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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[]

191view,2,634users 保存 要約 閉じる

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.

Applications of finite element simulation in orthopedic and trauma surgery.

Herrera Antonio , Ibarz Elena , Cegoñino José , Lobo-Escolar Antonio , Puértolas Sergio , López Enrique , Mateo Jesús , Gracia Luis
World J Orthop.2012 Apr 18 ; 3(4):25-41.
PMID: 22550621[]

152view,0users 保存 要約 閉じる

Research in different areas of orthopedic and trauma surgery requires a methodology that allows both a more economic approach and the ability to reproduce different situations in an easy way. Simulation models have been introduced recently in bioengineering and could become an essential tool in the study of any physiological unity, regardless of its complexity. The main problem in modeling with finite elements simulation is to achieve an accurate reproduction of the anatomy and a perfect correlation of the different structures, in any region of the human body. Authors have developed a mixed technique, joining the use of a three-dimensional laser scanner Roland Picza captured together with computed tomography (CT) and 3D CT images, to achieve a perfect reproduction of the anatomy. Finite element (FE) simulation lets us know the biomechanical changes that take place after hip prostheses or osteosynthesis implantation and biological responses of bone to biomechanical changes. The simulation models are able to predict changes in bone stress distribution around the implant, so allowing preventing future pathologies. The development of a FE model of lumbar spine is another interesting application of the simulation. The model allows research on the lumbar spine, not only in physiological conditions but also simulating different load conditions, to assess the impact on biomechanics. Different degrees of disc degeneration can also be simulated to determine the impact on adjacent anatomical elements. Finally, FE models may be useful to test different fixation systems, i.e., pedicular screws, interbody devices or rigid fixations compared with the dynamic ones. We have also developed models of lumbar spine and hip joint to predict the occurrence of osteoporotic fractures, based on densitometric determinations and specific biomechanical models, including approaches from damage and fracture mechanics. FE simulations also allow us to predict the behavior of orthopedic splints applied to the correction of deformities, providing the recovering force-displacement and angle-moment curves that characterize the mechanical behavior of the splint in the overall range of movement.

Quality, patient safety, and the board.

Curran Connie R , Totten Mary K
Nurs Econ.2010 Jul-Aug ; 28(4):273-5.
PMID: 21761613[]

133view,3,464users 保存 要約 閉じる

It is now broadly recognized that good outcomes for patients depend on more than a clinician's knowledge and skills and use of proven, effective practices or evidence-based medicine. Good outcomes also depend on the organization's culture, which affects how well providers and patients work together. Boards play a key role in helping their hospitals improve the quality and safety of the care they deliver--a governance imperative to ensure hospitals meet the needs of key stakeholders and perform effectively in an environment of reform. Nurse leaders who understand this key board responsibility will be better prepared to serve on boards and contribute to effective governance.

An Atopic Dermatitis-Like Skin Disease with Hyper-IgE-Emia Develops in Mice Carrying a Spontaneous Recessive Point Mutation in the Traf3ip2 (Act1/CIKS) Gene.

Matsushima Yoshibumi , Kikkawa Yoshiaki , Takada Toyoyuki , Matsuoka Kunie , Seki Yuta , Yoshida Hisahiro , Minegishi Yoshiyuki , Karasuyama Hajime , Yonekawa Hiromichi
J Immunol.2010 Jul 21 ; ():.
PMID: 20660351[]

130view,13users 保存 要約 閉じる

Spontaneous mutant mice that showed high levels of serum IgE and an atopic dermatitis (AD)-like skin disease were found in a colony of the KOR inbred strain that was derived from Japanese wild mice. No segregation was observed between hyper-IgE-emia and dermatitis in (BALB/c x KOR mutant) N(2) mice, suggesting that the mutation can be attributed to a single recessive locus, which we designated adjm (atopic dermatitis from Japanese mice). All four adjm congenic strains in different genetic backgrounds showed both hyper-IgE-emia and dermatitis, although the disease severity varied among strains. Linkage analysis using (BALB/c x KOR-adjm/adjm) N(2) mice restricted the potential adjm locus to the 940 kb between D10Stm216 and D10Stm238 on chromosome 10. Sequence analysis of genes located in this region revealed that the gene AI429613, which encodes the mouse homologue of the human TNFR-associated factor 3-interacting protein 2 (TRAF3IP2) protein (formerly known as NF-kappaB activator 1/connection to IkappaB kinase and stress-activated protein kinase/Jun kinase), carried a single point mutation leading to the substitution of a stop codon for glutamine at amino acid position 214. TRAF3IP2 has been shown to function as an adaptor protein in signaling pathways mediated by the TNFR superfamily members CD40 and B cell-activating factor in epithelial cells and B cells as well as in the IL-17-mediated signaling pathway. Our results suggest that malfunction of the TRAF3IP2 protein causes hyper-IgE-emia through the CD40- and B cell-activating factor-mediated pathway in B cells and causes skin inflammation through the IL-17-mediated pathway. This study demonstrates that the TRAF3IP2 protein plays an important role in AD and suggests the protein as a therapeutic target to treat AD.

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[]

99view,5users 保存 要約 閉じる

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.

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[]

98view,37users 保存 要約 閉じる

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.

