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olmesartan
pravastatin
valsartan
azelnidipine
candesartan
Carvedilol
Alzheimer
parkinson
Telmisartan
microglia

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The Journal of biological chemistry
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PloS one
PloS one
Nature
"Proceedings of the National Academy of Sciences of the United States of America"
Cancer research
Journal of agricultural and food chemistry
Proceedings of the National Academy of Sciences of the United States of America
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Wang Y
Zhang Y
Zhao L
Wang C
Lee SJ
Zhang S
Cheng CY
Singh N
Nakao K
Li X

Disease-corrected haematopoietic progenitors from Fanconi anaemia induced pluripotent stem cells.

Raya A , Rodríguez-Pizà I , Guenechea G , Vassena R , Navarro S , Barrero MJ , Consiglio A , Castellà M , Río P , Sleep E , González F , Tiscornia G , Garreta E , Aasen T , Veiga A , Verma IM , Surrallés J , Bueren J , Izpisúa Belmonte JC

Nature.2009 Jul 2 ; 460(7251):53-9.

PubMedで表示

Center for Regenerative Medicine in Barcelona, Dr. Aiguader 88, 08003 Barcelona, Spain.

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The generation of induced pluripotent stem (iPS) cells has enabled the derivation of patient-specific pluripotent cells and provided valuable experimental platforms to model human disease. Patient-specific iPS cells are also thought to hold great therapeutic potential, although direct evidence for this is still lacking. Here we show that, on correction of the genetic defect, somatic cells from Fanconi anaemia patients can be reprogrammed to pluripotency to generate patient-specific iPS cells. These cell lines appear indistinguishable from human embryonic stem cells and iPS cells from healthy individuals. Most importantly, we show that corrected Fanconi-anaemia-specific iPS cells can give rise to haematopoietic progenitors of the myeloid and erythroid lineages that are phenotypically normal, that is, disease-free. These data offer proof-of-concept that iPS cell technology can be used for the generation of disease-corrected, patient-specific cells with potential value for cell therapy applications.
PMID: 19483674 [PubMed - indexed for MEDLINE]

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Effects of bacterial toxins on endothelial tight junction in vitro: a mechanism-based investigation.

Singh Ashok K , Jiang Yin , Gupta Shveta
Toxicol Mech Methods.2007 ; 17(6):331-47.
PMID: 20020957[]

先週： 1位

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ABSTRACT Lipopolysaccharide (LPS) and lipoteichoic acid (LTA), principal cell wall components of Gram-negative and Gram-positive bacteria, respectively, play a central role in altering the blood-brain barrier and facilitate bacterial infection of the host brain. Despite the significance of bacterial toxins in disease pathogenesis, mechanisms by which toxins impair the barrier are not yet known. This study, using an in vitro cell culture model, showed that LPS and LTA interacted with the endothelial cells and disrupted the tight junction between the cells that increased the barrier's permeability. Both toxins increased inducible nitric oxide synthase (iNOS) mRNA that is indicative of an increase in intracellular NO release, disrupted architecture of the tight junction proteins, suppressed zonula occludens-1 (ZO-1) and occludin (OCL) and junctional adhesive molecules (JAM) mRNA levels, and increased tumor necrosis factor alpha (TNFalpha) and interleukin-1 beta (IL-1beta) mRNA levels. Anti-CD14 antibodies blocked the increase in TNFalpha and IL-1beta mRNA levels but did not affect either changes in the tight junction or iNOS, ZO-1, OCL, and JAM mRNA levels in endothelial cells and astrocytes. Although both toxins did not cross the endothelial barrier, the abluminal neurons exhibited high inflammatory activity characterized by a sequential increase in TNFalpha, IL-1beta, external receptor kinase (ERK), and RelA-p50 that induced inflammation, followed by an increase in anti-inflammatory/apoptotic factors including IL-10 and cysteine-aspartic acid protease-8 (CASPASE-8), which resolve inflammation and induce apoptosis. Anti-CD14 antibodies in luminal buffer blocked the pro- and anti-inflammatory effects of the toxins in neurons. Thus, the CD14-TLR cascade that participates in the inflammatory effects of toxins may not participate in the toxin-induced barrier disruption in vitro. Since the toxins did not cross the endothelial barrier, induction of inflammation in neurons was due to a release of proinflammatory cytokines in the abluminal fluid.

Prognostic impact of metastatic lymph node ratio on gastric cancer after curative distal gastrectomy.

Huang Chang-Ming , Lin Jian-Xian , Zheng Chao-Hui , Li Ping , Xie Jian-Wei , Lin Bi-Juan , Wang Jia-Bin
World J Gastroenterol.2010 Apr 28 ; 16(16):2055-60.
PMID: 20419845[]

先週： 2位

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AIM: To investigate the prognostic impact of metastatic lymph node ratio (rN) on gastric cancer after curative distal gastrectomy. METHODS: A total of 634 gastric cancer patients who underwent curative resection (R0) of lymph nodes at distal gastrectomy in 1995-2004. Correlations between positive nodes and retrieved nodes, between rN and retrieved nodes, and between rN and negative lymph node (LN) count were analyzed respectively. Prognostic factors were identified by univariate and multivariate analyses. Staging accuracy of the pN category (5th UICC/TNM system) and the rN category was compared according to the survival rates of patients. A linear regression model was used to identify the relation between rN and 5-year survival rate of the patients. RESULTS: The number of dissected LNs was related with metastatic LNs but not related with rN. Cox regression analysis showed that depth of invasion, pN and rN category were the independent predictors of survival (P < 0.05). There was a significant difference in survival between LN stages classified by the rN category or by the pN category (P < 0.05). However, no significant difference was found in survival rate between LN stages classified by the pN category or by the rN category (P > 0.05). Linear regression model showed a significant linear correlation between rN and the 5-year survival rate of gastric cancer patients (beta = 0.862, P < 0.001). Pearson's correlation test revealed that negative LN count was negatively correlated with rN (P < 0.001). CONCLUSION: rN category is a better prognostic tool than the 5th UICC pN category for gastric cancer patients after curative distal gastrectomy. Increased negative LN count can reduce rN and improve the survival rate of gastric cancer patients.

Effect of valsartan or olmesartan addition to amlodipine on ankle edema in hypertensive patients.

Fogari Roberto , Malamani Gian , Corradi Luca , Mugellini Amedeo , Preti Paola , Zoppi Annalisa , Derosa Giuseppe
Adv Ther.2010 Feb 19 ; ():.
PMID: 20174905[]

先週： 3位

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INTRODUCTION: The objective of this study was to compare the effect on ankle edema of adding valsartan (V) or olmesartan (O) to amlodipine (A) in the treatment of hypertension. METHODS: After a 4-week placebo period, 74 adult outpatients with essential hypertension (diastolic blood pressure [DBP] >90 and <110 mmHg, and systolic blood pressure [SBP] >140 mmHg) were treated with A 10 mg once daily for 4 weeks. Thereafter, nonresponder patients (DBP >90 mmHg and/or SBP >140 mmHg; n=51) were randomized to receive additional V 160 mg once daily or O 20 mg once daily for 8 weeks in two crossover periods, each separated by a 4-week placebo period. Clinic blood pressure (BP), heart rate, and ankle/foot volume (AFV) were evaluated and blood samples were drawn to evaluate plasma norepinephrine (NE) levels. RESULTS: Both V/A and O/A induced a greater SBP/DBP reduction than A monotherapy (-26.4/-20.8 mmHg and -24.4/-19.1 mmHg, respectively; all P<0.001 vs. baseline and P<0.01 vs. A). A monotherapy increased AFV by 24%, P<0.001 vs. baseline, while the addition of either V or A reduced such increases. However, with V/A the AFV increase (+9.7%, P<0.05 vs. baseline, P<0.01 vs. A) was lower than with O/A (+16.7%, P<0.01 vs. baseline, P<0.05 vs. A); the difference between the two combinations was significant. Plasma NE levels were significantly increased by A (+44.6%) and values did not change with the addition of V (+35.2%) or O (+33.7%). Plasma active renin (PAR) was unchanged by A but increased by V/A (+214.4%, P<0.05 vs. baseline) and further by O/A (+325.6%, P<0.01 vs. baseline; difference between the 2 combinations: P<0.05). An inverse correlation was found between the AFV decrease and PAR increase (r=-0.31, P<0.05). CONCLUSION: Adding V or O to A reduced ankle edema, but this effect was more pronounced with V. The greater degree of renin-angiotensin system activation observed with Ocould be related to such a difference.

[Effects of the flavonoids on cytochrome P-450 CYP1, 2E1, 3A4 and 19]

Zheng Jiao , Zhou Hong-Hao
Yao Xue Xue Bao.2007 Jan ; 42(1):8-12.
PMID: 17520800[]

先週： 9位

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Flavonoids are present in fruits, vegetables and beverages derived from plants, and in many dietary supplements or herbal remedies. A number of naturally occurring flavonoids have been shown to modulate the CYP450 system, including the induction or inhibition of these enzymes. This review focuses on the flavonoid effects on cytochrome P450 (CYP) enzyme CYP1, 2E1, 3A4 and 19. Flavonoids alter CYPs by various mechanisms, including the stimulation of gene expression via specific receptors and/or CYP protein, or mRNA stabilization and so on. But in vivo and in vitro, the effects of flavonoids are not always coincident as a result of concentrations of flavonoids, genetic and environmental factors. As well, flavonoids may interact with drugs through the induction or inhibition of their metabolism. Much attention should be paid to the metabolism interaction of the flavonoids when coadministered with other drugs.

