Immunoregulatory defects of V alpha 24V+ beta 11+ NKT cells in development of Wegener's granulomatosis and relapsing polychondritis.

The frequency of either CD4(-)8(-) (double negative; DN) or CD4(+) V alpha 24(+)V beta 11(+) NKT cells, the expression of CD1d and the binding of CD1d-tetramer loaded with alpha-galactosylceramide (alpha-GalCer) to NKT cells were analysed in peripheral blood mononuclear cells (PBMCs) of patients with Wegener's granulomatosis (WG), relapsing polychondritis (RP) and healthy subjects (HS). DN and CD4(+) V alpha 24(+)V beta 11(+) NKT cells as well as CD1d-alpha-GalCer tetramer-positive NKT cells, were significantly decreased in number in both WG and RP patients compared to those from HS. When cytokine profiles were analysed in these PBMCs upon stimulation with phorbol ester and calcium ionophore, CD4(+) T cells from patients with WG and RP exhibited a Th1 bias, whereas CD4(+) NKT cells from WG patients in remission showed a Th2 bias. These findings suggest that NKT cells (especially CD4(+) NKT cells) play a regulatory role in Th1 autoimmunity in patients with WG and RP. The reduction in NKT cell counts appears to be associated with the low responsiveness to alpha-GalCer. The dysfunction of NKT cells to recognize ligands such as alpha-GalCer may also contribute to the defects observed in NKT cells from WG and RP patients.

Myeloperoxidase-antineutrophil cytoplasmic antibody-associated sensorineural hearing loss.

A 36-year-old female with hyperthyroidism that had been treated with propilthiouracil (PTU) complained of tinnitus and hearing loss in both ears. She was treated with steroid administration by an otolaryngologist; however, hearing continued to fluctuate when the steroids were tapered. Laboratory evaluation revealed a decreased complement level and elevated levels of immunoglobulin M (IgM) and myeloperoxidase-antineutrophil cytoplasmic antibody (MPO-ANCA). With the withdrawal of PTU and high-dose methylprednisolone, she had excellent return of right-sided hearing. In recent years, there have been many reports about MPO-ANCA-associated small vessel vasculitis. Although any organ may be affected by this disease, there are no reports about MPO-ANCA-associated progressive hearing loss without any other organ involvement. The present case suggests the possibility that inner ear blood flow impairment due to ANCA-associated small vessel vasculitis induces the so-called autoimmune sensorineural hearing loss.

Relapsing polychondritis: a report of eight cases.

OBJECTIVE: To investigate clinical manifestations of relapsing polychondritis and to clarify the significance of type II collagen antibody in the disease. METHODS: Clinical manifestations and antibody titers were examined in eight cases of relapsing polychondritis which had been treated at Otolaryngology Department, Hokkaido University during the eight years from 1991 to 1998. Anti-type II collagen antibody titer was measured by ELISA method. RESULTS: The most frequent symptom was auricular chondritis; it was seen in 88% (7/8) of the cases. Ocular symptom, nasal chondritis, arthritis, respiratory tract chondritis, and audio-vestibular symptom were also common in the cases. Compared with previous reports, no difference was recognized in the manifestation frequency. Considering none of the samples from the controls was positive for anti-type II collagen antibody, two samples from the disease group were positive. The antibody positive rate was 25% (2/8). CONCLUSION: Though the measurement of type II collagen antibody titer is not a decisive factor for detection of relapsing polychondritis, it is useful as one of the complementary factors for the diagnosis, since there is no specific test for this disease.

Churg-Strauss syndrome with pachymeningitis refractory to steroid therapy atone--a case report.

Churg-Strauss syndrome (CSS) is a rare syndrome of unknown cause, which is characterized by bronchial asthma and hypereosinophilia followed by systemic symptoms of angiitis. In 1951, Churg and Strauss first distinguished this disease from periarteritis nodosa. Our patient in particular was also complicated with otorhinological symptoms, which have less frequently been reported in CSS cases. We have detailed her clinical symptoms.

Springtime pollinosis and oral allergy syndrome in Sapporo.

