BACKGROUND:: It is well known that enteric bacterial antigens drive the development of chronic colitis in a variety of different mouse models of the inflammatory bowel diseases (IBD). The objective of this study was to evaluate the role of gut-associated lymphoid tissue (GALT; Peyer's patches, isolated lymphoid follicles), mesenteric lymph nodes (MLNs) and spleen in the pathogenesis of chronic colitis in mice. METHODS:: Surgical as well as genetic approaches were used to generate lymphopenic mice devoid of one or more of these lymphoid tissues. For the first series of studies, we subjected recombinase activating gene-1-deficient mice (RAG(-/-)) to sham surgery (Sham), mesenteric lymphadenectomy (MLNx), splenectomy (Splx) or both (MLNx/Splx). In a second series of studies we intercrossed lymphotoxinbeta-deficient (LTbeta(-/-)) mice with RAG(-/-) animals to generate LTbeta(-/-) x RAG(-/-) offspring that were anticipated to contain functional MLNs but be devoid of GALT and most peripheral lymph nodes. Flow purified naïve (CD4(+)CD45RB(high)) T-cells were adoptively transferred into the different groups of RAG(-/-) recipients to induce chronic colitis. RESULTS:: We found that at 3-5 wks following T-cell transfer, all four of the surgically-manipulated RAG(-/-) groups (Sham, MLNx, Splx and MLNx/Splx) developed chronic colitis that was similar in onset and severity. Flow cytometric analysis revealed no differences among the different groups with respect to surface expression of different gut-homing markers nor were there any differences noted in IFN-gamma and IL-17 generation by mononuclear cells isolated among these surgically-manipulated mice. Although we anticipated that LTbeta(-/-) x RAG(-/-) mice would contain functional MLNs but be devoid of GALT and peripheral lymph nodes (PLNs), we found that LTbeta(-/-) x RAG(-/-)mice were in fact devoid of MLNs as well as GALT and PLNs. Adoptive transfer of CD45RB(high) T-cells into LTbeta(-/-) x RAG(-/-) mice or their littermate controls (LTbeta(+/+) x RAG(-/-)) induced rapid and severe colitis in both groups. CONCLUSIONS:: Taken together, our data demonstrate that: a) neither the GALT, MLNs nor PLNs are required for induction of chronic gut inflammation in this model of IBD and b) T-and/or B-cells may be required for the development of MLNs in LTbeta(-/-) mice. (Inflamm Bowel Dis 2010).

PURPOSE: T cell immunoglobulin and mucin domain-containing molecule 3 (TIM-3) could weaken the Th1-mediated anti-tumor responses and accelerate the tumor cell proliferation by inhabiting the production of IL-2 or IFN-gamma. This study was to assess the association between TIM-3 genetic variations and the development of gastric cancer. PATIENTS AND METHODS: Five polymorphisms located in the promoter or encoding region of TIM-3 gene were genotyped in 212 gastric cancer patients and 252 controls who matched with the patients on the frequency of age, gender, smoking, and drinking. Logistic regression was used to determine whether the inherited variations within TIM-3 gene were associated with gastric cancer risk. Linkage disequilibrium and Haplotype analyses were performed by using SHEsis program. RESULTS: By the individual genotype analysis, three polymorphisms (-574G/T, -882C/T, and -1516G/T) within TIM-3 gene were significantly associated with gastric cancer in the study population [ORs (95% CIs): 2.74 (1.21-6.20), 3.19 (1.29-7.91), and 2.03 (1.15-3.59); respectively]. Among the gastric cancer patients, the relationship between the -1516 polymorphic genotype and the distant metastasis of tumor was found (OR = 2.21, 95% CI = 1.05-4.63). Under the analysis of haplotypes, an even stronger association with haplotype TTGCT was observed in gastric cancer risk (OR = 5.57, 95% CI: 1.04-29.80, P = 0.024). CONCLUSION: These results indicated that the three genetic variations within the TIM-3 gene promoter may be associated with the increased susceptibility to gastric cancer, especially among the haplotypes with the risk.

The statistical properties of the spatial derivatives of the Stokes parameters for a random polarization field are studied. Based on the Gaussian assumption for the electric fields, the six-dimensional joint probability density function for the derivatives of the Stokes parameters is obtained from the statistics of the derivatives of the random polarization field. Subsequently, three two-dimensional probability density functions of derivatives of each Stokes parameter and the corresponding six marginal probability density functions are given. Finally, the joint and marginal density functions of the magnitude of the gradient of Stokes parameters are also derived for the first time, to our knowledge.

