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Myotonia congenita is a non-dystrophic skeletal muscle disorder characterized by muscle stiffness and an inability of the muscle to relax after voluntary contraction caused by a mutation in the gene encoding skeletal muscle chloride channel-1 (CLCN1). We encountered a case of Thomsen disease with ptosis. A short tau inversion recovery MR imaging demonstrated high-intensity lesions in the levator palpebrae superioris muscles. Molecular genetic testing revealed a heterozygosity for the c.1439C>A (p.P480H) mutation in the CLCN1 gene. The expression level of ClC-1 was significantly reduced on the sarcolemma of the biceps brachii muscle from the patient, compared with that from healthy volunteer. Functional analysis of the p.P480H mutation is required for further elucidating the pathogenesis of Thomsen disease.

Summary Background Pulmonary fibrosis is a manifestation of microscopic polyangitis (MPA), and often precedes the detection of MPA. The prevalence and sequence of myeloperoxidase anti-neutrophil cytoplasmic antibody (MPO-ANCA) and MPA in patients initially diagnosed with idiopathic pulmonary fibrosis (IPF) have not been precisely elucidated. Methods We enrolled 61 consecutive patients with IPF and measured the MPO-ANCA titers at initial presentation and during the follow-up period. Clinical, radiologic and histologic features of MPO-ANCA-positive cases were examined. Results Of 61 patients, 3 (4.9%) had positive MPO-ANCA titers at the initial presentation of IPF. During the disease course, MPO-ANCA-positive conversion occurred in 6 patients and the prevalence of ANCA increased to 14.8%. Among the nine patients positive for MPO-ANCA, two patients developed MPA during follow-up. Histologic features of MPO-ANCA-positive pulmonary fibrosis were compatible with the usual interstitial pneumonia pattern in which alveolar hemorrhage and capillaritis were not observed. The patients with MPO-ANCA-positive conversion showed increased percentages of bronchoalveolar lavage eosinophils and more frequent complication of pulmonary emphysema compared to those with MPO-ANCA-negative IPF. Conclusions The findings of the present study demonstrated that patients with an initial diagnosis of IPF occasionally acquire MPO-ANCA, which develops to MPA during the disease course of IPF. The presence of pulmonary eosinophilia and low attenuation areas on computed tomography scans might be predictive of MPO-ANCA positive conversion.

Background: This study examined the relationship between baseline white matter lesions (WMLs) and the progression of cognitive decline in patients with late-onset Alzheimer's disease (AD). Methods: Fifty-six patients with AD were included in the study (23 men, 33 women; mean age, 77.8 years). All subjects were treated with acetylcholinesterase inhibitors and followed up for approximately 1 year. The Mini-Mental State Examination (MMSE) score was assessed at least twice to evaluate the progressive cognitive impairment. All subjects underwent brain MRI at baseline and were divided into WMLs(-), mild WMLs(+), and moderate WMLs(+) groups based on WML severity. Changes in MMSE scores between baseline and follow-up were analyzed using the Wilcoxon signed-rank test. Results: MMSE scores at baseline did not differ significantly among the three groups (p = 0.1658), whereas MMSE scores at the follow-up evaluation were significantly lower in the moderate WMLs(+) group than in the WMLs(-) group (p = 0.0257). The mean MMSE scores remained above baseline values during the approximately 1-year follow-up in the WMLs(-) group, whereas they were decreased in the mild and moderate WMLs(+) groups. Moreover, the frequency of improvement in patients from the WMLs(-) group tended to be higher than that in patients from the WMLs(+) groups. Conclusion: Baseline WMLs may be associated with the heterogeneous progression of cognitive decline in patients with AD.

Background: Cerebrovascular white matter lesions (WMLs) are associated with cognitive impairment in patients with subcortical vascular dementia. We performed a comprehensive gene expression analysis to elucidate genes associated with WML development in a chronic cerebral hypoperfusion rat model. Methods: Brains of rats with bilateral carotid ligation (2VO, n = 10) and sham-operated rats (n = 5-10/group) were removed on days 1, 7, or 28 after surgery. Total RNA isolated from the corpus callosum was evaluated by microarray analysis and quantitative reverse transcription-polymerase chain reaction. Results: On days 7 and 28, WMLs exhibited histologic changes. On day 7, 16 genes were differentially expressed between groups. mRNA levels of Ptprb, Kcnj8, Crispld2, Bcl6b, and Gja5 were differentially expressed in 2VO rats on day 7, but then returned to normal, whereas mRNA levels of Vwf and Trappc6a were upregulated after day 7. Immunohistochemistry showed that GJA5 and vWF were detected in endothelial cells, KCNJ8 in endothelial cells and astrocytes, CRISPLD2 in neurons and astrocytes, and TRAPPC6A in neurons. Conclusion: Our findings indicate novel genes that may be associated with WML development in the chronic cerebral hypoperfusion rat model, and suggest an important role of neurovascular dysfunction in the pathophysiology.

