Real-World Clinical Efficacy of Antifibrotic Agents for Idiopathic Pulmonary Fibrosis: A Single-Center Retrospective Study in Japan.

BACKGROUND: The antifibrotic drugs, nintedanib and pirfenidone, inhibit the decline in forced vital capacity in patients with idiopathic pulmonary fibrosis (IPF). Nintedanib also inhibits the onset of acute exacerbation and reduces the risk of all-cause mortality. However, their effectiveness in real-world practice remains unclear. Our study aimed to investigate the changes in forced vital capacity, survival period, causes of death, and risk factors for mortality in patients with IPF receiving antifibrotic drugs. METHODS: This retrospective study enrolled Japanese patients who visited Toho University Sakura Medical Center who were diagnosed with IPF and received antifibrotic drugs. RESULTS: We included 102 patients [mean age ± standard deviation (SD): 71.8 ± 7.5 years], of whom 76 were males. The decline in forced vital capacity (mean ± SD) during the antifibrotic therapy period was - 154 ± 259 mL/year, which was significantly lower than before the antifibrotic therapy period (- 484 ± 589 mL/year; n = 80, p = 0.003). Altogether, 52 deaths were confirmed, and the median survival time from antifibrotic therapy initiation was 38.0 months (95% confidence interval: 25.9-50.1 months). Acute exacerbation accounted for 9.6% of all deaths (95% confidence interval: 1.6-17.6). The decline in forced vital capacity during antifibrotic therapy was a risk factor for mortality. CONCLUSIONS: In actual clinical practice in Japan, antifibrotic drugs suppressed the gradual decline in forced vital capacity, which is a risk factor for mortality. However, the median survival period remained poor at 38 months.

Serum IgG4-negative IgG4-related disease with a cardiac mass: A case report.

RATIONALE: Although IgG4-related disease (IgG4-RD) can affect various organs, its association with a cardiac mass is exceptionally rare. Here, we report a case of a woman with IgG4-RD and a cardiac mass and discuss 10 similar cases reported previously. PATIENT CONCERNS: A 65-year-old woman was referred to our hospital for chest discomfort and back pain. DIAGNOSES: In accordance with the 2019 ACR/EULAR diagnostic criteria for IgG4-RD, she was diagnosed with IgG4-RD based on dense lymphocytic infiltration on histopathology, IgG/IgG4-positive cell ratio <40%, >10/hpf IgG4-positive cells on immunostaining, and paraspinal zone soft tissue lesions in the chest. INTERVENTIONS: An external pacemaker was implanted for the complete atrioventricular block on the electrocardiogram. After the diagnosis of IgG4-RD, she was treated with glucocorticoids and rituximab. OUTCOMES: She remains under observation without disease recurrence. LESSONS: IgG4-RD are usually treated with glucocorticoids; however, in cases of a cardiac mass, life-threatening complications may occur and surgery is often needed. Combination therapy with glucocorticoids and rituximab may be effective even in patients with IgG4-RD and cardiac mass, which may avoid the need of invasive treatments, such as surgery.

Development of giant cell arteritis after vaccination against SARS-CoV2: A case report and literature review.

