Changes in HRCT findings in patients with respiratory bronchiolitis-associated interstitial lung disease after smoking cessation.

High-resolution computed tomography (HRCT) findings in patients with respiratory bronchiolitis-associated interstitial lung disease (RB-ILD) are varied and nonspecific. There is no known report of changes in HRCT findings and respiratory function test results for RB-ILD patients following the cessation of smoking. Five patients with RB-ILD, confirmed by surgical lung biopsy, were retrospectively studied. Each stopped cigarette smoking and did not receive corticosteroid therapy after diagnosis. The clinical symptoms, respiratory function test results and HRCT findings obtained at the final observation were compared with those from the time of diagnosis. Ground-glass opacity and centrilobular nodules corresponding to pathological respiratory bronchiolitis, as well as intralobular fine linear-reticular opacity corresponding to fibrosis involving the subpleural alveolar septa, showed computed tomography-pathological correlations. Both clinical symptoms and the diffusing capacity of the lungs for carbon monoxide improved significantly following smoking cessation, as did ground-glass opacity and centrilobular nodules seen during the initial HRCT examination. Centrilobular nodules and ground-glass opacity, which are the main features of high-resolution computed tomography of respiratory bronchiolitis-associated interstitial lung disease patients and represent pathological respiratory bronchiolitis, can be improved by smoking cessation. The diffusing capacity of the lung for carbon monoxide in respiratory function tests can be also improved.

Different effects of St John's wort on the pharmacokinetics of simvastatin and pravastatin.

OBJECTIVE: St John's Wort, a widely used herbal product, is an inducer of CYP3A4 and it decreases blood concentrations of CYP3A4 substrates. The effects of St John's Wort on the pharmacokinetics of 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors simvastatin (an inactive lactone pro-drug) and pravastatin were determined in this study. METHODS: Sixteen healthy male subjects (n = 8 in group 1 and n = 8 in group 2) took a St John's Wort caplet (300 mg) or matching placebo three times a day for 14 days in a double-blind, crossover study. On day 14, a single oral dose of 10 mg simvastatin and 20 mg pravastatin was given to subjects in group 1 and group 2, respectively. Blood samples were obtained during a 24-hour period after the administration of each drug. RESULTS: Repeated St John's Wort treatment tended to lower plasma simvastatin concentration and significantly (P <.05) lowered concentrations of simvastatin hydroxy acid, its active metabolite. The peak concentration in plasma (ratio, 0.72 of placebo) of simvastatin hydroxy acid tended to be decreased and its area under the plasma concentration-time curve between time zero and 24 hours after administration (ratio, 0.48 of placebo) was significantly decreased (P <.05) by St John's Wort. On the other hand, St John's Wort did not influence plasma pravastatin concentration. No significant differences were observed in the elimination half-life of simvastatin or pravastatin between the placebo and St John's Wort trials. CONCLUSIONS: This study showed that St John's Wort decreases plasma concentrations of simvastatin but not of pravastatin. Because simvastatin is extensively metabolized by CYP3A4 in the intestinal wall and liver, which are induced by St John's Wort, it is likely that this interaction is partly caused by the enhancement of the CYP3A4-mediated first-pass metabolism of simvastatin in the small intestine and liver.

[HRCT findings for four cases of measles pneumonia].

Although, in Western countries, adult-onset pneumonia that is associated with measles is not rare, reports of its incidence in Japan have been sparse. Among eight adolescent and adult (16-34-year-old) measles patients hospitalized in National Sanatorium Tsuruga Hospital, we found four in whom chest radiography and CT revealed pneumonia. The high-resolution lung CTs of these patients revealed features differing from those characteristic of bacterial pneumonia: bronchial wall thickness, centrilobular nodules in ground glass opacity, interstitial lesions (interlobular septal thickening, fissure thickening, pleural effusion) and lymphadenopathy. Of these findings, the centrilobular nodules in ground glass opacity were marked in these cases, and so this may be the most prominent finding in measles pneumonia; and furthermore, since interlobular septal thickening has not been reported in mycoplasma pneumonia or other atypical pneumonias, it may indicate a measles-specific, virus-induced pneumonia.