An update of the mechanisms of resistance to EGFR-tyrosine kinase inhibitors in breast cancer: Gefitinib (Iressa) -induced changes in the expression and nucleo-cytoplasmic trafficking of HER-ligands (Review).

Ferrer-Soler Laura , Vazquez-Martin Alejandro , Brunet Joan , Menendez Javier A , De Llorens Rafael , Colomer Ramon
Int J Mol Med.2007 Jul ; 20(1):3-10.
PMID: 17549382[]

96view,0users 保存 要約 閉じる

Intrinsic resistance to the epidermal growth factor receptor (EGFR; HER1) tyrosine kinase inhibitor (TKI) gefitinib, and more generally to EGFR TKIs, is a common phenomenon in breast cancer. The availability of molecular criteria for predicting sensitivity to EGFR-TKIs is, therefore, the most relevant issue for their correct use and for planning future research. Though it appears that in non-small-cell lung cancer (NSCLC) response to gefitinib is directly related to the occurrence of specific mutations in the EGFR TK domain, breast cancer patients cannot be selected for treatment with gefitinib on the same basis as such EGFR mutations have been reported neither in primary breast carcinomas nor in several breast cancer cell lines. Alternatively, there is a general agreement on the hypothesis that the occurrence of molecular alterations that activate transduction pathways downstream of EGFR (i.e., MEK1/MEK2 right curved arrow ERK1/2 MAPK and PI-3'K right curved arrow AKT growth/survival signaling cascades) significantly affect the response to EGFR TKIs in breast carcinomas. However, there are no studies so far addressing a role of EGF-related ligands as intrinsic breast cancer cell modulators of EGFR TKI efficacy. We recently monitored gene expression profiles and sub-cellular localization of HER-1/-2/-3/-4 related ligands (i.e., EGF, amphiregulin, transforming growth factor-alpha, beta-cellulin, epiregulin and neuregulins) prior to and after gefitinib treatment in a panel of human breast cancer cell lines. First, gefitinib-induced changes in the endogenous levels of EGF-related ligands correlated with the natural degree of breast cancer cell sensitivity to gefitinib. While breast cancer cells intrinsically resistant to gefitinib (IC50 > or =15 microM) markedly up-regulated (up to 600 times) the expression of genes codifying for HER-specific ligands, a significant down-regulation (up to 10(6) times) of HER ligand gene transcription was found in breast cancer cells intrinsically sensitive to gefitinib (IC50 < or =1 microM). Second, loss of HER1 function differentially regulated the nuclear trafficking of HER-related ligands. While gefitinib treatment induced an active import and nuclear accumulation of the HER ligand NRG in intrinsically gefitinib-resistant breast cancer cells, an active export and nuclear loss of NRG was observed in intrinsically gefitinib-sensitive breast cancer cells. In summary, through in vitro and pharmacodynamic studies we have learned that, besides mutations in the HER1 gene, oncogenic changes downstream of HER1 are the key players regulating gefitinib efficacy in breast cancer cells. It now appears that pharmacological inhibition of HER1 function also leads to striking changes in both the gene expression and the nucleo-cytoplasmic trafficking of HER-specific ligands, and that this response correlates with the intrinsic degree of breast cancer sensitivity to the EGFR TKI gefitinib. The relevance of this previously unrecognized intracrine feedback to gefitinib warrants further studies as cancer cells could bypass the antiproliferative effects of HER1-targeted therapeutics without a need for the overexpression and/or activation of other HER family members and/or the activation of HER-driven downstream signaling cascades.

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[]

88view,11users 保存 要約 閉じる

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.

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[]

63view,0users 保存 要約 閉じる

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.

A sensitive fluorescence strategy for telomerase detection in cancer cells based on T7 exonuclease-assisted target recycling amplification.

Wang Hai-Bo , Wu Shuang , Chu Xia , Yu Ru-Qin
Chem Commun (Camb).2012 May 4 ; ():.
PMID: 22558640[]

63view,0users 保存 要約 閉じる

A sensitive fluorescence strategy based on T7 exonuclease-assisted target recycling amplification was developed for telomerase detection in cancer cells. The novel strategy improved the fluorescence signal and sensitivity compared with the previously reported methods.

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週間人気論文ランキング - 保存数 (2012/05/12/ 06時更新)

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Germinal center B and follicular helper T cells: siblings, cousins or just good friends?

Nutt Stephen L , Tarlinton David M
Nat Immunol.2011 Jun ; 12(6):472-7.
PMID: 21739669[]

40view,4,073users 保存 要約 閉じる

Humoral immunity requires interaction between specialized populations of B cells and CD4(+) T cells, called follicular helper T cells (T(FH) cells), in the germinal center (GC) to produce memory B cells and long-lived plasma cells. Molecular crosstalk between GC B cells and T(FH) cells influences the survival, proliferation and differentiation of each cell type. This pairing of GC B cells and T(FH) cells also occurs at the transcriptional level as the Bcl-6–IRF4–Blimp-1 axis, which is crucial for B cell differentiation, is also essential for the T(FH) cell identity. Less is known about the memory B cells that arise from the GC pool, as they seem to be distinctly 'programmed' on the basis of their antigen receptor affinity to enter the long-lived memory pool.

Contribution of chymase-dependent angiotensin II formation to the progression of tubulointerstitial fibrosis in obstructed kidneys in hamsters.