Background Glucosamine (UDP-N-acetyl)-2-epimerase/ N -acetylmannosamine kinase (GNE) myopathy, also called distal myopathy with rimmed vacuoles (DMRV) or hereditary inclusion body myopathy (HIBM), is a rare, progressive autosomal recessive disorder caused by mutations in the GNE gene. Here, we examined the relationship between genotype and clinical phenotype in participants with GNE myopathy. Methods Participants with GNE myopathy were asked to complete a questionnaire regarding medical history and current symptoms. Results A total of 71 participants with genetically confirmed GNE myopathy (27 males and 44 females; mean age, 43.1±13.0 (mean±SD) years) completed the questionnaire. Initial symptoms ( e.g. , foot drop and lower limb weakness) appeared at a mean age of 24.8±8.3years. Among the 71 participants, 11 (15.5%) had the ability to walk, with a median time to loss of ambulation of 17.0±2.1years after disease onset. Participants with a homozygous mutation (p.V572L) in the N -acetylmannosamine kinase domain (KD/KD participants) had an earlier disease onset compared to compound heterozygous participants with mutations in the uridine diphosphate-N-acetylglucosamine (UDP-GlcNAc) 2-epimerase and N -acetylmannosamine kinase domains (ED/KD participants; 26.3±7.3 vs. 21.2±11.1years, respectively). KD/KD participants were more frequently non-ambulatory compared to ED/KD participants at the time of survey (80% vs. 50%). Data were verified using medical records available from 17 outpatient participants. Conclusions Homozygous KD/KD participants exhibited a more severe phenotype compared to heterozygous ED/KD participants.

Primary malignant melanoma of the trachea is extremely rare. We report here the first case of primary tracheal malignant melanoma in the asymptomatic stage. Incidentally, this 73-year-old man was found to have a flat tumor at the upper trachea on chest computed tomography scans. The tumor was surgically resected with end-to-end anastomosis and was diagnosed to be primary malignant melanoma of the trachea. Four months after the surgical resection, cervical lymph node metastasis was found. Despite the resection of metastatic lymph nodes and six courses of chemotherapy, he died of cachexia approximately two years after the discovery of the tracheal tumor.

BACKGROUND We attempt to evaluate objectively the regional cerebral blood flow (rCBF) changes during long-term donepezil therapy and the relationship between the clinical response and rCBF change in patients with Alzheimer's disease (AD). PATIENTS AND METHODS Thirty-one patients with mild-to-moderate AD (11 men, 20 female; mean age, 76.2 ± 6.7 years) were treated with donepezil and underwent brain perfusion single-photon emission computed tomography (SPECT) twice with an interval of 24.5 ± 4.2 months. The rCBF was calculated using 3-dimensional stereotaxic region of interest template, a fully automated each region of interest technique. We compared the differences in rCBF between baseline and follow-up SPECT studies. Moreover, all patients were divided into stabilized (n= 14) and nonstabilized subgroups (n= 17) based on Mini-Mental State Examination (MMSE) score changes and the changes in rCBF were compared between two subgroups. RESULTS The mean MMSE score significantly decreased from 20.7 ± 4.6 at baseline to 16.5 ± 6.5 after 2 years. The mean rCBF significantly decreased in the widespread brain regions between the baseline and follow-up SPECT studies. The nonstabilized subgroup showed a significant decrease in rCBF of the parietal and temporal segments compared to the stabilized subgroup. CONCLUSION The progression of cognitive deterioration may be related to rCBF affected by the neuropathologic changes of AD.

Subclinical thyroid disease and even variations in thyroid function within the normal range is associated with cognitive function and a risk of Alzheimer disease (AD). Several studies reported the effect of thyroid hormones on cerebral blood flow. The aim of this study was to objectively evaluate regional cerebral blood flow (rCBF) in association with thyroid hormone levels within the normal range in patients with AD. Serum thyroid-stimulating hormone (TSH), free T3, and free T4 levels were measured in 62 patients with AD (23 men and 39 women; age 56 to 91 y; mean age 77.3 y) and 27 control subjects (9 men and 18 women; age 61 to 93 y; mean age 75.8 y). The 99mTc ethylcysteinate dimer single photon emission computed tomography was performed in all subjects. The rCBF in the region of interest was measured by the noninvasive Patlak plot method and calculated using FineSRT, which is a fully automated region of interest technique. No significant correlation was found between thyroid hormone levels and Mini-Mental State Examination scores or global CBF values. Serum levels of TSH, but not free T3 or free T4, were significantly inversely correlated with rCBF in the middle and inferior temporal regions of right cerebral hemisphere in patients with AD. Control subjects showed no significant correlation between thyroid hormone levels and rCBF. Although these findings of a regional relationship must be considers preliminary, this study proposed the hypothesis that altered TSH levels within the normal range may be related to brain perfusion in right temporal region.

Objective: This study aimed to compare thin-section CT images from sarcoidosis patients who had either normal or elevated serum KL-6 levels. Methods: 101 patients with sarcoidosis who underwent thin-section CT examinations of the chest and serum KL-6 measurements between December 2003 and November 2008 were retrospectively identified. The study group comprised 75 sarcoidosis patients (23 male, 52 female; aged 19–82 years, mean 54.1 years) with normal KL-6 levels (152–499 Uml –1 , mean 305.7 Uml –1 ) and 26 sarcoidosis patients (7 male, 19 female; aged 19–75 years, mean 54.3 years) with elevated KL-6 levels (541–2940 Uml –1 , mean 802.4 Uml –1 ). Two chest radiologists, unaware of KL-6 levels, retrospectively and independently interpreted CT images for parenchymal abnormalities, enlarged lymph nodes and pleural effusion. Results: CT findings in sarcoidosis patients consisted mainly of lymph node enlargement (70/75 with normal KL-6 levels and 21/26 with elevated KL-6 levels), followed by nodules (50 and 25 with normal and elevated levels, respectively) and bronchial wall thickening (25 and 21 with normal and elevated levels, respectively). Ground-glass opacity, nodules, interlobular septal thickening, traction bronchiectasis, architectural distortion and bronchial wall thickening were significantly more frequent in patients with elevated KL-6 levels than those with normal levels (p,0.001, p,0.005, p,0.001, p,0.001, p,0.001 and p,0.001, respectively). By comparison, there was no significant difference in frequency of lymph node enlargement between the two groups. Conclusion: These results suggest that serum KL-6 levels may be a useful marker for indicating the severity of parenchymal sarcoidosis.