Sixteen AIDS patients complicated with toxoplasmic encephalitis (TE) were retrospectively analyzed between August 2008 to August 2009 with a mean age of (37.0 +/- 11.6) years. The most common clinical symptoms were headache (68.8%, 11/16) and fever (62.5%, 10/16), and 6 with Babinski sign (37.5%). 81.3%(13/16) were with CD4+ cells < 200/mm. Both sera and CSF showed 62.5% (10/16) TOXO-IgG positive by ELISA. CT and MRI scan demonstrated bilateral and multiple lesions with marked peripheral edema effect, and an enhanced scanning showed small finger ring as the major feature. 15 patients got improved by either oral sulphadiazine tablets or sulphadiazine tablets plus clindamycin capsule, 10 cases received combined HAART treatment, and 1 case died with septic shock.

Age-related metabolic changes in the hippocampus of APP(Swe)/PS1(dE9) mice were measured with long echo-time in vivo (1)H-magnetic resonance spectroscopy ((1)H-MRS). Thioflavine S staining and Nissl staining were used to characterize deposition of Abeta aggregates and neuronal degeneration in the transgenic animals, respectively. The results showed that the APP(Swe)/PS1(dE9) mice had significantly decreased hippocampal N-acetyl aspartate (NAA)/total creatine (tCr) level at 16 months of age, which was associated with degeneration of and intracellular deposition of thioflavine S-positive materials in hippocampal CA3 pyramidal neurons. The results of this study provide direct evidence showing association among Abeta pathology (intracellular deposition of thioflavine S-positive materials), neuronal degeneration, and metabolic changes observable with in vivo (1)H-MRS in the hippocampus of APP(Swe)/PS1(dE9) mice. (c) 2010 Wiley-Liss, Inc.

Though antiplatelet drugs are proven beneficial to patients with coronary heart disease and stroke, more effective and safer antiplatelet drugs are still needed. In this study we report the antiplatelet effects and mechanism of BF0801, a novel adenine derivative. BF0801 dramatically inhibited platelet aggregation and ATP release induced by ADP, 2MeSADP, AYPGKF, SFLLRN or convulxin without affecting shape change in vitro. It also potentiated the inhibitory effects of adenosine-based P2Y12 antagonist AR-C69931MX or phosphodiesterases inhibitor IBMX on platelet aggregation. The cAMP levels in both resting and forskolin-stimulated platelets were increased by BF0801 suggesting its phosphodiesterase inhibitor activity, which is further confirmed by the concentration-dependent suppression of BF0801 on the native and recombinant phosphodiesterases. Similar to AR-C69931MX, BF0801 drastically inhibited 2MeSADP-induced adenylyl cyclase inhibition in platelets indicating its P2Y12 antagonism activity, which is substantiated by the inhibition of BF0801 on the interaction between ADP and P2Y12 receptor expressed in CHO-K1 cells measured by atomic force microscopy. Moreover, we confirmed the antiplatelet effects of BF0801 using platelets from rats intravenously given BF0801. In summary, for the first time we developed a novel adenine derivative bearing dual activities of phosphodiesterase inhibition and P2Y12 antagonism, which may have therapeutic advantage as a potential antithrombotic drug.

The piezoelectric response of [001] poled domain engineered (1-x)Pb(Mg(13)Nb(23))O(3)-xPbTiO(3) (PMN-PT) crystals was investigated as a function of composition and phase using Rayleigh analysis. The results revealed that the intrinsic (reversible) contribution plays a dominant role in the high piezoelectric activity for PMN-PT crystals. The intrinsic piezoelectric response of the monoclinic (M(C)) PMN-xPT crystals, 0.31</=x</=0.35, exhibited peak values for compositions close to R-M(C) and M(C)-T phase boundaries, however, being less than 2000 pCN. In the rhombohedral phase region, x</=0.30, the intrinsic piezoelectric response was found to increase as the composition approached the rhombohedral-monoclinic (R-M(C)) phase boundary. The maximum piezoelectric response was observed in rhombohedral PMN-0.30PT crystals, being on the order of 2500 pCN. This ultrahigh piezoelectric response was determined to be related to the high shear piezoelectric activity of single domain state, corresponding to an ease in polarization rotation, for compositions close to a morphotropic phase boundary (MPB). The role of monoclinic phase is only to form a MPB with R phase, but not directly contribute to the ultrahigh piezoelectric activity in rhombohedral PMN-0.30PT crystals. The extrinsic contribution to piezoelectric activity was found to be less than 5% for the compositions away from R-M(C) and M(C)-T phase boundaries, due to a stable domain engineered structure. As the composition approached MPBs, the extrinsic contribution increased slightly (<10%), due to the enhanced motion of phase boundaries.

