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We determined whether a major Japanese cedar pollen allergen (Cry j 1) conjugated with CpG oligodeoxynucleotide would enhance allergen-specific Th1 responses in mice. Cry j 1 conjugated with CpG (Cry j 1-CpG) induced IL-12 in the spleen cells of naïve mice. Cry j 1-CpG immunization of BALB/c mice suppressed anti-Cry j 1 IgE response and enhanced anti-Cry j 1 IgG(2a) to subsequent Cry j 1 and alum adjuvant injection. CD4(+)T cells isolated from the spleens in mice immunized with Cry j 1-CpG produced higher IFN-γ levels than did CD4(+)T cells obtained from mice as negative controls. Our results suggested that Cry j 1-CpG immunization can induce Cry j 1-specific Th1 immune responses, thereby inhibiting IgE response to the pollen allergen.

Aims: Desquamative interstitial pneumonia (DIP) is a rare pattern of diffuse parenchymal lung disease known to overlap with respiratory bronchiolitis-interstitial lung disease (RB-ILD). The aim was to review biopsy-proven cases of DIP to investigate further the clinical, imaging and histological features of this disease. Methods and results: Twenty patients fulfilled the pathological criteria: 19 men and one woman with a mean age of 54 years. Clinical features, bronchoalveolar lavage (BAL) data, radiological findings, pathological findings other than criteria, effect of therapy and outcome were examined. The BAL data for 17 cases revealed marked eosinophilia (mean 18%) and moderate neutrophilia (mean 11%). Computed tomography in 17 patients showed peripheral involvement in all cases with a clear margin in 64% and thin-walled cysts in 35% of cases. Additional pathological features were a distinct lobular distribution (70%) and architectural destruction (70%) with cyst formation (55%). Eighteen of the 19 patients (95%) improved under steroid pulse and/or oral therapy. Sixteen subjects (80%) are alive, three died of other diseases and one died of DIP 74 months after the diagnosis. Percent vital capacity increased significantly and new thin-walled cysts appeared in one case. Conclusions: BAL eosinophilia, lobular distribution and architectural destruction with cyst formation are characteristic features of DIP.

Background: Distal myopathy with rimmed vacuoles (DMRV) is an autosomal-recessive disorder with preferential involvement of the tibialis anterior muscle that starts in young adulthood and spares quadriceps muscles. The disease locus has been mapped to chromosome 9p1-q1, the same region as the hereditary inclusion body myopathy (HIBM) locus. HIBM was originally described as rimmed vacuole myopathy sparing the quadriceps; therefore, the two diseases have been suspected to be allelic. Recently, HIBM was shown to be associated with the mutations in the gene encoding the bifunctional enzyme, UDP- N -acetylglucosamine 2-epimerase/ N -acetylmannosamine kinase ( GNE ). Objective: To determine whether DMRV and HIBM are allelic. Methods: The GNE gene was sequenced in 34 patients with DMRV. The epimerase activity in lymphocytes from eight DMRV patients was also measured. Results: The authors identified 27 unrelated DMRV patients with homozygous or compound-heterozygous mutations in the GNE gene. DMRV patients had markedly decreased epimerase activity. Conclusions: DMRV is allelic to HIBM. Various mutations are associated with DMRV in Japan. The loss-of-function mutations in the GNE gene appear to cause DMRV/HIBM.

