Virtual bronchoscopic navigation as an aid to CT-guided transbronchial biopsy improves the diagnostic yield for small peripheral pulmonary lesions.

BACKGROUND AND OBJECTIVE: Virtual bronchoscopic navigation (VBN) entails the provision of a virtual display of the bronchial routes that lead to small peripheral pulmonary lesions (PPL). It has been predicted that a combination of computed tomography (CT)-guided transbronchial biopsy (CT-TBB) with VBN might improve the diagnostic yield for small PPL. This study sought to investigate that prediction. METHODS: A total of 100 patients with small PPL (<20 mm) were enrolled for CT-TBB and randomly allocated to either a VBN+ or VBN- group (50 subjects per group). Group results were then compared in terms of diagnostic yield, whole procedure time, times at which the first CT scan and biopsy were taken and the number of lung biopsy specimens retrieved. RESULTS: The diagnostic yield for small PPL was significantly higher in the VBN+ group versus VBN- group (84% vs 58%, respectively (P = 0.013)), with no significant difference in (whole) examination time between groups (VBN+: 32:53 (32 min and 53 s) ± 12:01 vs VBN-: 33:06 ± 10:08 (P = NS)). However, the time periods between commencing the examination and either the first CT scan or first biopsy were significantly shorter for the VBN+ group, while the net biopsy time tended to be longer for this group with a significantly higher number of specimens collected (VBN+: 3.54 ± 1.07 specimens vs VBN-: 2.98 ± 1.06 specimens (P = 0.01)). CONCLUSION: Combining VBN with CT-TBB significantly improved the diagnostic yield for small PPL.

Development of an S-1 dosage formula based on renal function by a prospective pharmacokinetic study.

BACKGROUND: S-1 is an oral anticancer drug, containing tegafur (a prodrug of 5-fluorouracil, 5-FU), 5-chloro-2,4-dihydroxypyridine, and potassium oxonate. As renal dysfunction is known to increase exposure of 5-FU following S-1 administration, the incidence of severe adverse reactions is increased in patients with impaired renal function. However, no reliable information on its dose modification for patients with renal dysfunction has been provided. METHODS: We conducted a prospective pharmacokinetic study to develop an S-1 dosage formula based on renal function. Sixteen cancer patients with various degrees of renal function received a single dose of S-1 at 40 mg/m(2). A series of blood samples were collected at predefined times within 24 h to assess the plasma concentration profiles of 5-FU, 5-chloro-2,4-dihydroxypyridine, and tegafur. A mathematical model for the relationship between renal function and exposure of 5-FU was constructed by a population pharmacokinetic analysis. RESULTS: The clearance of 5-FU following S-1 administration was related to body surface area and creatinine clearance in the range 15.9-108.8 mL/min as estimated by the Cockcroft-Gault equation. The S-1 dosage formula was derived as follows:[Formula: see text]where AUC is the area under the concentration-time curve, CLcr is creatinine clearance, and BSA is body surface area. The recommended daily doses of S-1 in Asia and Europe were also proposed as nomograms according to exposure matching to the previously reported area under the concentration-time curve of 5-FU, which confirmed the efficacy and toxicity in pivotal registration studies. CONCLUSIONS: We have developed a novel formula for determining the S-1 dosage on the basis of renal function. Further validation is needed to confirm the formula for practical application.

Relationship between T-cell HLA-DR expression and intravenous immunoglobulin treatment response in Kawasaki disease.