Pulmonary hypertension as a risk factor for death in patients with sickle cell disease.

Gladwin Mark T , Sachdev Vandana , Jison Maria L , Shizukuda Yukitaka , Plehn Jonathan F , Minter Karin , Brown Bernice , Coles Wynona A , Nichols James S , Ernst Inez , Hunter Lori A , Blackwelder William C , Schechter Alan N , Rodgers Griffin P , Castro Oswaldo , Ognibene Frederick P
N Engl J Med.2004 Feb 26 ; 350(9):886-95.
PMID: 14985486[]

先週： 7位

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BACKGROUND: The prevalence of pulmonary hypertension in adults with sickle cell disease, the mechanism of its development, and its prospective prognostic significance are unknown. METHODS: We performed Doppler echocardiographic assessments of pulmonary-artery systolic pressure in 195 consecutive patients (82 men and 113 women; mean [+/-SD] age, 36+/-12 years). Pulmonary hypertension was prospectively defined as a tricuspid regurgitant jet velocity of at least 2.5 m per second. Patients were followed for a mean of 18 months, and data were censored at the time of death or loss to follow-up. RESULTS: Doppler-defined pulmonary hypertension occurred in 32 percent of patients. Multiple logistic-regression analysis, with the use of the dichotomous variable of a tricuspid regurgitant jet velocity of less than 2.5 m per second or 2.5 m per second or more, identified a self-reported history of cardiovascular or renal complications, increased systolic blood pressure, high lactate dehydrogenase levels (a marker of hemolysis), high levels of alkaline phosphatase, and low transferrin levels as significant independent correlates of pulmonary hypertension. The fetal hemoglobin level, white-cell count, and platelet count and the use of hydroxyurea therapy were unrelated to pulmonary hypertension. A tricuspid regurgitant jet velocity of at least 2.5 m per second, as compared with a velocity of less than 2.5 m per second, was strongly associated with an increased risk of death (rate ratio, 10.1; 95 percent confidence interval, 2.2 to 47.0; P<0.001) and remained so after adjustment for other possible risk factors in a proportional-hazards regression model. CONCLUSIONS: Pulmonary hypertension, diagnosed by Doppler echocardiography, is common in adults with sickle cell disease. It appears to be a complication of chronic hemolysis, is resistant to hydroxyurea therapy, and confers a high risk of death. Therapeutic trials targeting this population of patients are indicated.

Personality disorders and biosocial trait theories: The argument for radical legal reform.

Peters David C
Behav Sci Law.2010 Mar ; 28(2):289-302.
PMID: 20422651[]

先週： 6位

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This article reviews antisocial personality disorder, psychopathy, and violence and develops a three factor model of personality traits. Then a discussion of related personality disorders precedes the development of a categorical two factor model of impulsive versus remorseless violence. A paradigm of proactive, medical, and school based early intervention and prevention is advocated as a useful addition to the reactive detention of criminal justice. Integration of psychological tests, neuroimaging, and genomic data in early childhood and school based intervention strategies to prevent the development of conduct disorder and attenuate criminal propensity inform this approach.

Interferon-gamma: biologic functions and HCV therapy (type I/II) (1 of 2 parts).

Gattoni A , Parlato A , Vangieri B , Bresciani M , Derna R
Clin Ter.2006 Jul-Aug ; 157(4):377-86.
PMID: 17051976[]

先週： 8位

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PURPOSE: This review is aimed at exhaustively presenting and discussing the interferon-gamma (IFN-gamma), a cytokine that plays an important role in inducing and modulating an array of immune responses. DESIGN: A review of the most significant and recent clinical trials was performed. OVERVIEW: Although IFN-gamma has some antiviral activity, it is much less active in this regard than type I IFNs. IFN-gamma is involved in the regulation of nearly all phases of the immune and inflammatory responses, including the activation and differentiation of T cells, B cells, NK cells, macrophages, and others. It is therefore best regarded as a distint immunoregulatory cytokine. IFN-gamma secretion is a hallmark of Th1 lymphocytes. It is also secreted by nearly all CD8 T cells, by some Th0 cells, and by NK cells. Each of these cell types secretes IFN-gamma only when activated, usually as part of immune response and especially in response to IL-2 and IL-12. IFN-gamma production is inhibited by IL-4, IL-10, TGFbeta, glucocorticoids, cyclosporin A and FK506. Nearly all cell types express the heterodimeric receptor for IFN-beta and respond to this cytokine by increasing the surface expression of class I MHC proteins. As a result, virtually any cell in the vicinity of an IFN-beta-secreting cell becomes more efficient at presenting endogenous antigens and hence a better target for cytotoxic killing if it harbors an intracellular pathogen. Unlike the type I IFNs, IFN-gamma also increases the expression of class II MHC proteins on professional APCs, and so promotes antigen presentation to helper T cells as well. It also induces de novo expression of class II MHC proteins on venular endothelial cells and on some other epithelial and connective tissue cells that do not otherwise express them, thus enabling these cell types to function as temporary APCs at sites of intense immune reactions. The effector functions of NK cells are to lyse virus-infected cells and to secrete IFN-gamma, which activates macrofages to destroy phagocytosed microbes. The mechanism of NK cell-mediates cytolysis is essentially the same as that of cytolysis by CTLS. NK cells lyse virally infected cells before antigen specific CTLS came become fully active, that is, during the first few days after viral infection. NK cells are expanded and activated by cytokines of innate immunity, such as IL-12 and IL-15, and they kill infected cells, especially those that display reduced levels of class I molecoles. Some tumors, especially those of hematopoietic origin, are targets of NK cells, perlevels or types of class I MHC molecules. Therefore, IFN-gamma serves critical functions in innate immunity and in specific cell-mediated immunity (in addition, IFN activates neutrophilis and stimulates the cytolitic activity of NK cells). Many IFNs-gamma induced effects result in heigtened immune surveillance. CONCLUSIONS: IFN-gamma is a remarkable cytokine that orchestrates many distinct cellular programs through transcriptional control over large numbers of genes. Many IFNs-gamma-induced effects resulting in heightend immune surveillance and immune system function during infection have been discussed in this review. As the pathogens (microorganism with the potential to cause tissue injury or disease) augment local IFN-gamma production, and IFN-gamma augments the immune system response, an important function of IFN-gamma during in vivo infection is suggested. IFN-gamma is primarily secreted by activated T cells and natural killer cells, and can promote macrophage activation, mediate antiviral e antibacterial immunity, enhance antigen presentation, orchestrate activation of the innate immune system, coordinate lymphocyte-endothelium interaction, regulate Th1/Th2 balance, and control cellular proliferation and apoptosis.

The differentiation of rat adipose-derived stem cells into OEC-like cells on collagen scaffolds by co-culturing with OECs.

Wang Bin , Han Jin , Gao Yuan , Xiao Zhifeng , Chen Bing , Wang Xia , Zhao Wenxue , Dai Jianwu
Neurosci Lett.2007 Jun 29 ; 421(3):191-6.
PMID: 17574753[]

先週： 5位

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Olfactory ensheathing cells (OECs) transplantation is a promising or potential therapy for spinal cord injury (SCI). However, their clinical use is limited because of the availability. Adipose-derived stem cells (ADSCs) have been identified as an alternative source of adult stem cells in recent years. ADSCs could be differentiated into various mesenchymal tissues cells such as chondrocytes, adipocytes, osteoblasts, and myocytes and also could be differentiated into neural lineages. In this study, we examined the feasibility of using ADSCs as a source of stem cells for the differentiation of OECs by co-culture approach. When co-cultured with OECs, the ADSCs on three-dimensional collagen scaffolds were differentiated into OEC-like cells, with similar morphology and antigenic phenotypes (p75NTR+/Nestin+/GFAP-) of OECs. Co-cultured ADSCs were positive for several important functional markers of mature OECs such as neurotrophic factor GDNF, BDNF and myelin protein PLP and the conditioned medium of OEC-like cells could significantly promote DRG neuron growth and axon sprouting without NGF supporting in contrast to that of the ADSCs. Our results showed that ADSCs had the potential to differentiate into OEC-like cells on the three-dimensional collagen scaffolds in vitro.

Integration of the NF-kappaB and mitogen-activated protein kinase/AP-1 pathways at the collagenase-1 promoter: divergence of IL-1 and TNF-dependent signal transduction in rabbit primary synovial fibroblasts.