Cystic tumor (endodermal heterotopia) of the atrioventricular (AV) node in a 95-year-old female is described. Electrocardiograms showed complete AV blockage with a narrow QRS morphology resulting from the long-standing first degree of AV blockage since age 61. A cardiac pacemaker was implanted at age 83. The patient died of pneumonia at age 95. Autopsy demonstrated a normal heart weight (320 g), normal coronary artery and normal myocardium. Histological examination of the conduction system revealed a marked fibrotic sinoatrial (SA) node and a cystic lesion in the lower right atrium, including the approaches to the AV node. The bundle of His and its branches were completely intact. Cellular nests and cystically dilated tubules were scattered within a loose tissue stroma, which measured 18 x 12 x 5 mm. There were several mitotic figures among the tubules, as well as nuclear fragments similar to apoptotic bodies and exfoliation of the tumor cells. Immunohistochemical studies demonstrated a positive reaction for epithelial membrane antigen, carcinoembryonic antigen, CA19-9, cytokeratin and secretory component in the tubular cells, and a negative reaction for thrombomodulin. Endocrine cells among the tubules were positive only for calcitonin and serotonin. Ultrastructurally, sparse microvilli and desmosome-like structures between the tumor cells were observed. These findings support that this lesion originates from the endoderm. Moreover, it is likely that progression in the degree of AV block may be explained by the cell proliferation activity of the tumor.

This study was initiated to clarify the relationship between ovarian hormones and the granulomatous inflammatory process in the lung. To assess whether ovarian dysfunction influences the granulomatous inflammatory process, we compared immunological alterations in ovariectomized rats and in sham-operated rats. After a heat-killed, bacilli Calmette-Guerin (BCG)-elicited granulomatous reaction, the lung-body weight ratios, the number of lymphocytes and activated T-cells, and the interferon-gamma levels in the bronchoalveolar lavage fluid from the ovariectomized rats were significantly higher than those of the sham-operated rats. Moreover, exogenous ovarian steroids supplemented in vivo suppressed not only the granulomatous inflammatory process in the lungs, but also the parameters measured in the bronchoalveolar fluid. These results indicate that ovarian dysfunction may adversely affect the formation of granulomas in the lung.

Systolic anterior motion of the anterior mitral leaflet and asymmetric septal hypertrophy (ASH) are characteristic features of hypertrophic obstructive cardiomyopathy (HOCM) on an echocardiogram. Among 9,670 patients over 60 years old examined by echocardiography from January, 1984 to October, 1990, 55 patients showed systolic anterior motion of the anterior mitral leaflet and/or the chordae tendinae (SAM). We investigated clinical features and morphological features of the left ventricle on an echocardiogram in the 55 patients with SAM. They were classified into three groups according to the degree of SAM. Thirty eight cases (group I) had no mitral and/or chordal-septal contact, 10 (group II) had brief contact (less than 30% on the echocardiographic systole) and 7 (group III) had prolonged contact (greater than or equal to 30%). Ages ranged from 60 to 99 with a mean age of 78.2 years. There were 19 males and 36 females and there was a predominance of females in each group. Thirty five cases had hypertension and 34 left ventricular hypertrophy on electrocardiograms. One case of group I, 3 of group II and 7 of group III had a clinical diagnosis of HOCM. In comparison with each group, the incidence of LVH (SV1 + RV5 greater than or equal to 35 mm) was 52% in group I, 90% in group II and 83% in group III and that of LVH (SV1 + RV5 greater than or equal to 70 mm) was 29%, 20% and 67%, respectively. On echocardiographic examination, the diastolic descent rate of the anterior mitral leaflet in the 3 groups was 36.1 +/- 13.1 mm/sec, 19.4 +/- 13.1 mm/sec and 10.7 +/- 11.8 mm/sec (p less than 0.01).(ABSTRACT TRUNCATED AT 250 WORDS)