To understand the barriers to tuberculosis (TB) control and prevention in undergraduate students and to propose the strategies to improve this work, we conducted in-depth interviews with three groups of individuals in infirmaries of universities and colleges, TB departments of district Centers for Disease Control and Prevention (CDCs), and undergraduates with TB. The study identified four major themes: inadequate workforce and less than optimal functioning of infirmaries and district TB control agencies; poor cooperation in the process of discovery, treatment, and surveillance of undergraduates with TB; poor acceptance of the national TB policy; and inadequate attention to TB prevention. Failure to carry out the national TB policy was the major barrier to TB control and prevention in undergraduates. TB control agencies should strengthen the implementation of the national TB policy.

Interleukin 1beta (IL-1beta) is a key orchestrator of inflammation and host defense that exerts its effects through IL-1 receptor type I (IL-1RI) and IL-1 receptor accessory protein (IL-1RAcP). How IL-1RAcP is recruited by IL-1beta-IL-1RI to form the signaling-competent complex remains elusive. Here we present the crystal structure of IL-1beta bound to IL-1 receptor type II (IL-1RII) and IL-1RAcP. IL-1beta-IL-1RII generated a composite binding surface to recruit IL-1RAcP. Biochemical analysis demonstrated that IL-1beta-IL-1RI and IL-1beta-IL-1RII interacted similarly with IL-1RAcP. It also showed the importance of two loops of IL-1 receptor antagonist (IL-1Ra) in determining its antagonism. Our results provide a structural basis for assembly and activation of the IL-1 receptor and offer a general cytokine-receptor architecture that governs the IL-1 family of cytokines.

Exosomes released from tumor cells having been shown to induce interleukin-6 release from myeloid-derived suppressor cells in a Toll-like receptor 2/Stat3-dependent manner. In this study, we show that exosomes released from tumor cells re-isolated from syngeneic mice are capable of inducing interleukin-6 in a Toll-like receptor 2-independent manner, whereas the data generated from exosomes of tumor cells having undergone numerous in vitro passages induce interleukin-6 in a Toll-like receptor 2-dependent manner. This discrepancy may be due to the source of tumor cells used to generate the exosomes for this study. These results suggest that exosomes released from tumor cells that are not within a tumor microenvironment may not realistically represent the role of tumor exosomes in vivo. This is an important consideration since frequently passing tumor cells in vivo is an accepted practice for studying tumor exosome-mediated inflammatory responses.

A novel series of P2-P4 macrocyclic HCV NS3/4A protease inhibitors with alpha-amino cyclic boronates as warheads at the P1 site was designed and synthesized. When compared to their linear analogs, these macrocyclic inhibitors exhibited a remarkable improvement in cell-based replicon activities, with compounds 9a and 9e reaching sub-micromolar potency in replicon assay. The SAR around alpha-amino cyclic boronates clearly established the influence of ring size, chirality and of the substitution pattern. Furthermore, X-ray structure of the co-crystal of inhibitor 9a and NS3 protease revealed that Ser-139 in the enzyme active site traps boron in the warhead region of 9a, thus establishing its mode of action.

OBJECTIVE: The associations between air pollution and children's respiratory health in the high pollution range have not yet been clearly characterized. We evaluated the effects of outdoor air pollution on respiratory morbidity in children selected from multiple sites in a heavy industrial province of northeastern China. METHODS: The study included 11,860 children aged 3-12 years, selected from 18 districts of 6 cities in Liaoning province, the participation rate is 89.9%. Informed consent and written responses to surveys about children's historic and current health status, personal and household characteristics, and other information were obtained from parents. A two-stage regression approach was applied in data analyses. RESULTS: There were wide gradients for TSP (188-689 mug/m(3)), SO(2) (14-140 mug/m(3) and NO(2) (29-94 mug/m(3)) across the 18 districts of 6 cities. The three air pollutants significantly increased the prevalence of persistent cough (21-28%), persistent phlegm (21-30%) and current asthma (39-56%) for each interquartile range increment (172 mug/m(3) for TSP, 69 mug/m(3) for SO(2), 30 mug/m(3) for NO(2)), showing larger between-city effects than within-city. Rates of respiratory symptoms were significantly higher for children with younger age, atopy, respiratory disease in early age, family history of asthma or chronic bronchitis, and tobacco smoke exposure. CONCLUSION: The high levels of outdoor air pollution in north China are positively associated with children's respiratory symptoms, the associations with TSP appear to be stronger than SO(2) and NO(2).