Fan Yu-Yan , Nishiyama Akira , Fujisawa Yoshihide , Kobori Hiroyuki , Nakano Daisuke , Matsuura Junji , Hase Naoki , Hitomi Hirofumi , Kiyomoto Hideyasu , Urata Hidenori , Kohno Masakazu
J Pharmacol Sci.2009 Sep ; 111(1):82-90.
PMID: 19721329[]

23view,3,760users 保存 要約 閉じる

Recent studies indicate a role of chymase in the regulation of angiotensin II (AngII) formation in cardiovascular and renal tissues. We investigated a possible contribution of chymase to AngII formation and to renal fibrosis in unilateral ureteral obstruction (UUO). Eight-week-old Syrian hamsters were subjected to UUO and treated with vehicle, the specific chymase inhibitor (CI) 4-[1-(4-methyl-benzo[b]thiophen-3-ylmethyl)-1H-benzimidazol-2-ylsulfanyl]-butyric acid (50 mg/kg, twice a day, p.o.), or the selective AT(1)-receptor blocker olmesartan (10 mg/kg per day, p.o.) for 14 days. UUO-induced renal interstitial fibrosis was associated with increases in renal mRNA levels of alpha-smooth muscle actin (SMA), type I collagen, and transforming growth factor (TGF)-beta. The UUO hamsters showed markedly higher AngII contents and increased AT(1)-receptor mRNA level in the obstructed kidney than sham-operated ones. In contrast, angiotensin-converting enzyme (ACE) protein expression was significantly lower in UUO hamsters. In UUO hamsters, treatment with CI or olmesartan significantly decreased AngII levels in renal tissue and mRNA levels of alpha-SMA, type I collagen, and TGF-beta and ameliorated tubulointerstitial injury. On the other hand, neither CI nor olmesartan changed systolic blood pressure, renal ACE, and AT(1)-receptor protein levels. These data suggest that chymase-dependent intrarenal AngII formation contributes to the pathogenesis of interstitial fibrosis in obstructed kidneys of hamsters.

Quality, patient safety, and the board.

Curran Connie R , Totten Mary K
Nurs Econ.2010 Jul-Aug ; 28(4):273-5.
PMID: 21761613[]

133view,3,464users 保存 要約 閉じる

It is now broadly recognized that good outcomes for patients depend on more than a clinician's knowledge and skills and use of proven, effective practices or evidence-based medicine. Good outcomes also depend on the organization's culture, which affects how well providers and patients work together. Boards play a key role in helping their hospitals improve the quality and safety of the care they deliver--a governance imperative to ensure hospitals meet the needs of key stakeholders and perform effectively in an environment of reform. Nurse leaders who understand this key board responsibility will be better prepared to serve on boards and contribute to effective governance.

Anthocyanins in cardiovascular disease.

Wallace Taylor C
Adv Nutr (Bethesda).2011 Jan ; 2(1):1-7.
PMID: 22211184[]

28view,2,785users 保存 要約 閉じる

Anthocyanins are a group of abundant and widely consumed flavonoid constituents that occur ubiquitously in the plant kingdom, providing the bright red-orange to blue-violet colors present in many fruit- and vegetable-based food products. Their intake has been estimated to be up to 9-fold higher than that of other dietary flavonoids. Anthocyanins have become increasingly important to the food industry as their use as natural alternatives to artificial colors has become widespread and knowledge of their health-promoting properties has become more evident. Epidemiological studies suggest that increased consumption of anthocyanins lowers the risk of cardiovascular disease (CVD), the most common cause of mortality among men and women. Anthocyanins frequently interact with other phytochemicals, exhibiting synergistic biological effects but making contributions from individual components difficult to decipher. Over the past 2 decades, many peer-reviewed publications have demonstrated that in addition to their noted in vitro antioxidant activity, anthocyanins may regulate different signaling pathways involved in the development of CVD. This review summarizes the latest developments on the bioavailability/bioactivity and CVD preventative activities of anthocyanins, including results from in vitro cell culture and in vivo animal model systems as related to their multiple proposed mechanisms of action. Limited yet promising data from epidemiological studies and human clinical trials are also presented. Future studies aimed at enhancing the absorption of anthocyanins and characterizing their metabolic and/or breakdown products are necessary to ultimately evaluate their use for protection/prevention against the development of CVD.

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[]

191view,2,634users 保存 要約 閉じる

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.

Hospitals, providers collaborate on transitions.

Hosp Case Manag.2012 Jan ; 20(1):11-2.
PMID: 22263244[]

21view,2,527users 保存 要約 閉じる

Baystate Health, a three-hospital system with headquarters in Springfield, MA, is partnering with post-acute providers to improve transitions as patients move through the continuum of care. A multidisciplinary post-acute performance team partnered with post-acute providers to determine why patients are readmitted to the hospital and to work on ways to avoid readmissions. Facilities share information with the hospitals how they operate and what they need to ensure patients receive the care they need. The health system's director of post-acute services holds regular meetings with providers to brainstorm on improving patient care.

The RNase III enzyme Dicer is essential for germinal center B-cell formation.