Nonsteroidal anti-inflammatory drugs (NSAIDs) have been shown to enhance the symptoms of food-dependent exercise-induced anaphylaxis (1, 2). We report a rare case of wheat-induced anaphylaxis not related to exercise in which oral challenges with wheat and gluten-induced whole blood histamine release were enhanced by NSAIDs. A 59-year-old man was admitted to our hospital for investigation of recurrent food-induced anaphylaxis. He first developed urticaria after eating noodles at age 58. Since then he frequently had urticaria andoccasionally experienced anaphylaxis, including dyspnoea, wheezing, angioedema, and loss of consciousness after ingesting wheat, including noodles, bread, breaded cutlets, and tempura (Japanese deep-fried foods). It was determined that he had these episodes of anaphylaxis without exercise. Total IgE was 160 IU/ml. Skin-prick testing and specific IgEwere positive for wheat and gluten, the major allergen in wheat-induced allergy. To determine an elimination diet and to instruct the patient, open oral challenges were performed. Oral challenges with bread, noodles, cutlets, and tempura were all negative. However, when 30 mg of diclofenac sodium, an NSAID, was taken just before the challenge, he developed urticaria 1 h after eating noodles or tempura.He developed no symptoms after taking diclofenac sodium only. To clarify the effect of NSAIDs on wheat-induced anaphylaxis, we measured histamine release after in vitro exposure to gluten with or without tolmetin sodium, an NSAID, in this patient and a normal control subject. Heparinized whole blood samples were taken and incubated with gluten at concentrations ranging from 2.5 to 2500 lg/ml and with tolmetin sodium at concentrations ranging from 0.125 to 12.5 mg/ml for 30 min at 37 C. After centrifugation, histamine was measured in the cell-free supernatants by radioimmunoassay. Histamine release was found to be positive with gluten at the concentration of 2500 lg/ml in the patient. With tolmetin sodium at concentrations of 0.125 and 1.25 mg/ml, gluten-induced histamine release was not affected. However, tolmetin sodium at the concentration of 12.5 mg/ml enhanced the gluten-induced histamine release at all concentraions of gluten. Interestingly, tolmetin sodium enhanced histamine release even in the absence of gluten in the control subject as well as in the patient. Histamine release was not found in other conditions in the control subject. At follow-up 1 year after the discharge, he remained asymptomatic after strict elimination of wheat. The results of our in vitro study indicate that the induction of positive oral challenges with wheat after pretreatment with an NSAID is, at least partly, because of enhancement of histamine release. To our knowledge, this is the first report of wheatinduced anaphylaxis not related to exercise confirming thatNSAIDs enhance type I allergic reactions. Previous studies demonstrated that NSAIDs enhance in vitro histamine release induced by IgEor nonIgE-mediated mechanisms (3). In our study, histamine release was induced by tolmetin sodium even in the absence of allergen. In this regard, we speculate that the extent of enhancement of histamine releasemaydependon the type anddose of the NSAIDs as our patient developed no symptoms after taking diclofenac sodium only. We found that enhancement of the allergic symptoms induced by NSAIDs is not a specific phenomenon in fooddependent exercise-induced anaphylaxis, but can occur in other type I allergic diseases. Furthermore, pretreatment with NSAIDs under controlled conditions is useful for confirming the diagnosis of food-induced allergy when food challenge tests fail to induce positive reactions.

In the DNA binding domain of microphthalmia-associated transcription factor (MITF), four mutations are reported: mi, Mi wh, mi ew, and mi or. MITFs encoded by the mi, Mi wh, mi ew, and Mi or mutant alleles (mi-MITF, Mi wh-MITF, Mi ew-MITF, and Mi or-MITF, respectively) interfered with the DNA binding of wild-type MITF, TFE3, and another basic helix-loop-helix leucine zipper protein in vitro. Polyclonal antibody against MITF was produced and used for investigating the subcellular localization of mutant MITFs. Immunocytochemistry and immunoblotting revealed that more than 99% of wild-type MITF and Mi wh-MITF located in nuclei of transfected NIH 3T3 and 293T cells. In contrast, mi-MITF predominantly located in the cytoplasm of cells transfected with the corresponding plasmid. When the immunoglobulin G (IgG)-conjugated peptides representing a part of the DNA binding domain containing mi and Mi wh mutations were microinjected into the cytoplasm of NRK49F cells, wild-type peptide and Mi wh-type peptide-IgG conjugate localized in nuclei but mi-type peptide-IgG conjugate was detectable only in the cytoplasm. It was also demonstrated that the nuclear translocation potential of Mi or-MITF was normal but that Mi ew-MITF was impaired as well as mi-MITF. In cotransfection assay, a strong dominant negative effect of Mi wh-MITF against wild-type MITF-dependent transactivation system on tyrosinase promoter was observed, but mi-MITF had a small effect. However, by the conjugation of simian virus 40 large-T-antigen-derived nuclear localization signal to mi-MITF, the dominant negative effect was enhanced. Furthermore, we demonstrated that the interaction between wild-type MITF and mi-MITF occurred in the cytoplasm and that mi-MITF had an inhibitory effect on nuclear localization potential of wild-type MITF.

