Conditional deficiency of Rho-associated kinases disrupts endothelial cell junctions and impairs respiratory function in adult mice.

The Ras homology (Rho) family of GTPases serves various functions, including promotion of cell migration, adhesion, and transcription, through activation of effector molecule targets. One such pair of effectors, the Rho-associated coiled-coil kinases (ROCK1 and ROCK2), induce reorganization of actin cytoskeleton and focal adhesion through substrate phosphorylation. Studies on ROCK knockout mice have confirmed that ROCK proteins are essential for embryonic development, but their physiological functions in adult mice remain unknown. In this study, we aimed to examine the roles of ROCK1 and ROCK2 proteins in normal adult mice. Tamoxifen (TAM)-inducible ROCK1 and ROCK2 single and double knockout mice (ROCK1flox/flox and/or ROCK2flox/flox;Ubc-CreERT2) were generated and administered a 5-day course of TAM. No deaths occurred in either of the single knockout strains, whereas all of the ROCK1/ROCK2 double conditional knockout mice (DcKO) had died by Day 11 following the TAM course. DcKO mice exhibited increased lung tissue vascular permeability, thickening of alveolar walls, and a decrease in percutaneous oxygen saturation compared with noninducible ROCK1/ROCK2 double-floxed control mice. On Day 3 post-TAM, there was a decrease in phalloidin staining in the lungs in DcKO mice. On Day 5 post-TAM, immunohistochemical analysis also revealed reduced staining for vascular endothelial (VE)-cadherin, ß-catenin, and p120-catenin at cell-cell contact sites in vascular endothelial cells in DcKO mice. Additionally, VE-cadherin/ß-catenin complexes were decreased in DcKO mice, indicating that ROCK proteins play a crucial role in maintaining lung function by regulating cell-cell adhesion.

Presumed Septic Shock Caused by Actinotignum schaalii Bacteremia.

We herein report a case of presumed septic shock due to Actinotignum schaalii bacteremia with urinary tract infection. A 65-year-old Japanese man suffering from a fever was diagnosed with septic shock due to urinary tract infection. A urine sample was additionally incubated under 5% CO2 and anaerobic conditions after A. schaalii was identified in a blood culture, but A. schaalii was not detected in the urine culture. If Gram-positive rods are observed on Gram staining of a urine sample in symptomatic patients with a predisposing urogenital condition, 5% CO2 and an anaerobic culture of a urine sample should be performed immediately.

Septic shock due to Yersinia pseudotuberculosis infection in an adult immunocompetent patient: a case report and literature review.

BACKGROUND: Yersinia pseudotuberculosis infection can occur in an immunocompromised host. Although rare, bacteremia due to Y. pseudotuberculosis may also occur in immunocompetent hosts. The prognosis and therapeutic strategy, especially for immunocompetent patients with Y. pseudotuberculosis bacteremia, however, remains unknown. CASE PRESENTATION: A 38-year-old Japanese man with a mood disorder presented to our hospital with fever and diarrhea. Chest computed tomography revealed consolidation in the right upper lobe with air bronchograms. He was diagnosed with pneumonia, and treatment with intravenous ceftriaxone and azithromycin was initiated. The ceftriaxone was replaced with doripenem and the azithromycin was discontinued following the detection of Gram-negative rod bacteria in 2 sets of blood culture tests. The isolated Gram-negative rod bacteria were confirmed to be Y. pseudotuberculosis. Thereafter, he developed septic shock. Doripenem was switched to cefmetazole, which was continued for 14 days. He recovered without relapse. CONCLUSIONS: We herein report a case of septic shock due to Y. pseudotuberculosis infection in an adult immunocompetent patient. The appropriate microorganism tests and antibiotic therapy are necessary to treat patients with Y. pseudotuberculosis bacteremia.

A new anticoagulation strategy using recombinant human thrombomodulin in patients on veno-venous extracorporeal membrane oxygenation: a retrospective study.