Xu Shengli , Guo Ke , Zeng Qi , Huo Jianxin , Lam Kong-Peng
Blood.2011 Nov 23 ; ():.
PMID: 22117047[]

25view,2,097users 保存 要約 閉じる

MicroRNAs (miRNAs) are short non-coding RNAs that regulate gene expression and are important for pre-B and follicular B lymphopoiesis as demonstrated respectively, by mb-1-Cre- and cd19-Cre-mediated deletion of Dicer, the RNase III enzyme critical for generating mature miRNAs. To explore the role of miRNAs in B cell terminal differentiation, we use Aicda-Cre to specifically delete Dicer in activated B cells where activation-induced cytidine deaminase (AID) is highly expressed. We demonstrate that mutant mice fail to produce high-affinity class-switched antibodies and generate memory B and long-lived plasma cells (PCs) upon immunization with a T cell-dependent antigen. More importantly, germinal center (GC) B cell formation is drastically compromised in the absence of Dicer, as a result of defects in cell proliferation and survival. Dicer-deficient GC B cells express higher levels of cell cycle inhibitor genes and proapoptotic protein Bim. Ablation of Bim could partially rescue the defect in GC B cell formation in Dicer-deficient mice. Taken together, our data suggest that Dicer and likely, miRNAs are critical for GC B cell formation during B cell terminal differentiation.

Characteristics of Oral Mucosal Events Related to Bevacizumab Treatment.

Gavrilovic Igor T , Balagula Yevgeniy , Rosen Alyx C , Ramaswamy Vijay , Dickler Maura N , Dunkel Ira J , Lacouture Mario E
Oncologist.2012 Jan 26 ; ():.
PMID: 22282905[]

19view,1,514users 保存 要約 閉じる

AbstractBackground. Bevacizumab, a monoclonal antibody targeting a vascular endothelial growth factor (VEGF) protein, has been reported to induce mucosal toxicities. However, the clinical characteristics of these particular toxicities have not been well characterized. We aimed at providing a detailed clinical description of signs and symptoms limited to the tongue mucosa in patients treated with bevacizumab.Methods. A retrospective review of medical records and clinical photographs was performed with specific attention to clinical presentation, evolution, associated symptoms, concomitant medications, and treatment methods.Results. In total, four patients presented to the dermatology service with clinical findings characterized by multifocal, erythematous circinate and serpiginous erosions on the dorsal tongue surrounded by white hyperkeratotic rims that were temporally related to bevacizumab therapy. Associated increased sensitivity to spicy foods was frequently observed.Conclusion. These characteristic clinical findings are consistent with geographic tongue. However, large prospective evaluations are necessary to confirm this potential relationship. If bevacizumab is indeed associated with geographic tongue, increased awareness may result in improved reporting and characterization of this particular adverse event.

Ultra-performance liquid chromatography-tandem mass spectrometry method for the determination of nitrendipine in dog plasma and its application to a pharmacokinetic study of a solid self-emulsifying pellet formulation.

Liu Yanhua , Wang Zhiyuan , Sun Jin , Wang Yongjun , He Zhonggui
Arzneimittelforschung.2011 ; 61(12):674-80.
PMID: 22282953[]

26view,1,444users 保存 要約 閉じる

A rapid, sensitive and selective ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) method was developed and validated for the quantitative determination of nitrendipine (NTD, CAS 39562-70-4) in dog plasma. Using propranolol hydrochloride (CAS 318-98-9) as an internal standard (IS), plasma samples pretreatment adopted a simple liquid-liquid extraction process with diethyl ether. Separation was carried out by a gradient elution on an Acquity UPLC BEH C18 column with a mobile phase consisting of water (containing 0.1% formic acid) and acetonitrile. Detection was performed by a triple-quadrupole mass spectrometry with positive electrospray ionization (ESI) as source ionization in multiple-reaction monitoring (MRM) mode at m/z 361.0 --> 315.0 for NTD and m/z 260.2 --> 116.0 for IS. The method demonstrated good linearity at the concentrations ranged from 0.1-200 ng/mL and the lower limit of quantification (LLOQ) of NTD was 0.1 ng/mL. The intra- and inter-day relative standard deviations (RSD) were less than 10%. The mean extraction recoveries of NTD and IS were 90.2% and 82.4%, respectively. Finally, the method was successfully applied to a pharmacokinetic study of home-made solid self-emulsifying pellets and conventional NTD tablets in beagle dogs following a single oral administration.

Origins of CD4(+) effector and central memory T cells.

Pepper Marion , Jenkins Marc K
Nat Immunol.2011 Jun ; 12(6):467-71.
PMID: 21739668[]

30view,1,107users 保存 要約 閉じる

Lineage-committed effector CD4(+) T cells are generated at the peak of the primary response and are followed by heterogeneous populations of central and effector memory cells. Here we review the evidence that T helper type 1 (T(H)1) effector cells survive the contraction phase of the primary response and become effector memory cells. We discuss the applicability of this idea to the T(H)2 cell, T(H)17 helper T cell, follicular helper T cell (T(FH) cell) and induced regulatory T cell lineages. We also discuss how central memory cells are formed, with an emphasis on the role of B cells in this process.

