Familial Mitochondrial Encephalomyopathy with Stroke-like Episodes and Episodic Disturbances of Consciousness: A Study of Pedigree Including Three Generations with Multisystemic Abnormalities

Abstract: We report here two cases in a family with pleomorphic clinical features which include mitochondrial myopathy, encephalopathy, stroke-like episodes, episodic disturbances of consciousness and other multisystemic abnormalities. The other signs observed in multisystemic abnormalities were ophthalmoplegia, short stature, diabetes mellitus, diabetes insipidus, renal dysfunction, optic atrophy, retinal degeneration, impairment of hearing and mental retardation or deterioration. A symptomatological variation was observed in cases in the same family. It is suggested that these widely varying symptoms may be expressions caused by a common biochemical defect which involves different tissuesin different individuals in the family. The syndromes observed in the present cases were compared with other possibly-related mitochondrial encephalomyopathies.     

Bradykinin Stimulates Type II Alveolar Cells to Release Neutrophil and Monocyte Chemotactic Activity and Inflammatory Cytokines

In the present study, we evaluated the potential of bradykinin (BK) to induce the release of neutrophil and monocyte chemotactic activity (NCA and MCA) and cytokines from an alveolar type II epithelial cell line, A549 cells. BK stimulated A549 cells to release NCA and MCA in a dose- and time-dependent manner (P < 0.001). Checkerboard analysis revealed that both NCA and MCA involved chemotactic and chemokinetic activity. Molecular sieve column chromatography showed three molecular weight masses (near 19 kd, 8 kd, and 400 d) for NCA and several molecular weight peaks (near 66 kd, 25 kd, 19 kd, 16 kd, and 400 d) for MCA. The release of NCA and MCA was inhibited by cycloheximide and lipoxygenase inhibitors (P < 0.01). The NCA and MCA were inhibited by leukotriene B4 (LTB4) receptor antagonist (P < 0.01), and the concentration of LTB4 was high enough for NCA and MCA. Antibodies to interleukin (IL)-8 and granulocyte colony-stimulating factor (G-CSF) attenuated NCA (P < 0.01), and antibodies to monocyte chemotactic protein-1 (MCP-1), G-CSF, and transforming growth factor (TGF)-β attenuated MCA (P < 0.01). The levels of IL-8, G-CSF, MCP-1, and TGF-β increased time dependently (P < 0.01). BK also stimulated the release of ILeukin-6 from A549 cells (P < 0.001). The receptors responsible for the release of NCA, MCA, and individual chemokines involved both BKB1 and BKB2 receptors. These data suggest that BK may stimulate alveolar type II pneumocytes to release inflammatory cytokines, which then may modulate the lung inflammation.     

Serial evaluation of high-resolution computed tomography findings in patients with idiopathic pulmonary fibrosis in usual interstitial pneumonia

BACKGROUND: The development of well-matured fibrosis in usual interstitial pneumonia (UIP) is strongly associated with an unfavorable outcome of patients with idiopathic pulmonary fibrosis (IPF). However, differences in the rates of development are likely to result in variable clinical courses in IPF patients. OBJECTIVE: We tried to evaluate the progression of honeycombing and ground-glass opacity on CT using a scoring system, and to examine those serial changes in the clinical course of disease. METHODS: A hospital-based, retrospective cohort study. Twenty-three patients with IPF diagnosed as UIP by surgical lung biopsy were analyzed during the initial examination by scoring the presence of honeycombing (HC: range, 0-24) and ground-glass opacity (GG: range, 0-24) on CT scan. We also compared the serial changes observed in the CT scores (interval: 2-42 months, 2-6 examinations). RESULTS: (1) The serial change in the HC score in treated patients (n = 10) was similar to that in untreated patients (n = 16); (2) the HC score at the time of the initial examination and the rate of HC progression were both higher in the non-surviving patients (HC 12.3 +/- 3.7, mean +/- SD; deltaHC 4.2 +/- 1.3 per year) than in the surviving patients (HC 5.8 +/- 2.7; deltaHC 1.2 +/- 0.7 per year) (p < 0.05); (3) the GG score did not correlate with the HC score at any of the examinations; (4) the HC score was higher in the lower lung field than in the upper and middle lung fields. CONCLUSIONS: Scoring of the honeycombing and its serial changes using the high-resolution computed tomography scoring method was useful for predicting the prognosis in patients with IPF/UIP. Corticosteroid treatment did not prevent the progression of HC.     