RATIONALE: Giant cell arteritis (GCA) is an autoimmune vasculitis that affects large and medium-sized blood vessels. The mRNA vaccine against severe acute respiratory syndrome coronavirus 2 (SARS-CoV2) has been associated with the development of immune-mediated diseases. In this article, we present a case of GCA that developed after vaccination against SARS-CoV2. PATIENT CONCERNS: A 77-year-old man developed fever, general fatigue, and headache 1 day after the third dose of vaccination against SARS-CoV2. Nodular swelling and tenderness of the bilateral temporal arteries were observed. DIAGNOSES: Although right temporal artery biopsies were negative, the patient was diagnosed with GCA based on criteria established by the American College of Rheumatology for the classification of GCA. INTERVENTIONS: The patient received methylprednisolone 1000 mg for 3 days. This was followed by prednisolone 1 mg/kg/d, which was decreased by 10 mg every week to 30 mg. From day 16 of hospitalization, the patient received tocilizumab 162 mg/wk every other week. OUTCOMES: There was no occurrence of acute side effects. After 38 days of treatment, the condition improved and the patient was discharged from the hospital; as stated above, the dose of prednisolone was tapered to 30 mg/d. LESSONS: We experienced a case of GCA that occurred immediately after vaccination against SARS-CoV2 with an mRNA vaccine. Early signs of GCA include fever, fatigue, and headache, and often resemble those noted after vaccination against SARS-CoV2. The potential presence of GCA should be determined in individuals with persistent fever and headache after vaccination against SARS-CoV2.

Diffuse alveolar haemorrhage with suspected idiopathic pulmonary hemosiderosis and decrease in lung diffusing capacity and chronic respiratory failure.

Idiopathic pulmonary hemosiderosis (IPH) is a rare disease of unknown aetiology that causes recurrent episodes of diffuse alveolar haemorrhage (DAH). A male patient in his 50s had repeatedly experienced hemoptysis for the past 6 years, along with a decrease in the pulmonary diffusing capacity and chronic respiratory failure. After a 6-year follow-up, the patient experienced sudden exacerbation of hemoptysis and respiratory failure, and he was hospitalised. A CT of the chest revealed diffuse pulmonary infiltrates, whereas the bronchoalveolar lavage revealed hemosiderin-laden macrophages. Thus, the patient was diagnosed with DAH. As all diseases that cause DAH other than IPH were negative, the patient was suspected of IPH. He was treated with a combination of glucocorticoids and azathioprine, and his hemoptysis and chronic respiratory failure improved; however, the decrease in the pulmonary diffusing capacity did not improve. Treating adult-onset IPH with glucocorticoids and azathioprine might not improve pulmonary diffusing capacity.

High presepsin concentrations in bile and its marked elevation in biliary tract diseases: A retrospective analysis.

BACKGROUND: Presepsin is a diagnostic and prognostic biomarker of both bacterial infection and sepsis; however, elevated presepsin levels have also been observed without sepsis. We conducted several analyses to evaluate the clinical laboratory parameters affecting presepsin levels. METHOD: We analyzed the association between sequential organ failure assessment (SOFA) scores and plasma presepsin levels and then analyzed clinical laboratory parameters in 567 patients with univariate and multivariate regression analysis and analysis of covariance (ANCOVA). We also determined presepsin in the bile of 11 patients and examined the presepsin immunostaining in liver. RESULTS: Spearman's rank correlation analysis with loge change revealed that presepsin levels were closely associated with loge-transformed SOFA score (ρ = 0.541), alkaline phosphatase (ALP); (ρ = 0.454) and gamma-glutamyl transferase; (ρ = 0.505). Multivariate regression analysis revealed that loge-transformed SOFA score (ß-coefficient = 0.316), ALP level (ß-coefficient = 0.380), and creatinine level (ß-coefficient = 0.290) independently and significantly affected loge presepsin levels. ANCOVA revealed that presepsin levels were significantly higher in patients with hepatobiliary disease. Patients who presented with dilatation of the bile ducts and elevated ALP levels or total bilirubin levels exhibited high presepsin levels in the bile. Presepsin production in liver Kupffer cells was also confirmed by immunostaining. CONCLUSION: Presepsin levels is correlated with the elevation of biliary enzymes in patients without renal dysfunction or sepsis. Additionally, presepsin exists with high concentrations in the bile and is positive in Kupffer cells.

Lower airway microbiota in patients with clinically suspected Mycobacterium avium complex lung disease.