Barchowsky A , Frleta D , Vincenti M P
Cytokine.2000 Oct ; 12(10):1469-79.
PMID: 11023661[]

先週： 4位

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Collagenase-1 (MMP-1) is a protease that is expressed by stromal cells and that is involved in remodeling of the extracellular matrix. IL-1 and TNF-alpha enhance collagenase secretion by stromal cells, and chronic exposure of cells to these cytokines can contribute to connective tissue disease. In this study, we show that the NF-kappaB pathway is required for activation of collagenase-1 transcription in rabbit primary synovial fibroblasts (RSF). Although both IL-1 and TNF activate NF-kappaB in these cells, only IL-1 induces collagenase-1 transcription. We have reported previously that NF-kappaB and AP-1 cooperate to mediate IL-1-induced MMP-1 transcription. Here, we show that IL-1 is superior to TNF at inducing c-Jun synthesis, phosphorylation and binding activity in RSF. Similarly, IL-1 is more effective at activating the mitogen-activated protein kinases (MAPK), including the extracellular signal-regulated kinases (ERK), which are required for IL-1-induced MMP-1 transcription. Thus stimulation of the ERK and AP-1 pathways is an essential component of MMP-1 transcriptional activation, which is deficient in TNF-treated cells. These studies demonstrate cooperation between the MAPK and NF-kappaB signaling pathways for IL-1-dependent collagenase-1 transcription, and they define a dichotomy of IL-1- and TNF-elicited signaling that is relevant to cytokine-mediated connective tissue disease.

Effects of olmesartan, an angiotensin II receptor blocker, and amlodipine, a calcium channel blocker, on Cardio-Ankle Vascular Index (CAVI) in type 2 diabetic patients with hypertension.

Miyashita Yoh , Saiki Atsuhito , Endo Kei , Ban Noriko , Yamaguchi Takashi , Kawana Hidetoshi , Nagayama Daiji , Ohira Masahiro , Oyama Tomokazu , Shirai Kohji
J Atheroscler Thromb.2009 Oct ; 16(5):621-6.
PMID: 19907103[]

先週： 11位

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AIM: Recently, a novel device for measuring the cardio-ankle vascular index (CAVI) as an arterial stiffness parameter has been developed. In this study, we evaluated the effect of angiotensin II receptor blocker (ARB) and calcium channel (Ca) blocker on CAVI in type 2 diabetic patients with hypertension.METHODS: Seventy type 2 diabetes mellitus patients with hypertension were enrolled and randomly divided into two groups. One group was administered olmesartan medoxomil 10 mg/day for 12 months (ARB group), and the other group was administered amlodipine besilate 5 mg/day for 12 months (Ca blocker group).RESULTS: In the ARB group, a significant decrease in CAVI was observed after 12 months; however, no significant change in CAVI was observed in the Ca blocker group although changes in blood pressure were almost the same. By simple regression analyses, CAVI changes correlated positively with 8-OHdG changes.CONCLUSIONS: Olmesartan, an ARB, improved arterial stiffness more than amlodipine, and this effect might be due to not only the blood pressure-lowering effect but also to reducing the potential of oxidative stress recognized in olmesartan.

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A randomized, double-blind, four-arm parallel-group study of the efficacy and safety of azelnidipine and olmesartan medoxomil combination therapy compared with each monotherapy in Japanese patients with essential hypertension: the REZALT study.

Hypertens Res.2009 Oct 9 ; ():.
PMID: 19816505[]

先週： 1位

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A 12-week randomized, double-blind, four-arm parallel-group, comparative study was conducted in patients with essential hypertension to evaluate the antihypertensive effect and safety of combination therapy with olmesartan medoxomil (OLM, an angiotensin-receptor blocker) 20 mg plus azelnidipine (AZL, a long-acting dihydropyridine calcium channel blocker) 16 mg, (O/A (20/16)), or OLM 10 mg/AZL 8 mg (O/A (10/8)) compared with those of monotherapy with OLM 20 mg (OLM (20)) or AZL 16 mg (AZL (16)). The change from baseline to week 12 in seated blood pressure (SeBP) was -23.6/-14.2 mm Hg (systolic/diastolic BP) in the O/A (20/16) group, and -20.3/-13.0 mm Hg in the O/A (10/8) group, which was a significantly greater reduction in SeBP than in the monotherapy groups (-15.7/-9.9 mm Hg in OLM (20); -15.0/-9.4 mm Hg in AZL (16)). The change from baseline in 24-h ambulatory BP was also significantly greater in the O/A (20/16) and O/A (10/8) combination groups (-22.1/-13.5 and -18.2/-10.6 mm Hg, respectively) than in the OLM (20) and AZL (16) monotherapy groups (-12.1/-6.9 and -12.0/-6.9 mm Hg). The proportion of patients achieving the SeBP goal (<130/85 mm Hg for normal BP or <140/90 mm Hg for high-normal BP) was significantly higher in the O/A (20/16) combination group than in the monotherapy groups. The incidence of adverse events was similar in the O/A combination groups and the monotherapy groups. These results showed that combination therapy with O/A was well tolerated and exerted a stronger antihypertensive effect compared with monotherapy with OLM or AZL in patients with essential hypertension.Hypertension Research advance online publication, 9 October 2009; doi:10.1038/hr.2009.163.

Risk Factors for Idiosyncratic Drug-Induced Liver Injury.

Chalasani Naga , Björnsson Einar
Gastroenterology.2010 Apr 12 ; ():.
PMID: 20394749[]

先週： 2位

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Idiosyncratic drug-induced liver injury (DILI) is a rare disorder that is not directly related to dosage and little is known about individuals who are at increased risk. There are no suitable preclinical models for the study of idiosyncratic DILI and its pathogenesis is poorly understood. It is likely to arise from complex interactions among genetic, non-genetic host susceptibility, and environmental factors. Non-genetic risk factors include age, gender, and other diseases (e.g. chronic liver disease or HIV infection). Compound-specific risk factors include daily dose, metabolism characteristics, and propensity for drug interactions. Alcohol consumption has been proposed as a risk factor for DILI from medications, but there is insufficient evidence to support this. Many studies have explored genetic defects that might be involved in pathogenesis and focused on genes involved in drug metabolism and the immune response. Multicenter databases of patients with DILI (the United States Drug Induced Liver Injury Network [DILIN], DILIGEN, and the Spanish DILI registry) are important tools for clinical and genetic research. A genome-wide association study of flucloxacillin hepatotoxicity has yielded ground-breaking results and many similar studies are underway. Nontheless, DILI is challenging to investigate because of its rarity, the lack of experimental models, the number of medications that might cause it, and challenges to diagnosis.

Effect of valsartan or olmesartan addition to amlodipine on ankle edema in hypertensive patients.

Fogari Roberto , Malamani Gian , Corradi Luca , Mugellini Amedeo , Preti Paola , Zoppi Annalisa , Derosa Giuseppe
Adv Ther.2010 Feb 19 ; ():.
PMID: 20174905[]

先週： 3位

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Involvement of Th17 and Th1 Effector Responses in Patients with Hepatitis B.

Ye Yufu , Xie Xiaojun , Yu Jiwei , Zhou Lin , Xie Haiyang , Jiang Guoping , Yu Xiaobo , Zhang Wenjin , Wu Jian , Zheng Shusen
J Clin Immunol.2010 Apr 15 ; ():.
PMID: 20393789[]

先週： 4位

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BACKGROUND: Local production of cytokines within the liver may play a pivotal role in the regulation of pathophysiological processes during inflammation. CD4+ T cells are regarded as the most prolific cytokine producers. The purpose of this study was to quantify intrahepatic expression of Th1, Th2, Th17, and Treg-associated cytokines or transcription factors in patients with acute hepatitis B or chronic hepatitis B (CHB) and to analyze their relative roles in the promotion and regulation of hepatitis B virus (HBV)-associated liver diseases. METHODS: Distribution and expression of IL-17, IFN-gamma, IL-4, Foxp3, and other cytokines in liver tissues were detected by immunohistochemistry and real-time quantitative PCR. Patients with hepatitis B were compared with patients with chronic hepatitis C, primary biliary cirrhosis, alcoholic liver cirrhosis, and healthy controls. RESULTS: The frequencies of intrahepatic IL-17 and IFN-gamma-producing cells in patients with HBV-associated liver dysfunction were much higher than that of IL-4 and Foxp3-positive cells. The level of the IL-17/IFN-gamma-positive cell ratio of patients with Child-Pugh class C (1.57 +/- 0.09) was much higher than that of patients with Child-Pugh class B (1.00 +/- 0.02) or A (0.93 +/- 0.05). There are more IL-17-producing cells than IFN-gamma-producing cells accumulating in the liver with severe hepatocellular damage. Liver IL-17-producing cell infiltration was positively associated with the grade of liver inflammation in CHB and positively correlated to intrahepatic IL-8 expression (r = 0.801, p < 0.01) or neutrophil infiltration (r = 0.917, p < 0.01). CONCLUSIONS: These results suggest that the balance of effector CD4+ Th responses (Th17 and Th1 responses) and regulatory response is an important element of immune regulation. Inappropriate, excessive, and non-specific Th17 and Th1 effector responses may be involved in the pathogenesis of HBV-associated liver inflammation and hepatocellular damage. Th17 response, especially, may exacerbate the inflammatory processes leading to liver failure. IL-17-mediating liver neutrophil recruitment via induction of IL-8 may be one potential mechanism of liver injury in patients with hepatitis B. An improved understanding of the factors that influence the differentiation and function of these cell types in vivo will be of great importance to the future development of immune therapies in HBV-associated liver disease.

The differentiation of rat adipose-derived stem cells into OEC-like cells on collagen scaffolds by co-culturing with OECs.