[Acute eosinophilic pneumonia with positive response to smoking challenge test, suggesting the involvement of health food].

A 17-year-old girl was admitted to our hospital because of acute febrile illness, progressive dyspnea and severe hypoxemia. Chest radiography and HRCT showed bilateral diffuse ground-glass opacities, consolidation, Kerley lines and pleural effusion. Analysis of bronchoalveolar lavage fluid showed 41.9% eosinophils, and a transbronchial lung biopsy revealed infiltration of eosinophils into the alveolar septa and mild alveolar septal edema. The patient's condition was improved immediately by corticosteroid therapy. She had begun smoking and taking health food (chitosan) 3 months before the admission. A smoking challenge test was positive and a drug-induced lymphocyte stimulation test for chitosan was positive. These findings suggested acute eosinophilic pneumonia caused by smoking and health food. The concentration of interleukin-5 (IL-5) in the serum and BALF/granulocyte colony-stimulating factor (G-CSF) in the serum on admission were very high, but decreased after the improvement. Therefore, it is likely that IL-5 and G-CSF are important in the onset of acute eosinophilic pneumonia.

[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.

Genetic analysis of the cytochrome P-450c17alpha (CYP17) and aldosterone synthase (CYP11B2) in Japanese patients with 17alpha-hydroxylase deficiency.

OBJECTIVE: To determine the clinical and molecular genetic characterization of two Japanese patients with 17alpha-hydroxylase deficiency, we analysed the 17alpha-hydroxylase/17,20-lyase gene (CYP17). Next, to clarify the mechanism of hypoaldosteronism in 17alpha-hydroxylase deficiency, we analysed the expression of aldosterone synthase (CYP11B2) messenger RNA and sequenced CYP11B2 in these patients. PATIENTS: Patient 1 (46 XY), phenotypically female, sought medical attention for hypertension, amenorrhea and infantile genitalia. Patient 2 (46 XX), phenotypically female, presented for hypertension and amenorrhea. Hormonal data in both patients showed decreased levels of sex steroids, cortisol, aldosterone and plasma renin activity and extreme elevation of deoxycortisol. DESIGN: Direct sequencing of CYP17 and CYP11B2 was performed using genomic DNA from the patients. An expression studies of mutated forms of CYP17 was performed using COS-1 cells. The expression of CYP11B2 messenger RNA in mononuclear leucocytes (MNLs) of these patients and normal subjects was measured using the competitive polymerase chain reaction METHOD: The effect of renin secretion stimulation on the levels of CYP11B2 messenger RNA in MNLs of normal subjects was also studied. RESULTS: We detected two novel genetic defects in 17alpha-hydroxylase. Sequence analysis revealed one base pair deletion (T) at codon 243 in exon 4 in patient 1. CYP17 in patient 2 contained a point mutation (C to T) at position 415 in exon 8. Transfected cells of mutant from patient 1 had no 17alpha-hydroxylase or 17,20-lyase activity. The R415C mutant protein showed very weak activity of 17alpha-hydroxylase or 17,20-lyase activity. In the renin secretion stimulating test, the increase in CYP11B2 messenger RNA levels in MNLs was parallel with that of plasma aldosterone concentration. The expression of CYP11B2 mRNA in NMLs of these patients was lower compared to controls. No mutations in CYP11B2, including the 5' flanking region, were found. CONCLUSIONS: These results indicate that the novel mutations of the CYP17 gene found in these patients inactivate cytochrome P450c17 function, and that hypoaldosteronism in these patients may be partly explained by a decreased activity of aldosterone synthase, which is regulated at the transcriptional level.

Effects of high sodium intake on cardiovascular aldosterone synthesis in stroke-prone spontaneously hypertensive rats.