BACKGROUND: During veno-venous extracorporeal membrane oxygenation (VV-ECMO), systemic anticoagulation is required to prevent thrombotic complications within the circuit and oxygenator. The unfractionated heparin (UFH) is commonly administered as a standard anticoagulant, but in our institute recombinant human thrombomodulin (rhTM), instead of UFH, is used as an anticoagulant for VV-ECMO. In the present study, we reviewed whether rhTM could be applied effectively and safely as an anticoagulant agent during VV-ECMO. METHODS: All 15 patients with severe respiratory failure on VV-ECMO were analyzed retrospectively. The following data were collected: age, gender, underlying disease, APACHE-II score, SOFA score, Japanese association for acute medicine (JAAM) DIC score, the usage of anticoagulants, time course of coagulationrelated parameters during ECMO, hemorrhagic and thrombotic complications. RESULTS: The median age of the patients was 73 years. The median JAAM DIC score at day 0 was 5 points, indicating that 13 patients were diagnosed with DIC at the initiation of VV-ECMO. The total number of days of VV-ECMO runs combined was 193 days, with a median duration of VV-ECMO of 9 days. Among the 15 VV-ECMO runs, rhTM was used as monotherapy in 5 runs, and a combination of rhTM and (antithrombin) AT was used in 8 runs. UFH was used in combination with rhTM in only 2 runs. Median ACT and aPTT remained a little longer than normal range over the course of the 14 days of a VV-ECMO run. Bleeding events were observed in 6 cases (40%) and no major thromboses were observed in all patients. CONCLUSIONS: In this retrospective study, we analyzed 15 patients with severe respiratory failure who were administered rhTM as an anticoagulant during VV-ECMO and found that anticoagulation therapy with rhTM is maybe a feasible option which allows for effective and safe VV-ECMO.

Risk factors for disease-related deterioration following diagnostic bronchoalveolar lavage procedures in diffuse lung disease: a case-control study.

BACKGROUND: Although the risk factors for diagnostic bronchoalveolar lavage (BAL)-induced acute exacerbations in patients with idiopathic pulmonary fibrosis (IPF) have been previously reported, no study has assessed these in patients with non-IPF. We aimed to identify the risk factors for BAL-induced disease deterioration (BAL-DD) in all types of diffuse lung disease. METHODS: Patients with diffuse lung disease who underwent BAL at our hospital from April 2012 to November 2017 were retrospectively analyzed. The patient information, laboratory data, radiological findings, and BAL fluid analysis results in patients who developed BAL-DDs were compared with those in patients who did not. RESULTS: BAL-DDs occurred in 14 (3.3%) of the 429 patients included the study. The BAL-DD group had a significantly poorer performance status, higher C-reactive protein level, lower partial pressure of oxygen in the arterial blood at rest, greater proportion of desaturation on exertion and cases having followed a progressive clinical course before BAL, and more extensive consolidation and ground-glass opacity on chest high-resolution computed tomography (HRCT) than the non-BAL-DD group. A high total cell concentration and an increased number of eosinophils in the BAL fluid were more frequently found in patients with BAL-DD than in those without. CONCLUSIONS: Patients with decreased physical activity level, increased level of inflammatory markers, low oxygenation status, and extensive lung involvements on chest HRCT and following a progressive clinical course before BAL may be warned of the BAL-DD risk. Elevated eosinophil counts in the BAL fluid could be associated with the triggering of BAL-DDs.

A case report of primary sternal osteomyelitis caused by polymicrobial bacteria, including Actinomyces israelii.

We herein report a case of primary sternal osteomyelitis caused by polymicrobial bacteria, including Actinomyces israelii. A 72-year-old man presented with a fever and precordial pain. Chest computed tomography (CT) revealed peristernal fluid associated with an osteolytic lesion and a peripheral nodule in the right upper lobe. We suspected sternal osteomyelitis, and an incision and drainage were performed. Culture of the drainage fluid and bone tissue yielded A. israelii, Fusobacterium necrophorum, and Streptococcus constellatus. Treatment with benzylpenicillin potassium (PCG) was administered. A subsequent chest CT scan showed that the peripheral nodule decreased in size after antimicrobial therapy. We therefore presumed the peripheral nodule as septic pulmonary embolism(SPE). Antimicrobial agents were administered for a total of 6 months. To our knowledge, this is the first case report of primary sternal osteomyelitis associated with presumed SPE caused by polymicrobial bacteria, including A. israelii. It is important to identify the causative pathogen in osteomyelitis, which requires long-term antibiotic treatment.