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週間人気ジャーナルランキング - 閲覧数 (2012/05/12/ 07時更新)

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The Journal of biological chemistry

9,674view , 483users

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

5,900view , 289users

PloS one

4,648view , 1,169users

Journal of immunology (Baltimore, Md. : 1950)

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Blood

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Meta-Analysis of Efficacy and Safety of New Oral Anticoagulants (Dabigatran, Rivaroxaban, Apixaban) Versus Warfarin in Patients With Atrial Fibrillation.

Miller Corey S , Grandi Sonia M , Shimony Avi , Filion Kristian B , Eisenberg Mark J
Am J Cardiol.2012 Apr 24 ; ():.
PMID: 22537354[]

2012/04/27 保存 要約 閉じる

New oral anticoagulants, including apixaban, dabigatran, and rivaroxaban, have been developed as alternatives to warfarin, the standard oral anticoagulation therapy for patients with atrial fibrillation (AF). A systematic review and meta-analysis of randomized controlled trials was performed to compare the efficacy and safety of new oral anticoagulants to those of warfarin in patients with AF. The published research was systematically searched for randomized controlled trials of >1 year in duration that compared new oral anticoagulants to warfarin in patients with AF. Random-effects models were used to pool efficacy and safety data across randomized controlled trials. Three studies, including 44,563 patients, were identified. Patients randomized to new oral anticoagulants had a decreased risk for all-cause stroke and systemic embolism (relative risk [RR] 0.78, 95% confidence interval [CI] 0.67 to 0.92), ischemic and unidentified stroke (RR 0.87, 95% CI 0.77 to 0.99), hemorrhagic stroke (RR 0.45, 95% CI 0.31 to 0.68), all-cause mortality (RR 0.88, 95% CI 0.82 to 0.95), and vascular mortality (RR 0.87, 95% CI 0.77 to 0.98). Randomization to a new oral anticoagulant was associated with a lower risk for intracranial bleeding (RR 0.49, 95% CI 0.36 to 0.66). Data regarding the risks for major bleeding (RR 0.88, 95% CI 0.71 to 1.09) and gastrointestinal bleeding (RR 1.25, 95% CI 0.91 to 1.72) were inconclusive. In conclusion, the new oral anticoagulants are more efficacious than warfarin for the prevention of stroke and systemic embolism in patients with AF. With a decreased risk for intracranial bleeding, they appear to have a favorable safety profile, making them promising alternatives to warfarin.

Saccade abnormalities in autopsy-confirmed frontotemporal lobar degeneration and Alzheimer disease.

Boxer Adam L , Garbutt Siobhan , Seeley William W , Jafari Aria , Heuer Hilary W , Mirsky Jacob , Hellmuth Joanna , Trojanowski John Q , Huang Erik , Dearmond Steven , Neuhaus John , Miller Bruce L
Arch Neurol.2012 Apr ; 69(4):509-17.
PMID: 22491196[]

2012/04/11 保存 要約 閉じる

Deficits in the generation and control of saccades have been described in clinically defined frontotemporal dementia (FTD) and Alzheimer disease (AD).

Exposure of luminal membranes of LLC-PK1 cells to ANG II induces dimerization of AT1/AT2 receptors to activate SERCA and to promote Ca2+ mobilization.

Ferrão Fernanda M , Lara Lucienne Silva , Axelband Flavia , Dias Juliana , Carmona Adriana K , Reis Rosana I , Costa-Neto Claudio M , Vieyra Adalberto , Lowe Jennifer
Am J Physiol Renal Physiol.2012 Jan 4 ; ():.
PMID: 22218590[]

2012/01/05 保存 要約 閉じる

ANG II is secreted into the lumen of proximal tubules where it is also synthesized, thus increasing the local concentration of the peptide to levels of potential physiological relevance. In the present work we studied the effect of ANG II via the luminal membranes of LLC-PK(1) cells on Ca(2+)-ATPase of the sarco(endo)plasmic reticulum (SERCA) and plasma membrane (PMCA). ANG II (at concentrations found in the lumen) stimulated rapid (30 s) and persistent (30 min) SERCA activity by more than 100% and increased Ca(2+) mobilization. Pretreatment with ANG II for 30 min enhanced the ANG II-induced Ca(2+) spark, demonstrating a positively self-sustained stimulus of Ca(2+) mobilization by ANG II. ANG II in the medium facing the luminal side of the cells decreased with time with no formation of metabolites, indicating peptide internalization. ANG II increased heterodimerization of AT(1) and AT(2) receptors by 140%, and either losartan or PD123319 completely blocked the stimulation of SERCA by ANG II. Using the PLC inhibitor U73122, PMA and calphostin C it was possible to demonstrate the involvement of a PLC→DAG(PMA)→PKC pathway in the stimulation of SERCA by ANG II with no effect on PMCA. We conclude that ANG II triggers SERCA activation via the luminal membrane, increasing the Ca(2+) stock in the reticulum to ensure a more efficient subsequent mobilization of Ca(2+). This first report on the regulation of SERCA activity by ANG II shows a new mechanism for Ca(2+) homeostasis in renal cells and also for regulation of Ca(2+)-modulated fluid reabsorption in proximal tubules.

Cetuximab-based or bevacizumab-based first-line treatment in patients with KRAS p.G13D-mutated metastatic colorectal cancer: a pooled analysis.