Wang Bin , Han Jin , Gao Yuan , Xiao Zhifeng , Chen Bing , Wang Xia , Zhao Wenxue , Dai Jianwu
Neurosci Lett.2007 Jun 29 ; 421(3):191-6.
PMID: 17574753[]

先週： 5位

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Comparison of the long-term effects of candesartan and olmesartan on plasma angiotensin II and left ventricular mass index in patients with hypertension.

Hypertens Res.2009 Nov 20 ; ():.
PMID: 19927151[]

先週： 6位

27view,10users

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In general, treatment with most angiotensin receptor blockers (ARBs) increases plasma angiotensin II (Ang II) level because of a lack of negative feedback on renin activity. Olmesartan is a potential ARB inducing activation of angiotensin-converting enzyme 2 (ACE2) that hydrolyzes Ang II to Ang 1-7, and has shown a beneficial effect on ventricular remodeling. Indeed, a previous study reported that olmesartan treatment resulted in decreased plasma levels of Ang II and aldosterone. However, there has not yet been a study showing the relationship of chronic effects of olmesartan on Ang II and the left ventricular mass index (LVMI) in comparison with those of other ARB.A total of 50 stable outpatients with essential hypertension who had received candesartan for more than 1 year were randomized into two groups: control group (n=25): continuous candesartan treatment at a stable dose; and olmesartan group (n=25): candesartan (8 mg day(-1)) was changed to olmesartan given at a dose of 20 mg day(-1). There was no difference in the baseline characteristics between the two groups. In the control group, there were no significant changes in blood pressure, LVMI or biomarkers during 12 months of study. In the olmesartan group, blood pressure did not change and plasma levels of Ang II decreased during 12 months of study, whereas LVMI was significantly decreased after 12 months (135+/-36 vs. 123+/-29 g m(-2); P<0.01).These findings indicate that replacing candesartan with olmesartan decreased LVMI in association with a sustained decrease of plasma Ang II over a 12-month period without changing blood pressure or plasma aldosterone in patients with essential hypertension.Hypertension Research advance online publication, 20 November 2009; doi:10.1038/hr.2009.192.

Sodium-translocating NADH:Quinone oxidoreductase as a redox-driven ion pump.

Verkhovsky Michael I , Bogachev Alexander V
Biochim Biophys Acta.2010 Jan 4 ; ():.
PMID: 20056102[]

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The Na(+)-translocating NADH:ubiquinone oxidoreductase (Na(+)-NQR) is a component of the respiratory chain of various bacteria. This enzyme is an analogous but not homologous counterpart of mitochondrial Complex I. Na(+)-NQR drives the same chemistry and also uses released energy to translocate ions across the membrane, but it pumps Na(+) instead of H(+). Most likely the mechanism of sodium pumping is quite different from that of proton pumping (for example, it could not accommodate the Grotthuss mechanism of ion movement); this is why the enzyme structure, subunits and prosthetic groups are completely special. This review summarizes modern knowledge on the structural and catalytic properties of bacterial Na(+)-translocating NADH:quinone oxidoreductases. The sequence of electron transfer through the enzyme cofactors and thermodynamic properties of those cofactors are discussed. The resolution of the intermediates of the catalytic cycle and localization of sodium-dependent steps are combined in a possible molecular mechanism of sodium transfer by the enzyme.

Blood pressure goal achievement with olmesartan medoxomil-based treatment: additional analysis of the OLMEBEST study.

Barrios Vivencio , Escobar Carlos , Calderon Alberto , Böhm Michael
Vasc Health Risk Manag.2009 ; 5():723-9.
PMID: 19756164[]

先週： 8位

30view,7users

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AIMS: Guidelines recommend blood pressure (BP) in hypertensive patients should be <140 systolic BP (SBP) and <90 diastolic BP (DBP) mmHg. This analysis assessed goal rate achievement in hypertensive patients receiving olmesartan-based treatment in the OLMEBEST study. METHODS: Patients with essential hypertension (DBP > or = 90 mmHg and <110 mmHg) received open-label olmesartan medoxomil 20 mg/day (n = 2306). After 8 weeks, patients with DBP > or = 90 mmHg (n = 627) were randomized to 4 weeks' double-blind treatment with olmesartan 40 mg/day monotherapy or olmesartan 20 mg/day plus hydrochlorothiazide (HCTZ) 12.5 mg/day. For this analysis, the numbers and proportions of patients who achieved SBP < 140 mmHg and/or DBP < 90 mmHg at the end of the 4 weeks were calculated. RESULTS: In patients who achieved DBP normalization (<90 mmHg) at week 8 (n = 1546) and continued open-label olmesartan 20 mg/day, 66.7% achieved SBP/DBP < 140/90 mmHg at Week 12. In patients who did not achieve DBP normalization at Week 8, 26.8% of those randomized to olmesartan 40 mg/day and 42.5% of those randomized to olmesartan 20 mg/day plus HCTZ 12.5 mg/day achieved a SBP/DBP < 140/90 mmHg at Week 12. CONCLUSION: Olmesartan 40 mg/day and olmesartan 20 mg/day plus HCTZ 12.5 mg/day allow substantial proportions of patients to achieve BP goals.

Mesenchymal stem cells increase hippocampal neurogenesis and counteract depressive-like behavior.

Mol Psychiatry.2009 Oct 27 ; ():.
PMID: 19859069[]

先週： 9位

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Adult bone marrow-derived mesenchymal stem cells (MSCs) are regarded as potential candidates for treatment of neurodegenerative disorders, because of their ability to promote neurogenesis. MSCs promote neurogenesis by differentiating into neural lineages as well as by expressing neurotrophic factors that enhance the survival and differentiation of neural progenitor cells. Depression has been associated with impaired neurogenesis in the hippocampus and dentate gyrus. Therefore, the aim of this study was to analyze the therapeutic potential of MSCs in the Flinders sensitive line (FSL), a rat animal model for depression. Rats received an intracerebroventricular injection of culture-expanded and 1,1'-dioctadecyl-3,3,3',3'-tetramethylindocarbocyanine perchlorate (DiI)-labeled bone marrow-derived MSCs (10(5) cells). MSC-transplanted FSL rats showed significant improvement in their behavioral performance, as measured by the forced swim test and the dominant-submissive relationship (DSR) paradigm. After transplantation, MSCs migrated mainly to the ipsilateral dentate gyrus, CA1 and CA3 regions of the hippocampus, and to a lesser extent to the thalamus, hypothalamus, cortex and contralateral hippocampus. Neurogenesis was increased in the ipsilateral dentate gyrus and hippocampus of engrafted rats (granular cell layer) and was correlated with MSC engraftment and behavioral performance. We therefore postulate that MSCs may serve as a novel modality for treating depressive disorders.Molecular Psychiatry advance online publication, 27 October 2009; doi:10.1038/mp.2009.110.

Effects of olmesartan, an angiotensin II receptor blocker, and amlodipine, a calcium channel blocker, on Cardio-Ankle Vascular Index (CAVI) in type 2 diabetic patients with hypertension.

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The Journal of biological chemistry

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5,876view , 210users

Proceedings of the National Academy of Sciences of the United States of America

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3,522view , 141users

Journal of immunology (Baltimore, Md. : 1950)

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2,284view , 121users

Biochemistry

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1,926view , 19users

Cancer research

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1,811view , 55users

Blood

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1,799view , 57users

Journal of virology

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1,795view , 22users

Biochemical and biophysical research communications

先週： 8位

1,663view , 85users

Science (New York, N.Y.)

先週： 11位

1,460view , 61users

Giornale di psichiatria e di neuropatologia

先週： 10位

1,422view , 73users

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週間人気ジャーナルランキング - 保存数 (2010/09/04/ 09時更新)

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The Journal of biological chemistry

先週： 1位

5,876view , 210users

Proceedings of the National Academy of Sciences of the United States of America

先週： 2位

3,522view , 141users

Journal of immunology (Baltimore, Md. : 1950)

先週： 3位

2,284view , 121users

Developmental medicine and child neurology

先週： 4位

139view , 117users

PloS one

先週： 5位

1,309view , 108users

Journal of agricultural and food chemistry

先週： 6位

978view , 102users

Biochemical and biophysical research communications

先週： 7位

1,663view , 85users

Giornale di psichiatria e di neuropatologia

先週： 8位

1,422view , 73users

Neuroscience letters

先週： 9位

593view , 66users

Science (New York, N.Y.)

先週： 10位

1,460view , 61users

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Enhancement of antigen-specific Treg vaccination in vivo.

Daniel Carolin , Wennhold Kerstin , Kim Hye-Jung , von Boehmer Harald
Proc Natl Acad Sci U S A.2010 Aug 30 ; ():.
PMID: 20805478[]

2010/08/31

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The conversion of naive T cells into Treg can be achieved in vivo by delivery of antigen under subimmunogenic conditions. Here we have examined several drugs for their ability to enhance the conversion process in vivo and have found that the rapamycin analog everolimus potently enhances Treg conversion by interfering with T-cell costimulation, reducing cell division and thereby activation of DNA methyltransferase 1 as well as by reducing T-cell activation through the ATP-gated P2x7 receptor controlling Ca2(+) influx. The resulting Tregs exhibit increased stability of Foxp3 expression even when generated in TGFbeta-containing media in vitro. Thus the mammalian target of rapamycin (mTOR) inhibitor everolimus in addition to inhibiting immune responses enhances Treg conversion by several distinct pathways. The converted Tregs can be further expanded by injection of IL-2/IL-2ab complexes. These complexes also increase the number of CD25(+)Foxp3(-) cells that, however, do not represent cytokine secreting effector cells but anergic cells, some of which can secrete IL-10 and can themselves be considered regulatory T cells as well. The combined use of everolimus and IL-2/IL-2ab complexes in vivo makes it feasible to achieve highly effective antigen-driven conversion of naive T cells into Treg and their expansion in vivo and thereby the described protocols constitute important tools to achieve immunological tolerance by Treg vaccination.