BACKGROUND: Kawasaki disease (KD) is an acute febrile illness associated with the development of vasculitis. Administration of intravenous immunoglobulin (IVIG) is the standard treatment for KD. However, IVIG treatment is not effective in approximately 15% of children with KD. Some reports have presented evidence of immunological responses in IVIG-resistant KD patients. We assessed the possibility that T-cell activation is a contributing mechanism underlying this phenomenon. METHODS: We analyzed human leukocyte antigen-DR (HLA-DR) expression on peripheral blood CD4+ and CD8+ T cells in 82 children with KD who were admitted to the hospital between October 2007 and February 2012. We compared the percentages of HLA-DR+ T cells among the CD4+ T-cell and CD8+ T-cell populations for the IVIG-effective and IVIG-resistant groups. RESULTS: Among the 82 subjects, 51 had IVIG-effective KD and 31 children had IVIG-resistant KD. The percentages of HLA-DR+ T cells among the CD4+ T-cell and CD8+ T-cell populations in the IVIG-effective group were significantly lower than those in the IVIG-resistant group. CONCLUSION: Our results suggest that increased T-cell HLA-DR expression is associated with IVIG resistance in KD patients, indicating that HLA-DR expression would be a useful tool for predicting IVIG responsiveness during KD pathogenesis.

A Multinational Survey on Actual Diagnostics and Treatment of Subacute Sclerosing Panencephalitis.

Subacute sclerosing panencephalitis (SSPE) is a chronic infection of the central nervous system caused by the measles virus (MV). Its prevalence remains high in resource poor countries and is likely to increase in the Northern Europe as vaccination rates decrease. Clinical knowledge of this devastating condition, however, is limited. We therefore conducted this multinational survey summarizing experience obtained from more than 500 patients treated by 24 physicians in seven countries. SSPE should be considered in all patients presenting with otherwise unexplained acquired neurological symptoms. In most patients, the diagnosis will be established by the combination of typical clinical symptoms (characteristic repetitive myoclonic jerks), a strong intrathecal synthesis of antibodies to MV and typical electroencephalogram findings (Radermecker complexes). Whereas the therapeutic use of different antiviral (amantadine, ribavirin) and immunomodulatory drugs (isoprinosine, interferons) and of immunoglobulins has been reported repeatedly, optimum application regimen of these drugs has not been established. This is partly due to the absence of common diagnostic and clinical standards focusing on neurological and psychosocial aspects. Carbamazepine, levetiracetam, and clobazam are the drugs most frequently used to control myoclonic jerks. We have established a consensus on essential laboratory and clinical parameters that should facilitate collaborative studies. Those are urgently needed to improve outcome.

Cat-scratch disease with severe pleuritis in a 6-year-old girl.

We present the case of a 6-year-old girl with cat-scratch disease (CSD), who developed severe pleuritis without lymphadenitis. Bartonella henselae DNA was detected on real-time polymerase chain reaction (PCR) analysis of whole blood. This is the first report of CSD diagnosed on real-time PCR using whole blood.

Cytokine profile of bronchoalveolar lavage fluid from a mouse model of bronchial asthma during seasonal H1N1 infection.

BACKGROUND: Several studies support the role of viral infections in the pathogenesis of asthma exacerbation. However, several pediatricians believe that influenza virus infection does not exacerbate bronchial asthma, except for influenza A H1N1 2009 pandemic [A(H1N1)pdm09] virus infection. We previously reported that A(H1N1)pdm09 infection possibly induces severe pulmonary inflammation or severe asthmatic attack in a mouse model of bronchial asthma and in asthmatic children. However, the ability of seasonal H1N1 influenza (H1N1) infection to exacerbate asthmatic attacks in bronchial asthma patients has not been previously reported, and the differences in the pathogenicity profiles, such as cytokine profiles, remains unclear in bronchial asthma patients after A(H1N1)pdm09 and H1N1 infections. METHODS: The cytokine levels and viral titers in the bronchoalveolar lavage (BAL) fluid from mice with and without asthma after H1N1 infection (A/Yamagata and A/Puerto Rico strains) were compared. RESULTS: The interleukin (IL)-6, IL-10, tumor necrosis factor (TNF)-α, IL-5, interferon (IFN)-α, IFN-ß, and IFN-γ levels were significantly higher in the BAL fluids from the control/H1N1 mice than from the asthmatic/H1N1 mice. The viral titers in the BAL fluid were also significantly higher in the control/H1N1mice than in the asthmatic/H1N1 mice infected with either A/Yamagata or A/Puerto Rico. CONCLUSIONS: A(H1N1)pdm09 infection, but not H1N1 infection, can induce severe pulmonary inflammation through elevated cytokine levels in a mouse model of asthma.

