Amoxapine-associated acute respiratory distress.

A 37-year-old woman was admitted to our hospital because of acute respiratory distress. Two weeks previously, amoxapine (75 mg/day) had been administered for the first time. Ten days later she developed a high fever, severe hypoxaemia and pulmonary infiltrates on chest CT, including patchy areas of ground-glass opacity, thickening of the interlobular septae and bronchial walls and pleural effusions. BAL showed a predominance of neutrophils, lymphocytes and erythrocytes but not eosinophils. Amoxapine was stopped, resulting in complete resolution of the pulmonary infiltrates. When the patient was re-exposed to amoxapine (52.5 mg total dose), high fever, reduced SaO(2) and pulmonary infiltrates reappeared. We concluded that acute respiratory distress may be associated with amoxapine treatment.

Circulating levels of both Th1 and Th2 chemokines are elevated in patients with sarcoidosis.

BACKGROUND: In sarcoidosis, the T helper type 1 (Th1) response tends to predominate at affected disease sites; however, whether Th1/Th2 polarization occurs in the peripheral circulation is unknown. METHODS: Fifty-two patients with sarcoidosis and 21 healthy volunteers were investigated. The concentrations of interferon-inducible protein 10 (IP-10)/CXCL10 and thymus- and activation-regulated chemokine (TARC)/CCL17 in the serum, bronchoalveolar lavage fluid (BALF) and culture supernatant were measured by an enzyme-linked immunosorbent assay. The circulating CXCR3+ CD4+ T cells and CCR4+ CD4+ T cells were assessed by flow cytometry. RESULTS: The CXCR3- or CCR4-positive ratios among CD4+ T cells were both higher in sarcoidosis than in healthy volunteers. The serum levels of both IP-10 and TARC of the patients with sarcoidosis were significantly higher than those of the healthy volunteers. In patients with sarcoidosis, a larger amount of IP-10 was generated by the BALF cells, whereas IP-10 production by peripheral blood mononuclear cells did not increase in comparison to the control subjects. The TARC levels produced by peripheral blood mononuclear cells of sarcoidosis patients were significantly higher than those of the controls, while no difference existed between the 2 groups regarding TARC production by BALF cells. CONCLUSION: IP-10 is mainly produced at the lung and TARC in the peripheral circulation in sarcoidosis patients. Both IP-10 and TARC cooperatively play a role in the pathogenesis of sarcoidosis.

Circulating IL-12 p40 is increased in the patients with sarcoidosis, correlation with clinical markers.

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-12Rbeta1, and IL-12beta2 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 beta2 subunit was increased in sarcoid lymph nodes. CONCLUSION: 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.

Early assessment of rapidly progressive interstitial pneumonia associated with amyopathic dermatomyositis.

Amyopathic dermatomyositis (ADM) is occasionally complicated by rapidly progressive interstitial pneumonia (RPIP), and in such cases, diffuse alveolar damage (DAD) is usually diagnosed at autopsy. Here, we present three patients with RPIP accompanied by ADM in whom lung disease was assessed at an early stage. High-resolution computed tomography (HRCT) carried out before the onset of dyspnoea revealed uniformly subpleural reticular opacity with faint ground-glass attenuation. At that stage, surgical lung biopsies from two patients showed histological patterns typical of cellular nonspecific interstitial pneumonia (NSIP). Despite pulse methylprednisolone and subsequent high-dose oral administration of prednisolone, lung disease progressed in all patients, with extensive areas of ground-glass opacity and consolidation observed in HRCT scans. DAD was confirmed histologically in one case. Additional administration of cyclosporine, pulse cyclophosphamide or high-dose intravenous administration of immunoglobulin rescued all patients. Our data suggest that ADM-associated interstitial pneumonia takes an aggressive course even when the radiological and histological features are consistent with NSIP. Aggressive combination therapy with high-dose steroids and immunosuppressive agents is required as early as possible for patients with this life-threatening disorder.

Virus associated hemophagocytic syndrome accompanied by acute respiratory failure caused by influenza A (H3N2).

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.

National survey on status of steroid therapy for cardiac sarcoidosis in Japan.

AIM: This investigation was undertaken to clarify the current status of steroid therapy for cardiac sarcoidosis in Japan. METHODS: A questionnaire survey was conducted throughout Japan concerning cases in which steroid therapy had been administered. Replies describing 52 cases (15 men, 37 women; mean age +/- SD, 59.8 +/- 14.5 years) were analyzed. RESULTS: Of the 49 patients whose New York Heart Association (NYHA) functional classification was reported, 29 (55.8%) were in class I; 13 (25.0%) class II; 4 (7.7%) class III and 3 (5.8%) class IV. The most common initial steroid dose (used in 35 cases, or 67.3%) was 30 mg/day or 60 mg on alternate days. In most cases (85.4%), this dose was continued for 1 month followed by tapering by 5 mg every 2 to 4 weeks until reaching the maintenance dose of 5 to 10 mg/day. Steroid therapy was reported to result in improvement in 54%, no change in 40%, and deterioration in 6%. CONCLUSION: This nationwide questionnaire survey indicated fairly uniform patterns of steroid therapy for cardiac sarcoidosis in Japan, with clinical improvement in over one-half of cases and possible stabilization in most others.