OBJECTIVE: The purpose of this present study was to investigate pollinosis in the spring and oral allergy syndrome (OAS) in Sapporo to utilize it for future treatment. MATERIALS AND METHODS: Of the patients referred to our out-patient clinic during April and May in 1999. all those that were suspected to have pollinosis were asked to fill in a questionnaire. A 101 patients (30 males and 71 females) with a mean age of 33 years (range 7-74 years) answered the questionnaire. In all, the patients specific IgE tests were performed. RESULTS: The most common allergen was birch, affecting 54 of 87 patients (62%). In 61% of patients with birch allergy, we observed fruit and vegetable allergy. Among them, apple was the most prevalent allergen (97%), followed by peach (67%), cherry (58%), pear (40%), plum (40%) and melon (33%). The sensitivity of skin prick test with commercial extract to apple was low (11%). CONCLUSION: Patients with birch pollen allergy had OAS much more frequently than ever reported in Japan, although OAS has not widely been known in Japan. Patients with birch pollen allergy should be informed about the possibility of hypersensitivity to certain fruits.

Taxus cuspidata (Japanese yew) pollen nasal allergy.

We have investigated the Taxus cuspidata pollinosis that has never been studied before. We applied immunoblotting method in order to detect specific IgE antibody against T. cuspidata using its pollen itself. Out of 18 patients with seasonal allergic rhinitis suffering mainly in April and May, 5 patients were sensitized with this pollen. Furthermore, we were able to diagnose one case as T. cuspidata pollinosis from the clinical and laboratory findings. While the birch pollen is the main causative pollen in the spring, T. cuspidata is one of the minor allergens causing pollinosis in our district.

Histological findings in biopsies from patients with cytoplasmic-antineutrophil cytoplasmic antibody (cANCA)-positive Wegener's granulomatosis.

OBJECTIVE: Currently Wegener's granulomatosis (WG) is diagnosed from clinical features, a test for antineutrophil cytoplasmic antibody (ANCA) and histological confirmation. The purpose of our study was to evaluate histological findings, in particular those in the biopsy samples of head and neck region. METHODS: Fifty-one biopsy specimens from 24 WG patients who were confirmed to be positive for cANCA were examined retrospectively. RESULTS: Only 12 biopsies out of 51 biopsies (24%) were diagnosed as typical of WG, and diagnosis could be confirmed in only 10 patients (42%) as typical of WG from the results of multiple biopsy specimens. CONCLUSION: In the diagnosis of WG. biopsy can be utilized restrictedly only in the cases when cANCA is negative or clinical symptoms are atypical of WG.

Correlation between the levels of circulating adhesion molecules and PR3-ANCA in Wegener's granulomatosis.

OBJECTIVE: The adhesion of neutrophils to the vascular endothelial cells appears to be important for the pathogenesis of vasculitis in Wegener's granulomatosis (WG). To determine the pathological significance of the neutrophil adhesion, we have examined and evaluated the relationships between the levels of adhesion molecules and proteinase-3 anti-neutrophil cytoplasmic antibodies (PR3-ANCA), and between the levels of TNF-alpha and disease activities in WG. METHODS: sELAM-1 and sICAM-1 in sera from WG and healthy donors were detected by ELISA. SLex and LFA-1 on neutrophils were detected by flow cytometry. RESULTS: The level of sICAM-1 was significantly higher in active WG than in inactive WG, tending to reflect individual disease activities. There was no difference in the level of sELAM-1 between WG patients and healthy donors. CONCLUSION: Our study suggests that the adhesion of neutrophils to the vascular endothelium is significant for the pathogenesis of the vasculitis in WG.

[Nasal allergies in Kushiro].

