C.-L. Lin

Assessment of hypermucoviscosity as a virulence factor for experimental Klebsiella pneumoniae infections: comparative virulence analysis with hypermucoviscosity-negative strain

BackgroundKlebsiella pneumoniae displaying the hypermucoviscosity (HV) phenotype are considered more virulent than HV-negative strains. Nevertheless, the emergence of tissue-abscesses-associated HV-negative isolates motivated us to re-evaluate the role of HV-phenotype.ResultsInstead of genetically manipulating the HV-phenotype of K. pneumoniae, we selected two clinically isolated K1 strains, 1112 (HV-positive) and 1084 (HV-negative), to avoid possible interference from defects in the capsule. These well-encapsulated strains with similar genetic backgrounds were used for comparative analysis of bacterial virulence in a pneumoniae or a liver abscess model generated in either naïve or diabetic mice. In the pneumonia model, the HV-positive strain 1112 proliferated to higher loads in the lungs and blood of naïve mice, but was less prone to disseminate into the blood of diabetic mice compared to the HV-negative strain 1084. In the liver abscess model, 1084 was as potent as 1112 in inducing liver abscesses in both the naïve and diabetic mice. The 1084-infected diabetic mice were more inclined to develop bacteremia and had a higher mortality rate than those infected by 1112. A mini-Tn5 mutant of 1112, isolated due to its loss of HV-phenotype, was avirulent to mice.ConclusionThese results indicate that the HV-phenotype is required for the virulence of the clinically isolated HV-positive strain 1112. The superior ability of the HV-negative stain 1084 over 1112 to cause bacteremia in diabetic mice suggests that factors other than the HV phenotype were required for the systemic dissemination of K. pneumoniae in an immunocompromised setting.

Tuberculosis increases the subsequent risk of acute coronary syndrome: a nationwide population-based cohort study.

OBJECTIVEnTo evaluate the effects of pulmonary tuberculosis (PTB) on the risk of subsequent acute coronary syndrome (ACS) development.nnnMETHODSnThe incidence and risk factors of ACS were investigated in 10u2009168 newly diagnosed tuberculosis (TB) patients from Taiwans National Health Insurance Research Database between 1997 and 2010, and 40u2009672 controls without TB from the general population. The follow-up period ran from the diagnosis of new TB to the date of the ACS event, censoring or 31 December 2010.nnnRESULTSnDuring the follow-up period, the overall incidence of ACS was higher in TB patients than in non-TB patients (2.10 vs. 1.51 per 1000 person-years). The incidence of ACS increased by 40% in TB patients after adjusting for age, sex and co-morbidities. Male sex, age, hypertension and diabetes were independent factors for the risk of ACS development. The probability of ACS increased in the years following the TB diagnosis.nnnCONCLUSIONnThis nationwide population-based cohort study provides compelling evidence that TB patients are at higher risk of developing ACS, and that the risk increases with age. Clinicians should be aware of this and strive to reduce ACS risk factors in TB patients.

Naringenin Suppresses Neuroinflammatory Responses Through Inducing Suppressor of Cytokine Signaling 3 Expression

Accumulating evidence suggests that neuroinflammation is closely associated with the pathogenesis of neurodegenerative disorders such as Parkinson’s disease and Alzheimer’s disease. The hallmark of neuroinflammation is considered to be microglial activation in the central nervous systemxa0(CNS). Activated microglia release pro-inflammatory cytokines which cause neuroinflammation and progressive neuronal cell death. Therefore, inhibition of microglial activation is considered an important strategy in the development of neuroprotective strategy. Naringenin, a flavonoid found in citrus fruits and tomatoes, has been reported to have anti-oxidant, anti-cancer, and anti-inflammatory properties. However, the mechanism of its beneficial anti-inflammatory effects in the CNS is poorly understood. In this study, we demonstrated that naringenin inhibites the release of nitric oxide (NO), the expression of inducible nitric oxide synthase (iNOS), and cyclooxygenase-2 (COX-2), as well as pro-inflammatory cytokines in microglial cells. Treatment of naringenin also induced suppressors of cytokine signaling (SOCS)-3 expression in microglia. The SOCS-3 expression and anti-inflammatory effects of naringenin were found to be regulated by adenosine monophosphate-activated protein kinase α (AMPKα) and protein kinase C δ (PKCδ). Besides, naringenin exerted protective property against neurotoxicity caused by LPS-induced microglial activation. Our findings suggest that naringenin-inhibited iNOS and COX-2 expression is mediated by SOCS-3 activation through AMPKα and PKCδ signaling pathways. In a mouse model, naringenin also showed significant protective effects on microglial activation and improved motor coordination function as well. Therefore, naringenin that involves in anti-neuroinflammatory responses and neuroprotection might be a potential agent for treatment of inflammation-associated disorders.

Effects of Paeonol on Anti-Neuroinflammatory Responses in Microglial Cells

Increasing studies suggest that inflammatory processes in the central nervous system mediated by microglial activation plays an important role in numerous neurodegenerative diseases. Development of planning for microglial suppression is considered a key strategy in the search for neuroprotection. Paeonol is a major phenolic component of Moutan Cortex, widely used as a nutrient supplement in Chinese medicine. In this study, we investigated the effects of paeonol on microglial cells stimulated by inflammagens. Paeonol significantly inhibited the release of nitric oxide (NO) and the expressions of inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2). Treatment with paeonol also reduced reactive oxygen species (ROS) production and inhibited an ATP-induced increased cell migratory activity. Furthermore, the inhibitory effects of neuroinflammation by paeonol were found to be regulated by phosphorylated adenosine monophosphate-activated protein kinase-α (AMPK-α) and glycogen synthase kinase 3 α/β (GSK 3α/β). Treatment with AMPK or GSK3 inhibitors reverse the inhibitory effect of neuroinflammation by paeonol in microglial cells. Furthermore, paeonol treatment also showed significant improvement in the rotarod performance and microglial activation in the mouse model as well. The present study is the first to report a novel inhibitory role of paeonol on neuroinflammation, and presents a new candidate agent for the development of therapies for inflammation-related neurodegenerative diseases.

