesion of the right fifth rib were acid-fast bacilli positive by smear (Gaffky v). The administration of four drugs, INH, RFP, EB and SM, was introduced, then corticosteroid was added, and the case became afebrile. Later, acid-fast bacilli were also isolated from bronchial washing and aspirated specimen from bone marrow, and all of them were identified as MAC. Based on these findings, the case was diagnosed as generalized disseminated mycobacteriosis. After several months remission, tenderness over the fifth lumbar vertebra deteriorated, and MRI scan on lumbar vertebrae showed high-intensity area both on T1-weighted and T2-weighted images. MAC was isolated from the pus of the fifth lumbar vertebra. Lumbar lesions deteriorated gradually, and a giant gravitation abscess which involved right ilium was revealed by CT scan of the pelvis. In spite of vigorous treatment including chemotherapy, aspiration of pus and drainage, general condition of the case deteriorated, and the case finally died of renal insufficiency.

[The clinical study on KL-6 and SP-D in sera of patients with various pulmonary diseases].

It has been reported that serum levels of KL-6 and surfactant protein D(SP-D) can be useful indicators for interstitial pneumonia(IP). In the present study, we evaluated the clinical significance of KL-6 and SP-D by measuring the serum levels of patients with various pulmonary diseases by enzyme-linked immunosorbent assay. Serum levels of KL-6 in patients with idiopathic interstitial pneumonia(IIP), collagen disease with interstitial pneumonia(CDIP), lung cancer(LC) and LC with idiopathic interstitial pneumonia were significantly higher than of those in healthy controls. Moreover, serum levels of KL-6 were significantly higher in patients with active IP than in those with inactive IP. Serum levels of SP-D in patients with IIP and CDIP were significantly higher than of those in healthy controls. When a cut-off level of KL-6 or SP-D in sera was defined as a value of healthy controls representing the means + 2SD, the serum KL-6 positive diagnostic rate for IP(79.2%) was higher than that of SP-D(66.7%). The SP-D positive diagnostic rate for lung diseases other than IP(11.6%) was lower than that of KL-6(34.9%). The serum concentration of KL-6 in patients with the pulmonary diseases significantly correlated with that of SP-D. These findings suggest that KL-6 may be superior in the sensitivity of IP and can be used to evaluate the disease activity of IP. In addition, SP-D may be more specific for IP than KL-6.

[Clinical significance of sialyl SSEA-1 (SLX) in patients with idiopathic interstitial pneumonia].

Serum SLX levels were measured in 29 patients with idiopathic interstitial pneumonia (IIP) to evaluate its clinical significance. Serum SLX had positive correlations with the BALF neutrophil ratio but not with the severity or the disease activity in patients with IIP, and bronchoalveolar lavage fluid (BALF) SLX had positive correlations with the BALF neutrophil count. Epithelial lining fluid (ELF) SLX levels showed positive correlations with serum SLX, but were much higher. These results suggest that increases of serum SLX may reflect increases of SLX in the lung tissues. Thus, we speculate that increases of the serum SLX level may represent increases of the BALF neutrophil count. Patients with higher SLX showed poor therapeutic responses and poor prognoses in comparison with those with normal SLX for the reason that serum SLX level represents BALF neutrophil level.

[A case of pulmonary thromboembolism with heparin-induced thrombocytopenia].

In February 2000, a 70-year-old man was admitted to our hospital complaining of back pain and dyspnea on exertion. Pulmonary thromboembolism was diagnosed, and he was treated with intravenous urokinase and heparin. The pulmonary thromboembolism improved, though heparin-induced thrombocytopenia (HIT) was subsequently observed. The thrombocytopenia was then improved by withdrawing the intravenous heparin, but thrombosis appeared extending from both femoral veins to the inferior vena cava. The thrombosis was dispersed by catheter-directed thrombolysis. There have been few reports of HIT in Japan. Heparin is frequently used for the treatment of pulmonary thromboembolism, but special care must be taken, since severe thrombotic complications are associated with HIT.

[A case of lymphocytic interstitial pneumonia with Sjögren's syndrome and systemic lupus erythematosus in which human herpes virus-6 infection was the suspected pathogen].

A 47-year-old-woman was admitted to our hospital complaining of thirst and dry cough after catching cold. Sjögren's syndrome (SjS) and systemic lupus erythematosus (SLE) were diagnosed. Chest X-P and CT findings suggested strongly that she had interstitial pneumonia. Thoracoscopic lung biopsy was therefore performed, and the biopsy specimens showed marked infiltration of small lymphocytes and of plasma cells into the alveolar walls and interlobular septa. Since the infiltrating cells were not atypical and gene analysis did not show mono-clonality, we made a diagnosis of lymphocytic interstitial pneumonia (LIP). Because the patient's symptoms appeared only after she caught cold, we suspected that virus infections were somewhat involved in the etiology of these diseases. The level of human herpesvirus-6 (HHV-6) antibody was high, and furthermore, HHV-6 was detected using the polymerase chain reaction from lung biopsy specimens. We suspected in this case that LIP, SjS, and SLE had appeared concomitantly after an active HHV-6 infection.

[Silicosis characterized by increasing serum CA 19-9 in parallel with progression of lung fibrosis].