A clinical study of 107 patients with nasal allergies who were treated at Kushiro General Hospital between April 1998 and March 2000 was performed. Radioallergosorbent tests (RAST), X-rays, and nasal smears for the detection of eosinophilia were performed to obtain a diagnosis of nasal allergy. The patients (50 males, 57 females) ranged in age from 3 to 71 years. The RAST was positive for timothy in 22.4% of the patients, 14.0% for birch and 12.1% for mugwort. The most common pollinosis allergen in the Kushiro area was grass pollen. Other pollinosis allergens were birch pollen and mugwort pollen. We measured the daily count of dispersed birch pollen and timothy pollen in Kushiro and Sapporo. Birch pollen and timothy pollen was dispersed earlier in Kushiro than in Sapporo. Nasal allergies in the Kushiro area appear to be related to local characteristics, such as climate and geographical features.

Different expression of hepatic and renal cytochrome P450s between the streptozotocin-induced diabetic mouse and rat.

1. Since limited information is available about alterations of cytochrome P450 levels in diabetic animals other than rat, expression of P450s in the liver and kidney of the streptozotocin (STZ)-induced diabetic mouse was investigated. 2. The mRNA levels of CYP2B10, 3A11, 4A10 and 4A14 in the liver were increased in the STZ-induced diabetic mouse of both sexes. The CYP2B9 mRNA level was increased in the liver of the male diabetic mouse. These alterations were observed even at 2 weeks after administration. Insulin treatment restored these changes. The findings were consistent with changes reported in rat. 3. The levels of hepatic CYP1A2 and 2E1 and renal 2E1 and 4A did not change in the diabetic mouse at any time-point examined. No changes were seen in CYP2A- or 2C-related proteins in the diabetic mouse. These findings were in contrast to those in rat. 4. The results indicate that mouse P450s respond to insulin-dependent diabetes mellitus differently from those of the rat, and suggest that the expression of P450s in diabetes is not generally the same across animal species.

A mitochondrial encephalo-myo-neuropathy with a nucleotide position 3271 (T-C) point mutation in the mitochondrial DNA.

We report three members of a family, who exhibited a phenotype similar to 'myoclonus epilepsy with ragged-red fibers' but had a genotype usually associated with 'mitochondrial encephalomyopathy with lactic acidosis and stroke-like episodes'. The patients, a 48-year-old female, and her two sons, aged 21 and 19 respectively, presented with photo-reactive syncopal episodes, disturbances of gait and writing, dysarthria and finger tremor since the 3rd and 2nd decade of life, respectively, that were accompanied also by numbness and weakness of the extremities. Subsequently, cerebellar ataxia and myoclonus were also noted. Electromyography revealed both myogenic and neurogenic muscular changes, and nerve conduction studies demonstrated a sensory-motor neuropathy. Biopsy showed ragged-red fibers with strongly stained SDH-positive vessels in skeletal muscles, and a marked loss of myelinated fibers of the sural nerves. Mitochondrial (mt) DNA analyses of peripheral blood, muscles and nerves revealed that all members had a heteroplasmic np3271 (T-C) point mutation in the mitochondrial tRNA-Leu gene (UUR). This family is unique, in that all patients presented with a myoclonus epilepsy with ragged-red fibers-like phenotype and had a distinctive peripheral neuropathy, while the detected mtDNA 327l (T-C) mutation has been reported to date only in rare cases of mitochondrial encephalomyopathy with lactic acidosis and stroke-like episodes

P-ANCA-positive Wegener's granulomatosis presenting with hypertrophic pachymeningitis and multiple cranial neuropathies: case report and review of literature.

An autopsy case of hypertrophic pachymeningitis and multiple cranial neuropathies is reported. A 53-year-old woman with paraplegia and various neurological signs which developed over a 2 year period was diagnosed as having an epidural mass with thickened dura mater extending from the lower cervical to the thoracic spinal cord. In addition, bilateral episcleritis, blephaloptosis, and blindness of the right eye with various cranial nerve deficits were found to be caused by the mass lesions involving the paranasal sinuses, orbit, and the cavernous sinus. Perinuclear antineutrophil cytoplasmic antibody (p-ANCA) was positive, but cytoplasmic antineutrophil cytoplasmic antibody (c-ANCA) was negative by enzyme-linked immunosorbent assay. The partially removed epidural mass with hypertrophied dura mater and biopsy of the paranasal lesions showed chronic granulomatous inflammation with vasculitis. The remaining lesions resolved with steroid therapy with remarkable neurological improvement. The positive p-ANCA test, paranasal involvement, the report of a similar histopathological case and a review of the literature on granulomatous pachymeningitis suggest the presence of p-ANCA-positive Wegener's granulomatosis with central nervous system involvement characterized by hypertrophic pachymeningitis and/or multiple cranial neuropathies.

