Clinical implications of correlation between peripheral eosinophil count and serum levels of IL-5 and tryptase in acute eosinophilic pneumonia

SummaryBackgroundThe peripheral eosinophil count (PEC) tends to increase during the course of acute eosinophilic pneumonia (AEP), and an initially elevated PEC is associated with milder disease. However, there is a lack of data regarding these phenomena and inflammatory process of AEP.MethodsWe prospectively evaluated serial changes in serum interleukin (IL)-5 levels and the correlation between the initial level of IL-5 and the PEC to investigate whether the initial PEC indicates a resolving state of inflammation. We also evaluated serum tryptase levels to investigate the possibility of involvement of mast cell activity in AEP.ResultsTwenty-one AEP patients were included, and all patients improved within 10 days after corticosteroid treatment. The median initial serum IL-5 level among all patients was 561.0 pg/mL, which decreased to zero at 10 days of follow-up (n = 15, P < 0.001). The median initial serum tryptase level (detectable in 20 of 21 patients) was 3.7 ng/mL and decreased to a median of 1.1 ng/mL at 10 days of follow-up (n = 15, P < 0.001). The initial serum IL-5 and C-reactive protein levels were positively correlated (P = 0.009, r = 0.556), and the initial serum IL-5 level was inversely correlated with the initial PEC (P = 0.004, r = −0.603).ConclusionsOur data suggest that IL-5 is an important cytokine involved in the recruitment of eosinophils from peripheral blood into the lungs, that an initially elevated PEC is associated with a resolving state of inflammation, and that mast cells are potentially involved in the inflammatory process of AEP

Toll-like receptor 4-dependent upregulation of cytokines in a transgenic mouse model of Alzheimer's disease

<p>Abstract</p> <p>Background</p> <p>Aβ deposits in the brains of patients with Alzheimer's disease (AD) are closely associated with innate immune responses such as activated microglia and increased cytokines. Accumulating evidence supports the hypothesis that innate immune/inflammatory responses play a pivotal role in the pathogenesis of AD: either beneficial or harmful effects on the AD progression. The molecular mechanisms by which the innate immune system modulates the AD progression are not well understood. Toll-like receptors (TLRs) are first-line molecules for initiating the innate immune responses. When activated through TLR signaling, microglia respond to pathogens and damaged host cells by secreting chemokines and cytokines and express the co-stimulatory molecules needed for protective immune responses to pathogens and efficient clearance of damaged tissues. We previously demonstrated that an AD mouse model homozygous for a destructive mutation of TLR4 has increases in diffuse and fibrillar Aβ deposits as well as buffer-soluble and insoluble Aβ in the brain as compared with a TLR4 wild-type AD mouse model. Here, we investigated the roles of TLR4 in Aβ-induced upregulation of cytokines and chemokines, Aβ-induced activation of microglia and astrocytes and Aβ-induced immigration of leukocytes.</p> <p>Methods</p> <p>Using the same model, levels of cytokines and chemokines in the brain were determined by multiplex cytokine/chemokine array. Activation of microglia and astrocytes and immigration of leukocytes were determined by immunoblotting and immunohistochemistry followed by densitometry and morphometry, respectively.</p> <p>Results</p> <p>Levels of tumor necrosis factor (TNF)-α, interleukin (IL)-1β, IL-10 and IL-17 in the brains of TLR4 wild-type AD mice were significantly higher than those in TLR4 wild-type non-transgenic littermates. Such increases in cytokines were not found in TLR4 mutant AD mice as compared with TLR4 mutant non-transgenic littermates. Although expression levels of CD11b (a microglia marker) and GFAP (a reactive astrocyte marker) in the brains of TLR4 mutant AD mice were higher than those in TLR4 wild type AD mice, no difference was found in levels of CD45 (common leukocyte antigen).</p> <p>Conclusion</p> <p>This is the first demonstration of TLR4-dependent upregulation of cytokines in an AD mouse model. Our results suggest that TLR4 signaling is involved in AD progression and that TLR4 signaling can be a new therapeutic target for AD.</p

TLR4 Mutation Reduces Microglial Activation, Increases Aβ Deposits and Exacerbates Cognitive Deficits in a Mouse Model of Alzheimer\u27s Disease