OBJECTIVES: Aldosterone is synthesized in extra-adrenal tissues such as the vasculature, heart and brain. The mechanisms underlying the effect of high salt intake on the development and acceleration of vascular injury and cardiac hypertrophy in the stroke-prone spontaneously hypertensive rats (SHRSP) are still not clear. The goal of this study was to determine whether high salt intake increases cardiovascular aldosterone synthesis in SHRSP. METHODS: Four-week-old SHRSP were given tap water or 0.9% NaCl solution for hydration for 4 weeks in addition to a normal salt diet. Isolated rat mesenteric arteries and hearts were perfused for 2 h, and the perfusate was analysed by high-performance liquid chromatography. The concentrations of aldosterone synthase gene (CYP11B2) mRNA and angiotensin II receptor (AT1R) mRNA were determined by competitive polymerase chain reaction. RESULTS: Salt-loaded SHRSP had higher blood pressures than SHRSP with normal salt intake. Plasma aldosterone concentrations and plasma renin activity were decreased by high salt intake. Aldosterone production, the expression of CYP11B2 mRNA and AT1R mRNA in mesenteric arteries and hearts were significantly increased by high salt intake. CONCLUSIONS: These results suggest that high salt intake increases aldosterone production and expression of the AT1R mRNA in the cardiovascular tissue in SHRSP, which may contribute to the development of malignant hypertension in salt-loaded SHRSP.

[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.

A missense mutation, A156T, in the alpha-galactosidase A gene causes typical Fabry disease.

AIMS: Fabry disease is a rare but important cause of end-stage renal disease. Recent molecular investigations on alpha-galactosidase A (alpha-Gal A) have proven the existence of atypical variants in Fabry disease, making genotype assessment of each phenotype indispensable. We report here a missense mutation, which causes a typical form of Fabry disease. MATERIAL AND METHODS: The proband, a 45-year-old man, presented with acroparesthesias, hypohidrosis, left ventricular hypertrophy, renal involvement (proteinuria and renal insufficiency) with typical microscopic findings and extremely reduced plasma alpha-Gal A activity, indicating the typical form of the disease. Total RNA was isolated from the proband's cultured fibroblasts, reverse-transcribed and amplified for direct sequencing of alpha-Gal A. Genomic DNA of the proband's mother and 75 controls (50 males and 25 females) living in the same area as the proband was also examined. RESULTS: Sequencing of the cDNA revealed a substitution of G to A in codon 156 of alpha-Gal A, resulting in a single amino acid change from alanine to threonine (A156T). The mutation can be detected with PCR-RFLP with SfaNI digestion. This technique revealed that the mother was a heterozygote of A156T with no A156T noted in the 100 haplotypes of the controls. With a vigorous search of the same mutation in the literature, no previous description was found other than one case listed in several review papers as a classic phenotype without any other information. In our study, we examined A156T in a pedigree and demonstrated that the mutation was not a polymorphic variant in our area. CONCLUSION: Taken together, the present results strongly suggest that the missense mutation, A156T, in the alpha-Gal A gene causes typical Fabry disease.

The property of a novel v2 receptor mutant in a patient with nephrogenic diabetes insipidus.

Nephrogenic diabetes insipidus (NDI) is characterized by resistance of the kidneys to the action of arginine vasopressin (AVP); X-linked recessive NDI is caused by an inactivating mutation of the vasopressin type-2 (V2) receptor. Several missense mutations in the first or second extracellular loop of the V2 receptor have been reported, and some of these mutant receptors were confirmed to have reduced affinities for ligand binding. We detected a novel V2 receptor gene mutation, a substitution of cysteine for arginine-104 (R104C) located in the first extracellular loop of the V2 receptor, in a patient with congenital NDI. Functional analysis by transient expression studies with COS-7 cells showed binding capacity of R104C mutant diminished as 10% of wild type, but binding affinity was strong rather than wild type. In the result of AVP stimulation studies, maximum cAMP accumulation of R104C decreased as 50% of wild type. On the other hand, a designed mutant receptor, substituted serine for arginine-104 as a model of modified R104C mutant receptor removed the influence of the sulfhydryl group in cysteine-104, recovered binding capacity up to 50% of wild type and maximum cAMP accumulation as 82% of wild type. Our study demonstrated that the R104C mutation of the V2 receptor was a cause of NDI. The mechanism of renal resistance to AVP was the reduction of ligand binding, and adenylyl cyclase activation depended on the V2 receptor. In addition, we confirmed that the sulfhydryl group of the cysteine-104 caused most part of R104C mutant receptor dysfunction.