Serum levels of matrix metalloproteinase-9 and tissue inhibitor of metalloproteinases-1 in human herpesvirus-6-infected infants with or without febrile seizures.

Human herpesvirus-6 (HHV-6) is a cause of exanthema subitum and, sometimes, of febrile seizures. However, the pathogenesis of febrile seizures associated with HHV-6 infection remains unclear. We investigated serum matrix metalloproteinase-9 (MMP-9) and tissue inhibitor of metalloproteinases-1 (TIMP-1) levels in infants with HHV-6 infection. Serum levels of both MMP-9 and TIMP-1 were significantly higher in infants with HHV-6 infection than in controls. Serum TIMP-1 levels were significantly higher in infants with febrile seizures than in infants without febrile seizures. Serum MMP-9/TIMP-1 ratios were significantly lower in infants with febrile seizures than in infants without febrile seizures. In infants with HHV-6 infection, positive correlations were found between serum MMP-9 concentrations and the white blood cells (WBC) count, and between serum TIMP-1 concentrations and the WBC count. Positive correlations were also found between the amounts of HHV-6 DNA and the ratios of MMP-9/TIMP-1 in infants with HHV-6 infection. In conclusion, we suggest that high serum levels of MMP-9 and TIMP-1 in infants with HHV-6 infection may induce dysfunction of the blood-brain barrier, eventually causing febrile seizures.

Traumatic head injury mimicking acute encephalopathy with biphasic seizures and late reduced diffusion.

Many studies have reported acute encephalopathy with biphasic seizures and late reduced diffusion (AESD) associated with viral infection at onset, but few studies have reported AESD without infection. We report the case of a 9-month-old boy who had a clinical course mimicking AESD after a traffic accident. The traffic accident caused a mild subdural hematoma without neurological abnormalities on admission. The boy became unconscious on the second day, and he was diagnosed with non-convulsive status epilepticus on the third day. Diffusion-weighted imaging showed reduced water diffusion in the subcortical white matter. On laboratory analysis interleukin (IL)-6 was elevated in the cerebrospinal fluid (CSF), but not in the serum. He had severe neurological sequelae with mental retardation, spastic tetraplegia, and epilepsy. We suggest that brain damage mimicking AESD was caused by the traffic accident and the prolonged seizure during infancy.

Effect of multidrug therapy on the prognosis of Mycobacterium avium complex pulmonary disease.

Multidrug therapy for Mycobacterium avium complex pulmonary disease (MAC-PD) results in negative sputum cultures. However, the prognostic value of this treatment approach remains unclear. This study aimed to clarify whether multidrug therapy reduces the incidence of events related to MAC-PD and improves the mortality rate. Patients who met the diagnostic criteria for MAC-PD at our hospital between 2003 and 2019 were retrospectively evaluated using medical records. Events related to MAC-PD were defined as hospitalisation for haemoptysis or respiratory infection and the development of chronic respiratory failure. There were 90 and 108 patients in the multidrug and observation groups, respectively. The median observation period was 86 months. Intergroup differences in body mass index, proportion of patients with cavities, and erythrocyte sedimentation rate were not significant. However, the observation group was older with a higher mean age (multidrug group: 62 years, observation group: 69 years; P < 0.001) and had a higher proportion of male patients (multidrug group: 13/90 [14.4%], observation group: 35/108 [32.4%]; P < 0.01). Furthermore, intergroup differences in the incidence of events related to MAC-PD (multidrug group: 26.69/1000 person-years, observation group: 25.49/1000 person-years), MAC-PD-associated mortality rate (multidrug group: 12.13/1000 person-years, observation group: 12.74/1000 person-years), and total mortality (multidrug group: 24.26/1000 person-years, observation group: 29.50/1000 person-years) were not significant. Many patients relapse even after multidrug therapy, and our findings suggest that multidrug therapy has no effect in preventing the onset of respiratory events or prolonging life expectancy.