BACKGROUND: Amyloid plaques, a pathological hallmark of Alzheimer\u27s disease (AD), are accompanied by activated microglia. The role of activated microglia in the pathogenesis of AD remains controversial: either clearing Aβ deposits by phagocytosis or releasing proinflammatory cytokines and cytotoxic substances. Microglia can be activated via toll-like receptors (TLRs), a class of pattern-recognition receptors in the innate immune system. We previously demonstrated that an AD mouse model homozygous for a loss-of-function mutation of TLR4 had increases in Aβ deposits and buffer-soluble Aβ in the brain as compared with a TLR4 wild-type AD mouse model at 14-16 months of age. However, it is unknown if TLR4 signaling is involved in initiation of Aβ deposition as well as activation and recruitment of microglia at the early stage of AD. Here, we investigated the role of TLR4 signaling and microglial activation in early stages using 5-month-old AD mouse models when Aβ deposits start. METHODS: Microglial activation and amyloid deposition in the brain were determined by immunohistochemistry in the AD models. Levels of cerebral soluble Aβ were determined by ELISA. mRNA levels of cytokines and chemokines in the brain and Aβ-stimulated monocytes were quantified by real-time PCR. Cognitive functions were assessed by the Morris water maze. RESULTS: While no difference was found in cerebral Aβ load between AD mouse models at 5 months with and without TLR4 mutation, microglial activation in a TLR4 mutant AD model (TLR4M Tg) was less than that in a TLR4 wild-type AD model (TLR4W Tg). At 9 months, TLR4M Tg mice had increased Aβ deposition and soluble Aβ42 in the brain, which were associated with decrements in cognitive functions and expression levels of IL-1β, CCL3, and CCL4 in the hippocampus compared to TLR4W Tg mice. TLR4 mutation diminished Aβ-induced IL-1β, CCL3, and CCL4 expression in monocytes. CONCLUSION: This is the first demonstration of TLR4-dependent activation of microglia at the early stage of β-amyloidosis. Our results indicate that TLR4 is not involved in the initiation of Aβ deposition and that, as Aβ deposits start, microglia are activated via TLR4 signaling to reduce Aβ deposits and preserve cognitive functions from Aβ-mediated neurotoxicity

Simvastatin Enhances Immune Responses to Aβ Vaccination and Attenuates Vaccination-Induced Behavioral Alterations

Statins are widely used to lower cholesterol levels by inhibiting cholesterol biosynthesis. Some evidence has indicated that statins might have therapeutic and preventive benefits for Alzheimer\u27s disease (AD). We and others also have shown the beneficial effect of statin treatment in reversing learning and memory deficits in animal models of AD. However, data from clinical trials are inconclusive. We previously documented that the adenovirus vector encoding 11 tandem repeats of Aβ1-6 fused to the receptor-binding domain (Ia) of Pseudomonas exotoxin A, AdPEDI-(Aβ1-6)(11), is effective in inducing an immune response against amyloid-β protein (Aβ) and reducing brain Aβ load in Alzheimer\u27s mouse models. In the present study, we examined whether the administration of simvastatin can modulate immune and behavioral responses of C57BL/6 mice to vaccination. Simvastatin was given to the animals as a diet admixture for four weeks, followed by nasal vaccination with AdPEDI-(Aβ1-6)(11) once per week for four weeks. The cholesterol-lowering action of simvastatin was monitored by measuring the cholesterol levels in plasma. Simvastatin significantly increased the number of the mice responding to vaccination compared with the mice receiving only AdPEDI-(Aβ1-6)(11). Immunoglobulin isotyping revealed that the vaccination predominantly induced Th2 immune responses. Simvastatin treatment prevented Aβ-induced production of IFN-γ in splenocytes. The adenovirus vaccination altered mouse behavior in T- and elevated plus-maze tests and simvastatin counteracted such behavioral changes. Our results indicate that simvastatin clearly enhances the immune responses of C57BL/6 mice to the nasal vaccination with AdPEDI-(Aβ1-6)(11). Simvastatin may be effective in preventing behavioral changes associated with vaccination

Serum high mobility group box-1 (HMGB1) is closely associated with the clinical and pathologic features of gastric cancer

<p>Abstract</p> <p>Background</p> <p>High mobility group box-1 (HMGB1) is a newly recognized factor regulating cancer cell tumorigenesis, expansion and invasion. We investigated the correlation between the serum HMGB1 levels and the clinical and pathologic features of gastric cancer and evaluated the validity of HMGB1 as a potential biomarker for the early diagnosis of gastric cancer.</p> <p>Methods</p> <p>A total of 227 subjects were classified into 5 disease groups according to the 'gastritis-dysplasia-carcinoma' sequence of gastric carcinogenesis and their serum levels of HMGB1 were analyzed by an enzyme-linked immunosorbent assay (ELISA) method. Clinical parameters, International Union Against Cancer (UICC) TNM stage, cancer size, differentiation or lymphatic invasion, vascular or perineural invasion and prognosis were used as analysis variables.</p> <p>Results</p> <p>The serum HMGB1 levels were significantly different among disease groups (ANOVA, <it>p < 0.05</it>) and HMGB1 levels tended to increase according to the progression of gastric carcinogenesis. Serum HMGB1 levels were significantly associated with depth of invasion, lymph node metastasis, tumor size, and poor prognosis (<it>p < 0.05</it>). However, HMGB1 levels were not associated with patient gender or age, differentiation of tumor cells, or lymphatic, vascular and perineural invasion, or the existence of distant metastasis in advanced cancer (<it>p > 0.05</it>). The sensitivity and specificity of serum HMGB1 was 71% and 67% (cut-off value of 5 ng/ml) for the diagnosis of early gastric cancer, and 70% and 64% (cut-off value of 4 ng/ml) for the diagnosis of high-risk lesions, respectively. These values were greater than those for carcinoembryonic antigen (CEA) (30–40% of sensitivity).</p> <p>Conclusion</p> <p>HMGB1 appears to be a useful serological biomarker for early diagnosis as well as evaluating the tumorigenesis, stage, and prognosis of gastric cancer.</p

