Novel role for the innate immune receptor toll-like receptor 4 (TLR4) in the regulation of the wnt signaling pathway and photoreceptor apoptosis

Recent evidence has implicated innate immunity in regulating neuronal survival in the brain during stroke and other neurodegenerations. Photoreceptors are specialized light-detecting neurons in the retina that are essential for vision. In this study, we investigated the role of the innate immunity receptor TLR4 in photoreceptors. TLR4 activation by lipopolysaccharide (LPS) significantly reduced the survival of cultured mouse photoreceptors exposed to oxidative stress. With respect to mechanism, TLR4 suppressed Wnt signaling, decreased phosphorylation and activation of the Wnt receptor LRP6, and blocked the protective effect of the Wnt3a ligand. Paradoxically, TLR4 activation prior to oxidative injury protected photoreceptors, in a phenomenon known as preconditioning. Expression of TNFα and its receptors TNFR1 and TNFR2 decreased during preconditioning, and preconditioning was mimicked by TNFα antagonists, but was independent of Wnt signaling. Therefore, TLR4 is a novel regulator of photoreceptor survival that acts through the Wnt and TNFα pathways. © 2012 Yi et al

Diesel Exhaust Particles Activate the Matrix-Metalloproteinase-1 Gene in Human Bronchial Epithelia in a β-Arrestin–Dependent Manner via Activation of RAS

BACKGROUND: Diesel exhaust particles (DEPs) are globally relevant air pollutants that exert a detrimental human health impact. However, mechanisms of damage by DEP exposure to human respiratory health and human susceptibility factors are only partially known. Matrix metalloproteinase-1 (MMP-1) has been implied as an (etio)pathogenic factor in human lung and airway diseases such as emphysema, chronic obstructive pulmonary disease, chronic asthma, tuberculosis, and bronchial carcinoma and has been reported to be regulated by DEPs. OBJECTIVE: We elucidated the molecular mechanisms of DEPs' up-regulation of MMP-1. METHODS/RESULTS: Using permanent and primary human bronchial epithelial (HBE) cells at air-liquid interface, we show that DEPs activate the human MMP-1 gene via RAS and subsequent activation of RAF-MEK-ERK1/2 mitogen-activated protein kinase signaling, which can be scaffolded by beta-arrestins. Short interfering RNA mediated beta-arrestin1/2 knockout eliminated formation, subsequent nuclear trafficking of phosphorylated ERK1/2, and resulting MMP-1 transcriptional activation. Transcriptional regulation of the human MMP-1 promoter was strongly influenced by the presence of the -1607GG polymorphism, present in 60-80% of humans, which led to striking up-regulation of MMP-1 transcriptional activation. CONCLUSION: Our results confirm up-regulation of MMP-1 in response to DEPs in HBE and provide new mechanistic insight into how these epithelia, the first line of protection against environmental insults, up-regulate MMP-1 in response to DEP inhalation. These mechanisms include a role for the human -1607GG polymorphism as a susceptibility factor for an accentuated response, which critically depends on the ability of beta-arrestin1/2 to generate scaffolding and nuclear trafficking of phosphorylated ERK1/2

Using a Powered Bone Marrow Biopsy System Results in Shorter Procedures, Causes Less Residual Pain to Adult Patients, and Yields Larger Specimens