An 80-year-old woman was admitted to our hospital because of developed sense of constriction in the trunk and gradually progressive numbness and muscle weakness in the upper and lower extremities. Cerebrospinal fluid analysis showed increased cell count and protein level. Gadolinium enhanced magnetic resonance imaging (MRI) of spine showed the enhancement and swelling of bilateral nerve root in the cervical and lumbar segments. Although chest computed tomography showed neither bilateral hilar lymphoadenopathy nor lung lesions and serum angiotensin converting enzyme and lysozyme (ACE) were normal, tuberculin skin test was negative and cell count and CD4/CD8 elevated in bronchoalveolar lavage fluid. Biopsy specimen of scalene lymph node showed noncaseating granuloma. The patient was treated with oral predonisolone, which improved her symptoms and abnormalities on MRI. It is important to consider neurosarcoidosis in the differential diagnosis of polyradiculopathy with swelling and gadolinium enhancement of spinal nerve roots.

Background Cysteinyl-leukotrienes (CysLTs; LTC4, LTD4, and LTE4) play a considerable role in the pathophysiology of aspirin-intolerant asthma (AIA). Saliva has recently been validated as novel, simple, and noninvasive method for investigating inflammation in patients with asthma. The aim of this study is to clarify the molecular species of CysLT in saliva and to evaluate the CysLT and LTB4 concentrations in saliva in AIA patients. We also examined how the CysLT concentration in saliva reflects that of their corresponding urinary metabolite. Methods We preformed an analytical cross-sectional study. CysLT and LTB4 concentrations in saliva were quantified by enzyme immunoassay (EIA) following purification by high-performance liquid chromatography (HPLC). Results: 1. When analyzed by EIA in combination with HPLC, saliva was found to consist of LTC4, LTD4 and LTE4 in similar amounts. 2. In saliva analysis among the three groups (AIA patients, aspirin-tolerant asthma [ATA] patients, and healthy subjects), both the concentrations of CysLTs and LTB4 were significantly higher in AIA patients than in ATA patients and healthy subjects. 3. We found significant correlations between CysLT concentration and LTB4 concentration in saliva in each group. 4. No significant correlation was found between the concentration of LTE4 in urine and that of CysLTs in saliva. Conclusions In this study, we found higher concentrations of CysLTs and LTB4 in saliva from AIA patients than in saliva from ATA patients, suggesting that the quantification of CysLT and LTB4 concentrations in saliva may be another diagnostic strategy for AIA.

Introduction This study examined the frequency of hypertrophic pulmonary osteoarthropathy (HPO) and the clinical characteristics of lung cancer with HPO. Methods The results of 2625 lung cancer patients who underwent bone scintigraphy were reviewed to identify patients with HPO, which was diagnosed when the bone scintigram showed a diffuse, symmetric pattern of bilateral increased uptake in the long tubular bones. Clinical characteristics were investigated based on the clinical and pathologic records. Results Nineteen patients (0.72%) were found to have HPO: 17 were men, 17 were heavy smokers, and 13 had clinical stage IIIB or IV disease. Ten patients complained of pain or edema in the extremities, and seven of them had stage IIIB or IV disease. In four patients with clinical stage IIIB or IV disease, HPO was not detected at the first presentation, and the diagnosis was made after disease progression. The symptoms of HPO improved in two patients who underwent surgical resection but in only three of five patients who received chemotherapy. The HPO findings on the bone scintigram improved in 2 of 3 patients who underwent surgical resection and 5 of 11 patients who received chemotherapy. Conclusions Less than 1% of the lung cancer patients developed HPO as a paraneoplastic manifestation. Males, heavy smokers, and advanced disease predominated in lung cancer patients with HPO. The symptoms and bone scintigram findings of HPO improved in half of the patients on treating the lung cancer.

Objective: The aim of the present study was to clarify the expression of uridine diphospho-N-acetylglucosamine 2-epimerase/N-acetylmannosamine kinase (GNE) protein and mRNA in damaged or regenerating myofibers. Methods: We investigated the muscle expression pattern of GNE protein by immunohistochemistry using a murine model involving intramuscular injection of cardiotoxin (CTX), and the expression level of GNE mRNA by quantitative real-time polymerase chain reaction analysis of damaged or regenerating myofibers that had been collected directly from tissue sections using laser-capture microdissection. Results: The expression of GNE protein was increased in severely damaged myofibers as well as in regenerating myofibers with central nuclei, both of which also showed an increase in the expression of GNE mRNA. In regenerating myofibers, immunoreactivity for GNE protein in nuclei relative to that in the cytoplasm was higher at 7 days than at 4 days after CTX injection. Conclusion: Our findings suggest that GNE expression is induced when myofibers are damaged or regenerating, and that GNE plays a role in muscle regeneration.

In adult asthmatics the incidence of gastro-oesophageal reflux disease (GERD) reportedly ranges from 34% to 89%. Oesophageal pH monitoring and endoscopy are not required in the patient with typical GERD symptoms before the initiation of a therapeutic trial. Diagnosis of GERD on the basis of history is the simplest and quickest method, placing no demand on patients. Recently, a new questionnaire (FSSG; Frequency Scale for the Symptoms of GERD) was produced to evaluate the severity and the therapeutic response of GERD. The FSSG (F-scale) was used to assess the GERD in subjects with persistent moderate to severe asthma treated with anti-inflammatory asthma medication. In the present study, 27.4% of the patients with asthma had symptoms suggestive of GERD. There is significant correlation between GERD symptom (F-scale score) and severity of cough and sputum. The observations suggested that reflux symptoms, not gastric dysmotility symptoms, significantly associated with severity of cough, not of sputum. It is the first such study to use a FSSG as incidence of GERD symptoms in asthmatics and examine the relationship between F-scale score and asthmatic symptoms.