Effects of branched-chain amino acid-enriched nutrient for patients with hepatocellular carcinoma following radiofrequency ablation: A one-year prospective trial.

Kuroda Hidekatsu , Ushio Akira , Miyamoto Yasuhiro , Sawara Kei , Oikawa Kanta , Kasai Kazuhiro , Endo Ryujin , Takikawa Yasuhiro , Kato Akinobu , Suzuki Kazuyuki
J Gastroenterol Hepatol.2010 Sep ; 25(9):1550-5.
PMID: 20796154[]

2010/08/27

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Abstract Background and Aim: This prospective control study examined whether supplementation with branched-chain amino acid (BCAA)-enriched nutrients can help maintain and improve residual liver function and nutritional status in cirrhotic patients with hepatocellular carcinoma (HCC) after radiofrequency ablation (RFA). Methods: Subjects were 49 patients with hepatitis C-related HCC who underwent RFA. Two groups were formed: BCAA group (BCAA-enriched nutrient, aminoleban EN) and controls (standard diet only). Event-free survival rate, liver function tests, and Short Form (SF)-8 scores were evaluated in both groups before and one year after RFA. Energy metabolism using indirect calorimetry was measured before and after 3 months. Results: Complete data were obtained from 35 patients (BCAA group, n = 20; controls, n = 15). Six events (death, recurrence of HCC, rupture of esophageal varices and liver failure) occurred during the observation period, but frequencies of these events did not differ between groups. Event-free survival rate tended to be higher in the BCA group than in controls. Among the parameters of liver function, serum albumin level was only significantly increased over 6 months, and remained at similar values for one year (P < 0.05). SF-8 scores for general health, physical functioning, and social functioning were significantly elevated in the BCAA group (P < 0.05). Non-protein respiratory quotient was significantly improved in the BCAA group (P < 0.01). Conclusion: Supplementation with BCAA-enriched nutrients for one year in cirrhotic patients with HCC after RFA therapy can perform safety and improve both nutritional state and quality of life.

Endosaccular embolization for internal carotid artery aneurysms at the c3 portion.

Nakahara I , Hashimoto N , Nishi S , Iwama T , Yanamoto H , Akiyama Y , Kojima M , Todaka T , Sawada M , Kojima A , Kawakami O , Horiguchi S
Interv Neuroradiol.1998 Nov 30 ; 4 Suppl 1():81-3.
PMID: 20673449[]

2010/08/02

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Summary: Direct surgery for the aneurysms at the C3 portion of the internal carotid artery (ICA) requires relatively complicated procedures. We present three patients with this aneurysm who underwent endovascular embolization. The remodelling technique was utilized in two of these patients with unruptured aneurysms. Sufficient obliteration was achieved in every case. Endovascular embolization may be an important alternative for ICA C3 aneurysms.

Autologous fibrin-cultured limbal stem cells permanently restore the corneal surface of patients with total limbal stem cell deficiency.

Rama P , Bonini S , Lambiase A , Golisano O , Paterna P , De Luca M , Pellegrini G
Transplantation.2001 Nov 15 ; 72(9):1478-85.
PMID: 11707733[]

2001/11/14

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BACKGROUND: Ocular burns cause depletion of limbal stem cells, which leads to corneal opacification and visual loss. Autologous cultured epithelial cells can restore damaged corneas, but this technology is still developing. We sought to establish a culture system that allows preservation of limbal stem cells and preparation of manageable epithelial sheets and to investigate whether such cultures can permanently restore total limbal stem cell deficiency. METHODS: We selected a homogeneous group of patients whose limbal cell deficiency was evaluated by scoring the gravity of the clinical picture and the keratin expression pattern. Stem cells, obtained from the limbus of the contralateral eye, were cultivated onto a fibrin substrate and their preservation was evaluated by clonal analysis. Fibrin cultures were grafted onto damaged corneas. RESULTS: Fibrin-cultured limbal stem cells were successful in 14 of 18 patients. Re-epithelialization occurred within the first week. Inflammation and vascularization regressed within the first 3-4 weeks. By the first month, the corneal surface was covered by a transparent, normal-looking epithelium. At 12-27 months follow-up, corneal surfaces were clinically and cytologically stable. Three patients had a penetrating keratoplasty approximately 1 year after restoration of their corneal surface. Their visual acuity improved from light perception or counting fingers to 0.8-1.0. CONCLUSIONS: Preservation of limbal stem cells in culture gives new perspectives on the treatment of ocular disorders characterized by complete limbal stem cell deficiency. The multicenter nature of this study and the handiness and ease of long-distance transportation of the fibrin-cultured epithelial sheets suggest that this technology can now be widely applied.

The influence of folic acid supplementation on maternal and fetal bone turnover.

Hossein-Nezhad Arash , Mirzaei Khadijeh , Maghbooli Zhila , Najmafshar Azam , Larijani Bagher
J Bone Miner Metab.2010 Jul 3 ; ():.
PMID: 20602129[]

2010/07/05

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The aim of our study was to investigate the relationship between maternal and fetal bone turnover markers and folic acid supplementation during pregnancy. In an observational study performed in Tehran University of Medical Sciences related hospitals, 113 healthy pregnant women with gestational age between 8 and 12 weeks and aged between 15 and 42 years were recruited and followed until delivery time. The participants were divided into two groups; women who took 1 mg of folic acid daily supplement from the beginning of the pregnancy until the end of the second trimester entered into group I and women who choose to continue their daily intake of folic acid until the delivery time entered into group II. The two groups were matched based on the maternal anthropometric data, energy, calcium and vitamin D intake. Following the delivery, venous blood samples were collected from mothers and umbilical cords of the neonates. Maternal and fetal serum concentrations of 25-hydroxy vitamin D3, PTH, osteocalcin (OC), crosslaps and maternal serum level of homocysteine, folate, soluble receptor activator of NF-kappaB ligand (sRANKL), osteoprotegerin (OPG), calcium, and phosphate were measured. Measured birth outcome parameters included weight, length, head circumference, appearance, and respiration. With regard to maternal assessment, the serum levels of OC and OPG and folate were significantly higher in group II compared to group I, while the serum levels of RANKL and homocysteine were significantly higher in group I. We did not find significant differences in serum levels of 25-OH vitamin D, PTH, crosslaps, calcium, or phosphate between the two groups. The neonates from mothers recruited in group II had higher (but not significantly) serum level of OC. We observed that the neonates born from mothers in group II had overall better birth outcome parameters and apgar scores compare to the neonates born from mothers in group I. Our results show that daily supplementation of folic acid during pregnancy could have a positive impact on the bone turnover markers in mothers and their newborns. This may suggest that both pregnant mothers and their fetuses could benefit from positive effects of folic acid taken during the whole period of pregnancy.

The A-Z of bacterial translation inhibitors.

Wilson Daniel N
Crit Rev Biochem Mol Biol.2009 Nov-Dec ; 44(6):393-433.
PMID: 19929179[]

2009/11/25

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Protein synthesis is one of the major targets in the cell for antibiotics. This review endeavors to provide a comprehensive "post-ribosome structure" A-Z of the huge diversity of antibiotics that target the bacterial translation apparatus, with an emphasis on correlating the vast wealth of biochemical data with more recently available ribosome structures, in order to understand function. The binding site, mechanism of action, and modes of resistance for 26 different classes of protein synthesis inhibitors are presented, ranging from ABT-773 to Zyvox. In addition to improving our understanding of the process of translation, insight into the mechanism of action of antibiotics is essential to the development of novel and more effective antimicrobial agents to combat emerging bacterial resistance to many clinically-relevant drugs.

Branching Hormone is Busy Both Underground and Overground.

Yamaguchi Shinjiro , Kyozuka Junko
Plant Cell Physiol.2010 Jul ; 51(7):1091-4.
PMID: 20621958[]

2010/07/12

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Anxiety and depressive symptoms in Fibromyalgia are related to low health esteem but not to pain sensitivity or cerebral processing of pain.