Modest Dominik Paul , Reinacher-Schick Anke , Stintzing Sebastian , Giessen Clemens , Tannapfel Andrea , Laubender Ruediger Paul , Brodowicz Thomas , Knittelfelder Regina , Vrbanec Damir , Schmiegel Wolff , Heinemann Volker , Zielinski Christoph C
Anticancer Drugs.2012 Mar 21 ; ():.
PMID: 22441566[]

2012/03/23 保存 要約 閉じる

KRAS p.G13D mutant metastatic colorectal cancer (mCRC) has been identified as representing a cetuximab-sensitive subtype of KRAS mutant mCRC. This analysis aims to answer the question of whether first-line treatment of p.G13D mCRCs should include cetuximab or bevacizumab. Fifty-four patients with p.G13D mutant mCRC were pooled in this analysis. All patients underwent systemic first-line treatment with a fluoropyrimidine and oxaliplatin/irinotecan that was combined with either cetuximab or bevacizumab. The analysis of cetuximab-based and bevacizumab-based regimens in mCRC patients with p.G13D-mutated tumours indicated comparable data for the overall response rate (58 vs. 57%) and progression-free survival (8.0 vs. 8.7 months; hazard ratio: 0.96, P=0.9). Overall survival (OS) was 20.1 months in patients treated with cetuximab-based first-line therapy compared with 14.9 months in patients receiving bevacizumab-containing regimens (hazard ratio: 0.70, P=0.29). Logistic regressions modelling OS revealed oxaliplatin-based first-line treatment to correlate with a poor outcome (P=0.03). Moreover, a strong trend in favour of capecitabine compared with infusional 5-FU (P=0.06) was observed. Response to treatment correlated with OS in patients receiving cetuximab-based, but not bevacizumab-based regimens. This retrospective pooled analysis suggests comparable efficacy of cetuximab-based and bevacizumab-based first-line therapy in patients with p.G13D mutant mCRC. The combination with capecitabine and irinotecan was associated with a more favourable outcome compared with infusional 5-FU and oxaliplatin.

Efficacy of iloperidone in the short-term treatment of schizophrenia: a post hoc analysis of pooled patient data from four phase III, placebo- and active-controlled trials.

Citrome Leslie , Meng Xiangyi , Hochfeld Marla , Stahl Stephen M
Hum Psychopharmacol.2011 Dec 7 ; ():.
PMID: 22161738[]

2011/12/13 保存 要約 閉じる

OBJECTIVES: The efficacy and tolerability characteristics of an antipsychotic are difficult to determine from a single registration study. We thus conducted an analysis that assessed key efficacy and tolerability outcomes post hoc from four pooled short-term (4-6 weeks) phase III studies that evaluated iloperidone versus placebo in patients with schizophrenia or schizoaffective disorder. METHODS: Patient-level data were pooled from four prospective, randomized, double-blind, placebo-controlled and active-controlled, multicenter trials of iloperidone in patients with schizophrenia or schizoaffective disorder aged 18-65 years. Iloperidone 4-8, 10-16, and 20-24 mg/day (all dosed twice daily) were compared with placebo. Active controls used for assay sensitivity included risperidone 4-8 mg/day, haloperidol 15 mg/day, and ziprasidone 160 mg/day. Outcomes of interest were change from baseline to endpoint in the Brief Psychiatric Rating Scale (derived) (BPRSd), Positive and Negative Syndrome Scale (PANSS)-total (PANSS-T) score, and PANSS-positive (PANSS-P) and PANSS-negative (PANSS-N) subscale scores. An analysis of covariance (with treatment and study as factors, baseline as a covariate) was performed to compare changes between the iloperidone treatment groups versus placebo, on the basis of a last-observation-carried-forward approach for the intent-to-treat (ITT) populations. Tolerability outcomes were obtained from spontaneously reported adverse events (AEs), and number needed to harm was calculated for each antipsychotic versus placebo for the total population. RESULTS: The ITT population included both schizoaffective and schizophrenia patients (N = 2401): n = 370, n = 494, and n = 424 for iloperidone 4-8, 10-16, and 20-24 mg/day, respectively; n = 294 for risperidone; n = 114 for haloperidol; n = 144 for ziprasidone; and n = 561 for placebo. Treatment with iloperidone 10-16 mg/day or 20-24 mg/day was associated with significantly improved BPRSd, PANSS-T, PANSS-P, and PANSS-N scores versus treatment with placebo. When only patients with schizophrenia were included (n = 1941), the pattern of results was essentially unchanged. The active controls confirmed assay sensitivity. Across all iloperidone dose groups, the incidences of extrapyramidal disorders and akathisia were similar to those observed with placebo. AEs for which the frequency was greater for iloperidone than placebo and for which the 95% confidence interval for number needed to harm did not contain infinity were dizziness, dry mouth, somnolence, nasal congestion, fatigue, sedation, and tachycardia; in general, for these AEs, frequency was higher with higher doses, resulting in a lower number needed to harm. CONCLUSIONS: Consistent with product labeling, iloperidone 10-16 mg/day or 20-24 mg/day demonstrated significant improvement over placebo on BPRSd and PANSS-T scores, as well as on PANSS-P and PANSS-N subscale scores over 6 weeks of treatment in patients with schizophrenia and in the ITT population, which includes patients with schizoaffective disorder. Iloperidone did not differ from placebo in terms of extrapyramidal disorders and akathisia. Copyright © 2011 John Wiley & Sons, Ltd.