The desire to visualize noninvasively physiological processes at high temporal resolution has been a driving force for the development of MRI since its inception in 1973. In this article, we describe a unique method for real-time MRI that reduces image acquisition times to only 20 ms. Although approaching the ultimate limit of MRI technology, the method yields high image quality in terms of spatial resolution, signal-to-noise ratio and the absence of artifacts. As proposed previously, a fast low-angle shot (FLASH) gradient-echo MRI technique (which allows for rapid and continuous image acquisitions) is combined with a radial encoding scheme (which offers motion robustness and moderate tolerance to data undersampling) and, most importantly, an iterative image reconstruction by regularized nonlinear inversion (which exploits the advantages of parallel imaging with multiple receiver coils). In this article, the extension of regularization and filtering to the temporal domain exploits consistencies in successive data acquisitions and thereby enhances the degree of radial undersampling in a hitherto unexpected manner by one order of magnitude. The results obtained for turbulent flow, human speech production and human heart function demonstrate considerable potential for real-time MRI studies of dynamic processes in a wide range of scientific and clinical settings. Copyright (c) 2010 John Wiley & Sons, Ltd.

Background/Aims: Excessive endoplasmic reticulum stress (ERS) triggers apoptosis in various conditions including diabetic cardiomyopathy and pressure overload-induced cardiac hypertrophy and heart failure. The primary function of 14-3-3 protein is to inhibit apoptosis, but the roles of this protein in protecting against cardiac ERS and apoptosis are largely unknown. Methods: We investigated the roles of 14-3-3 protein in vivo during cardiac ERS and apoptosis induced by pressure overload or thapsigargin injection using transgenic (TG) mice that showed cardiac-specific expression of dominant negative (DN) 14-3-3eta. Results: Cardiac positive apoptotic cells and the expression of glucose-regulated protein (GRP)78, inositol-requiring enzyme (Ire)1alpha, tumor necrosis factor receptor (TNFR)-associated factor (TRAF)2, CCAAT/enhancer binding protein homology protein (CHOP), caspase-12, and cleaved caspase-12 protein were significantly increased in the pressure-overload induced DN 14-3-3eta mice compared with that in the WT mice. Furthermore, thapsigargin injection significantly increased the expression of GRP78 and TRAF2 expression in DN 14-3-3eta mice compared with that in the WT mice. Conclusion: The enhancement of 14-3-3 protein may provide a novel protective therapy against cardiac ERS and ERS-initiated apoptosis, at least in part, through the regulation of CHOP and caspase-12 via the Ire1alpha/TRAF2 pathway.

The complete nucleotide sequence of the mitochondrial genome of the clam Meretrix lusoria (Bivalvia: Veneridae) was determined. It comprises 20,268 base pairs (bp) and contains 13 protein-coding genes, including ATPase subunit 8 (atp8), two ribosomal RNAs, 22 transfer RNAs, and a non-coding control region. The atp8 encodes a protein of 39 amino acids. All genes are encoded on the same strand. A putative control region (CR or D-loop) was identified in the major non-coding region (NCR) between the tRNA(Gly) and tRNA(Gln). A 1087bp tandem repeat fragment was identified that comprises nearly 11 copies of a 101bp motif and accounts for approximately 41% of the NCR. The 101bp tandem repeat motif of the NCR can be folded into a stem-loop secondary structure. Samples of eight individuals from Hainan and Fujian provinces were collected and their NCR regions were successfully amplified and sequenced. The data revealed a highly polymorphic VNTR (variable number of tandem repeats) associated with high levels of heteroplasmy in the D-loop region. The size of the CR ranged from 1942 to 3354bp depending upon the copy number of the repeat sequence.