Veno-Venous Extracorporeal Membrane Oxygenation for Severe Pneumocystis jirovecii Pneumonia in an Immunocompromised Patient without HIV Infection.

Pneumocystis jirovecii pneumonia (PJP) occurs in immunocompromised hosts and is classified as PJP with human immunodeficiency virus (HIV) infection (HIV-PJP) and PJP without HIV infection (non-HIV PJP). Non-HIV PJP rapidly progresses to respiratory failure compared with HIV-PJP possibly due to the difference in immune conditions; namely, the prognosis of non-HIV PJP is worse than that of HIV PJP. However, the diagnosis of non-HIV PJP at the early stage is difficult. Herein, we report a case of severe non-HIV PJP successfully managed with veno-venous extracorporeal membrane oxygenation (V-V ECMO). A 54-year-old woman with neuromyelitis optica was treated with oral corticosteroid, azathioprine, and methotrexate. She admitted to our hospital for fever, dry cough, and dyspnea which developed a week ago. On admission, she required endotracheal intubation and invasive ventilation for hypoxia. A chest computed tomography (CT) scan revealed ground-glass opacity and consolidation in the both lungs. Grocott staining and PCR analysis of bronchoalveolar lavage fluid indicated the presence of fungi and Pneumocystis jirovecii, respectively, whereas serum HIV-antibody was negative. The patient was thus diagnosed with non-HIV PJP and was treated with intravenous pentamidine and corticosteroid pulse therapy for PJP. However, hypoxia was worsened; consequently, V-V ECMO assistance was initiated on day 7. The abnormal chest CT findings and hypoxia were gradually improved. The V-V ECMO support was successfully discontinued on day 14 and mechanical ventilation was discontinued on day 15. V-V ECMO could be a useful choice for respiratory assistance in severe cases of PJP among patients without HIV infection.

Diffuse Large B-Cell Lymphoma Arising from the Lesion of Chronic Lobar Atelectasis.

Pulmonary lymphoma is rare, accounting for < 1% of primary lung cancers. Most primary pulmonary lymphomas (PPL) are low-grade mucosa-associated lymphoid tissue (MALT)-type, and among PPL, diffuse large B-cell lymphoma (DLBCL) is extremely rare. In contrast, there has been an increase in the incidence of DLBCL among patients with autoimmune disorders and recurrent or chronic bacterial infection. A subset of DLBCL has been reported to develop through transformation of preexisting or concurrent MALT. The respiratory symptoms are non-specific, and the chest X-ray findings demonstrate the presence of interstitial and mixed alveolar infiltrates, nodular lesions, and localized homogeneous consolidations; the diagnosis of pulmonary DLBCL is thus challenging and often leads to a misdiagnosis or delayed diagnosis. We herein report a case of DLBCL which was assumed to have arisen from the lesion of chronic atelectasis that was successfully diagnosed by endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA). A 74-year-old woman with diffuse bronchiectasis and chronic atelectasis of the left lower lobe suffered from productive cough and high fever. Increased airway filling with mucoid secretion was repeatedly observed within the area of atelectasis with bronchiectasis, and left lower lobe atelectasis developed. Subsequently, the hilar and mediastinal lymph nodes gradually became enlarged, and DLBCL was pathologically confirmed. In the present case, DLBCL was considered to have arisen in the lesion of chronic atelectasis. Physicians should recognize that DLBCL may develop at the site of chronic atelectasis during disease course of diffuse bronchiectasis, and thus DLBCL may be misdiagnosed as superimposed infection of chronic atelectasis.

Factors associated with false negative interferon-γ release assay results in patients with tuberculosis: A systematic review with meta-analysis.