The relationship between the lower airway microbiota in humans and respiratory illness has gained attention recently. However, the relationship between nontuberculous mycobacterial lung disease (NTM-LD) and the lower airway microbiota is not fully understood yet. We conducted a study to characterize the lower airway microbiota in Mycobacterium avium complex lung disease (MAC-LD), a representative subclass of the NTM-LD. The subject sample included 25 patients clinically suspected of having mild MAC disease whose condition could not be diagnosed using sputum culture. Upon testing MAC antibodies (anti-glycopeptidolipid (GPL)-core IgA antibodies), mycobacterial culture of bronchoalveolar lavage fluid (BALF), and performing BALF 16S rRNA gene sequencing, we divided the subjects into two groups of patients: those in whom MAC was detected in BALF mycobacterial culture (MAC-LD group) and in whom MAC was not detected in BALF mycobacterial culture (non-MAC-LD group), which was then comparatively examined. BALF mycobacterial culture showed that 9 out of 25 patients were positive for NTM; the detected Mycobacterium was MAC in all. No patients were positive for acid-fast bacteria other than MAC. Eighteen patients were positive for MAC antibodies (anti-glycopeptidolipid (GPL)-core IgA antibodies), including nine patients positive for mycobacterial culture. On BALF 16S rRNA gene sequencing, six patients were positive for the genus Mycobacterium and were culture-positive. Among the 16 patients in the non-MAC-LD group, the genus Pseudomonas was detected by 16S rRNA gene sequencing in 7 patients, 4 among whom were positive for MAC antibodies (anti-GPL-core IgA antibodies). Conversely, the genus Pseudomonas was not detected among the nine patients in the MAC-LD group. Other than the genus Pseudomonas, there was no clear difference in the composition of and no significant difference in the diversity of the bacterial flora between the MAC-LD and non-MAC-LD groups. However, we found that the genus Pseudomonas and MAC tended to exist exclusively.

Surgical Treatment for Spinal Tuberculosis without Elevation of Inflammatory Biomarkers at the Initial Visit Mimicking Spinal Metastasis.

Here, we report a case of spinal tuberculosis without elevation of C-reactive protein (CRP) at the initial visit mimicking spinal metastasis. A 70-year-old woman developed progressive paraplegia without a history of injury and came to our hospital for evaluation. Severe compression to the spinal cord with osteolytic destruction of the spinal vertebrae at T6-7 was observed without elevation of CRP. A T4-9 posterior decompression and fusion were performed. Although the pathology revealed no malignant tumor cells, a positron emission tomography-computed tomography (PET-CT) showed upregulation of the thyroid gland and aspiration cytology revealed a thyroid carcinoma. Thus, we diagnosed her with spinal metastases from thyroid carcinoma. Conservative treatment was chosen with the hope of a significant neurologic recovery; however, 9 months after the primary surgery, she returned to our hospital with reprogressive paraplegia. In addition to progression of osteolytic changes to the T5-7 vertebrae, a coin lesion on the right side of the lung and elevation of CRP were observed. Finally, we diagnosed her with spinal tuberculosis based on the results of a CT-guided needle culture. Two-stage surgeries (posterior and anterior) were performed in addition to administering antituberculosis medications. At the 1-year postoperative follow-up evaluation, both neurologic function and laboratory data were improved with T5-9 complete fusion. It is difficult to determine based on imaging findings alone whether osteolytic vertebrae represent spinal metastases or tuberculosis. Even though inflammatory biomarkers, such as CRP, were not elevated, we should consider the possibility of not only spinal metastases but also tuberculosis when planning surgery involving osteolytic vertebrae. In addition, the combination of neurological, imaging, and pathological findings is important for the diagnosis of spinal tuberculosis.

Fatal fulminant community-acquired pneumonia caused by hypervirulent Klebsiella pneumoniae K2-ST86: Case report.