The Clara cell10 adenine38guanine polymorphism and sarcoidosis susceptibility in Dutch and Japanese subjects

CC10 (CC16, uteroglobin) is a pulmonary protein postulated to play a counter regulatory role in sarcoidosis pathogenesis. The adenine38guanine (A38G) polymorphism of the encoding CC10 gene (SCGB1A1) is functional. Recently, an association between the low CC10 producing 38A allele and sarcoidosis susceptibility has been reported in Japanese patients from Hokkaido. The aim of the present study was to confirm this association in a clinically well characterized population of Dutch white and Kyoto Japanese patients with sarcoidosis and control subjects. No difference in genotype or allele frequency was found between patients with sarcoidosis and control subjects in either ethnic population. Remarkably, however, a significant difference was found between the control subjects from Kyoto and Hokkaido, but not between the Japanese groups of patients with sarcoidosis. Furthermore, review of previously published A38G genotyping results showed a consistent difference in CC10 A38G allele frequencies between whites and Japanese subjects. We conclude that the CC10 A38G polymorphism does not influence sarcoidosis susceptibility in Dutch whites or in Japanese subjects from Kyoto. This stresses the importance of studying the influence of polymorphisms on disease susceptibility in multiple ethnically and geographically distinct disease and control populations before reaching conclusions.     

Multiple bone fractures found in a young sarcoidosis patient with long stable disease

A 22-year-old Japanese man was found to have bilateral hilar lymphadenopathy (BHL), and was diagnosed with sarcoidosis in 1995. He was followed without treatment until 2002, when a bone fracture due to osseous sarcoidosis was found in his left thumb. Despite systemic treatment with corticosteroid and methotrexate, a new bone lesion developed in his right foot and his right middle finger was fractured. The patient also suffered multiple organ involvements including brain and muscle lesions. This is the first report of a sarcoidosis patient who presented with BHL, and developed bone fractures after a long stable period of more than 5 years.     

Significance of lung shrinkage on CXR as a prognostic factor in patients with idiopathic pulmonary fibrosis

OBJECTIVE: The aim of this study was to determine whether the presence of lung shrinkage on CXR can predict diminished survival in patients with idiopathic pulmonary fibrosis (IPF)/usual interstitial pneumonia (UIP). METHODOLOGY: In a hospital-based cohort study 68 subjects diagnosed with IPF/UIP by surgical lung biopsy or at autopsy were observed for a mean of 7.6 years. The radiographic scores from Cherniack's method, pulmonary function tests, arterial blood gas, and haematological data were obtained at initial presentation. Longitudinal radiographic changes over a mean interval of 2.7 years were measured. Survival analysis was performed using Kaplan-Meier and Cox's proportional hazards regression analysis. RESULTS: At some point during the observation period 36 (53%) of 68 patients did not exhibit lung shrinkage and 32 (47%) of 68 patients showed lung shrinkage. Patients with lung shrinkage were more likely to have a diminished survival than those with lung preservation; median survival was 4.4 vs 7.8 years, respectively. Lung shrinkage during the observation period (hazard ratio, 3.89; 95% CI = 1.68-9.01; P= 0.001) was associated with lower rates of survival. CONCLUSION: In patients with IPF/UIP, lung shrinkage on CXR during the observation period was a poor prognostic factor.     