In November 1997, a 61-year-old man was admitted to our hospital complaining of dyspnea. He had worked as a miner for 10 years and had received medical treatment based on a diagnosis of idiopathic interstitial pneumonia at our hospital since 1984. In conjunction with the progression of interstitial pneumonia, the patient's serum CA 19-9 had gradually increased since 1992, reaching 9,920 U/ml in 1997. Though cancer of the pancreas or other organs was suspected, an extensive examination revealed no malignancy. In April 1998, the patient died of bacterial pneumonia. Lung autopsy specimens disclosed severe interstitial fibrosis with prominent silicotic nodules. Based on these findings, silicosis was diagnosed. In immunohistochemical staining for CA 19-9, the lumina of severely fibrotic lesions covered with epithelial cells stained positively with anti-CA 19-9 antibody. These findings suggested that serum CA 19-9 may have been produced in the epithelial cells. We speculated that increased serum CA 19-9 levels in patients with interstitial pneumonia may occasionally be more indicative of the magnitude of destruction of lung architecture than the degree of disease activity.

[The usefulness of serum KL-6 levels for the diagnosis of disease activity in idiopathic interstitial pneumonia].

Serum KL-6 levels were measured in 29 patients with idiopathic interstitial pneumonia (IIP) as a means of evaluating disease activity. Levels of serum KL-6 were significantly higher in patients with active IIP (n = 11) than in those with inactive IIP (n = 18). The levels of serum KL-6 were 2,546 +/- 1,703 U/ml in patients with active IIP and 795 +/- 385 U/ml in patients with inactive IIP, respectively. The levels of serum LDH, CEA, P-III-P, and 7 S collagen in patients with active IIP did not differ significantly from those in patients with inactive IIP. For the diagnosis of active IIP, the sensitivity of serum KL-6 (cut off value of 1,500 U/ml) was 81.8% and the specificity, 94.4%. These results were almost identical to findings obtained with chest Ga-67 scintigraphy. Furthermore, they suggested that serum KL-6 levels may be a useful marker for the diagnosis of disease activity in IIP, as well as a useful indicator for the administration of steroid therapy to patients with IIP.

[Two cases of lung metastasis of malignant melanoma].

We report 2 cases of lung metastasis of malignant melanoma. Patient 1 was a 71-year-old woman who had undergone an operation for enucleation of her left eye 13 years earlier. Chest magnetic resonance imaging (MRI) demonstrated intermediate intensity including partially high intensity on T 1 weighted images, and high intensity including partially low intensity on T 2 weighted images. Microscopic findings from a transbronchial lung biopsy specimen disclosed melanotic melanoma. Patient 2 was a 54-year-old man who had undergone surgery for malignant melanoma in the left upper arm 4 years earlier. Chest MRI films demonstrated low intensity on T 1 weighted images, and high intensity on T 2 weighted images. Microscopic findings from specimens of the primary lesion in the left upper arm revealed melanotic melanoma, but the findings from the lower right lobectomy disclosed amelanotic melanoma. It has been reported that MRI is useful in the diagnosis of malignant melanoma, and that melanin content reflects MRI signal intensity. The MRI findings were consistent with the histopathologic findings in each of the 2 cases we reported.

[Evaluation of fluorine-18-fluorodeoxyglucose whole body positron emission tomography imaging in the clinical diagnosis of lung cancer].

In recent years the use of positron emission tomography (PET) with fluorine-18-fluorodeoxyglucose (FDG) has become a valuable tool in the detection of a variety of tumors including lung cancer. To determine its role in the diagnosis of patients with suspected lung cancer, we compared the results of FDG-PET with those of the other scintigraphic imaging techniques (67Ga-planar image, 201Tl-SPECT and 99mTc-bone scintigraphy) used worldwide in patients with lung cancer. The analysis group consists of 178 patients, 159 malignant pulmonary diseases and 19 benign pulmonary diseases. FDG-PET was performed in 65 patients (51 malignant pulmonary diseases, 14 benign pulmonary diseases). FDG-PET had a sensitivity, specificity and accuracy of 98.0%, 78.6% and 93.8%, respectively, in detecting malignant pulmonary nodules. In N staging, sensitivity, specificity and accuracy were 66.7%, 81.3% and 76.0%, respectively. In M staging, the accuracy was 100%. Thus, FDG-PET imaging was more accurate than the other types of scintigraphic imaging. In our observations, whole-body 18FDG-PET images improved diagnostic accuracy in the evaluation of lung lesions and the staging of lung cancer.

[A case of radiologically negative small-cell lung carcinoma successfully detected early by whole-body FDG-PET].

A 68-year-old man was referred to our hospital after being treated for early gastric cancer to investigate the causative malignancy, as his serum carcinoembryonic antigen (CEA) level was increased. Chest radiography showed no abnormal opacities. Subsequently, a whole-body FDG-PET was performed, which detected some tiny lesions in the mediastinum and the right lower lung field. A diagnosis of small-cell lung carcinoma was made after mediastinoscopic and bronchoscopic examinations. After chemoradiotherapy, the previously abnormal uptake of FDG was attenuated and the bronchoscopic appearance was improved, while the serum CEA and NSE levels returned to normal. Our findings demonstrated that whole-body scanning by FDG-PET could be useful for early detection of lung cancer, especially in cases of small-cell lung cancer.

[Neurally mediated syncope in association with small cell lung carcinoma].

A 66-year-old woman was admitted to our hospital because of frequent syncopal episodes and for treatment of small cell lung carcinoma. Neurally mediated syncope was diagnosed by the head-up tilt test, which evoked early severe hypotension (after 12 min at the 80-degree tilt position). Treatment of carcinoma by chemotherapy and radiotherapy promptly eliminated the syncopal episodes. This was an unusual case of neurally mediated syncope associated with small cell lung carcinoma.