BACKGROUND--The migration and proliferation of fibroblasts may be important in the pathogenesis of pulmonary fibrosis. Considerable data are available on the proliferation of fibroblasts, but very few on their migration. METHODS--The migratory activity of fibroblasts obtained from lung biopsy specimens from 11 patients with idiopathic pulmonary fibrosis (IPF) was studied using a 96-well chemotaxis chamber. Fibroblasts from eight normal controls, seven patients with interstitial fibrosis associated with a collagen vascular disease (IP-CVD), and 13 patients with sarcoidosis were also examined. Migratory activity was tested in a serum-free medium in the presence and absence of platelet derived growth factor (PDGF), 30 ng/ml, as a chemoattractant. RESULTS--Migration of fibroblasts from patients with IPF was enhanced in serum-free maintenance medium alone (mean (SD) controls v IPF: 183 (86) v 689 (491) cells/field), and was also enhanced when cells were stimulated by PDGF (controls v IPF: 829 (222) v 1928 (600) cells/field). Fibroblasts from tissues with dense fibrosis had a greater capacity for migration than those from an earlier stage of fibrosis. No correlation was found between migratory activity and proliferative capacity of the individual cells. CONCLUSIONS--The fact that fibroblasts from fibrotic lungs migrate faster than those from controls suggests that migration is related to the initiation of the pulmonary fibrotic process. These in vitro studies suggest that fibroblasts derived from the lungs of patients with pulmonary fibrosis have a migratory phenotype. Such a change in fibroblast phenotype, if it occurred in vivo, may be important in the context of the pathogenesis of pulmonary fibrosis.

To maintain epidermal homeostasis, the balance between keratinocyte proliferation and differentiation is tightly controlled. However, the molecular mechanisms underlying this balance remain unclear. In 3D organotypic coculture with mouse keratinocytes and fibroblasts, the thickness of stratified cell layers was prolonged, and growth arrest and terminal differentiation were delayed when PKCη-null keratinocytes were used. Re-expression of PKCη in PKCη-null keratinocytes restored stratified cell layer thickness, growth arrest and terminal differentiation. We show that in 3D cocultured PKCη-null keratinocytes, p27(Kip1) mRNA was downregulated, whereas JNK/c-Jun signaling was enhanced. Furthermore, inhibition of JNK/c-Jun signaling in PKCη-null keratinocytes led to upregulation of p27(Kip1) mRNA, and to thinner stratified cell layers. Collectively, our findings indicate that PKCη upregulates p27(Kip1) mRNA through suppression of JNK/c-Jun signaling. This results in promoting a proliferation to differentiation switch in keratinocytes.

We used CT to make a quantitative evaluation of the pontine volumes of 55 patients with adult-onset cerebellar degeneration and compared the results with their clinical records. Patients with pontine atrophy showed significantly more autonomic dysfunction and extrapyramidal signs; their other clinical features did not differ from patients without pontine atrophy. After dividing the patients into 2 groups, those with and without autonomic dysfunction or extrapyramidal signs, we found that those with these manifestations also had pontine atrophy, a later onset and shorter duration of the disease, and impairment of higher brain functions. The group without these manifestations had relatively normal pontine volume, a greater familial tendency for cerebellar degeneration, and longer duration of the disease. Our results suggest that quantitative volume evaluation of the pons by CT is important for the clinical categorization of cerebellar degeneration.