OBJECTIVE: To explore the significance of the expression of carcinoembryonic antigen receptors (CEAR) in digestive organs. METHODS: Specimens were procured from 20 male BALB/c mice including esophagus, small intestine, stomach, colon, pancreas, and liver. Kupffer cells were obtained by density gradient centrifugation following enzymatic digestion of the fresh liver specimen. Immunohistochemistry and immunocytochemistry methods were used to detect CEAR in those organs or Kupffer cells. RESULTS: CEAR was found both in cytoplasm and nuclei of the digestive tract mucosal epithelial cells and pancreas islet cells, but only in the cytoplasm of liver cells, Kupffer cells, and smooth muscle cells of the whole digestive tract. The mean ranks of CEAR expression were 174.33 in the mucosal epithelial cells of colon, 160.70 in epithelial cells of small intestine, 139.18 in Kupffer cells, 137.43 in pancreas islet cells, 131.70 in liver cells, 124.23 in gastric epithelial cells, 77.15 in esophageal epithelial cells and 57.80-71.00 in smooth muscle cells of the entire digestive tract examined. There were significantly differences in the CEAR expression intensity among those positive cells (chi(2)=99.58,P<0.01) while CEAR was not present in submucosal connective tissue cells, pancreatic exocrine cells, or hepatic sinusoid endothelial cells. CONCLUSION: There are significantly differences in the expression of CEAR in the main digestive organs according to the different tissue and cells, which may play an important role in the carcinogenesis and hepatic metastasis from tumors of the digestive system.

Asymmetric addition under mild conditions of dialkyl phosphites on aldimines derived from cinnamaldehyde catalyzed by the inexpensive chiral organocatalyst (R)-3,3'-[4-fluorophenyl](2)-1,1'-binaphthol phosphate has been found effective to give new alpha-amino-phosphonates 9 in moderate yields (30-65%) and enantiomeric excess (8.4%-61.9%).

TMPRSS2 gene fusions with ETS transcription factor family members ERG, ETV1, or ETV4 have been recently discovered as a common molecular event in prostate cancer. Much attention has been focused on exploring their clinical application as a genetic tumor marker for the diagnosis, prognosis, and prediction of response to therapy. Although several studies have been done, the clinical utility of TMPRSS2 genetic alterations as biomarkers for prostate carcinoma remains indeterminate. In this study, we examined adenocarcinomas, prostatic intraepithelial neoplasia (PIN), and normal epithelium of the prostate retrieved from radical prostatectomy specimens to determine the frequency, specificity, tissue heterogeneity, and prognostic value of TMPRSS2 genetic alterations using a direct-labeled TMPRSS2 dual-color break-apart fluorescence in situ hybridization (FISH) probe cocktail designed to detect all known TMPRSS2-associated deletions or translocations. Seventy-one patients (161 samples) with normal prostate tissue, 60 patients (153 samples) with PIN, and 61 patients (142 samples) with carcinoma in formalin-fixed paraffin-embedded tissue microarrays were tested. None of the 161 normal prostate samples showed TMPRSS2 translocation or deletion. Sixty-two percent patients of prostate carcinomas demonstrated TMPRSS2 gene alterations, including 39% with translocation, 16% with deletion, and 7% with a mixed pattern. Tissue heterogeneity for TMPRSS2 gene alterations was identified in 28% of prostate carcinomas. No difference in the frequency of TMPRSS2 gene alterations was found between Gleason 6 and 7 tumors. Seventeen percent of PIN had TMPRSS2 gene alterations and showed the same FISH patterns as in the carcinomas from respective prostatectomy specimens. The TMPRSS2 dual-color break-apart FISH probe cocktail provides a simple and reliable method for the detection of TMPRSS2-related genetic alterations in formalin-fixed paraffin-embedded tissue. TMPRSS2 genetic alterations detectable by this method are strictly restricted in prostate neoplasia, and can be identified in the majority of prostate carcinomas. Tissue heterogeneity for TMPRSS2 alterations is common, and it should be considered when sampling and evaluating biopsy specimens.

The evaluation of bilingual children is a complicated endeavor because there are various views of how bilingualism affects brain organization and functioning. Added to that is the challenge of determining language development of Hispanic children living in a monolingual Spanish-speaking home in a Spanish-speaking country, but mostly exposed to English language television programming and, in some cases, English language school curriculum. Our case will review the evaluation process of a 14-year-old Puerto Rican boy with previous diagnoses of expressive language disorder and Attention-deficit/Hyperactivity Disorder (ADHD). The neuropsychological evaluation revealed an IQ within the average range, with significant differences between the perceptual reasoning, verbal comprehension, and processing speed. The case will summarize performance in verbal, executive, and psycho-educational measures with a thorough review of his developmental history and the interpretation of these neuropsychological achievement and behavioral measures in light of other variables influencing his difficulties.