We previously reported that administration of a potent calpain inhibitor, E-64-d, which protects protein kinase C (PKC) from proteolysis, in a mouse model of Chediak–Higashi syndrome (CHS) (beige mice), decreases its susceptibility to Staphylococcus aureus infection. In the present study, we examined the in vitro effect of E-64-d on both deficient natural killer (NK) and delayed bactericidal activities of leukocytes from six CHS patients. Our results showed that pretreatment of peripheral blood mononuclear cells (PBMCs) obtained from CHS patients with E-64-d (1 μg/ml) significantly enhanced NK activity against K562 cells. The delayed bactericidal activity of polymorphonuclear cells (PMNs) against S. aureus also showed marked improvement. This was recovered to almost normal levels when PMNs were pretreated with E-64-d (1 μg/ml). On the other hand, the same concentration of E-64-d did not affect either the NK or bactericidal activity of normal controls. In addition, we confirmed that following E-64-d treatment, the abnormal down-regulation of PKC activity after concanavalin A (Con A) stimulation was eliminated in PBMCs obtained from CHS patients. To examine whether PKC is involved in the NK cell-mediated cytolysis and bactericidal activity of PMNs, two potent PKC inhibitors, chelerythrin and GO6976, were used. We found that chelerythrin inhibits NK activity of normal PBMCs in a dose-dependent manner, and GO6976 inhibits NK activity at doses that inhibit Ca 2+ -dependent PKC isozymes. These inhibitors also suppressed the bactericidal activity of PMNs against S. aureus . Taken together, our findings suggested that E-64-d improved the compromised NK and bactericidal activity of leukocytes from CHS patients by reversing the down-regulation of PKC activity.

50歳，男性。強い疼痛を伴う手指の冷感にて発症し，全指趾末節が暗紫色調となり，肢端が壊疽となった。38度台の発熱，好中球優位の白血球増多，CRP高値，低酸素血症を伴い，肺血流シンチにて左下葉，右肺尖部に欠損を認めた。前腕伸側の大豆大の皮下硬結の病理組織検査では，血栓を伴った動脈炎の所見のみしか得られなかった。理学的に，四肢末梢の知覚過敏が有り，多発性単神経炎と診断した。1ヵ月で約15kgの体重減少も認めた。発熱に対して抗生剤は無効であった。臨床症状から結節性多発動脈炎を疑い，ヘパリン投与下のステロイドパルス療法とその後のプレドニゾロンおよびシクロホスファミド内服により炎症所見と低酸素血症は改善した。交感神経節ブロック，高圧酸素療法などを併用し，切断を要した左第4趾以外は救指し得た。

Background Anaphylaxis is a life-threatening syndrome resulting from the sudden release of mast cell- and basophil-derived mediators into the circulation. However, pathological evidence of the association between inflammatory mediators and human anaphylaxis is insufficient. Objective The aim of this study was to better understand the relationship between in vivo production of inflammatory mediators and the pathogenesis of anaphylaxis. We also sought to evaluate mast cell activation in anaphylaxis. Methods We measured the concentrations of various inflammatory mediators in urine samples, which were collected from 32 anaphylactic patients during the onset of anaphylaxis and during clinical remission, 21 patients with asthma on acute exacerbation and 15 healthy control subjects. Blood and urine specimens were collected from the patients after provocation test. Urinary leukotriene E4 (LTE4), 9alpha, 11beta-prostaglandin F2 (9alpha, 11beta-PGF2), eosinophil-derived neurotoxin (EDN) and leukotriene B4 glucuronide (LTBG) concentrations were determined by enzyme immunoassay, and the activity of plasma platelet-activating factor acetylhydrolase and serum tryptase concentration were measured using commercially available kits. Results Significantly higher concentrations of urinary LTE4 and 9alpha, 11beta-PGF2, which immediately decreased during clinical remission, were observed in the anaphylactic patients than in asthmatic patients on acute exacerbation and healthy control subjects. Concentrations of EDN and LTBG were not significantly different among the anaphylactic patients, asthmatic patients on acute exacerbation and healthy subjects. There was a significant correlation between urinary LTE4 and 9alpha, 11beta-PGF2 concentrations in the anaphylactic patients (r=0.672, P=0.005, n=32). In addition, LTE4 concentration in patients with anaphylactic shock is significantly elevated compared with that in patients without anaphylactic shock. Conclusions This is a report on the significant increase in urinary LTE4 and 9alpha, 11beta-PGF2 concentrations during anaphylaxis. Urinary LTE4 and 9alpha, 11beta-PGF2 concentrations may be a reliable marker of endogenous production of inflammatory mediators associated with anaphylaxis.

ADAM (a disintegrin and metalloprotease) family members are membrane-anchored proteins with wide ranging functions, including proteolytic cleavage of cell surface molecules, cell fusion, cell adhesion and intracellular signaling. ADAM8, also known as CD156a, is expressed mainly in cells of the immune system, such as monocytes, neutrophils, eosinophils, dendritic cells, and B cells. It can cleave a variety of substrates and is a sheddase for CD23 and L-selectin. ADAM8 has an important role in allergic inflammation. ADAM8 mRNA expression is increased with disease progression in asthma. ADAM8 is strongly induced by allergens and Th2 cytokines in the lung in experimental asthma. Soluble ADAM8 is elevated in the bronchoalveolar lavage fluid of patients with eosinophilic pneumonia and has a physiologic role in protecting against allergic pulmonary disease in experimental murine asthma. Together, these findings support the view that ADAM8 might be a therapeutic target for allergic respiratory diseases. This review discusses novel strategies for immune intervention in allergic respiratory disease.