CC chemokine receptor 4 ligand production by bronchoalveolar lavage fluid cells in cigarette-smoke-associated acute eosinophilic pneumonia.

We examined the production of macrophage-derived chemokine (MDC/CCL22) and thymus- and activation-regulated chemokine (TARC/CCL17) by bronchoalveolar lavage fluid (BALF) cells in cigarette-smoke-associated acute eosinophilic pneumonia (CS-AEP). The CC Chemokine Receptor 4 (CCR4) ligand levels in BALF from patients with CS-AEP were considerably higher than those in healthy volunteers and correlated well with Th2 cytokine levels. Interleukin-4 enhanced CCR4 ligand production. MDC expression was observed in CD68-positive cells from patients with CS-AEP and in healthy control smokers. In contrast, TARC expression in CD68- or CD1a-positive cells was detected only in CS-AEP. An in vivo cigarette smoke challenge test induced increases in CCR4 ligands in the BALF and in the cultured supernatant of BALF adherent cells. These results suggest that alveolar macrophages and dendritic cells contribute to the pathogenesis of CS-AEP by generating CCR4 ligands, probably in response to cigarette smoke.

Myosin loss in denervated rat soleus muscle after dexamethasone treatment.

OBJECTIVE: Critical illness myopathy (CIM) is an acute myopathy that appears in the setting of critical illness or during exposure to corticosteroids and neuromuscular blocking agents. Its pathological feature is selective loss of thick myosin filaments. Our aim is to gain further insight into the pathomechanism of myosin loss in this myopathy. METHODS: To clarify the expression of myosin heavy chain (MHC) and ubiquitin ligase atrogin-1 in this myopathy, histological, immunohistochemical, SDS-PAGE, and semiquantitative reverse transcriptase-polymerase chain reaction studies were performed on innervated and denervated rat soleus muscles after saline and dexamethasone treatments. RESULTS: Denervated muscles from dexamethasone-treated rats showed marked MHC loss. The mRNA expression of ubiquitin ligase atrogin-1 was significantly increased in denervated dexamethasone-treated muscles, suggesting that the ubiquitin-proteasome pathway plays an important role in muscular wasting in CIM. Furthermore, mRNA levels of MHC I, a myosin isoform, were decreased in the denervated dexamethasone-treated muscles. CONCLUSION: Our findings suggest that an altered transcription rate of myosin, as well as the upregulation of multiple ubiquitin ligases, may be responsible for selective myosin loss in this myopathy.

Identification of a functional CBF-binding CCAAT-like motif in the core promoter of the mouse pro-alpha 1(V) collagen gene (Col5a1).

We used structure-function analysis of the core promoter region to elucidate the transcriptional features of the mouse alpha 1(V) collagen gene (Col5a1). The core promoter, which lacks a typical TATA motif and has a high GC content, was defined within the 231 bp immediately upstream from the major transcription start site by transient transfection experiments. In this region, we identified three nuclear-factor binding sites by electrophoretic mobility shift assay: BS1 (-195 to -167), BS2 (-134 to -106), and BS3 (-110 to -80). Oligonucleotide competition and supershift assays revealed that Sp1, CBF, and Sp1-related protein specifically bind to BS1, BS2, and BS3, respectively. The CCAAT-like motif, CAAAT, and flanking sequences are conserved between the mouse and human gene. CBF, which recognizes this motif, activated the Col5a1 promoter, as previously reported for Col1a1 and Col1a2. Furthermore, overexpression of a wild-type and mutant forms of CBF-B subunit altered this activity. These results suggest that CBF is a key factor in the coordinated expression of type I and V collagen genes.

Impaired IFN-gamma production of Valpha24 NKT cells in non-remitting sarcoidosis.

Sarcoidosis is a systemic disorder associated with granuloma characterized by an abnormal T(h)1-type cytokine production and accumulation of T(h)1 CD4 T cells in the granuloma lesions, suggesting an importance of T(h)1 responses in sarcoidosis. However, the pathogenesis of sarcoidosis remains to be solved. Here, we investigated the nature of V(alpha)24 NKT cells with immunoregulatory functions in sarcoidosis. Patients with non-remitting sarcoidosis displayed a decrease in the number of V(alpha)24 NKT cells in peripheral blood, but an accumulation of these cells in granulomatous lesions. When stimulated with the specific glycolipid ligand, alpha-galactosylceramide, peripheral blood V(alpha)24 NKT cells from patients with non-remitting disease produced significantly less IFN-gamma than those from healthy volunteers, but normal levels of IL-4. The reduced IFN-gamma production was observed only in V(alpha)24 NKT cells and not conventional CD4 T cells, but was normal in patients with remitting disease, suggesting that non-remitting sarcoidosis involves an insufficient IFN-gamma production of V(alpha)24 NKT cells which is well correlated with disease activity. Thus, these results suggest that V(alpha)24 NKT cells play a crucial role in the disease status of sarcoidosis.