Which factors are related to false negative results of the interferon-γ release assay (IGRA) is unclear. This systematic review described the risk factors associated with false negative IGRA results. Two authors independently identified studies designed to evaluate risk factors for false negative IGRA results from PubMed, the Cochrane Register of Control Trial database, and EMBASE, accessed on October 22, 2018. Meta-analyses were conducted with random-effect models, and heterogeneity was calculated with the I2 method. Of 1,377 titles and abstracts screened, 47 full texts were selected for review, and we finally included 17 studies in this systematic review. The most commonly studied risk factor (14 studies) was advanced age, followed by low peripheral lymphocyte counts (7 studies), and these factors were associated with false negative results even with different tuberculosis incidences (pooled odds ratio 2.06; 95% CI, 1.68-2.52 in advanced age and 2.68; 95% CI, 2.00-3.61 in low peripheral lymphocyte counts). Advanced age and low peripheral lymphocyte counts may be common risk factors for false negative IGRA results, suggesting that people with these factors need to be carefully followed, even if they have negative IGRA results.

Asthma Exacerbation Coincident with Saddle Pulmonary Embolism and Paradoxical Embolism.

Saddle pulmonary embolism (PE) and paradoxical embolism (PDE) are life-threatening disorders carrying a risk of sudden death, and their prompt diagnosis is extremely important. Saddle PE is a radiologic definition and refers to a thrombus that straddles the bifurcation of the pulmonary artery trunk, carrying a risk of sudden hemodynamic collapse. PDE is defined as a systemic arterial embolus due to the passage of a venous thrombus though a right-to-left shunt, such as patent foramen ovale (PFO). We herein present the rare case of asthma exacerbation coincident with saddle PE and PDE. A 69-year-old woman with asthma was suffering from dyspnea, pulse attenuation of the left radial artery and left upper limb pain. An arterial blood gas analysis revealed hypoxemia, and a pulmonary function test demonstrated an obstructive pattern. Enhanced computed tomography (CT) revealed saddle PE, right popliteal venous thrombosis, and left brachial artery occlusion. After the treatment with edoxaban, an anticoagulant, and aspirin, the PE was significantly alleviated, and the brachial artery occlusion was recanalized. Subsequently, the right-to-left shunt through PFO was confirmed, and PDE was suspected of inducting her brachial artery embolism. In the present case, the pulse attenuation of the radial artery and upper limb pain prompted us to consider peripheral vascular disease or coagulation disorders. Physicians should keep in mind that patients with asthma are at considerable risk of PE, and it is important to be aware of possible PFO in patients presenting with the coexistence of PE and systemic arterial embolism.

A Pitfall of Treatment with Tosufloxacin for Pneumonia That Might Be Lung Tuberculosis.

Tosufloxacin, which is not used to treat Mycobacterium tuberculosis, is a fluoroquinolone recommended for pneumonia when the possibility of tuberculosis infection cannot be excluded. In the present case, symptoms and chest infiltrative shadow initially improved by tosufloxacin. Therefore, we regarded this patient as having general pneumonia and did not perform follow-up chest X-ray until the infiltrates had completely disappeared. However, a few weeks later, the symptoms and the infiltrates had worsened, so M. tuberculosis was isolated from the patient's sputum. This case suggests that patients suspected of having pulmonary tuberculosis should be monitored carefully, even if antibiotics without antituberculous activity are initially effective.

A mini systematic review of prognostic factors in elderly patients with tuberculosis.

BACKGROUND: While advanced age has been suggested as a prognostic factor in patients with tuberculosis, the characteristics associated with a poor outcome in elderly patients have remained unclear. The aim of this systematic review was to describe the risk factors for a poor outcome in elderly patients with tuberculosis. METHODS: We identified 1255 studies published between 1919 and 2017 from the PubMed database by using combinations of the keywords "tuberculosis [Title/Abstract]" and "elderly [Title/Abstract]". Full texts of the studies that met the inclusion criteria were further evaluated by two independent investigators. RESULTS: even retrospective cohort studies were included in this systematic review. More advanced age, comorbidities, and nutritional status were likely to be prognostic factors in Taiwan (aging country) and Japan (super-aged country), while human immunodeficiency virus infection and severe tuberculosis were associated with a poor outcome in low-income countries. Two studies from Taiwan investigated the prognostic factors of tuberculosis-specific death and non-tuberculosis-specific death separately, but no significant differences were found in the factors between the two types of death. CONCLUSIONS: The prognostic factors of tuberculosis in elderly patients varied according to the income levels of the countries. The factors in Taiwan and Japan were mainly associated with host factors, irrespective of the cause of death, which may reflect senile deterioration due to old age.