SummaryClinically there are several different types of eosinophilic pneumonia (EP), but other than for tropical pulmonary eosinophilia, the humoral immune response between different types of EP, such as acute eosinophilic pneumonia (AEP), chronic EP, drug-induced EP, allergic bronchopulmonary aspergillosis, and Churg–Strauss syndrome, has not been examined. Immunoglobulin G (IgG) and E (IgE) serum concentrations were analyzed in patients with EP, or bacterial pneumonia, and in age-matched controls. Patients with AEP had lower IgG levels than the age-matched controls. Serum IgG levels in patients with AEP were significantly lower than in patients with other types EP or bacterial pneumonia. IgG2 and IgG4 were also significantly decreased in AEP, compared to age-matched controls. In AEP, the serum IgG levels were significantly decreased during active disease and increased during remission, but the serum IgE levels did not change significantly, indicating a decrease in serum IgG is a common feature of AEP. Low IgG levels were significantly correlated with serum surfactant protein D and absolute eosinophil counts in the bronchoalveolar lavage fluid of patients with AEP. This is the first reported study of immunoglobulin levels in AEP. The pathogenesis of AEP might negatively affect serum IgG levels, but not IgE levels. The present findings might indicate that serum IgG reflects the inflammatory response in AEP.

We report the case of a woman with primary progressive aphasia (PPA) presenting with conduction aphasia. Neurological findings showed bilateral finger tremor and signe de poignet fige in her right hand. Memory, orientation, and activities of daily living were well preserved. Linguistic examination showed severe impairment in repetition, fluent spontaneous speech with phonemic paraphasia, and relatively well preserved comprehension. Limb-kinetic apraxia and parkinsonism were not observed during the course of her illness. T1-weighted magnetic resonance imaging revealed severe atrophy of the left temporal lobe and dilatation of the left Sylvian fissure. Neuropathological findings demonstrated the most severe atrophy in the left superior temporal gyrus and Gallyas–Braak-positive or phosphorylated tau-immunoreactive cytoskeletal structures, which were consistent with corticobasal degeneration (CBD). We speculate that the progressive conduction aphasia of our patient might have been caused by left temporal lobe impairment. We suggest that progressive conduction aphasia may be a feature of CBD presenting with PPA.

Objective To evaluate the affective state biochemically and quantitatively in amyotrophic lateral sclerosis (ALS) patients using salivary chromogranin A (CgA) measurement. Subjects and Methods Twelve moderate and 12 terminal ALS patients defined using the ALS Health State Scale were studied. The correlation between salivary CgA levels and the 40-item ALS assessment questionnaire (ALSAQ-40) scores was investigated in 12 moderate ALS patients. Moreover, salivary CgA levels in 12 terminal ALS patients, in whom the emotional functioning score could not be assessed, were compared with those in 12 moderate ALS patients, 7 patients with tube-fed vascular dementia, and in 26 healthy volunteers. Results There were individual differences in salivary CgA levels in spite of similar severity of disease; however, mean salivary CgA levels in terminal ALS patients, in whom the emotional functioning score based on interview could not be assessed, was significantly higher (12.58±2.79 pmol/mL) than in patients with moderate ALS (6.36±1.62 pmol/mL, p

Background: Sinusitis occurs frequently in asthmatic patients. Epidemiologic data on sinusitis and lower airway disease must be evaluated with caution because they are based mostly on symptoms and do not include nasal endoscopic or computed tomography (CT) findings. Clinical support and evidence for this association are lacking. We evaluated the impact of sinusitis on lower airway disease in patients with well-characterized asthma. Methods: Subjects (n = 188) completed a questionnaire designed to provide information about their signs and symptoms related to asthma, allergic rhinitis (AR) and sinus disease. Patients (n = 104) were divided into four groups based on the presence or absence of sinusitis and/or AR. Clinical findings were compared in asthma patients with and without diagnosed sinusitis, by an otorhinolaryngologist or based on sinus CT findings. Results: The prevalence of sinusitis in patients with asthma was 36.7%. Sinus CT scan abnormalities were detected in 66.3% of patients with asthma. The scans revealed abnormal opacity in 17.9% of asthmatic patients without a history of sinusitis. There was a significant correlation between the rate of asthma severity and sinus morphologic abnormalities in patients with and without sinusitis. In adult-onset asthma (≧16 years old), sinusitis frequently preceded asthma, whereas in non-adult-onset asthma (Conclusions: Our findings suggest that bronchial asthma is closely related to sinusitis and the onset age of asthma is important when considering allergic disease frequency. Whether sinus disease directly affects the intensity of bronchial inflammation remains to be elucidated.

We describe a 39-year-old Japanese man with rippling muscle disease who carried a novel homozygous mutation (Trp70 to a stop codon) in the caveolin-3 gene. The patient also had extraocular muscle paresis showing atrophy of the extraocular muscles on orbital MRI. The involvement of the extraocular muscles of patients with caveolinopathy is discussed.