Oculopharyngeal muscular dystrophy in a Japanese family with a short GCG expansion (GCG)(11) in PABP2 gene.

Clinicopathological and molecular genetic findings on a new Japanese family with oculopharyngeal muscular dystrophy are reported. The family has 54 members, ten of whom are affected (seven male and three female), in 3 generations. Three affected males, one affected female and one unaffected female of seven living siblings in the third generation were examined. Bilateral ptosis developed in the 4th and 5th decades in the three male cases, and in the 7th decade in the female, and this was followed by diplopia, nasal voice, dysphagia and muscle weakness. In addition, severe external ophthalmoplegia, dysphonia, and proximal amyotrophy were prominent in this family. Electromyographs revealed myogenic/neurogenic changes, and computed tomography disclosed selective muscle wasting with fatty replacement, predominantly in the lower extremities. Muscle biopsy in the four affected patients showed variation in fiber size, and the presence of small angulated fibers and occasional rimmed vacuoles. Electron microscopic examination revealed an accumulation of filamentous inclusions in muscle fiber nuclei. DNA analysis identified that (GCG)(6) in the PABP2 gene was expanded to (GCG)(11) in the four affected cases examined. All studies were negative in the one unaffected. These results confirm that OPMD is caused by GCG short expansion and provides insights into the genetic mechanisms which may contribute to adult onset myopathy, confined to oculopharyngeal muscles.

A case of bilateral optic neuropathy and recurrent transverse myelopathy associated with perinuclear anti-neutrophil cytoplasmic antibodies (p-ANCA).

A case involving a 52-year-old man having bilateral optic neuropathy and recurrent transverse myelopathy is reported. His clinical features resembled multiple sclerosis, but neuroimaging failed to show evidence of demyelination or inflammation in the brain or the optic nerves. The patient experienced sudden visual loss despite massive steroid therapy. Positive perinuclear anti-neutrophil cytoplasmic antibody (p-ANCA) is suggestive that optic neuropathy and recurrent transverse myelopathy may have been caused by some common inflammatory processes associated with p-ANCA, however, having a different etiology from multiple sclerosis.

The association between human leukocyte antigens (HLA) and cytoplasmic-antineutrophil cytoplasmic antibody (cANCA)-positive Wegener's granulomatosis in a Japanese population.

The present study examined the association between various human leukocyte antigens (HLA) and cytoplasmic-antineutrophil cytoplasmic antibody (cANCA)-positive Wegener's granulomatosis (WG) in Japanese subjects to determine whether HLA antigens are involved in the pathogenesis of this disease. The study involved 16 subjects with cANCA-positive WG treated in our department. HLA-typing of the lymphocytes was performed using a lymphocyte microcytotoxicity assay. Of the subjects with cANCA-positive WG, 62.5% (10/16) were positive for HLA-DR9, as compared to 26% of the healthy control subjects. This HLA-DR9 elevation was statistically significant (p < 0.01, Pc < 0.05); we also noted a weaker association between HLA-B55 and cANCA-positive WG (p < 0.05). The results indicate that an association may exist between certain HLA-class allotypes and WG.

Thyroplasty type I with ceramic shim.

To prevent side effects from a silicone shim in Isshiki thyroplasty type I, we used a ceramic shim in 10 patients with unilateral recurrent laryngeal nerve paralysis. No published reports have described the use of ceramic in this type of surgery. According to the degree of glottic insufficiency, ceramic shims of various heights were inserted into the fenestration made in the thyroid ala. All patients experienced subjective improvement of voice postoperatively. Laryngoscopies in most cases showed that glottic insufficiency improved postoperatively. In the postoperative examination, the maximum phonation time improved an average of 3.7 s, and the mean flow rate improved an average of 331 ml/s. We have analyzed the relationship of these improvements to the degree of glottic insufficiency and have compared our results with those of other investigators.