Social science: Carrot or stick?

Gächter Simon
Nature.2012 Mar 1 ; 483(7387):39-40.
PMID: 22382974[]

2012/03/02 保存 要約はありません

Tocilizumab improves cardiac disease in a hemodialysis patient with AA amyloidosis secondary to rheumatoid arthritis.

Hattori Yoshinari , Ubara Yoshifumi , Sumida Keiichi , Hiramatsu Rikako , Hasegawa Eiko , Yamanouchi Masayuki , Hayami Noriko , Suwabe Tatsuya , Hoshino Junichi , Sawa Naoki , Oohashi Kenichi , Takaichi Kenmei
Amyloid.2012 Jan 20 ; ():.
PMID: 22260742[]

2012/01/20 保存 要約 閉じる

A 58-year-old Japanese woman on hemodialysis (HD) was admitted for intractable rheumatoid arthritis. Even after HD was started due to end-stage renal failure in 2004, her arthropathy worsened. A soluble tumor necrosis factor receptor inhibitor (etanercept at 25 mg twice weekly), tacrolimus (2 mg daily), and prednisolone (10 mg daily) had been administered since 2005, but high disease activity had persisted. She was admitted to our hospital in July 2007. C-reactive protein (CRP) was 6.8 mg/dL, and the DAS-CRP score was calculated to be 8.3. The cardiothoracic ratio (CTR) was 62% on a chest radiograph, but dialysis hypotension was remarkable. Left ventricular mass (LVM) was calculated as 320 g using echocardiography. Endoscopic biopsy of the stomach and duodenum revealed heavy deposition of AA amyloid. Etanercept was discontinued and tocilizumab was started at a dose of 320 mg (8 mg/kg) monthly. Even after predonisolone and tacrolimus were tapered gradually and discontinued because of her good response, CRP and DAS-CRP became 0.0 mg/dL and 1.5, respectively. In September 2011, re-evaluation was performed. CTR was reduced to 51% and LVM was decreased to 180 g. Endoscopic biopsy of the stomach and duodenum revealed disappearance of AA amyloid. Although AA amyloidosis of the gastrointestinal tract has already been reported to be improved by tocilizumab, this is the first report on improvement of myocardial hypertrophy as well as dialysis hypotension.

BDNF induces polarized signaling of small GTPase (Rac1) at the onset of Schwann cell myelination through partitioning-defective 3 (Par3).

Tep Chhavy , Kim Mi Lyang , Opincariu Laura I , Limpert Allison S , Chan Jonah R , Appel Bruce , Carter Bruce D , Yoon Sung Ok
J Biol Chem.2011 Nov 29 ; ():.
PMID: 22128191[]

2011/11/30 保存 要約 閉じる

BDNF was shown to play a role in Schwann cell myelination by recruiting Par3 to exon-glial interface, but the underlying mechanism has remained unclear. Here we report that Par3 regulates Rac1 activation by BDNF, but not by NRG1-Type III in Schwann cells, although both ligands activate Rac1 in vivo. During development, active Rac1 signaling is localized in a polarized manner to axon-glial interface in Schwann cells. Knockdown of p75 and Par3 individually inhibits Rac1 activation, while constitutive activation of Rac1 disturbs the polarized activation of Rac1 in vivo. Polarized Rac1 activation is necessary for myelination as Par3 knockdown attenuates myelination in mouse sciatic nerves as well as in zebrafish. Specifically, Par3 knockdown in zebrafish disrupts proper alignment between the axon and Schwann cells without perturbing Schwann cell migration, suggesting that localized Rac1 activation at the axon-glial interface helps identifying the initial wrapping sites. We therefore conclude that polarized activation of Rac1 activation is critical for myelination.

Mutational analysis supports a core role for Drosophila α-Catenin in adherens junction function.

Sarpal Ritu , Pellikka Milena , Patel Ridhdhi R , Hui Felix Yan Wai , Godt Dorothea , Tepass Ulrich
J Cell Sci.2012 Jan 20 ; ():.
PMID: 22266901[]

2012/01/23 保存 要約 閉じる

α-catenin associates the cadherin-catenin complex with the actin cytoskeleton. α-catenin binds to β-catenin, which links it to the cadherin cytoplasmic tail, and F-actin, but also to a multitude of actin-associated proteins. These interactions suggest a highly complex cadherin-actin interface. Moreover, mammalian αΕ-catenin has been implicated in a cadherin-independent cytoplasmic function in Arp2/3-dependent actin regulation, and in cell signaling. The function and regulation of individual molecular interactions of α-catenin, in particular during development, are not well understood. We have generated mutations in Drosophila α-Catenin (α-Cat) to investigate α-Catenin function in this model, and to establish a setup for testing α-Catenin-related constructs in α-Cat-null mutant cells in vivo. Our analysis of α-Cat mutants in embryogenesis, imaginal discs and oogenesis reveals defects consistent with a loss of cadherin function. Compromising components of the Arp2/3 complex or its regulator SCAR ameliorate the α-Cat loss-of-function phenotype in embryos but not in ovaries, suggesting negative regulatory interactions between α-Catenin and the Arp2/3 complex in some tissues. We also show that the α-Cat mutant phenotype can be rescued by the expression of a DE-cadherin::α-Catenin fusion protein, which argues against an essential cytosolic, cadherin-independent role of Drosophila α-Catenin.