Objective Sarcoidosis is considered to be provocated by highly activated Th1 lymphocytes. Because interleukin 12 (IL-12) is one of the most important cytokines for promoting Th1 reaction, we tried to detect IL-12 and its ligand IL-12 receptor in sarcoidosis patients. Patients and methods We measured the serum concentration of IL -12 p40 and IL-12 p70 by ELISA method with serum obtained from 60 sarcoidosis patients, and compared the serum concentration of IL-12 p40 with other clinical markers of disease activity. Next, we examined mRNA production of IL-12 p35, IL-12 p40, IL-12Rβ1, and IL-12β2 of sarcoid lymph nodes with semi-quantitative RT-PCR method. Results First, we showed that circulating IL-12 p40 was highly increased in sarcoidosis patients and was related to various other clinical markers. In particular, it was correlated with the number of involved organs which means systemic disease expansion. Second, we showed that the mRNA expression of IL-12 p40 and IL-12 receptor β2 subunit was increased in sarcoid lymph nodes. Conclution Our data suggest that increased circulating IL-12 p40 is an important systemic marker for disease activity, and it reflects the increased interaction between Il-12 and its ligand IL-12R in sarcoid lesions of involved organs.

Objective: Chloroquine modulates autophagocytic protein degradation in the lysosome system, thereby inducing the formation of rimmed vacuoles consisting of autophagosomes and autolysosomes in skeletal muscle. The goal of this study was to investigate the contribution of the lysosomal system, particularly autophagosome formation (an autophagic process) at the molecular level, to the abnormal accumulation of vacuoles in an experimental model of chloroquine-induced myopathy. Methods: Histological, immunohistochemical and semiquantitative reverse transcriptase-polymerase chain reaction studies were performed on innervated and denervated rat soleus muscles after treatment with either saline or chloroquine. Results: Accumulation of rimmed vacuoles was observed only in chloroquine-treated denervated muscles. Microtubule-associated protein-1 light chain-3 (LC3) protein and mRNA levels were significantly increased exclusively in denervated muscles from chloroquine-treated rats, whereas Apg5 and Apg12 mRNA levels did not change significantly. Further, the mRNA levels of UDP-N-acetylglucosamine 2-epimerase/N-acetylmannosamine kinase (GNE), which are associated with distal myopathy with rimmed vacuoles showing numerous rimmed vacuoles in its skeletal muscle, were not decreased in denervatedmuscles treated with chloroquine. Conclusions: LC3 mRNA may increase in association with rimmed vacuole formation in denervated muscles from chloroquine-treated rats, suggesting an increase in autophagy at the molecular level. Abnormal accumulation of rimmed vacuoles in this myopathy does not appear to be mediated by inhibition of autophagosome-related genes or GNE gene.

Background: ADAM (a disintegrin and metalloprotease) family members, characterized by a metalloprotease and a disintegrin domain, are membrane-anchored glycoproteins involved in proteolysis and cell adhesion. ADAM8 might have an important role in allergic inflammation. It can cleave a variety of substrates and is a sheddase for VCAM-1 and CD23, the low-affinity IgE receptors. Methods: To evaluate the contribution of ADAM8 to the pathogenesis of eosinophilic pneumonia (EP), we measured the concentrations of soluble ADAM8 (sADAM8) and its substrates, soluble VCAM-1 (sVCAM-1) and soluble CD23 (sCD23), in bronchoalveolar lavage fluid from patients with smoking-induced acute eosinophilic pneumonia (AEP), chronic idiopathic eosinophilic pneumonia (CEP), and drug-induced eosinophilic pneumonia (drug-EP). Results: The sADAM8 and sVCAM-1 concentrations were increased in AEP and CEP. The sCD23 concentration was elevated in AEP. In AEP, but not CEP, the sADAM8 concentration significantly correlated with those of both sVCAM and sCD23. Conclusion: The pathogenesis of AEP, CEP, and drug-EP was distinct with regard to ADAM8. Our results are the first to associate ADAM8 with eosinophilic responses and lung inflammation in humans.

A disintegrin and metalloprotease (ADAM) family members, characterized by a metalloprotease and a disintegrin domain, are membrane-anchored glycoproteins involved in proteolysis and cell adhesion. ADAM8 is specifically induced in the experimental murine asthmatic lung. To evaluate novel pathways involved in asthma pathogenesis, using ADAM8 transgenic mice (ATMS2) in a murine model of asthma. Massive cellular infiltrates in peribronchovascular and interstitial lesions were observed in control mice, while in ATMS2 mice there were only occasional. Vascular cell adhesion molecule (VCAM-1) is involved in specific eosinophil adhesions via alpha4beta1 integrin. VCAM-1 shedding was mediated by the ADAM8 metalloprotease. Endothelial cell shedding of VCAM-1 was increased in ATMS2-stimulated human umbilical endothelial cells. ADAM8-mediated shedding of VCAM-1 might be important for the suppression of experimental asthma. Our data suggest that ADAM8 is a useful therapeutic target.

A 40-year-old Japanese woman was admitted to Oita University Hospital with progressive dyspnea, consciousness disturbance and severe cytopenias. Her chest roentgenogram showed diffuse bilateral infiltrates. She was therefore forced to receive mechanical ventilation. Bone marrow aspiration disclosed numerous hemophagocytic histiocytes, thus suggesting her condition to be hemophagocytic syndrome. In addition, she also developed myocarditis and renal failure. Pulsed methylprednisolone, gamma-globulin, granulocyte colony-stimulating factor and sivelestat sodium hydrate were administrated, and thereafter the patient recovered from cytopenia and organ failure. Afterwards, influenza A H3N2 was detected from bronchial extracts. We should recognize that an influenza A virus infection can induce hemophagocytic syndrome and acute respiratory failure as the initial manifestations of multiple organ failure.