Outcomes of critically ill patients with liver failure who require mechanical ventilation: A retrospective, single-center study.

Background and Aims: Critically ill patients with liver failure have high mortality. Besides the management of organ-specific complications, liver transplantation constitutes a definitive treatment. However, clinicians may hesitate to introduce mechanical ventilation for patients on liver transplantation waitlists because of poor prognosis. This study investigated the outcomes of intensive care and ventilation support therapy effects in patients with liver failure. Methods: This single-center study retrospectively enrolled 32 consecutive patients with liver failure who were admitted to the intensive care unit from January 2014 to December 2020. The medical records were reviewed and analyzed retrospectively for Acute Physiologic and Chronic Health Evaluation (APACHE)-II. The model for end-stage liver disease scores, 90-day mortality, and survival was assessed using the Kaplan-Meier method. Results: The average patient age was 45.5 ± 20.1 years, and 53% of patients were women. On intensive care unit admission, APACHE-II and model for end-stage liver disease scores were 20 and 28, respectively. Among 13 patients considered for liver transplantation, 4 received transplants. Thirteen patients (40.6%) were intubated and mechanically ventilated in the intensive care unit. The 90-day mortality rate of patients with and without mechanical ventilation in the intensive care unit (13, 61.5% vs. 19, 47.4%, p = 0.4905) was similar. APACHE-II score >21 was an independent predictor of mechanical ventilation requirement in patients with liver failure during intensive care unit stay. Conclusion: Although critically ill patients with liver failure are at risk of multiorgan failure with poor outcomes, mechanical ventilation did not negatively affect the 90-day mortality or performance rates of liver transplantation. Clinicians should consider mechanical ventilation-based life support in critically ill patients with liver failure who are awaiting liver transplantation.

Analysis of bronchoalveolar lavage fluid in a mouse model of bronchial asthma and H1N1 2009 infection.

BACKGROUND: Bronchial asthma is known as a risk factor of admission to the intensive care unit. However, the mechanism by which pandemic 2009 H1N1 (A(H1N1)pdm09) infection increases the severity of symptoms in patients with bronchial asthma is unknown; therefore, we aimed at determining this mechanism. METHODS: Inflammatory cell levels in the bronchoalveolar lavage (BAL) fluid from the non-asthma/mock, non-asthma/A(H1N1)pdm09, asthma/mock, and asthma/A(H1N1)pdm09 groups were determined using BALB/c mice. Cell infiltration levels, cytokine levels, and viral titers were compared among the groups. RESULTS: Neutrophil, monocyte, interleukin (IL)-5, IL-6, IL-10, IL-13, and tumor necrosis factor (TNF)-α levels were significantly higher in the BAL fluid from the non-asthma/A(H1N1)pdm09 and asthma/A(H1N1)pdm09 groups than in the mock groups (p<0.05 for neutrophils and monocytes; p<0.01 for the rest). The number of eosinophils and CD8(+) lymphocytes and the level of transforming growth factor beta 1 (TGF-ß1) in BAL fluid in the asthma/A(H1N1)pdm09 group were significantly higher among all groups (p<0.05 for eosinophils and CD8(+) lymphocytes; p<0.01 for TGF-ß1). The levels of IL-6, IL-10, IL-13, and TNF-α were significantly higher in the asthma/A(H1N1)pdm09 group than in the non-asthma/A(H1N1)pdm09 group (p<0.05 for IL-6 and IL-10; p<0.01 for IL-13 and TNF-α). The level of IFN-γ in the asthma/A(H1N1)pdm09 group was significantly lower than that in the non-asthma/A(H1N1)pdm09 group (p<0.05). The viral titers in the BAL fluids were higher in the asthma/A(H1N1)pdm09 group than in the non-asthma/A(H1N1)pdm09 group (p<0.05). Histopathological examination showed more severe infiltration of inflammatory cells and destruction of lung tissue in the asthma/A(H1N1)pdm09 group than in the non-asthma/A(H1N1)pdm09 group. CONCLUSIONS: Severe pulmonary inflammation induced by elevated levels of cytokines, combined with increased viral replication due to decreased IFN-γ levels, may contribute to worsening respiratory symptoms in patients with bronchial asthma and A(H1N1)pdm09 infection.