Jensen Karin B , Petzke Frank , Carville Serena , Fransson Peter , Marcus Hanke , Williams Steven C R , Choy Ernest , Mainguy Yves , Gracely Richard , Ingvar Martin , Kosek Eva
Arthritis Rheum.2010 Jul 8 ; ():.
PMID: 20617526[]

2010/07/09

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OBJECTIVES:: Mood disturbance is common in patients with Fibromyalgia syndrome (FM) but the influence of psychological symptoms on pain processing in this disorder is unknown. We investigated the differential impact of depressive symptoms, anxiety and catastrophizing on; a) pain symptoms and subjective ratings of general health status; b) sensitivity to pain and cerebral processing of pressure pain. METHODS:: Female FM patients (n=83), mean age 44.2 (SD=8.2), fulfilling the ACR 1990 diagnostic criteria participated. Patients rated pain intensity (VAS), severity of FM (FIQ), general health status (SF-36), depressive symptoms (BDI), anxiety (STAI) and catastrophizing (CSQ). Experimental pain was induced to the thumb using a computer-controlled pressure stimulator. Event-related functional magnetic resonance imaging (fMRI) was performed during individually calibrated painful stimuli representing VAS 50 mm, as well as non-painful pressures. RESULTS:: A correlation analysis including all self-ratings showed that depressive symptoms, anxiety and catastrophizing scores were correlated (p<.001), but did not correlate with ratings of clinical pain, nor with sensitivity to pressure pain. However, the subjective rating of general health was correlated with depressive symptoms and anxiety (p<.001). Results from imaging analyses using self-rated psychological measures as co-variates, showed that brain activity during experimental pain was not modulated by depressive symptoms, anxiety, or catastrophizing. CONCLUSION:: Negative mood in FM patients can lead to a poor perception of one's physical health (and vice versa) but do not influence the performance in clinical and experimental pain assessments. Our data provide evidence for two partially segregated mechanisms involved in the neural processing of experimental pain and negative affect.

In or out stemness: comparing growth factor signalling in mouse embryonic stem cells and primordial germ cells.

De Felici Massimo , Farini Donatella , Dolci Susanna
Curr Stem Cell Res Ther.2009 May ; 4(2):87-97.
PMID: 19442193[]

2009/05/15

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Embryonic stem (ES) cells do not exist in nature but, usually produced from the inner cell mass (ICM) of the blastocyst, are considered equivalent to ICM cells captured during a short period of transient self-renewal and pluripotency capability. Although, artificial, ES cells represent a formidable model to investigate fundamental aspects of cell stemness and early embryo development. ES cells are indeed the only stem cell type able to indefinite self-renewal and to differentiate into cellular derivates of ectodermal, mesodermal and endodermal lineages. Recent extensive studies have revealed that ES cells maintain self-renewal and pluripotency because of a self-organizing network of transcription factors and intracellular pathways activated by extracellular signalling that together prevent their differentiation and promote their proliferation, and because of epigenetic processes that maintain the chromatin in a plastic differentiation status. Primordial germ cells (PGCs), the embryonic precursors of gametes, because of their unique ability to retain true developmental totipotency, are considered the mother of all stem cells. Despite several similarities with ES cells, they display only transient self-renewal capability and distinct lineage-specific characteristics. In fact, in normal condition PGCs are believed to differentiate into germ cells only, oogonia/oocytes in the female, and prospermatogonia in the male which ultimately produce eggs and sperm, respectively. It is not until the fertilization of the egg or parthenogenesis that the intrinsic germ cell totipotency program is revealed. Many aspects of the extrinsic factors and signalling required for ES cell self-renewal and pluripotency have been identified and dissected. On the other hand, several extrinsic factors controlling PGC development have been identified, but the underlying molecular signalling remains little defined. In the present review, by comparing the available information about signalling elicited by four growth factors such as leukaemia inhibitory factor (LIF), bone morphogenic protein 4 (BMP4), fibroblast growth factor 2 (FGF2) and kit ligand (KL) in mouse ES cells and PGCs, on which most of such studies have been performed, we aimed to give clues for the molecular understanding of the similarities and differences between these two unique cell types and to explain how apparent contradictory properties such as lineage-specific characteristics and pluripotency may coexist within PGCs. The first two growth factors have been demonstrated to control key aspects of the self-renewal and pluripotency of ES cells. BMP4 and KL are known for their crucial role in regulating various process of PGC development in the embryo from the formation of PGC precursors and PGC specification (BMP4) to their survival, proliferation and migration (KL). Moreover, the combined action of LIF, FGF2 and KL is necessary and sufficient for PGC transformation into ES-like cells termed embryonic germ (EG) cells.

Low density lipoprotein receptor-related protein 5 (LRP5) mutations and osteoporosis, impaired glucose metabolism and hypercholesterolaemia.

Saarinen Anne , Saukkonen Tero , Kivelä Tero , Lahtinen Ulla , Laine Christine , Somer Mirja , Toiviainen-Salo Sanna , Cole William G , Lehesjoki Anna-Elina , Mäkitie Outi
Clin Endocrinol (Oxf).2010 Apr ; 72(4):481-8.
PMID: 19673927[]

2010/05/07

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OBJECTIVE: Mutations in the low-density lipoprotein receptor-related protein 5 gene (LRP5) underlie osteoporosis-pseudoglioma syndrome. Animal models implicate a role for LRP5 in lipid and glucose homeostasis. The objective was to evaluate metabolic consequences of LRP5 mutations in humans. DESIGN AND PATIENTS: Thirteen Finnish individuals with homozygous or heterozygous LRP5 mutations were assessed for bone health, glucose and lipid metabolism, and for serum serotonin concentration. Results were compared with findings in family members without mutations. MEASUREMENTS: Bone mineral density (BMD), vertebral morphology, oral and intravenous glucose tolerance tests, lipid profile and serum serotonin concentrations. RESULTS: Two individuals were homozygous for R570W, one compound heterozygous for R570W and R1036Q, and 10 were heterozygous (six for R570W, three for R1036Q and one for R925C). Subjects with two LRP5 mutations had multiple spinal fractures and low BMD. Subjects with one mutation had significantly lower median lumbar spine (P = 0.004) and femoral neck (P = 0.005) BMD Z-scores, and more often vertebral fractures than the 18 individuals without mutations. Of the 12 subjects with LRP5 mutation six had diabetes and one had impaired glucose tolerance. Intravenous glucose tolerance tests suggested impaired beta-cell function; no insulin resistance was observed. Prevalence of hypercholesterolaemia was similar in mutation positive and negative subjects. Serum serotonin concentrations showed a trend towards higher concentrations in subjects with LRP5 mutation. CONCLUSIONS: We found high prevalence of osteoporosis and abnormal glucose metabolism in subjects with LRP5 mutation(s). Further studies are needed to establish the role of LRP5 in glucose and lipid metabolism.

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Low density lipoprotein receptor-related protein 5 (LRP5) mutations and osteoporosis, impaired glucose metabolism and hypercholesterolaemia.

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Toll-like Receptor 2 Signaling in CD4(+) T Lymphocytes Promotes T Helper 17 Responses and Regulates the Pathogenesis of Autoimmune Disease.

Reynolds Joseph M , Pappu Bhanu P , Peng Juan , Martinez Gustavo J , Zhang Yongliang , Chung Yeonseok , Ma Li , Yang Xuexian O , Nurieva Roza I , Tian Qiang , Dong Chen
Immunity.2010 Apr 28 ; ():.
PMID: 20434372[]

先週： 15位

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Toll-like receptors (TLRs) have previously been shown to play critical roles in the activation of innate immunity. Here, we describe that T cell expression of TLR2 regulates T helper 17 (Th17) cell responses. Stimulation with TLR2 agonists promoted Th17 differentiation in vitro and led to more robust proliferation and Th17 cytokine production. Using the experimental autoimmune encephalomyelitis (EAE) model, we found that TLR2 regulated Th17 cell-mediated autoimmunity in vivo and that loss of TLR2 in CD4(+) T cells dramatically ameliorated EAE. This study thus reveals a critical role of a TLR in the direct regulation of adaptive immune response and pathogenesis of autoimmune diseases.

Effects of bacterial toxins on endothelial tight junction in vitro: a mechanism-based investigation.

Singh Ashok K , Jiang Yin , Gupta Shveta
Toxicol Mech Methods.2007 ; 17(6):331-47.
PMID: 20020957[]

先週： 14位

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Effects of olmesartan, an angiotensin II receptor blocker, and amlodipine, a calcium channel blocker, on Cardio-Ankle Vascular Index (CAVI) in type 2 diabetic patients with hypertension.

先週： 13位

1,832view,1users

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Identification of Wnt family inhibitors: A pituitary tumor directed whole genome approach.

Elston Marianne S , Clifton-Bligh Roderick J
Mol Cell Endocrinol.2010 Mar 5 ; ():.
PMID: 20211224[]

先週： 12位

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Wnt signaling pathways are important regulators of normal embryological development including that of the pituitary gland. Altered Wnt pathway expression is common in many human tumors however until recently the role of these pathways in human pituitary tumorigenesis has received little attention. The advent of microarray analysis has identified several Wnt pathway inhibitors that are frequently perturbed in pituitary tumors. In this review we summarize the role of these inhibitors in other human tumor types and review the current state of knowledge of Wnt inhibitor expression in pituitary tumors.

RORgamma-expressing Th17 cells induce murine chronic intestinal inflammation via redundant effects of IL-17A and IL-17F.