A case of maoto-induced interstitial pneumonia.

A 64-year-old man was prescribed maoto, a prevailing Chinese herbal, for a cold with upper respiratory inflammation. Two days later, he developed a high fever, progressive dyspnea and pulmonary infiltration on chest high-resolution computed tomography (HRCT) including diffuse ground-glass opacity mainly around bronchovascular bundles and partial distribution of subpleural cysts resembling honeycombing. Despite the administration of azithromycin and pazufloxacin, the pulmonary infiltration and hypoxemia has rapidly progressed, so he was referred to our hospital. Although fulminant pneumonia or the acute exacerbation of idiopathic pulmonary fibrosis (IPF) was considered, his respiratory symptoms and pulmonary infiltration immediately improved and oxygen therapy was not needed on the fifth hospital day. Based on the clinical course, laboratory findings and the chest imaging findings, drug induced interstitial lung disease was suspected. The drug-induced lymphocyte test (DLST) as well as a scratch test against maoto demonstrated positive results. This is the first case report of maoto-induced interstitial pneumonia that was diagnosed based on the patient's clinical course, chest imaging findings and laboratory findings.

Significant elevation of the levels of B-cell activating factor (BAFF) in patients with sarcoidosis.

B-cell activating factor (BAFF) plays an important role in the survival and differentiation of B-cells and production of antibodies. Recent studies show that the serum BAFF levels are elevated in patients with sarcoidosis; however, they have not studied the relationship of the finding with the clinical features of the disease. The purpose of the present study is to analyze the BAFF and to elucidate the relationship between BAFF levels and the disease activity or severity of sarcoidosis. Eighty-eight patients with sarcoidosis and 21 healthy volunteers were enrolled in the present study. The BAFF levels were measured by an enzyme-linked immunosorbent assay. To assess the disease severity, we examined the number of affected organs, Schadding stages, respiratory function impairment (RFI), and the scoring system developed by Wasfi et al. The serum BAFF levels in sarcoidosis patients were significantly higher than those in healthy volunteers (median 1553.0 vs 984.6 pg/ml, p < 0.001). There were positive correlations between the serum BAFF level and disease activity markers. In addition, there were positive correlations between the BAFF levels and the disease severity score in both the serum (R = 0.367, p < 0.001) and bronchoalveolar lavage fluid (BALF) (R = 0.376, p < 0.001). This study demonstrated that the BAFF levels in both the serum and BALF were positively correlated with the disease activity markers and disease severity. BAFF may be useful as an indicator of both the disease activity and severity.

Expression of mutant Sftpc in murine alveolar epithelia drives spontaneous lung fibrosis.

Epithelial cell dysfunction is postulated as an important component in the pathogenesis of idiopathic pulmonary fibrosis (IPF). Mutations in the surfactant protein C (SP-C) gene (SFTPC), an alveolar type II (AT2) cell-restricted protein, have been found in sporadic and familial IPF. To causally link these events, we developed a knockin mouse model capable of regulated expression of an IPF-associated isoleucine-to-threonine substitution at codon 73 (I73T) in Sftpc (SP-CI73T). Tamoxifen-treated SP-CI73T cohorts developed rapid increases in SftpcI73T mRNA and misprocessed proSP-CI73T protein accompanied by increased early mortality (days 7-14). This acute phase was marked by diffuse parenchymal lung injury, tissue infiltration by monocytes, polycellular alveolitis, and elevations in bronchoalveolar lavage and AT2 mRNA content of select inflammatory cytokines. Resolution of alveolitis (2-4 weeks), commensurate with a rise in TGF-ß1, was followed by aberrant remodeling marked by collagen deposition, AT2 cell hyperplasia, α-smooth muscle actin-positive (α-SMA-positive) cells, and restrictive lung physiology. The translational relevance of the model was supported by detection of multiple IPF biomarkers previously reported in human cohorts. These data provide proof of principle that mutant SP-C expression in vivo causes spontaneous lung fibrosis, strengthening the role of AT2 cell dysfunction as a key upstream driver of IPF pathogenesis.