Prognostic value of brain injury biomarkers in acute encephalitis/encephalopathy.

BACKGROUND: Acute encephalitis/encephalopathy (AEE) is a devastating cause of severe neurodevelopmental sequelae or death in children. Assessing ongoing brain injury and predicting outcomes using bedside point-of-care testing is expected to be extremely valuable. METHODS: For this study, three brain injury markers, S-100B, glial fibrillary acidic protein (GFAP), and tau protein, were measured in early cerebrospinal fluid samples of children with AEE. Subjects comprised three groups: Group 1 (non-AEE control, n = 27); Group 2 (AEE with normal resolution or mild sequelae, n = 13); and Group 3 (AEE with severe sequelae or death, i.e. "poor outcome," n = 10). RESULTS: All marker levels were significantly higher in Group 3 than in Group 1 or 2. In Group 3, only S-100B was significantly higher in non-survivors than in survivors. For scoring assessment (range: 0-3 points), the predictive accuracies of 3 points for poor outcomes in children with AEE (i.e. Group 2 and 3, n = 23) were 91% (21/23) for S-100B, 74% (17/23) for GFAP, and 78% (18/23) for tau. When the scores were summed up for S-100B, GFAP, and tau (range: 0-9 points), and for S-100B and tau (range: 0-6 points), the patients with poor outcomes were identified more accurately using the respective thresholds of 6 points and 4 points (96% [22/23] and 100% [23/23], respectively). CONCLUSION: Our findings suggest that combined measurement and scoring assessment of the markers, especially S-100B and tau, show promise as predictors of clinical outcomes in children with AEE.

Effects and Usefulness of Inspiratory Muscle Training Load in Patients with Advanced Lung Cancer with Dyspnea.

BACKGROUND: Patients with advanced lung cancer tend to experience dyspnea. Pulmonary rehabilitation has been reported as a method for relieving dyspnea. However, exercise therapy imposes a high burden on patients, and it is difficult to sustain in many cases. Inspiratory muscle training (IMT) imposes a relatively low burden on patients with advanced lung cancer; however, its benefits have not been demonstrated. METHODS: We retrospectively analyzed 71 patients who were hospitalized for medical treatment. The participants were divided into an exercise therapy group and an IMT load + exercise therapy group. Changes in maximal inspiratory pressure (MIP) and dyspnea were examined using a two-way repeated measures analysis of variance. RESULTS: MIP variations significantly increase in the IMT load group, with significant differences between baseline and week 1, between week 1 and week 2, and between baseline and week 2. The analysis also showed that the variations in dyspnea decreased in the IMT load + exercise therapy group with significant differences between baseline and week 1 and between baseline and week 2. CONCLUSIONS: The results show that IMT is useful and has a high persistence rate in patients with advanced lung cancer who present dyspnea and cannot perform high-intensity exercise therapy.

Report of a combination of remdesivir, intravenous methylprednisolone pulse, and tocilizumab for severe coronavirus disease: 20-case series at a single institution.

Many drugs have been marketed for treating coronavirus disease 2019 (COVID-19) infection, the disease that has caused a worldwide pandemic. However, in reported clinical trials, almost 30% of patients with COVID-19 did not show any health improvement. The 28-day survival rate was 69.5% when patients who required highflow oxygen therapy (HFNC), ventilation, and extracorporeal membrane oxygenation (ECMO) management were treated with remdesivir. The mortality rate of patients receiving 6 mg dexamethasone was 27%, and that of patients treated with tocilizumab and steroids was 31%. These results are unsatisfactory, and treatment for patients with severe respiratory failure has not yet been established. In our institution, we used remdesivir, methylprednisolone (mPSL) pulse therapy, and tocilizumab in 20 patients with COVID-19 whose PaO2/FIO2 (P/F) ratio was <200, and obtained good results for this combination therapy without any adverse events. In this study, we report the possible efficacy and safety of this treatment.