11beta-hydroxysteroid dehydrogenase activity in human aortic smooth muscle cells.

11beta-Hydroxysteroid dehydrogenases (11beta-HSD) interconvert cortisol, the physiological glucocorticoid, and its inactive metabolite cortisone in humans. There are two isoforms. The type 1 isoform (11beta-HSD1) catalyzes both 11beta-dehydrogenation (cortisol to cortisone) and the reverse oxoreduction (cortisone to cortisol), but the type 2 isoform (11beta-HSD2) catalyzes only 11beta-dehydrogenation. The diminished dehydrogenase activity has been demonstrated in resistance vessels of genetically hypertensive rats. However, the isoform(s) that plays a significant role in conferring the dehydrogenase activity on vasculature has not been determined. We investigated 11beta-HSD activities in human vascular smooth muscle cells by manipulating 11beta-HSD expressions with antisense oligonucleotides. The results showed that 11beta-HSD2 dominates functioning in the dehydrogenase mode in these cells. This indicates that impairment of 11beta-HSD2 activity in vascular wall may be related to the pathogenesis of hypertension.

Evidence of macrophage foam cell formation by very low-density lipoprotein receptor: interferon-gamma inhibition of very low-density lipoprotein receptor expression and foam cell formation in macrophages.

BACKGROUND: Expression of the VLDL receptor, primarily in macrophages, has been confirmed in human and rabbit atherosclerotic lesions. The high binding affinity of the VLDL receptor for remnant particles implicates the VLDL receptor pathway in the foam cell formation mechanism in macrophages. This study investigates the effect of interferon (IFN)-gamma on VLDL receptor expression in phorbol-12-myristate-13-acetate (PMA)-treated THP-1, HL-60 macrophages, and human monocyte-derived macrophages. METHODS AND RESULTS: THP-1 cells were induced to differentiate into macrophages by PMA treatment. IFN-gamma was added to the medium, and expression of the VLDL receptor was determined. (125)I-beta-VLDL degradation study and oil red O staining were examined. In THP-1 macrophages, VLDL receptor protein expression decreased at 2 days after PMA treatment but increased at 3 days and increased up to 5 days. Scavenger receptor proteins, which were not originally present, appeared at 3 days after PMA treatment. IFN-gamma inhibited VLDL receptor expression in a dose-and time-dependent manner in macrophages. However, no inhibitory effect was observed in monocytes. Moreover, IFN-gamma receptor mRNA increased during differentiation to macrophages. (125)I-beta-VLDL degradation study and oil red O staining showed that IFN-gamma significantly inhibited foam cell formation after the uptake of beta-VLDL. LDL receptor-related protein (LRP) and LDL receptor mRNAs were not expressed in macrophages. In PMA-treated HL-60 macrophages and human monocyte-derived macrophages, IFN-gamma also inhibited VLDL receptor expression and foam cell formation by beta-VLDL. CONCLUSIONS: VLDL receptor expression is upregulated during monocyte-macrophage differentiation. IFN-gamma inhibits VLDL receptor expression and foam cell formation only in macrophages. Remnant particles induce macrophage foam cell formation through the VLDL receptor pathway.

Effect of ACE gene polymorphism on age at renal death in polycystic kidney disease in Japan.