Leppkes Moritz , Becker Christoph , Ivanov Ivaylo I , Hirth Sebastian , Wirtz Stefan , Neufert Clemens , Pouly Sandrine , Murphy Andrew J , Valenzuela David M , Yancopoulos George D , Becher Burkhard , Littman Dan R , Neurath Markus F
Gastroenterology.2009 Jan ; 136(1):257-67.
PMID: 18992745[]

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BACKGROUND AND AIMS: IL-17-producing CD4(+) T-helper cells (Th17) contribute to chronic autoimmune inflammation in the brain, and levels of Th17-derived cytokines increase in patients with colitis, suggesting a role in pathogenesis. We analyzed the roles of Th17 cells and the transcription factor retinoic acid receptor-related organ receptor (ROR)gamma, which regulates Th17 differentiation, in chronic intestinal inflammation. METHODS: Using an adoptive transfer model of colitis, we compared the colitogenic potential of wild-type, interleukin-17A (IL-17A)-, IL-17F-, IL-22-, and RORgamma-deficient CD4(+)CD25(-) T cells in RAG1-null mice. RESULTS: Adoptive transfer of IL-17A-, IL-17F-, or IL-22-deficient T lymphocytes into RAG1-null mice caused severe colitis that was indistinguishable from that caused by wild-type cells. In contrast, transfer of RORgamma-null T cells failed to increase mucosal IL-17 cytokine levels and did not induce colitis. Treatment with IL-17A was able to restore colitis after transfer of RORgamma-null T cells, indicating a crucial role for Th17 cells in pathogenesis. Treatment of RAG1 mice that received IL-17F-null (but not wild-type) T cells with a neutralizing anti-IL-17A antibody significantly suppressed disease, indicating redundant biological effects of IL-17A and IL-17F. CONCLUSIONS: We have identified a crucial role of RORgamma-expressing Th17 cells in chronic intestinal inflammation. RORgamma controls IL-17A and IL-17F production, and these cytokines have a redundant but highly pathogenic role in gut inflammation. Reagents that target RORgamma or a combination of anti-IL-17A and anti-IL-17F might be developed as therapeutics for chronic colitis.

Enhancement of antigen-specific Treg vaccination in vivo.

Daniel Carolin , Wennhold Kerstin , Kim Hye-Jung , von Boehmer Harald
Proc Natl Acad Sci U S A.2010 Aug 30 ; ():.
PMID: 20805478[]

7view,1users

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2',5,7-Trihydroxy-4',5'-(2,2-dimethylchromeno)-8-(3-hydroxy-3-methylbutyl) flavanone purified from Cudrania tricuspidata induces apoptotic cell death of human leukemia U937 cells.

Rho Yoon-Hwa , Yoon Soo-Hyun , Kim Eun-Kyung , Kang Ji-Young , Lee Byong-Won , Park Ki-Hun , Bae Young-Seuk
Nat Prod Res.2007 Jun ; 21(7):616-24.
PMID: 17613819[]

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Cellular DNA topoisomerase I is an important target in cancer chemotherapy. A chloroform extract of the root barks of Cudrania tricuspidata showed an inhibitory effect on mammalian DNA topoisomerase I. The topoisomerase I inhibitory compound was purified and identified as 2',5,7-trihydroxy-4',5'-(2,2-dimethylchromeno)-8-(3-hydroxy-3-methylbutyl) flavanone. The compound, temporarily designated as PKH-3, was shown to inhibit the activity of topoisomerase I with IC50 about 1.0 mM. Concentration of 10 microM PKH-3 caused 50% growth inhibition of human cancer cell U937. PKH-3-induced cell death was characterized with the cleavage of poly(ADP-ribose) polymerase (PARP) and pro-caspase 3. Furthermore, PKH-3 induced the fragmentation of DNA into multiples of 180 b.p. (an apoptotic DNA ladder), indicating that the inhibitor triggered apoptosis. This induction of apoptosis by PKH-3 was also confirmed using flow cytometry analysis. Taken together, these results suggest that PKH-3 may function by inhibiting oncogenic disease, at least in part, through the inhibition of topoisomerase I activity.

Effects of branched-chain amino acid-enriched nutrient for patients with hepatocellular carcinoma following radiofrequency ablation: A one-year prospective trial.

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The type Ia supernova SNLS-03D3bb from a super-Chandrasekhar-mass white dwarf star.

Howell D Andrew , Sullivan Mark , Nugent Peter E , Ellis Richard S , Conley Alexander J , Le Borgne Damien , Carlberg Raymond G , Guy Julien , Balam David , Basa Stephane , Fouchez Dominique , Hook Isobel M , Hsiao Eric Y , Neill James D , Pain Reynald , Perrett Kathryn M , Pritchet Christopher J
Nature.2006 Sep 21 ; 443(7109):308-11.
PMID: 16988705[]

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The accelerating expansion of the Universe, and the need for dark energy, were inferred from observations of type Ia supernovae. There is a consensus that type Ia supernovae are thermonuclear explosions that destroy carbon-oxygen white dwarf stars that have accreted matter from a companion star, although the nature of this companion remains uncertain. These supernovae are thought to be reliable distance indicators because they have a standard amount of fuel and a uniform trigger: they are predicted to explode when the mass of the white dwarf nears the Chandrasekhar mass of 1.4 solar masses (M(o)). Here we show that the high-redshift supernova SNLS-03D3bb has an exceptionally high luminosity and low kinetic energy that both imply a super-Chandrasekhar-mass progenitor. Super-Chandrasekhar-mass supernovae should occur preferentially in a young stellar population, so this may provide an explanation for the observed trend that overluminous type Ia supernovae occur only in 'young' environments. As this supernova does not obey the relations that allow type Ia supernovae to be calibrated as standard candles, and as no counterparts have been found at low redshift, future cosmology studies will have to consider possible contamination from such events.

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Red mold dioscorea-induced G2/M arrest and apoptosis in human oral cancer cells.

Hsu Wei-Hsuan , Lee Bao-Hong , Pan Tzu-Ming
J Sci Food Agric.2010 Sep 2 ; ():.
PMID: 20812379[]

2010/09/02

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BACKGROUND: Monascus-fermented products are among the most commonly used traditional food supplements. Dioscorea is known to exhibit anticancer properties. In this study the effects of the ethanol extract of red mold dioscorea (RMDE) on cell proliferation, cell cycle and apoptosis in human oral cancer cells were investigated.RESULTS: RMDE exercised growth inhibition on squamous cell carcinoma-25 (SCC-25) cells. RMDE-mediated G2/M phase arrest was associated with the down-regulation of NF-kappaB, resulting in the inhibition of cyclin B1 and CDK1 expression; this may be the mechanism by which RMDE inhibits cancer cells. Furthermore, the proapoptotic activity of RMDE was revealed by the Annexin V-FITC/PI double-staining assay. In addition, the proapoptotic effect of RMDE was evident by the inhibition of Bax expression in the mitochondria, resulting in the activation of caspase-9 and caspase-3 and subsequent triggering of the mitochondrial apoptotic pathway. RMDE also enhanced caspase-8 activity, indicating the involvement of the death receptor pathway in RMDE-mediated SCC-25 cell apoptosis.CONCLUSION: RMDE treatment inhibited the growth of SCC-25 cells by arresting cell cycle at the G2/M phase and induced apoptosis in a time- and dose-dependent manner. Therefore RMDE may be a good candidate for development as a dietary supplement against oral cancer. Copyright (c) 2010 Society of Chemical Industry.

Peptide vaccine candidates against classical swine fever virus: T cell and neutralizing antibody responses of dendrimers displaying E2 and NS2-3 epitopes.

Monsó Marta , Tarradas Joan , de la Torre Beatriz G , Sobrino Francisco , Ganges Llilianne , Andreu David
J Pept Sci.2010 Sep 2 ; ():.
PMID: 20812373[]

2010/09/02

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Three peptide-based systems integrating B and T antigenic sites of CSFV and displaying the B epitopes in fourfold presentation have been designed and produced, and shown to bring about significant enhancements in immunogenicity over the peptides in monomeric form. Of the different strategies tested for producing the dendrimeric constructs, stepwise SPPS using 3,6-dioxaoctanoic acid as flexible, PEG-like spacer units at the branching points is clearly advantageous, in particular over ligation in solution. The constructs have been used for immunization of domestic pigs, in order to evaluate the protective response induced by each peptide constructs, and to characterize the B- and T-cell response against CSFV in the natural host. Copyright (c) 2010 European Peptide Society and John Wiley & Sons, Ltd.

Twelve-week posttreatment follow-up predicts a sustained virological response to pegylated interferon and ribavirin therapy.

Aghemo Alessio , Rumi Maria Grazia , De Nicola Stella , Colombo Massimo
Hepatology.2010 Sep ; 52(3):1170-1.
PMID: 20812363[]

2010/09/02

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Kirchweger Gina
Int J Cancer.2010 Nov 1 ; 127(9):vi.
PMID: 20812350[]

2010/09/02

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IGF-1 synergizes with BMP7-mediated anabolism in bovine intervertebral disc cells.