RATIONALE: Invasive community-acquired infections, including pyogenic liver abscesses, caused by hypervirulent Klebsiella pneumoniae (hvKp) strains have been well recognized worldwide. Among these, sporadic hvKp-related community-acquired pneumonia (CAP) is an acute-onset, rapidly progressing disease that can likely turn fatal, if left untreated. However, the clinical diagnosis of hvKp infection remains challenging due to its non-specific symptoms, lack of awareness regarding this disease, and no consensus definition of hvKp. PATIENT CONCERNS: A 39-year-old man presented with high-grade fever and sudden-onset chest pain. Laboratory testing revealed an elevated white blood cell count of 11,600 cells/µl and C-reactive protein level (>32 mg/dl). A chest X-ray and computed tomography revealed a focal consolidation in the left lower lung field. DIAGNOSIS: Diagnosis of fulminant CAP caused by a hvKp K2-ST86 strain was made based upon multilocus sequencing typing (MLST). INTERVENTIONS: The patient was treated with ampicillin/sulbactam. OUTCOMES: The pneumonia became fulminant. Despite intensive care and treatment, he eventually died 15.5 hours after admission. LESSONS: This is the first case of fatal fulminant CAP caused by a hvKp K2-ST86 strain reported in Japan. MLST was extremely useful for providing a definitive diagnosis for this infection. Thus, we propose that a biomarker-based approach should be considered even for an exploratory diagnosis of CAP related to hvKp infection.

Thrombomodulin Alfa for Acute Exacerbation of Idiopathic Pulmonary Fibrosis. A Randomized, Double-Blind Placebo-controlled Trial.

Rationale: Acute exacerbation during the course of idiopathic pulmonary fibrosis causes a poor prognosis. Coagulation abnormalities and endothelial damage are involved in its pathogenesis. Thrombomodulin alfa, a recombinant human soluble thrombomodulin, has anticoagulant and antiinflammatory effects. Several clinical studies have shown that thrombomodulin alfa may improve survival of acute exacerbation.Objectives: To determine the efficacy and safety of thrombomodulin alfa compared with placebo in acute exacerbation of idiopathic pulmonary fibrosis.Methods: This randomized, double-blind placebo-controlled phase 3 study conducted at 27 sites in Japan involved patients with an acute exacerbation of idiopathic pulmonary fibrosis. Subjects were randomized 1:1 to receive placebo or thrombomodulin alfa (380 U/kg/d for 14 d by intravenous drip infusion). All subjects were treated with high-dose corticosteroid therapy. The primary endpoint was the survival proportion on Day 90.Measurements and Main Results: Of the 82 randomized subjects, 77 completed the study and were included in the full analysis set (thrombomodulin alfa, n = 40; placebo, n = 37). The survival proportions on Day 90 were 72.5% (29 of 40) in the thrombomodulin alfa group and 89.2% (33 of 37) in the placebo group, a difference of -16.7 percentage points (95% confidence interval, -33.8 to 0.4%; P = 0.0863). In the safety population (n = 80), bleeding adverse events occurred in the thrombomodulin alfa group (10 of 42; 23.8%) and the placebo group (4 of 38; 10.5%).Conclusions: Thrombomodulin alfa did not improve the 90-day survival proportion. The present results suggest that the use of thrombomodulin alfa for the treatment of acute exacerbation of idiopathic pulmonary fibrosis not be recommended.Clinical trial registered with www.clinicaltrials.gov (NCT02739165).

Serum oxidative stress in patients with pulmonary Mycobacterium avium complex disease.