Despite the unknown etiology and pathogenesis of sporadic inclusion body myositis (s-IBM), investigators have speculated that the lysosome system in muscle fiber plays a central role in rimmed vacuole formation, a hallmark of s-IBM. We explored the role of receptor-mediated intracellular transport and autophagy in the lysosomal system in the abnormal accumulation of rimmed vacuoles in s-IBM. Expressions of mannose 6-phosphate receptor (M6PR), clathrin and hApg5 and hApg12 were analyzed in muscle biopsy specimens from patients with s-IBM, amyotrophic lateral sclerosis (ALS) or peripheral neuropathy and in normal human muscle specimens by means of immunohistochemistry and reverse transcriptase-polymerase chain reaction (RT-PCR). Most muscle fibers in control specimens showed little or no immunoreactivity for clathrin and M6PR, which are involved in the receptor-mediated intracellular transport. Abnormal increases in both proteins were observed mainly in the sarcoplasm of atrophic fibers in all diseased specimens. In s-IBM muscles in particular, clathrin and M6PR were often observed inside rimmed vacuoles and in the sarcoplasm of vacuolated or non-vacuolated fibers. mRNA levels of hApg5 and hApg12, which are involved in autophagic vacuole formation, as well as of M6PR and clathrin were significantly increased in s-IBM muscles in comparison to levels in normal and ALS/peripheral neuropathy muscles. Our results suggest that the transport of newly synthesized lysosomal enzymes from the secretory pathway via the trans-Golgi network of the Golgi apparatus and autophagic vacuole formation (i.e., autophagy) in the lysosome system are activated in s-IBM muscles. Remarkable accumulation of rimmed vacuoles is thought to occur because of abnormal lysosome function, especially the formation or turnover of autolysosomes after the fusion of autophagic vacuoles with the early endosomes or because of the increase in the rate of muscle fiber breakdown.

Only a few cases of paraneoplastic neurologic syndrome with multiple cranial palsies have been reported. This is the case report of a patient with small-cell lung cancer and a high titer of anti-Hu antibodies who developed a tonic left pupil and multiple cranial nerve palsies, including palsies of the left fifth through tenth nerves and both twelfth nerves, as in Garcin syndrome showing at least more than seven ipsilateral cranial nerve palsies, in the course of paraneoplastic sensory neuronopathy (PSN). Pathologic examination revealed no metastasis or direct invasion of malignancy with gliosis and perivascular inflammation throughout the brainstem, indicating paraneoplastic encephalomyelitis (PEM). The numbers of EBM11+ cells (probably reactive microglia), CD8+ cells, and CD4+ cells increased. Intracellular adhesion molecule-1 and lymphocyte function associated molecule-1 were expressed intensely on the endothelia of microvessels and were found to have infiltrated mononuclear cells around microvessels in the brainstem. Multiple cranial nerve palsies and their effects including the tonic pupil are likely due to the paraneoplastic effect of the primary systemic malignancy.

Experimental allergic myositis (EAM) in Lewis rats, induced with partially purified myosin, is regarded as a model of human polymyositis. To clarify the role of adhesion molecules in the pathogenesis of EAM in Lewis rats, we investigated intramysial expressions of the intercellular adhesion molecule (ICAM)-1 and vascular cell adhesion molecule (VCAM)-1, and the serum level of soluble ICAM-1 in EAM rats. All the EAM rat muscles had scattered inflammatory foci, as well as cell infiltration and necrosis, by week 4 after the initial immunization (i.e., day 0 after the last immunization). As compared with the control muscles, ICAM-1 and VCAM-1 were strongly expressed immunohistochemically in the endothelium of vessels in the endomysium and perimysium, and to lesser extents in the inflammatory infiltrates and on the sarcolemma of nonnecrotic muscle fibers adjacent to the inflammatory infiltrates or invaded muscle fibers. ICAM-1 in the muscle extracts and sera from EAM rats increased on each test day, as compared with extracts from the normal controls. The values peaked on day 0 after the last immunization, then gradually decreased with time. ICAM-1 elevations in the muscle extracts were correlated with the percent of sections that had inflammatory lesions (P = 0.032) and the histological scores (P = 0.005) on day 0, whereas there was no significance on days 3 and 7. These findings suggest that the adhesion molecules ICAM-1 and VCAM-1 increase in the early stage of EAM, and function in the initiation of the inflammatory process of myositis.

We described two patients with chronic sensory neuronopathy who had anti-HTLV-I antibody in serum and cerebrospinal fluid but no signs of myelopathy, A sural nerve specimen revealed severe degeneration of myelinated and unmyelinated axons. The second patient had subclinical Sjogren's syndrome suggestive of a possible link among human T-cell lymphotropic virus type I (HTLV-I), Sjogren's syndrome and sensory neuronopathy, respectively. The broad spectrum of neurologic disorders associated with HTLV-T infection now would include chronic sensory neuronopathy.

We treated a 55-year-old woman with delayed-onset traumatic cerebrospinal fluid (CSF) rhinorrhea. She developed CSF rhinorrhea 17 months after a closed head injury followed by meningitis 24 months after the incident. Fistula of the right lamina was closed with fascia temporalis under endoscopic sinus surgery (ESS) 26 months after the trauma occurred. There was no recurrence of CSF rhinorrhea or meningitis during the subsequent 18-month follow-up. We compared the clinical features of delayed-onset traumatic CSF rhinorrhea with spontaneous CSF rhinorrhea. CT scanning and ESS were useful in determining of the precise location of the fistula.