Hearing loss may be a non-motor feature of Parkinson's disease in older people in Taiwan

The aim of this study was to explore whether hearing loss is associated with the risk of Parkinsons disease in the elderly in Taiwan.

Chronic obstructive pulmonary disease and allied conditions is a strong independent risk factor for osteoporosis and pathologic fractures: a population-based cohort study

BACKGROUNDnChronic obstructive pulmonary disease and allied conditions (COPD) is frequently associated with various comorbidities. This study examined the association between osteoporosis and pathologic fractures in a sample of patients with COPD.nnnMETHODSnIn this cohort study, claims data from the National Health Insurance Research Database of Taiwan were used to evaluate the risk between COPD and osteoporosis. Using data from the Longitudinal Health Insurance Database 2000, we conducted a retrospective cohort study by investigating patients aged 20 years and older who were newly diagnosed with COPD and comparing them with controls without COPD during 2000-2010. In addition, we used univariable and multivariable Cox proportional hazards regression models to measure the association between COPD and the risk of osteoporosis.nnnRESULTSnOur results revealed that COPD was significantly associated with a high risk of osteoporosis, regardless of whether the patients with COPD were corticosteroid users and irrespective of age and sex. After adjustment for covariates, the COPD patients exhibited a 1.54-fold higher risk of developing osteoporosis (hazard ratio 1.54, 95% confidence interval 1.44-1.64). COPD was a stronger risk factor for osteoporosis in men. Moreover, patients with severe COPD had a higher risk of osteoporosis or pathologic fractures.nnnCONCLUSIONnThis study revealed that COPD, which shares the characteristics of inflammatory diseases, is associated with a higher risk of osteoporosis after adjustment for comorbidities.

Anti-Neuroinflammatory Effects of the Calcium Channel Blocker Nicardipine on Microglial Cells: Implications for Neuroprotection

Background/Objective Nicardipine is a calcium channel blocker that has been widely used to control blood pressure in severe hypertension following events such as ischemic stroke, traumatic brain injury, and intracerebral hemorrhage. However, accumulating evidence suggests that inflammatory processes in the central nervous system that are mediated by microglial activation play important roles in neurodegeneration, and the effect of nicardipine on microglial activation remains unresolved. Methodology/Principal Findings In the present study, using murine BV-2 microglia, we demonstrated that nicardipine significantly inhibits microglia-related neuroinflammatory responses. Treatment with nicardipine inhibited microglial cell migration. Nicardipine also significantly inhibited LPS plus IFN-γ-induced release of nitric oxide (NO), and the expression of inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2). Furthermore, nicardipine also inhibited microglial activation by peptidoglycan, the major component of the Gram-positive bacterium cell wall. Notably, nicardipine also showed significant anti-neuroinflammatory effects on microglial activation in mice in vivo. Conclusion/Significance The present study is the first to report a novel inhibitory role of nicardipine on neuroinflammation and provides a new candidate agent for the development of therapies for inflammation-related neurodegenerative diseases.

The association between chronic obstructive pulmonary disease and dementia: A population-based retrospective cohort study

Chronic obstructive pulmonary disease (COPD) is frequently associated with various comorbidities. However, the proportion of COPD patients with dementia has not been adequately examined. This retrospective cohort study investigated the association between COPD and dementia by using a nationwide population‐based database in Taiwan.

Regulatory effects of fisetin on microglial activation.

Increasing evidence suggests that inflammatory processes in the central nervous system that are mediated by microglial activation play a key role in neurodegeneration. Fisetin, a plant flavonol commonly found in fruits and vegetables, is frequently added to nutritional supplements due to its antioxidant properties. In the present study, treatment with fisetin inhibited microglial cell migration and ROS (reactive oxygen species) production. Treatment with fisetin also effectively inhibited LPS plus IFN-γ-induced nitric oxide (NO) production, and inducible nitric oxide synthase (iNOS) expression in microglial cells. Furthermore, fisetin also reduced expressions of iNOS and NO by stimulation of peptidoglycan, the major component of the Gram-positive bacterium cell wall. Fisetin also inhibited the enhancement of LPS/IFN-γ- or peptidoglycan-induced inflammatory mediator IL (interlukin)-1 β expression. Besides the antioxidative and anti-inflammatory effects of fisetin, our study also elucidates the manner in fisetin-induced an endogenous anti-oxidative enzyme HO (heme oxygenase)-1 expression. Moreover, the regulatory molecular mechanism of fisetin-induced HO-1 expression operates through the PI-3 kinase/AKT and p38 signaling pathways in microglia. Notably, fisetin also significantly attenuated inflammation-related microglial activation and coordination deficit in mice in vivo. These findings suggest that fisetin may be a candidate agent for the development of therapies for inflammation-related neurodegenerative diseases.

Increased risk of varicella zoster virus infection in inflammatory bowel disease in an Asian population: a nationwide population-based cohort study.

Whether patients with inflammatory bowel disease (IBD) exhibit a high risk of developing varicella zoster virus (VZV) infection in Asian populations remains inconclusive. We investigated the causal relationship between two diseases by analysing the Taiwan National Health Insurance Research Database.