Patient characteristics and clinical features of Japanese sarcoidosis patients with low bronchoalveolar lavage CD4/CD8 ratios

BACKGROUND: Previous studies have shown that there is an association between low BALF (bronchoalveolar lavage fluid) CD4/CD8 ratio and lower remission rates in sarcoidosis patients. AIM: To investigate the patient characteristics and clinical features of Japanese sarcoidosis patients with low BALF CD4/CD8 ratios. METHODS: 322 Japanese sarcoidosis patients were retrospectively analyzed, and 3 groups were selected according to BALF CD4/CD8 ratios as follows: patients with the BALF CD4/CD8 ratio in the lowest 5 percentile (Group 1: 0.43-1.41), median 5 percentile (Group II: 4.68-5.47), and top 5 percentile (Group III: 12.6-60.1). Each group consisted of 16 patients (5% of 322 patients). The patient characteristics, clinical features, and the short-term prognosis for at least 2 years (average 116 months) were compared among the groups. Multivariate analysis was performed for 322 patients to investigate the determinants of BALF CD4/CD8 ratios. RESULTS: The number of BALF CD8+ cells were greater in Group I than in the other two groups. In Group I, there were higher incidences of younger age, male gender, and lower number of extrathoracic lesions compared with Group III. Multivariate analysis showed that younger age and male gender were independently associated with low BALF CD4/CD8 ratios. The frequency of treatment with corticosteroid and progression to pulmonary fibrosis tended to be higher in Group I. CONCLUSIONS: Low BALF CD4/CD8 ratios were due to increased number of BALF CD8+ cells. Younger age and male gender were independently associated with low BALF CD4/CD8 ratios in sarcoidosis patients.     

Abnormal intracellular trafficking of high affinity nerve growth factor receptor, Trk, in stable transfectants expressing presenilin 1 protein

The pathogenesis of Alzheimer's disease (AD) is now thought to be tightly linked to Abeta deposition and oxidative stress, but it is still unknown how these factors result in neuronal dysfunction and cell death. Mutations of presenilin 1 (PS1) gene are the causative gene for early onset familial AD (FAD) due to the overproduction and deposition of pathogenic Abeta1-42 peptides. We report here the molecular influences of the overexpression of PS1 protein by stable transfection of PS1 cDNA into SH-SY5Y neuroblastoma cells on the function of high affinity nerve growth factor receptor, Trk, that is essential for neuronal survival and differentiation. We examined the sensitivity of these transfectants to oxidative stress and found that mutant (I143T) PS1-expressing clones showed the highest vulnerability to an oxidative stress inducer, hydrogen peroxide treatment compared with that of mock-transfected clones, whereas wild PS1-expressing cells were less vulnerable to the treatment than mutant PS1 transfectants. Because nerve growth factor (NGF) is known to protect neuronal cells from oxidative stress-induced cell death, we examined the NGF-Trk-mediated intracellular signaling pathway in these transfectants. In the wild and mutant PS1 cDNA-transfected cells, NGF did not elicit the autophosphorylation response of Trk, although their basal levels of tyrosine phosphorylation were higher than those of mock-transfected cells. Immunocytochemical and subcellular fractionation studies revealed that most of Trk proteins are abnormally located in the cytoplasm as well as in the nucleus in PS1-overexpressing clones irrespective of wild and mutant forms. These results strongly indicate that the expression level of PS1 protein has a cross talk with the Trk-dependent neuroprotective intracellular signaling pathway.     

Impairment of Trk-neurotrophin receptor by the serum of a patient with subacute sensory neuropathy

BACKGROUND: Paraneoplastic peripheral neuropathy is sometimes associated with unidentified neuronal autoantibodies. OBJECTIVE: To examine the effects of serum from a patient with subacute sensory axonopathy on the function of the Trk high-affinity nerve growth factor receptor. PATIENT: An 86-year-old man with sensory neuropathy exhibiting an autoantibody to Trk. METHODS: Immunoblot analyses of the brain homogenates and immunoprecipitation were performed with human sera. We further examined the effect of sera on nerve growth factor-induced neurite outgrowth and Trk autophosphorylation. RESULTS: The patient showed sensory nerve axonopathy without well-known paraneoplastic autoantibodies. His serum inhibited nerve growth factor-induced neurite outgrowth and Trk autophosphorylation in PCtrk cells. Moreover, the patient's serum, but not control serum, immunoprecipitated Trk and recognized Trk in brain homogenates as well as in Trk immunoprecipitates. CONCLUSION: These data strongly suggest that an anti-Trk autoantibody might cause subacute sensory neuropathy.