BACKGROUND: The mechanism of progressive airway destruction in incurable chronic infection of the lung - termed pulmonary Mycobacterium avium complex (pMAC) disease - is currently unknown. The involvement of oxidative stress in a variety of progressive chronic respiratory diseases has been previously reported. It has been hypothesized that oxidative stress may be involved in the progression of airway destruction in pMAC disease. PATIENTS AND METHODS: The study included 28 untreated patients with pMAC disease. The level of serum oxidative stress was quantitatively evaluated through the diacron reactive oxygen metabolites (d-ROMs) test, which indirectly measures the level of hydroperoxide in the serum. In addition, patients were divided into three groups based on the severity shown in the computed tomographic image. RESULTS: The level of serum oxidative stress exceeded the normal range (250-300 U.Carr [Carratelli Units]) in all patients with pMAC disease (mean: 495.5 ± 102.6 U.Carr; minimum-maximum: 340-734 U.Carr). The level of serum oxidative stress in patients with severe disease was significantly higher compared with that observed in patients with mild disease (434.6 ± 30.2 vs. 583.4 ± 95.1, respectively, p = 0.009). CONCLUSIONS: In patients with pMAC disease, an elevation was observed in the level of serum oxidative stress. This increase in oxidative stress was more pronounced in patients with severe disease.

Comparison of clinical and pathological features of lung lesions of systemic IgG4-related disease and idiopathic multicentric Castleman's disease.

AIMS: The lung lesion [immunoglobulin (Ig)G4-L] of IgG4-related disease (IgG4-RD) is a condition that occurs together with IgG4-RD and often mimics the lung lesion [idiopathic multicentric Castleman's disease (iMCD-L)] of idiopathic multicentric Castleman's disease (iMCD). Because no clinical and pathological studies had previously compared features of these diseases, we undertook this comparison with clinical and histological data. METHODS AND RESULTS: Nine patients had IgG4-L (high levels of serum IgG4 and of IgG4+ cells in lung specimens; typical extrapulmonary manifestations). Fifteen patients had iMCD-L (polyclonal hyperimmunoglobulinaemia, elevated serum interleukin-6 levels and polylymphadenopathy with typical lymphadenopathic lesions). Mean values for age, serum haemoglobin levels and IgG4/IgG ratios were higher in the IgG4-L group and C-reactive protein levels were higher in the iMCD-L group. All IgG4-RD lung lesions showed myxomatous granulation-like fibrosis (active fibrosis), with infiltration of lymphoplasmacytes and scattered eosinophils within the perilymphatic stromal area, such as interlobular septa and pleura with obstructive vasculitis. All 15 lung lesions of iMCD, however, had marked accumulation of polyclonal lymphoplasmacytes in lesions with lymphoid follicles and dense fibrosis, mainly in the alveolar area adjacent to interlobular septa and pleura without obstructive vasculitis. CONCLUSIONS: Although both lesions had lymphoplasmacytic infiltration, lung lesions of IgG4-RD were characterized by active fibrosis with eosinophilic infiltration within the perilymphatic stromal area with obstructive vasculitis, whereas lung lesions of iMCD had lymphoplasmacyte proliferating lesions mainly in the alveolar area adjacent to the perilymphatic stromal area. These clinicopathological features may help to differentiate the two diseases.

The Simultaneous Elevation of Oxidative Stress Markers and Wilms' Tumor 1 Gene during the Progression of Myelodysplastic Syndrome.

Oxidative stress is closely related to iron overload in myelodysplastic syndrome (MDS) and induces DNA damage. We evaluated the oxidative stress markers derivatives of reactive oxidative metabolites (dROM) and 8-hydroxy-2'-deoxyguanosine (8-OHdG) during azacitidine treatment in an MDS patient. Simultaneous with an increase in the expression of Wilms' Tumor 1 (WT1) gene in the peripheral blood, the serum dROM level was elevated, and this increase was observed earlier than the increases in ferritin and 8-OHdG. Throughout the clinical course, dROM and 8-OHdG correlated significantly with WT1 and with ferritin, suggesting that changes in the oxidative stress marker levels reflect not only iron overload but also disease progression of MDS.

Efficacy of recombinant human soluble thrombomodulin for the treatment of acute exacerbation of idiopathic pulmonary fibrosis: a single arm, non-randomized prospective clinical trial.