Successful Rescue of Life-threatening Hemoptysis Caused by Pulmonary Tuberculosis Bridging with Extracorporeal Membrane Oxygenation.

Massive hemoptysis is a fatal complication associated with pulmonary tuberculosis (TB). It can lead to severe respiratory failure. Extracorporeal membrane oxygenation (ECMO) is a life-saving technology that is rarely indicated for bleeding disorders. We herein report a 26-year-old man who presented with severe respiratory failure caused by massive hemoptysis with pulmonary TB. Transcatheter artery embolization was successfully performed with venovenous ECMO support. The hemostatic procedure allowed concomitant anticoagulant use, and neither bleeding nor thrombotic complications occurred throughout the clinical course. Administering the appropriate hemostatic procedure with subsequent management, including anticoagulant therapy, supported ECMO application in a case of bleeding.

Tolerability of nintedanib in the elderly with idiopathic pulmonary fibrosis: A single-center retrospective study.

Idiopathic pulmonary fibrosis (IPF), a fibrosing interstitial lung disease, predominantly affects the elderly and is associated with a high mortality risk. Nintedanib, a tyrosine kinase inhibitor, significantly reduces IPF progression. However, data on the tolerability and efficacy of nintedanib in the elderly with IPF are limited. Therefore, this study aimed to examine the tolerability and efficacy of nintedanib in the elderly with IPF in a real-world setting. Medical records of 19 elderly IPF patients (≥ 75 years) and 46 non-elderly IPF patients (< 75 years) newly administered nintedanib were retrospectively analyzed. We compared the forced vital capacity (FVC) level, incidence and severity of adverse events, and continuation rates of nintedanib between the two groups. FVC and percent predicted diffusing capacity of the lung for carbon monoxide (DLco) were lower in the elderly IPF group at baseline. Although the elderly IPF patients had a significantly higher incidence of adverse events, such as diarrhea, nausea, and elevation of hepatic enzymes, the rate of discontinuation of nintedanib owing to adverse events was not different between the groups. The continuation rates of nintedanib treatment at 6 months and 1 year in the elderly IPF group were equivalent. Furthermore, there was a similar trend in the reduction of the annual FVC decline after nintedanib initiation between the groups. Our study demonstrated that nintedanib was tolerable in both the IPF patient groups in a real-world setting. Proper management of adverse events in the elderly with IPF would lead to a better clinical outcome.

Improvement of catatonia-induced rapid respiratory failure with electroconvulsive therapy: A case report.

We encountered a case of sudden respiratory failure during treatment of catatonia that required intensive care. Electroconvulsive therapy (ECT) was administered in the intensive care unit while the patient was under systemic control. The catatonia symptom was relieved, and respiratory failure improved. Although a proximal venous thrombus was observed, anticoagulation therapy was continued during ECT, and the patient was successfully treated without causing a pulmonary embolism. It is crucial to monitor the patient's physical and psychological symptoms because respiratory status may deteriorate rapidly in a catatonic state.

Clinical Outcomes and Prevalence of Sarcopenia in Patients with Moderate to Severe COVID-19.