Objective To clarify the clinical heterogeneity and genotype-phenotype correlation in dysferlinopathy. Methods We evaluated clinical parameters of 74 dysferlinopathy patients with known dysferlin gene mutations who were previously reported in the literature. Results The age at onset varied from 12 to 59 years (mean 21.7 years). Based on the initial distribution of muscle involvement, clinical phenotypes were divided into four subtypes: limb-girdle type, Miyoshi's type, distal anterior compartment type, or scapuloperoneal type. These phenotypic differences were prominent at the early stages, but were difficult to recognize later in the progression of the disease. Patients with missense mutations had significantly more severe functional status at examination and higher creatine kinase levels than those with frameshift or nonsense mutations. Conclusion Dysferlinopathy exhibited marked heterogeneity in the age at onset, initial distribution of muscle involvement, and rate of disease progression. As this heterogeneity was observed even within the same family, some additional factors distinct from dysferlin might be involved.(Internal Medicine 41: 532-536, 2002)

In an attempt to understand the role of interleukin-18 (IL-18) in the pathogenesis of sarcoidosis, we examined the expression of IL-18 in normal muscle and in muscle biopsies from six patients with muscular sarcoidosis. Western blot analysis demonstrated that IL-18 was identified only in homogenates of granulomatous muscle tissues, but not in normal muscle tissue homogenates. By immunohistochemistry, strongly IL-18-positive cells were distributed predominantly at the boundary zone of the granulomas. They were recognized as activated macrophages by double staining with anti-CD68. Epithelioid cells showed only faint reactivity. Serum IL-18 levels of patients with sarcoidosis were significantly increased compared to those of healthy volunteers. Unlike protein expression, IL-18 mRNA expression was detected even in normal muscles. Our results coupled with those of previous investigations demonstrating activity of IL-18 in inducing interferon-gamma production suggest a significant role of IL-18 in the pathogenesis of sarcoidosis.

A 58-year-old male was admitted to our hospital because of periungual nailfold an erythema and erythematous rash on the dorsal joints of his hands and feet, but no muscle weakness. He was thus diagnosed to have amyopathic dermatomyositis. He had moderate hypoxemia and his chest computed tomography scans demonstrated bilateral ground-glass opacities, implicating complication with interstitial pneumonia. Therapy was initiated with pulsed methylprednisolone followed by high-dose corticosteroids, pulsed cyclophosphamide, and cyclosporine. The skin manifestations improved; however, the pulmonary infiltrates and hypoxemia deteriorated during the 2-month period of the treatment. The treatment was switched from cyclosporine to tacrolimus because of an inadequate clinical response to the therapy, and this resulted in the resolution of interstitial pneumonia. This case indicates that tacrolimus administration should be considered for patients with this life-threatening disorder when it is judged to be refractory to cyclosporine.

A 78-year-old female presented with coexisting primary angiitis of the central nervous system (CNS) and cerebral amyloid angiopathy (CAA) manifesting as motor aphasia caused by a left frontal lobe lesion. Magnetic resonance imaging revealed an enhanced lesion with moderate surrounding edema.Technetium-99m propylene amine oxime single-photon emission computed tomography showed decreased cerebral blood flow (CBF) in the lesions, and high serum soluble-interleukin-2 level was detected, suggesting intravascular lymphoma of the CNS. Cerebral biopsy revealed CAA with secondary florid vasculitic appearance. The CBF and neurological symptoms, such as aphasia and dementia, recovered following steroid treatment. Cerebral vasculitis associated with CAA should be included in the differential diagnosis of an unusually enhanced lesion, because timely diagnosis and aggressive treatment are critical to successful recovery in such elderly patients.

Objective - We determined the prevalence and clinical characteristics of elderly people with cognitively impaired but not demented (CIND) in the community. Material and methods - We examined 945 elderly residents (aged 65 years or more) in a cross-sectional study of a standardized clinical examination in 27 randomly selected communities in the town of Mifune, a standard farming town in Japan. Results - The prevalence of CIND and dementia were 10.8% and 4.8%, respectively, with both rates increasing with age. The frequency of most neurological signs in CIND elderly was greater than that found in subjects with no cognitive impairment (NCI) and less than that in subjects with dementia. The mean ADL disability score in CIND subjects also lay between the mean values for those with NCI and those with dementia. There were no differences in lifestyles between the CIND group and the other groups. Conclusion -The results suggest that a majority of CIND elderly suffer from brain dysfunction due to chronic neurological disorders or aging itself.

McLeod syndrome is a rare X-linked hematologic and neuromuscular disorder manifested by chorea, myopathy, cardiomyopathy, areflexia, hyperCKemia, and acanthocytosis. Only four mutations have been reported in the gene responsible for McLeod syndrome. We report a novel gene mutation in a Japanese family. Direct sequencing of the PCR-amplified genomic DNA revealed the mutation was a single C-nucleotide insertion at codon 151 in exon 2 of the XK gene, which resulted in a 3′-frameshift. Study of family members revealed that the patient’s mother was a manifesting carrier heterozygous for this mutation.

We report a case of neurogenic pulmonary edema occurring in association with primary medullary hemorrhage. A pervious healthy 28-year-old man suddenly developed severe dyspnea without cardiac failure. Radiographs and computed tomography of the chest showed pulmonary edema. A diagnosis of primary medullary hemorrhage was made some weeks later by cranial magnetic resonance imaging showing an area of low signal intensity in both T1- and T2-weighted images in the right ventrolateral, medial, and dorsal medulla, extending from low to mid levels. We suspect that edema surrounding the lesion had superimposed an element of left dorsal medullary dysfunction and that bilateral dorsal medullary involvement had induced neurogenic pulmonary edema.