BACKGROUND: Coagulation abnormalities are involved in the pathogenesis of acute exacerbations of idiopathic pulmonary fibrosis (AE-IPF). The administration of recombinant human soluble thrombomodulin (rhTM), which has both anti-inflammatory and anticoagulant activities, improves outcomes and respiratory function in patients with acute respiratory distress syndrome. Therefore, we conducted a prospective clinical study to examine the effects of rhTM on respiratory function, coagulation markers, and outcomes for patients with AE-IPF. METHODS: After registration of the protocol, the patients with AE-IPF who satisfied the study inclusion criteria were treated daily with 380 U/kg of rhTM for 7 days and steroid pulse therapy. The concomitant administration of immunosuppressants and polymyxin B-immobilized fiber column treatment was prohibited. The sample size was 10 subjects. The primary study outcome was the improvement of PaO2/FiO2 ratio a week after treatment initiation. Secondary outcomes were change in D-dimer level over time and 28-day survival rate in patients without intubation. Study data were compared with historical untreated comparison group, including 13 patients with AE-IPF who were treated without rhTM before the registration. RESULTS: The mean PaO2/FiO2 ratio for the rhTM treatment group (n = 10) on day 8 significantly improved compared with that on day one (two-way analysis of variance, p = 0.01). The mean D-dimer level tended to decrease in the rhTM group on day 8, but the change was not significant. The 28-day survival rate was 50 % higher in the rhTM group than in the historical untreated comparison group, but the difference was not significant. A post hoc analysis showed that overall survival time was significantly longer in the treated group compared with that of the historical untreated comparison group (p = 0.04, log-rank test). CONCLUSION: rhTM plus steroid pulse therapy improves respiratory functions in patients with AE-IPF and is expected to improve overall patient survival without using other combination therapies. TRIAL REGISTRATION: The study was registered with University Hospital Medical Information Network Clinical Trial Registry (UMIN-CTR) in October 2012 (UMIN000009082).

Change in serum marker of oxidative stress in the progression of idiopathic pulmonary fibrosis.

BACKGROUND: Increased oxidative stress is supposed to be involved in the etiology of idiopathic pulmonary fibrosis (IPF). It was reported that oxidative stress values measured by a spectrophotometric technique (d-ROMs test) were significantly higher in IPF patients than in controls, and were negatively correlated with Forced Vital Capacity (FVC) and Carbon Monoxide Diffusing Capacity (DLCO). However, the relationship between progression of IPF over time and change in serum oxidative stress marker remains unclarified. AIMS: This study aimed to investigate the change in serum oxidative stress marker during progression of IPF. SUBJECTS AND METHODS: The levels of oxidative stress in blood samples of 43 treatment-naïve IPF patients were measured by the d-ROMs test. FVC and DLCO were measured concurrently. The changes in oxidative stress and pulmonary function were evaluated in 27 untreated patients 6 months later. Oxidative stress levels of 13 patients with acute exacerbation of IPF (AE-IPF) and 30 healthy controls were also evaluated. RESULTS: Oxidative stress values [median, interquartile range (IQR); Carratelli units (U.CARR)] were significantly higher in 43 IPF patients than in controls (366, 339-443 vs. 289, 257-329, p < 0.01) and were significantly increased 6 months later in 27 untreated patients (353, 311-398 at baseline to 385, 345-417 at follow-up, p < 0.01). The increase in oxidative stress values (24.0, 6.0-49.0 U.CARR/6 months) was negatively correlated with baseline DLCO (rs = -0.44, p < 0.05) and FVC changes after 6 months (rs = -0.54, p < 0.01). Oxidative stress values were significantly higher in IPF patients with acute exacerbation than in those with stable disease (587, 523-667 vs. 366, 339-443 U.CARR, respectively; p < 0.01). CONCLUSIONS: Serum oxidative stress values increased with disease progression in IPF patients.

Evaluation of reactive oxygen metabolites in patients with non-small cell lung cancer after chemotherapy.