<p>Abstract</p> <p>Background</p> <p>In recent years, a battery-powered bone marrow biopsy system was developed and cleared by the U.S. Food and Drug Administration to allow health care providers to access the bone marrow space quickly and efficiently. A multicenter randomized clinical trial was designed for adult patients to determine if the powered device had advantages over traditional manually-inserted needles in regard to length of procedure, patient pain, complications, user satisfaction, and pathological analysis of the specimens.</p> <p>Methods</p> <p>Adult patients requiring marrow sampling procedures were randomized for a Manual or Powered device. Visual Analog Scale (VAS) pain scores were captured immediately following the procedure and 1 and 7 days later. Procedure time was measured and core specimens were submitted to pathology for grading.</p> <p>Results</p> <p>Ten sites enrolled 102 patients into the study (Powered, n = 52; Manual, n = 50). Mean VAS scores for overall procedural pain were not significantly different between the arms (3.8 ± 2.8 for Powered, 3.5 ± 2.3 for Manual [p = 0.623]). A day later, more patients who underwent the Powered procedure were pain-free (67%) than those patients in the Manual group (33%; p = 0.003). One week later, there was no difference (83% for Powered patients; 76% for Manual patients.) Mean procedure time was 102.1 ± 86.4 seconds for the Powered group and 203.1 ± 149.5 seconds for the Manual group (p < 0.001). Pathology assessment was similar in specimen quality, but there was a significant difference in the specimen volume between the devices (Powered: 36.8 ± 21.2 mm³; Manual: 20.4 ± 9.0 mm³; p = 0.039). Two non-serious complications were experienced during Powered procedures (4%); but none during Manual procedures (p = 0.495).</p> <p>Conclusions</p> <p>The results of this first trial provide evidence that the Powered device delivers larger-volume bone marrow specimens for pathology evaluation. In addition, bone marrow specimens were secured more rapidly and subjects experienced less intermediate term pain when the Powered device was employed. Further study is needed to determine if clinicians more experienced with the Powered device will be able to use it in a manner that significantly reduces needle insertion pain; and to compare a larger sample of pathology specimens obtained using the Powered device to those obtained using traditional manual biopsy needles.</p

Increased activation of blood neutrophils after cigarette smoking in young individuals susceptible to COPD

Background: Cigarette smoking is the most important risk factor for Chronic Obstructive Pulmonary Disease (COPD). Only a subgroup of smokers develops COPD and it is unclear why these individuals are more susceptible to the detrimental effects of cigarette smoking. The risk to develop COPD is known to be higher in individuals with familial aggregation of COPD. This study aimed to investigate if acute systemic and local immune responses to cigarette smoke differentiate between individuals susceptible or non-susceptible to develop COPD, both at young (18-40 years) and old (40-75 years) age. Methods: All participants smoked three cigarettes in one hour. Changes in inflammatory markers in peripheral blood (at 0 and 3 hours) and in bronchial biopsies (at 0 and 24 hours) were investigated. Acute effects of smoking were analyzed within and between susceptible and non-susceptible individuals, and by multiple regression analysis. Results: Young susceptible individuals showed significantly higher increases in the expression of Fc gamma RII (CD32) in its active forms (A17 and A27) on neutrophils after smoking (p = 0.016 and 0.028 respectively), independently of age, smoking status and expression of the respective markers at baseline. Smoking had no significant effect on mediators in blood or inflammatory cell counts in bronchial biopsies. In the old group, acute effects of smoking were comparable between healthy controls and COPD patients. Conclusions: We show for the first time that COPD susceptibility at young age associates with an increased systemic innate immune response to cigarette smoking. This suggests a role of systemic inflammation in the early induction phase of COPD

Quercetin Inhibits IL-1β-Induced Inflammation, Hyaluronan Production and Adipogenesis in Orbital Fibroblasts from Graves' Orbitopathy

Management of Graves' orbitopathy (GO) is challenging, as no reliable, specific, and safe medical therapeutic agents have yet been developed. We investigated the effect of quercetin in primary cultured orbital fibroblasts from GO, targeting pathways of inflammation, aberrant accumulation of extracellular matrix macromolecules, and adipose tissue expansion. Quercetin significantly attenuated intercellular adhesion molecule-1 (ICAM-1), interleukin (IL) -6, IL-8, and cyclooxygenase (COX) -2 mRNA expression, and inhibited IL-1β-induced increases in ICAM-1, IL-6, and IL-8 mRNA. Increased hyaluronan production induced by IL-1β or tumor necrosis factor-α was suppressed by quercetin in a dose- and time-dependent manner. Treatment with noncytotoxic doses of quercetin inhibited accumulation of intracytoplasmic lipid droplets and resulted in a dose-dependent decrease in expression of peroxisome proliferator-activated receptor γ, CCAAT/enhancer-binding protein (C/EBP) α, and C/EBPβ proteins. In conclusion, inhibition of inflammation, hyaluronan production, and adipogenesis by the natural plant product quercetin in vitro provides the basis for further study of its potential use in the treatment of GO

Methylenetetrahydrofolate reductase C677T polymorphism in patients with gastric and colorectal cancer in a Korean population