Elevated Serum Anti-GM-CSF Antibodies before the Onset of Autoimmune Pulmonary Alveolar Proteinosis in a Patient with Sarcoidosis and Systemic Sclerosis.

Pulmonary alveolar proteinosis (PAP) is characterized by the accumulation of periodic acid-schiff stain-positive lipoproteinaceous materials in the alveolar space due to impaired surfactant clearance by alveolar macrophage. Autoimmune PAP is the most common form of PAP, but rarely accompanies collagen disease or sarcoidosis. We report here a rare case of autoimmune PAP preceded by systemic sclerosis and sarcoidosis. A 64-year-old woman was admitted to our hospital for blurred vision, muscle weakness of extremities, Raynaud's phenomenon, and exertional dyspnea. We diagnosed her as having systemic sclerosis complicated with sarcoidosis. Chest computed tomography (CT) and transbronchial lung biopsy showed the findings of pulmonary fibrosis without PAP. We treated her with corticosteroid and intravenous cyclophosphamide therapy, followed by tacrolimus therapy. Thereafter, her symptoms improved except for exertional dyspnea, and she began to complain of productive cough thirteen months after corticosteroid and immunosuppressant therapy. On the second admission, a chest CT scan detected the emergence of crazy-paving pattern in bilateral upper lobes. Bronchoalveolar lavage (BAL) fluid with milky appearance and a lung biopsy specimen revealed acellular periodic acid-schiff stain-positive bodies. The serum titer of anti-granulocyte macrophage colony stimulating factor (GM-CSF) antibodies was elevated on first admission and remained high on second admission. We thus diagnosed her as having autoimmune PAP. Reducing the dose of immunosuppressive agents and repeating the segmental BAL resulted in the improvement of her symptoms and radiological findings. Immunosuppressant therapy may trigger the onset of autoimmune PAP in a subset of patients with systemic sclerosis and/or sarcoidosis.

Intrascrotal and osseous sarcoidosis mimicking intrascrotal organ cancer and bony metastasis.

We report a case of sarcoidosis with concomitant epididymis, testes, and phalanxes involvement mimicking intrascrotal organ cancer and metastatic bony disease. A 23-year-old man developed blurred vision and hyperemia of the left eye, and was diagnosed as having left iritis. A chest computed tomography scan detected bilateral hilar lymphadenopathy and lung nodular shadows. A transbronchial lung biopsy revealed a non-caseating granuloma and he was diagnosed with sarcoidosis. One year after the onset of his eye symptoms, he noticed enlargement of his right scrotum. Magnetic resonance imaging detected lesions of the right epididymis, bilateral testes, and bilateral phalanxes. A technetium-99m scintigram revealed a high accumulation in the bilateral bones of extremities. These radiological findings mimicked intrascrotal organ cancer and metastatic bony disease. Pathologic evaluation following the right epididymectomy revealed non-caseating granulomas compatible with sarcoidosis. Three and half years after the appearance of intrascrotal and bony lesions, they improved spontaneously. (Sarcoidosis Vasc Diffuse Lung Dis 2017; 34: 373-376).

Disseminated Mycobacterium tuberculosis Infection Masquerading as Metastasis after Heavy Ion Radiotherapy for Prostate Cancer.

Fluorodeoxyglucose (FDG)-positron emission tomography with computed tomography (FDG-PET/CT) is useful in disease monitoring of malignancies after therapy, while an FDG uptake may also be present in benign diseases. We herein demonstrate a case of disseminated Mycobacterium tuberculosis mimicking systemic metastasis of prostate cancer. This case highlights that clinicians should consider Mycobacterium tuberculosis in patients with prostate cancer who demonstrate multifocal FDG uptakes masquerading as metastasis, even when the chest photographs reveal a normal appearance and a sputum examination demonstrates negative results. An invasive surgical biopsy may be required and a pathological analysis would be critical in the diagnosis of Mycobacterium tuberculosis.