Kim Jaesung , Ellman Michael B , An Howard S , van Wijnen Andre J , Borgia Jeffrey A , Im Hee-Jeong
Arthritis Rheum.2010 Sep 1 ; ():.
PMID: 20812336[]

2010/09/02

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OBJECTIVE.: To assess therapeutic benefits for intervertebral disc matrix repair and regeneration, the potential synergism of IGF-1 and BMP7 on bovine spine discs were evaluated, and molecular/cellular mechanisms were elucidated. METHODS.: Bovine nucleus pulposus (NP) cells were treated with BMP7 and IGF-1. The subsequent anabolic effects driven by NP cells were assessed for proteoglycan synthesis by (35)S-sulfate incorporation and accumulation by DMMB assays, respectively. Matrix formation was visualized by particle exclusion assay. Key matrix components and transcription factors were analyzed by real-time PCR to determine the signaling pathways by which IGF-1 suppresses noggin, a potent inhibitor of BMP7. Western blot and nuclear translocalization experiments were performed to assess the activation of SMAD proteins. RESULTS.: Stimulation of bovine NP cells by both IGF-1 and BMP7 greatly potentiates anabolism through complementary and synergistic mechanisms on matrix formation when compared to treatment with either growth factor alone. Exogenously added decoy ligand, noggin attenuates the anabolic effects of BMP7, and noggin is substantially increased by BMP7, suggesting a negative feedback regulatory mechanism. On the other hand, IGF-1 significantly suppresses noggin expression via the PI3K/Akt pathways and thus potentiating BMP7 signaling in bovine NP cells. Upon combination treatment, IGF-1 activates SMAD2, while BMP7 activates SMAD1/5/8 and SMAD3, thus inducing all SMAD signaling pathways and mimicking the combinatorial effects of TGFbeta plus BMP7. CONCLUSION.: Combination growth factor therapy using BMP7 and IGF-1 may have considerable promise in the treatment of spine disc degeneration.

Role of the gut-associated and secondary lymphoid tissue in the induction of chronic colitis.

Takebayashi Koichi , Koboziev Iurii , Ostanin Dmitry V , Gray Laura , Karlsson Fridrik , Robinson-Jackson Sherry A , Kosloski-Davidson Melissa , Dooley Angela Burrows , Zhang Songlin , Grisham Matthew B
Inflamm Bowel Dis.2010 Sep 1 ; ():.
PMID: 20812332[]

2010/09/02

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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).

Competitive dopamine receptor antagonists increase the equiactive cocaine concentration during self-administration.

Norman Andrew B , Norman Mantana K , Tabet Michael R , Tsibulsky Vladimir L , Pesce Amadeo J
Synapse.2010 Sep 1 ; ():.
PMID: 20812328[]

2010/09/02

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Competitive dopamine receptor antagonists increase the rate of cocaine self-administration. As the rate of self-administration at a particular unit dose is determined by the satiety threshold and the elimination half-life (t(1/2)) of cocaine, we investigated whether dopamine receptor antagonists altered these parameters. The plasma cocaine concentration at the time of each self-administration was constant during a session demonstrating that this satiety threshold concentration represents an equiactive cocaine concentration. The plasma cocaine concentration at the time of self-administration was increased by SCH23390, consistent with pharmacological theory. In rats trained to reliably self-administer cocaine, SCH23390 had no effect on the plasma steady-state cocaine concentration produced by constant infusions of cocaine. Therefore, this antagonist had no effect on cocaine t(1/2) at a dose that accelerated cocaine self-administration. A continuous cocaine infusion at a rate that maintained steady state concentrations above the satiety threshold stopped self-administration. SCH23390, or the D(2) dopamine receptor antagonist (-)eticlopride, reinstated self-administration in the presence of the constant cocaine infusion. This is consistent with SCH23390 and eticlopride raising the satiety threshold above the steady state level produced by the constant cocaine infusion. It is concluded that the antagonist-induced acceleration of cocaine self-administration is the result of a pharmacokinetic/pharmacodynamic interaction whereby the rate of cocaine elimination is faster at the higher concentrations, as dictated by first-order kinetics, so that cocaine levels decline more rapidly to the elevated satiety threshold. This results in the decreased inter-injection intervals. Synapse, 2010. (c) 2010 Wiley-Liss, Inc.

Large-scale, long-term nonadiabatic electron molecular dynamics for describing material properties and phenomena in extreme environments.

Jaramillo-Botero Andres , Su Julius , Qi An , Goddard William A
J Comput Chem.2010 Sep 1 ; ():.
PMID: 20812325[]

2010/09/02

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We describe the first principle-based electron force field (eFF) methodology for modeling the simultaneous dynamics of electrons and nuclei (eMD) evolving nonadiabatically under transient extreme conditions. We introduce the parallel implementation of eFF (pEFF) that makes it practical to perform simulations of the nonadiabatic dynamics of materials in extreme environments involving millions of nuclei and electrons, over multi-picoseconds time scales, and demonstrate its application to: (i) accurately determine density and predict percent ionization of hydrogen at high pressure ( approximately 61 GPa) and temperatures up to 15,300 K and (ii) determine, the single shock Hugoniot for lithium metal directly from the shock wave kinematics, i.e., mass velocities (U(p)) and shock wave velocities (U(s)), and shock density data. For (i), the density and ionization fractions of hydrogen atoms were calculated using the isobaric-isothermal ensemble at an isotropic pressure of 61.4 GPa and for temperatures between 300 K and 15,300 K. The results at 15,300 K describe a molecular fluid with density rho = 0.36 g/cm(3), in close agreement with existing experiments and theory, and approximately 0.5% ionization. This result provides no indication of the existence of a critical plasma phase-transition point at this particular temperature and pressure, as previously predicted by others. For (ii), the relationship between U(p) and U(s) was characterized to be linear and plastic in the range 1-20 km/s, and the single shock Hugoniot was determined in close agreement with published results for experimentally reported U(p)s. In addition to this, we provide a description of the materials' behavior for large U(p)s in terms of the appearance of a weak metallic plasma phase by U(p) = 10 km/s, with approximately 8% ionization, gradually transitioning to a denser plasma with an estimated approximately 35% ionization by U(p) = 15 km/s. Last but not least, we confirm the computational efficiency and scalability of pEFF by comparing its single processor performance against the fastest existing serial code, which results in a linear speedup approximately 10x faster for every 16,000 particles in favor of pEFF, and by evaluating its parallel performance in terms of its strong and weak scaling capabilities. Our results, on Los Alamos's Lobo supercomputer (a 38TFLOPSs Linux HPC with Quad-core AMD Opteron nodes interconnected with an Infiniband), show strong scaling with near ideal speedups for loads >62 particles per processor. Weak scaling is shown to be close to linear under the same per-processor load range. As an absolute reference, an NVT run with 2 million particle lithium bulk system (0.5 M nuclei and 1.5 M electrons) on Lobo takes approximately 0.44 s/timestep on 1024 processors ( approximately 1 day/ps using an integration timestep of 0.005 fs). (c) 2010 Wiley Periodicals, Inc. J Comput Chem, 2010.

Increased natural killer cell cytotoxicity and NKp30 expression protects against hepatitis C virus infection in high-risk individuals and inhibits replication in vitro.

Golden-Mason Lucy , Cox Andrea L , Randall Jessica A , Cheng Linling , Rosen Hugo R
Hepatology.2010 Aug 19 ; ():.
PMID: 20812318[]

2010/09/02

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CD56(pos) natural killer (NK)/natural T (NT) cells are important innate effectors providing the first line of defense against viral infection. Enhanced NK activity has been shown to protect from human immunodeficiency virus-1 infection. However, the role played by these innate effectors in protection against or development of hepatitis C virus (HCV) infection is unknown. We characterized CD56(pos) populations in 11 injection drug users (IDUs) who remained uninfected despite being repeatedly exposed to HCV. NK profiles in exposed but uninfected (EU) individuals were compared with preinfection samples (median 90 days prior to HCV seroconversion) collected from 14 IDUs who were exposed and subsequently became infected (EI) and unexposed normal control subjects (n = 8). Flow cytometric analysis of CD56(pos) populations demonstrated that EUs had a higher proportion of CD56(low) mature (P = 0.0011) NK cells compared with EI subjects. Bead-isolated NKs (>90% purity) from EUs had significantly higher interleukin-2 (IL-2)-induced cytolytic activity against the NK-sensitive cell line K562 at an effector-to-target ratio of 10:1 (P < 0.0001). NKp30, a natural cytotoxicity receptor involved in NK activation, is highest on NK/NT cells in EUs relative to infected subjects. Using the JFH-1 infection system, we demonstrated that NKp30(high) cells in the absence of exogenous stimulation significantly reduce infection of hepatocytes. Conclusion: CD56(pos) populations in EUs are enriched for effector NKs displaying enhanced IL-2-induced cytolytic activity and higher levels of the natural cytotoxicity receptor NKp30-activating receptor. In addition, NKp30(high) cells are more effective in preventing infection of Huh-7.5 cells than their NKp30(low/neg) counterparts. These data support the hypothesis that NK cells contribute to anti-HCV defense in vivo in the earliest stages of infection, providing innate protection from HCV acquisition. (HEPATOLOGY 2010).

Ion Dynamics in Confined Spaces: Sodium Ion Mobility in Icosahedral Container Molecules.

Podewitz Maren , van Beek Jacco D , Wörle Michael , Ott Timo , Stein Daniel , Rüegger Heinz , Meier Beat H , Reiher Markus , Grützmacher Hansjörg
Angew Chem Int Ed Engl.2010 Sep 1 ; ():.
PMID: 20812315[]

2010/09/02

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Disease-corrected haematopoietic progenitors from Fanconi anaemia induced pluripotent stem cells.

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