Autonomic function mediating cardiovascular regulation was evaluated in amyotrophic lateral sclerosis (ALS) in comparison with Shy-Drager syndrome. The subjects were 14 normal controls and 9 patients each with ALS and Shy-Drager syndrome. To evaluate the autonomic function in detail, a new series of quantitative autonomic function tests was conducted, in conjunction with conventional tests. In patients with ALS, the data indicated subclinical sympathetic hyperfunction and parasympathetic (vagal) hypofunction, probably resulting in cardiovascular dysfunction.

Peripheral nerve tumor is one of the diseases liable to be overlooked in the usual clinic.Recently we have had four successive cases of peripheral nerve tumor. One of them was at the right plexus brachialis and the others were at the sciatic nerve and its ramification.As the results of histological examination, they were all found to be Schwannoma.

Case: 78-year-old woman. She was aware of a spontaneous tender swelling of the first metatarsal part of the right foot since June '62.The tumor had been incompletely incised or excised six times during the last four years, but within about six months local recurrence has repeated.At the time of her first appearance at our clinic (21st June '66), the tumor was as large as child's fist, and X-ray photograph of the right foot showed the remarkable bone destruction of the first, second and third metatarsus. Clinically it was diagnosed synovial sarcoma. Her right lower leg was amputated according to Syme's method (29th June '66).The patient remains well four months later, and chest X-ray photograph revealed no signs of lung metastasis.

Pain and stiffness of the neck are not uncommonly seen in the patient with rheumatoid arthritis. The x-ray of those patients shows various degree of subluxations of the cervical spine.In our cases the subluxation is most often situated at the atlanto-axial level, but is also less often observed below the second cervical level. One patient reveals the vertical subluxation of odontoid and other shows the posterior displacement of the third cervical spine. Those two patients developed the tetraparesis due to the probable damage of the spinal cord.The degree of the cervical subluxation are closely related to the duration of disease, rheumatoid involvement of the peripheral joint, and the adequacy of the glucocorticoid therapy.

Case 1.Age: 40. Sex: Female. The patient complained of pain in the left shoulder and radiating pain to the left upper arm for two months before admission. Chest x-ray showed an expanding lesion of the left 1st rib. Resection was carried out July 24-1969. The resection specimen microscopically revealed at fibrous dysplasia of bone.Case 2.Age: 59. Sex: Male. The patient first noticed pain in the left shoulder on December 1968, and the pain gradually increased in intensity, radiating to the left upper arm. He was admitted to Nagasaki Atomic Bomb Hospital June 25-1969. Chest x-ray showed an osteolytic lesion of the left 1st rib. Surgical resection of the tumor was carried out July 10-1969. Section of the tumor mass revealed metastatic adenocarcinoma.

At the treatment of patients with rheumatoid arthritis, it is great important to prevent articular deformities, because, once a deformity is established, these correction is very difficult.Recently, we have made an attempt at various corrective procedures; indirect or direct traction, Quengel plaster cast, arthrodesis and protective apparatus, for nine patients with such articular deformities of the leg caused by rheumatoid arthritis. Five of nine were inability of gait, four of nine difficulty.An analysis of our end results shows that five patients were able to walk with no stick, one with stick, and three no change.

Pontine volume was measured and evaluated by computer tomography (CT) in 37 healthy adults and in 29 adult autopsied brains which did not have chronic neurologic diseases. The pons was cut serially into 5 mm slices in the autopsied brains. In the CT examinations both 5 mm and 2 mm slices were studied. Pontine areas in horizontal planes were measured using an image analyzer, then pontine volume was calculated by accumulation of the mean value of the areas and cranio-caudal length. Pontine volume was approximately 19 cm3 and pontine atrophy could be defined as less than 12 cm3 (i.e. the mean — 2 SD) in both methods, which heretofore have not been reported.