Expression of lysosome-related proteins and genes in the skeletal muscles of inclusion body myositis.

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.

Clinical characteristics of 195 Japanese sarcoidosis patients treated with oral corticosteroids.

Questionnaires were sent to 46 hospitals of all over Japan in order to obtain the clinical data on sarcoidosis patients who were treated with oral corticosteroids. The number of female patients was greater than that of male patients (1.5:1), and the average age was 44.9 +/- 16.5 with peaks at 20 and at 50 to 60. The markers of disease activity were high in serum or bronchoalveolar lavage fluids (BALF): specifically, the serum angiotensin-converting enzyme (sACE) was 27.9 +/- 31.9 IU/ml (n.v. < 21.4), and the CD4/CD8 lymphocyte ratio was 6.5 +/- 5.7. Eye involvement was the most common reason for systemic steroid therapy, followed in order by lung and heart involvement. The main reasons for steroid therapy were the exacerbation of ocular symptoms, visual disturbance, respiratory symptoms, such as cough or exertional dyspnea, progression of chest radiographic findings, heart failure and severe arrhythmia, such as AV block. The initial corticosteroid dose was usually 30 mg of predinisolone per day, but for some refractory cases, a 40-60 mg per day was used. Immunosuppressive drugs, such as methotrexate, were also used in the small number of patients who responded poorly to the steroid. Overall, a good clinical response to the drug was found in 70-80% of the steroid treated patients, but in those with cardiac disease, the response rate was only 48%.

Solitary metastasis of prostatic cancer to the internal auditory canal.

We report a 56-year-old man with a metastatic prostatic tumor who developed left orbital meatus syndrome as the first manifestation. Magnetic resonance imaging (MRI) showed a swollen lesion in the left internal auditory canal that was isointense on T1-weighted images, hyperintense on T2-weighted images, and marked by enhanced after the administration of gadolinium. A biopsy of the affected lesion confirmed the prostatic origin of the metastasis.

[Characterization of distribution of immunological competent cells in sarcoid granuloma].

Sarcoidosis is a systemic, immunological disorder that is histologically defined the presence of noncaseating granuloma in the involved tissue. Granuloma formation follows the accumulation of large numbers of T lymphocytes within the lesions. To elucidate the immunopathologic situation of granuloma-formation in sarcoidosis, the relationship between activated T lymphocyte subsets including Th-1 and Th-2 cells has been studied by using immunohistochemical, RT-TCR, and in situ hybridization techniques for functional T cell subsets and by using RT-PCR-SSCP analysis for T cell clonotypes. The results of analysis of functional T cell subsets showed that T cells in internal area (core) of granulomas were predominantly Th-2 subset. On the other hand, Th-1 cells were present in abundance in the surrounding areas(rind). The additional results showed the presence of common T-cell clones in samples from different tissues, supporting the underlying Ag-specific mechanism in pathogenesis of sarcoidosis.

Clinical heterogeneity in dysferlinopathy.

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.

Cellular distribution of proteolytic enzymes in the skeletal muscle of sarcoid myopathy.

To clarify the mechanism of muscle fiber destruction in sarcoid myopathy, muscle biopsy specimens were examined from patients with sarcoid myopathy, polymyositis, or dermatomyositis. In sarcoid myopathy, noncaseating granulomatous lesions were located in the perimysium or endomysium or both. Little fiber atrophy, caused by mechanical compression of the granuloma, was seen, and there was no evidence of ischemia-induced changes (i.e., perifascicular atrophy) due to microangiopathy in muscles. Immunoreactivity for membrane-associated cytoskeletal proteins such as dystrophin and merosin was detected homogeneously along the surface of many small granulomas in intrafascicular lesions. These granulomas showed a characteristic phenotypic cellular distribution: CD68(+) and CD4(+) cells were present in the center, and some CD8(+) cells were found at the periphery, indicating typical sarcoid granuloma formation in each muscle fiber. Strong expression of proteases such as cathepsin B, calpain II and ubiquitin-proteasome was observed in macrophages and epithelioid cells but not in lymphocytes in granulomas within muscle fibers or those in the endomysium or perimysium. The expression intensity was stronger in premature-stage granulomas than in late-stage granulomas. Weak expression of these proteases was detected mainly in some muscle fibers invaded by epithelioid cells and macrophages and in a few atrophic or necrotic fibers adjacent to inflammatory foci but not in fibers of fascicles without granuloma formation or in fibers in perifascicular areas. Our results suggest that muscle fiber destruction in sarcoid myopathy is caused mainly by direct invasion of granulomatous inflammatory cells into muscle fibers during the process of granuloma formation rather than by mechanical compression or ischemia. Furthermore, the proteases derived from epithelioid cells and macrophages may play an important role in muscle fiber destruction.

A clinicopathological study of a patient with anti-Hu-associated paraneoplastic sensory neuronopathy with multiple cranial nerve palsies.

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.