TLR4 mutation reduces microglial activation, increases Aβ deposits and exacerbates cognitive deficits in a mouse model of Alzheimer's disease

<p>Abstract</p> <p>Background</p> <p>Amyloid plaques, a pathological hallmark of Alzheimer's disease (AD), are accompanied by activated microglia. The role of activated microglia in the pathogenesis of AD remains controversial: either clearing Aβ deposits by phagocytosis or releasing proinflammatory cytokines and cytotoxic substances. Microglia can be activated via toll-like receptors (TLRs), a class of pattern-recognition receptors in the innate immune system. We previously demonstrated that an AD mouse model homozygous for a loss-of-function mutation of TLR4 had increases in Aβ deposits and buffer-soluble Aβ in the brain as compared with a TLR4 wild-type AD mouse model at 14-16 months of age. However, it is unknown if TLR4 signaling is involved in initiation of Aβ deposition as well as activation and recruitment of microglia at the early stage of AD. Here, we investigated the role of TLR4 signaling and microglial activation in early stages using 5-month-old AD mouse models when Aβ deposits start.</p> <p>Methods</p> <p>Microglial activation and amyloid deposition in the brain were determined by immunohistochemistry in the AD models. Levels of cerebral soluble Aβ were determined by ELISA. mRNA levels of cytokines and chemokines in the brain and Aβ-stimulated monocytes were quantified by real-time PCR. Cognitive functions were assessed by the Morris water maze.</p> <p>Results</p> <p>While no difference was found in cerebral Aβ load between AD mouse models at 5 months with and without TLR4 mutation, microglial activation in a TLR4 mutant AD model (TLR4M Tg) was less than that in a TLR4 wild-type AD model (TLR4W Tg). At 9 months, TLR4M Tg mice had increased Aβ deposition and soluble Aβ42 in the brain, which were associated with decrements in cognitive functions and expression levels of IL-1β, CCL3, and CCL4 in the hippocampus compared to TLR4W Tg mice. TLR4 mutation diminished Aβ-induced IL-1β, CCL3, and CCL4 expression in monocytes.</p> <p>Conclusion</p> <p>This is the first demonstration of TLR4-dependent activation of microglia at the early stage of β-amyloidosis. Our results indicate that TLR4 is not involved in the initiation of Aβ deposition and that, as Aβ deposits start, microglia are activated via TLR4 signaling to reduce Aβ deposits and preserve cognitive functions from Aβ-mediated neurotoxicity.</p

Transient cortical blindness after heart surgery in a child patient -A case report-

Visual loss occurring after pediatric cardiac surgery employing cardiopulmonary bypass (CPB) is relatively rare but the risk is substantial. Compromised cerebral perfusion due to a CPB related micro-embolization and inflammatory vascular changes as well as reduced oxygen carrying capacity in hemodilution and hypothermia during CPB might be major contributing factors to the development of postoperative visual loss after cardiac surgery with CPB. A case of immediate but transient postoperative visual loss was encountered in a 21-month-old male who underwent tricuspid valve surgery. Despite routine intraoperative measures to maintain an adequate perfusion pressure throughout the procedure, postoperative computed tomography revealed a subacute infarct in his occipital lobe. Recovery began on postoperative day 28, and the patient's vision was restored by 31 days

Clinical and Genetic Analysis of Korean Patients with Miyoshi Myopathy: Identification of Three Novel Mutations in the DYSF Gene

Miyoshi myopathy (MM) is an autosomal recessive distal muscular dystrophy caused by mutations in the dysferlin gene (DYSF) on chromosome 2p13. Although MM patients and their mutations in the DYSF gene have been found from all over the world, there is only one report of genetically confirmed case of MM in Korea. Recently, we encountered three unrelated Korean patients with MM and two of them have previously been considered as having a type of inflammatory myopathy. The clinical and laboratory evaluation showed typical features of muscle involvement in MM in all patients but one patient initially had moderate proximal muscle involvement and another showed incomplete quadriparesis with rapid progression. Direct sequencing analysis of the DYSF gene revealed that each patient had compound heterozygous mutations (Gln832X and Trp992Arg, Gln832X and Trp999Cys, and Lys1103X and Ile1401HisfsX8, respectively) among which three were novel. Although MM has been thought to be quite rare in Korea, it should be considered in a differential diagnosis of patients exhibiting distal myopathy