BACKGROUND: The aim of this study was to evaluate the level of reactive oxygen metabolites (ROMs) after chemotherapy in patients with non-small cell lung cancer (NSCLC) and its association with response to treatment. METHODS: Fifty-eight untreated NSCLC patients and twenty-three healthy subjects were selected for the study. Patients received two courses of platinum-based chemotherapy and were evaluated for oxidative stress and treatment response. As a marker of reactive oxygen species, ROMs levels were measured using the d-ROMs test. RESULTS: ROMs level (mean ± standard deviation) before chemotherapy in NSCLC patients (416 ± 135 U.CARR) was significantly elevated (p = 0.016) compared to normal healthy subjects (320 ± 59 U.CARR). Patients who responded to chemotherapy showed significantly decreased (p = 0.014) ROMs levels after chemotherapy, whereas patients who had stable disease or progressive disease showed no change in ROMs level (p = 0.387). CONCLUSIONS: NSCLC patients had significantly elevated ROMs levels before chemotherapy compared with normal healthy subjects. Chemotherapy may suppress ROMs production in responders but not in non-responders. ROMs level may be a predictor of clinical outcome in patients receiving chemotherapy for NSCLC.

Contrary effects of sphingosine-1-phosphate on expression of α-smooth muscle actin in transforming growth factor ß1-stimulated lung fibroblasts.

Transforming growth factor-ß1 (TGFß1) plays a pivotal role in fibrosis in various organs including the lung. Following pulmonary injury, TGFß1 stimulates conversion of fibroblasts to myofibroblasts that are mainly characterized by up-regulation of α-smooth muscle actin (αSMA) expression, and the resulting excess production of extracellular matrix proteins causes fibrosis with loss of alveolar function. The present study was undertaken to define the role of the sphingosine-1-phosphate (S1P) pathway in TGFß1-induced expression of αSMA in human fetal lung fibroblasts, HFL1 cells. Analysis of mRNA revealed the existence of S1P(1), S1P(2), and S1P(3) receptor mRNAs. Treatment with TGFß1 increased sphingosine kinase (SphK) activity and S1P(3) receptor mRNA at 24h after stimulation, and pharmacological data showed the involvement of sphingomyelinase, SphK, and S1P(3) receptor in the TGFß1-induced up-regulation of αSMA with and without serum. Treatment with pertussis toxin and S1P(1) receptor antagonist W146 enhanced αSMA expression by TGFß1/serum, and S1P decreased and increased αSMA levels with and without serum, respectively. TGFß1 increased cyclooxygenase-2 expression in a manner dependent on serum and the sphingomyelinase/SphK pathway, and the response was decreased by pertussis toxin. Prostaglandin E(2), formed by TGFß1/serum stimulation, decreased the TGFß1-induced expression of αSMA via EP prostanoid receptor. These data suggest that S1P formed by TGFß1 stimulation has diverse effects on the expression of αSMA, inhibition via the S1P(1) receptor-mediated and serum-dependent expression of cyclooxygenase-2 and the resulting formation of prostaglandin E(2), and stimulation via the S1P(3) receptor in a serum-independent manner.

Inhibitory effects of clinical reagents having anti-oxidative activity on transforming growth factor-ß1-induced expression of α-smooth muscle actin in human fetal lung fibroblasts.