<p>Abstract</p> <p>Background</p> <p>This study was designed to investigate an association between the methylenetetrahydrofolate reductase (MTHFR) C677T polymorphism and the risk of gastric and colorectal cancer in the Korean population.</p> <p>Methods</p> <p>We conducted a population-based large-scale case-control study involving 2,213 patients with newly diagnosed gastric cancer, 1,829 patients with newly diagnosed colorectal cancer, and 1,700 healthy controls. Genotyping was performed with peripheral blood DNA for MTHFR C677T polymorphisms. The statistical significance was estimated by logistic regression analysis.</p> <p>Results</p> <p>The MTHFR C677T frequencies of CC, CT, and TT genotypes were 35.2%, 47.5%, and 17.3% among stomach cancer, 34%, 50.5%, and 15.5% in colorectal cancer, and 31.8%, 50.7%, and 17.5% in the controls, respectively. The MTHFR 677TT genotype showed a weak opposite association with colorectal cancer compared to the homozygous CC genotype [adjusted age and sex odds ratio (OR) = 0.792, 95% confidence interval (CI) = 0.638-0.984, <it>P </it>= 0.035]. Subjects with the MTHFR 677CT showed a significantly reduced risk of gastric cancer compared whose with the 677CC genotype (age- and sex-adjusted OR = 0.810; 95% CI = 0.696-0.942, <it>P </it>= 0.006). We also observed no significant interactions between the MTHFR C677T polymorphism and smoking or drinking in the risk of gastric and colorectal cancer.</p> <p>Conclusions</p> <p>The T allele was found to provide a weak protective association with gastric cancer and colorectal cancer.</p

Acupuncture for dry eye: a randomised controlled trial protocol

<p>Abstract</p> <p>Background</p> <p>Dry eye is usually managed by conventional medical interventions such as artificial tears, anti-inflammatory drugs and surgical treatment. However, since dry eye is one of the most frequent ophthalmologic disorders, safer and more effective methods for its treatment are necessary, especially for vulnerable patients. Acupuncture has been widely used to treat patients with dry eye. Our aim is to evaluate the effectiveness and safety of acupuncture for this condition.</p> <p>Methods/Design</p> <p>A randomised, patient-assessor blinded, sham (non-acupuncture point, shallow acupuncture) controlled study was established. Participants allocated to verum acupuncture and sham acupuncture groups will be treated three times weekly for three weeks for a total of nine sessions per participant. Seventeen points (GV23; bilateral BL2, GB4, TE23, Ex1 (Taiyang), ST1 and GB20; and left SP3, LU9, LU10 and HT8 for men, right for women) have been selected for the verum acupuncture; for the sham acupuncture, points have been selected that do not coincide with a classical acupuncture point and that are located close to the verum points, except in the case of the rim of the eye. Ocular surface disease index, tear film breakup time, the Schirmer I test, medication quantification scale and general assessment of improvement will be used as outcome variables for evaluating the effectiveness of acupuncture. Safety will also be assessed at every visit. Primary and secondary outcomes will be assessed four weeks after screening. All statistical analyses will be performed using analysis of covariance.</p> <p>Discussion</p> <p>The results of this trial will be used as a basis for clarifying the efficacy of acupuncture for dry eye.</p> <p>Trial registration</p> <p>ClinicalTrials.gov NCT00969280.</p

Perpendicular Magnetic Anisotropy in FePt Patterned Media Employing a CrV Seed Layer

A thin FePt film was deposited onto a CrV seed layer at 400°C and showed a high coercivity (~3,400 Oe) and high magnetization (900–1,000 emu/cm3) characteristic of L10 phase. However, the magnetic properties of patterned media fabricated from the film stack were degraded due to the Ar-ion bombardment. We employed a deposition-last process, in which FePt film deposited at room temperature underwent lift-off and post-annealing processes, to avoid the exposure of FePt to Ar plasma. A patterned medium with 100-nm nano-columns showed an out-of-plane coercivity fivefold larger than its in-plane counterpart and a remanent magnetization comparable to saturation magnetization in the out-of-plane direction, indicating a high perpendicular anisotropy. These results demonstrate the high perpendicular anisotropy in FePt patterned media using a Cr-based compound seed layer for the first time and suggest that ultra-high-density magnetic recording media can be achieved using this optimized top-down approach