Polycystic kidney disease (PKD) is one of the most common genetic disorders and a major cause of renal death or end-stage renal disease (ESRD) requiring regular hemodialysis. The responsible genes recently have been cloned; however, genetic factors influencing the rate of progression to ESRD in patients with PKD have yet to be defined. Several studies have shown increased activity of the renin-angiotensin system (RAS) in patients with PKD. In addition, genetic polymorphisms of the RAS have been associated with the development of cardiovascular diseases. Therefore, these polymorphisms are good candidates for disease-modifying genetic factors or markers in PKD. In two previous reports of white subjects with a cumulative survival analysis, it was suggested that patients with P:KD1 homozygous for the deletion allele of the angiotensin-converting enzyme (ACE) gene are at increased risk for early renal death. To confirm this hypothesis in Japanese subjects, 103 individuals with PKD were genotyped for several components of the RAS, ie, ACE insertion/deletion (I/D) polymorphism, angiotensinogen (AGT) M235T, and angiotensin II type 1 receptor (AT1) A1166C. Seventy-six of the 103 patients (73.8%) reached ESRD at an average age of 52.1 +/- 11.3 years. The frequencies of each genotype of the genes were similar to those expected from Hardy-Weinberg equilibrium. There was a tendency to an excess of patients homozygous for the D allele in patients with ESRD (DD in patients with ESRD, 11.8%; DD in patients without ESRD, 3.7%; chi-square, 1.505; P: = 0.22). Cumulative renal survival was significantly less in those with the DD genotype compared with ID/II genotypes. Estimated mean renal survival was 46.4 years (95% confidence interval, 39.5 to 53.3) in subjects with the DD genotype and 57.2 years (95% confidence interval, 54.2 to 60.2) in ID/II genotypes (chi-square, 7.76; P: = 0.0053). There was no association between age at onset of ESRD and either M235T or A1166C polymorphism. These findings suggest that Japanese patients with PKD homozygous for the D allele of the ACE gene are at increased risk for developing ESRD at an early age.

[The effect of O2 therapy on mixed venous concentration of endothelin-1 in chronic obstructive pulmonary disease].

Pulmonary hypertension (PH) is an important factor in the prognosis of cases of chronic obstructive pulmonary disease (COPD), and endothelin-1 (ET-1) is a major factor in the development of PH in COPD. Oxygen (O2) therapy improves the prognosis of COPD by suppressing the development of PH. We therefore assessed the correlation of PH and ET-1, and the effect of O2 therapy on the plasma ET-1 concentration. In COPD patients, the plasma ET-1 level in mixed venous blood, but not in arterial blood, was negatively correlated with mixed venous O2 tension and positively correlated with pulmonary vascular resistance. No such correlation, however, was observed in the case of plasma HANP or plasma BNP. O2 administration significantly suppressed the plasma ET-1 level. This level in mixed venous blood was thought to serve as a marker of PH in COPD. and O2 administration decreased the plasma ET-1 level in mixed venous blood. It consequently attenuated PH.

[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.

[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.

Functional adrenocorticotropic hormone receptor in cultured human vascular endothelial cells : possible role in control of blood pressure.

Hypertension is a prominent feature of patients with Cushing's disease and ectopic adrenocorticotropic hormone (ACTH) syndrome, who have elevated ACTH levels. Chronic administration of ACTH (1-24) also raises blood pressure in humans. This effect has been postulated to be due to ACTH-induced increases in cortisol secretion in the adrenal gland. It is well known that cortisol increases vascular tone by potentiating the vasoconstrictor action of a number of pressor hormones. In the present study, we show direct evidence that human aortic endothelial cells possess the ACTH receptor. 11beta-Dehydrogenation, converting cortisol to its inactive metabolite, cortisone, mediated by vascular 11beta-hydroxysteroid dehydrogenase type 2 is essential for the control of vascular tone, and the reduced activity may be relevant to the pathogenesis of hypertension. We found that ACTH (1-24) dose-dependently decreased the gene expression and enzyme activity of 11beta-hydroxysteroid dehydrogenase type 2 in these cells, and the decrease was partially abolished by a selective ACTH receptor antagonist. This may indicate that ACTH potentiates the action of cortisol through its direct effect on the vasculature. Therefore, the present study provides important information for understanding the mechanism of ACTH-induced hypertension.