Background: The purpose of this study was to investigate the effectiveness and clinical outcomes of inpatient rehabilitation for patients with severe COVID-19 in Japan. Methods: Patients with severe COVID-19 who underwent rehabilitation during hospitalization were included. The Medical Research Council (MRC) score and short physical performance battery (SPPB), such as physical function assessment and the intensive care unit (ICU) mobility scale, the functional status score for the ICU, and Barthel index as activities of daily living (ADLs) were evaluated at admission and discharge or transfer from the hospital. The correlation between SPPB at discharge and each factor at admission were also analyzed. Furthermore, the prevalence of sarcopenia was evaluated by defining SPPB of <9 points at discharge as sarcopenia. Results: The median age of the total of 23 patients was 59 years (interquartile range (IQR): 47−67), 73.9% were male, and the median PaO2/FiO2 at admission was 172.0 (IQR: 123.0−209.0). All physical function and ADL parameters were significantly improved from the time of admission to discharge (p = 0.014 for the MRC score and p < 0.001 for all others). Moreover, SPPB at discharge significantly correlated with WBC (Spearman's rho = −0.473, p = 0.041), C-reactive protein (Spearman's rho = −0.468, p = 0.044), and exhibited a significant trend with PaO2/FiO2 (Spearman's rho = 0.429, p = 0.067) and age (Spearman's rho = 0.409, p = 0.083). Although the median Barthel index at discharge was 90 points, 47% of patients had sarcopenia as defined by an SPPB of <9 points. Conclusions: Early rehabilitation for patients with severe COVID-19 improved physical function and ADLs during hospitalization. However, 47% of patients had the same level of sarcopenia at discharge.

Serum and cerebrospinal fluid cytokine profile of patients with 2009 pandemic H1N1 influenza virus-associated encephalopathy.

PURPOSE: Since April 2009, the number of patients with 2009 pandemic H1N1 influenza virus infection has been increasing in Japan just as in the rest of the world. Patients with 2009 pandemic H1N1 influenza-associated encephalopathy (pIE) have also been reported. The common clinical symptoms of this condition are seizures and progressive coma with high-grade fever. We previously reported the possible association between seasonal influenza-associated encephalopathy (sIE) and proinflammatory cytokines. However, the pathogenesis of pIE remains to be elucidated. RESULTS: In pIE patients with a poor outcome, the serum levels of interleukin (IL)-6, IL-10, and soluble tumor necrosis factor (TNF) receptor (sTNFR1) were significantly higher than those in pIE patients without neurological sequelae. Similarly, the cerebrospinal fluid (CSF) IL-6 levels in pIE patients with a poor outcome were significantly higher than those in pIE patients without neurological sequelae. CONCLUSION: Our results suggest that IL-6, TNF-α, and IL-10 play important roles in pIE, and that the serum levels of IL-6, IL-10, and sTNFR1 and the CSF levels of IL-6 are related to neurological complications.

Leukotriene D4 enhances tumor necrosis factor-α-induced vascular endothelial growth factor production in human monocytes/macrophages.

BACKGROUND: Vascular endothelial growth factor (VEGF) is one of the most potent angiogenic mitogens specific for vascular endothelial cells. It also induces vascular hyperpermeability and protein leakage into the extracellular space. Leukotriene D(4) (LTD(4)), one of the cysteinyl leukotrienes (CysLTs), is known to be one of the key molecules of allergic inflammation. The interaction between LTD(4) and VEGF production in human monocytes/macrophages is not well characterized. METHODS: We examined VEGF production by THP-1 cells, a human monocytic leukemia cell line, and human peripheral blood CD14+monocytes/macrophages stimulated with LTD(4) and/or tumor necrosis factor-α (TNF-α). We also determined the inhibitory effects of pranlukast, a CysLT(1) receptor antagonist, on VEGF production by LTD(4) stimulation. RESULTS: LTD(4) significantly induced VEGF production and enhanced TNF-α-induced VEGF release in THP-1 cells and human peripheral blood CD14+monocytes/macrophages. VEGF mRNA expression was also induced by stimulation of THP-1 cells with LTD(4) and TNF-α. In addition, 10(-7)-10(-10)M pranlukast completely inhibited VEGF production enhanced by LTD(4). The 50% inhibitory concentration (IC50) for VEGF production in THP-1 cells was 10(-10)-10(-11)M. CONCLUSIONS: LTD(4) induced VEGF production and enhanced VEGF release induced by TNF-α via CysLT(1) receptors in human monocytes/macrophages. These effects were completely inhibited by pranlukast.