[Antineutrophil cytoplasmic antibody (C-ANCA) levels in relation to the treatment of Wegener's granulomatosis].

We assessed the clinical significance of cANCA in relation to the diagnosis and follow-up of Wegener's granulomatosis patients using NephroScholor C-ANC, the ELISA kit for the detection of cANCA. The NephroScholor C-ANC test for cANCA was revealed to be useful for the diagnosis of Wegener's granulomatosis, but slightly less sensitive than the indirect immunofluorescence assay using human neutrophils, which has been in widespread use for the detection of ANCAs. With NephroScholor C-ANC, the cANCA titer can be estimated conveniently and expressed quantitatively. When conventional immunosuppressive therapy with prednisolone and cyclophosphamide was applied, the patients' symptoms subsided as the cANCA titer decreased, and thus it also seemed useful for the follow-up of Wegener's granulomatosis patients. However, a rising ANCA titer during the course of the disease was not always correlated with the occurrence of a relapse as previously reported. Based on these findings, it is not recommended that treatment be changed immediately because of elevation of the ANCA titer alone, and it never seemed too late to increase immunosuppressive therapy, even after a clinical exacerbation was observed. Several treatments other than the conventional immunosuppressive therapy have often been applied for our patients, especially in the limited type of this disease, and these treatments, including sulfamethoxazole-trimethoprim alone, low-dose prednisolone alone, and cyclophosphamide alone, have often been useful. We conclude that the choice of therapy must depend on the severity or the condition of the individual patient, and this therapeutic policy should reduce unnecessary side effects of potentially toxic drugs.

[Effect of oak pollen on patients with birch pollinosis].

The author reviewed 53 cases of birch pollinosis treated in our ENT-clinic between 1990 and 1991. Of interest is the fact that many of these patients complained of typical symptoms in and after June, when birch pollen has usually disappeared. We considered this discrepancy to be attributable to the effects of grass pollen, one of the common causal agents in this period. However, only a few patients tested positive for grass pollinosis. We therefore postulated that cross-reactivity between birch and oak pollen accounted for this phenomenon, because both trees belong to same order, Fagales. A strong correlation between RAST scores for birch and oak pollen was detected, and the oak pollen RAST score was significantly reduced by birch pollen extract in an inhibition test. These findings demonstrated actual cross-reactivity between birch and oak pollen. Birch pollinosis patients in Sapporo therefore have allergic symptoms from March to July.

[Clinical study of subglottic carcinoma].

Recently, therapy for laryngeal carcinoma has been becoming established, particularly in the early stage. The prognosis of laryngeal carcinoma is said to be better than that of other head and neck carcinomas. Laryngeal carcinoma is divided into 3 subtypes, supraglottic, glottic and subglottic, according to origin. We analyzed the subglottic carcinomas diagnosed and treated in our department between 1972 and 1990. During that period we treated 515 cases of laryngeal carcinoma, 204 cases of the supraglottic type, 284 cases of the glottic type, and 27 cases (5.2%) of the subglottic type. The 5-year survival rate in subglottic carcinoma was 44% (T1: 83%, T2:55%, T3: 17%, T4: 0%), worse than in the other types of laryngeal carcinoma. We think that there were 2 main reasons for the worse prognosis. The first was their high rate of local recurrence after radiation therapy particularly in the early stage. Although 15 T1 and T2 patients who received full dose (65Gy) radiotherapy had a complete response, 8 patients developed local recurrence. The results of the salvage operation were good in T1 cases, but were followed by death because of metastasis or second recurrence in 2 of the 3 T2 patients. The second reason for the worse prognosis appeared to be metastasis in the advanced cases. Five (50%) T3 and T4 patients developed metastasis to the lung, mediastinum and cervical lymph nodes, resulting in death. Thus, we believe that the main therapy for subglottic carcinoma, except T1, should be surgery to obtain a better outcome, and that adjuvant chemotherapy after irradiation or neck (paratracheal) dissection with total laryngectomy should be performed in advanced cases.