Excessive production of transforming growth factor-ß1 (TGFß1) plays an important role in lung fibrosis, in which the differentiation of fibroblasts into myofibroblasts is a key process. Increased formation of reactive oxygen species (ROS) induced by TGFß1 is a common pathological feature of fibrosis. In the present study, probucol and lovastatin, which are therapeutics used for hyperlipidemia and proposed to act as anti-oxidants, were examined in terms of their effect on TGFß1-induced formation of ROS and expression of α-smooth muscle actin (αSMA), a myofibroblast marker, in human fetal lung fibroblasts (HFL1 cells). The effects of anti-oxidative enzymes and reagents including N-acetyl-L-cysteine, α-tocopherol, and lecithinized-superoxide dismutase (SOD) on TGFß1-induced expression of αSMA were also examined. Treatment with probucol (30 µM) and lovastatin (1 µM and 3 µM), in addition to lecithinized-SOD, significantly inhibited the TGFß1-induced formation of ROS and αSMA. Other anti-oxidants including N-acetyl-L-cysteine had marginal effects on αSMA expression under the conditions. Probucol and lovastatin, established therapeutics, may be worth trying in patients with both lung fibrosis and hypercholesterolemia.

Development of an enzyme-linked immunosorbent assay system to determine the presence of antibodies specific for taxane structures.

Taxanes, which are widely used in treatment of numerous cancer types, are well-known to induce hypersensitivity reactions (HSR), especially in the case of paclitaxel. Although the cause of the HSR is commonly thought to be a non-immunological direct effect of the diluent which is used to dissolve paclitaxel, some reports suggest the possibility of the presence of an immunological reaction to the common taxane structure. The aim of this study was to establish a method to determine the presence of anti-taxane antibodies in body fluids of patients who have previously received paclitaxel, in order to estimate the risk of the occurrence of HSR to other taxane compounds, such as docetaxel. To prepare an enzyme-linked immunosorbent assay (ELISA) plate for determining taxanes, 10-deacetylbaccatin III (DAB) was first succinylated by use of dimethylaminopyridine and succinic anhydride in dried pyridine. After the succinylation reaction, three different products were obtained, and these were confirmed as 7-succinoyl DAB (7-DAB), 10-succinoyl DAB (10-DAB), and 7,10-disuccinoyl DAB (7,10-DAB) by (1)H-NMR analysis. Each of these three products was conjugated with bovine serum albumin (BSA), and adsorbed on an ELISA plate. By using a commercially available anti-taxane monoclonal antibody as a model antibody, the detection limit of the anti-taxane antibodies on the 7-DAB-BSA-, 10-DAB-BSA-, and 7,10-DAB-BSA-conjugated ELISA plate was estimated as 0.3, 1 and 10 ng/ml, respectively. The ELISA system established in this study may therefore be useful for estimating the risk of HSR to taxanes in a patient prior to the use of these drugs.

Mediastinal lymphadenopathy without cervical lymphadenopathy in a case of Kikuchi-Fujimoto disease.

A 44-year-old man was referred to our hospital because of persistent high fever. Both CT and PET-CT demonstrated lymph node lesions limited to the mediastinal region without cervical lymphadenopathy. Histology of a mediastinal lymph node obtained by video-assisted thoroscopic excision confirmed the diagnosis of histiocytic necrotizing lymphadenitis. To our knowledge, this is the first report of Kikuchi-Fujimoto disease with isolated mediastinal lymphadenopathy. Although Kikuchi-Fujimoto disease is rare, we should consider this disease in patients with a high fever and no other symptoms.

Incidence of dehydration encephalopathy among patients with disturbed consciousness at a hospital emergency unit.

Systemic dehydration and diffuse central nervous system signs without any other illness is referred to as dehydration encephalopathy (DE). However, the incidence of DE at emergency units remains uncertain. We investigated the incidence of DE among persons with disturbed consciousness who visited the emergency unit. We reviewed the medical case records of the emergency unit at our university hospital during a 6-month period. Among them, 132 patients presented with disturbed consciousness as the sole initial manifestation on arrival. They were 75 men, 47 women; mean age 68 years (16-95 years). After carefully excluding other etiologies, the incidence of DE was 2% among all persons in the emergency unit and 4% among persons older than 68 years. In conclusion, the incidence of DE in our emergency unit was not common. Nevertheless, recognition of DE is extremely important in order to avoid unnecessary medication in elderly subjects.