A crucial role for Nox 1 in redox-dependent regulation of Wnt-β-catenin signaling.

Kajla Seheli , Mondol Abdus S , Nagasawa Atsushi , Zhang Yugen , Kato Masayoshi , Matsuno Kuniharu , Yabe-Nishimura Chihiro , Kamata Tohru
FASEB J.2012 Jan 25 ; ():.
PMID: 22278940[]

2012/01/26 保存 要約 閉じる

Canonical Wnt signaling critically regulates cell fate and proliferation in developmental stages and adult tissues. Redox regulation through nucleoredoxin (NRX) has recently been identified in canonical Wnt signaling. However, the source of reactive oxygen species (ROS) affecting the redox state of NRX remains elusive. Our principal aim in this study was to investigate whether superoxide-generating NADPH oxidase1 (Nox1) is involved in NRX-regulated Wnt signaling in intestinal and colon epithelial cells. Here, we demonstrate that Wnt treatment of mouse intestinal cells induces production of ROS through Nox1. This Nox1 action is regulated by Rac1 GTPase through Wnt-induced activation of the Rac1 guanine nucleotide exchange factor Vav2 by Src-mediated tyrosine phosphorylation. Nox1-generated ROS oxidize and inactivate NRX, thereby releasing the NRX-dependent suppression of Wnt-β-catenin signaling through dissociation of NRX from Dvl. Nox1 small-interference RNA inhibits cell response to Wnt, including stabilization of β-catenin, expression of cyclin D1 and c-Myc via the TCF transcription factor, and accelerated cell proliferation. Nox1 mediates Wnt-induced cell growth in colon cancer cells with the normal Wnt pathway, but not in APC-deficient colon cancer cells, which are constitutively active in Wnt signaling. Together, these results suggest the mediating role of Nox1 in redox-dependent regulation of canonical Wnt-β-catenin signaling and provide further insight into the regulatory mechanism of the Wnt pathway.-Kajla, S., Mondol, A. S., Nagasawa, A., Zhang, Y., Kato, M., Matsuno, K., Yabe-Nishimura, C., Kamata, T. A crucial role for Nox 1 in redox-dependent regulation of Wnt-β-catenin signaling.

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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： 50位 14,036view,1users 保存 要約 閉じる

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.

A G-protein gamma subunit mimic is a general antagonist of prion propagation in Saccharomyces cerevisiae.

Ishiwata Masao , Kurahashi Hiroshi , Nakamura Yoshikazu
Proc Natl Acad Sci U S A.2009 Jan 20 ; 106(3):791-6.
PMID: 19129493[]

先週： 63位 1,669view,1users 保存 要約 閉じる

The Gpg1 protein is a Ggamma subunit mimic implicated in the G-protein glucose-signaling pathway in Saccharomyces cerevisiae, and its function is largely unknown. Here we report that Gpg1 blocks the maintenance of [PSI(+)], an aggregated prion form of the translation termination factor Sup35. Although the GPG1 gene is normally not expressed, over-expression of GPG1 inhibits propagation of not only [PSI(+)] but also [PIN(+)], [URE3] prions, and the toxic polyglutamine aggregate in S. cerevisiae. Over-expression of Gpg1 does not affect expression and activity of Hsp104, a protein-remodeling factor required for prion propagation, showing that Gpg1 does not target Hsp104 directly. Nevertheless, prion elimination by Gpg1 is weakened by over-expression of Hsp104. Importantly, Gpg1 protein is prone to self-aggregate and transiently colocalized with Sup35NM-prion aggregates when expressed in [PSI(+)] cells. Genetic selection and characterization of loss-of-activity gpg1 mutations revealed that multiple mutations on the hydrophobic one-side surface of predicted alpha-helices of the Gpg1 protein hampered the activity. Prion elimination by Gpg1 is unaffected in the gpa2Delta and gpb1Delta strains lacking the supposed physiological G-protein partners of Gpg1. These findings suggest a general inhibitory interaction of the Gpg1 protein with other transmissible and nontransmissible amyloids, resulting in prion elimination. Assuming the ability of Gpg1 to form G-protein heterotrimeric complexes, Gpg1 is likely to play a versatile function of reversing the prion state and modulating the G-protein signaling pathway.

Germinal center B and follicular helper T cells: siblings, cousins or just good friends?

Nutt Stephen L , Tarlinton David M
Nat Immunol.2011 Jun ; 12(6):472-7.
PMID: 21739669[]

先週： 64位 1,048view,1users 保存 要約 閉じる

Humoral immunity requires interaction between specialized populations of B cells and CD4(+) T cells, called follicular helper T cells (T(FH) cells), in the germinal center (GC) to produce memory B cells and long-lived plasma cells. Molecular crosstalk between GC B cells and T(FH) cells influences the survival, proliferation and differentiation of each cell type. This pairing of GC B cells and T(FH) cells also occurs at the transcriptional level as the Bcl-6–IRF4–Blimp-1 axis, which is crucial for B cell differentiation, is also essential for the T(FH) cell identity. Less is known about the memory B cells that arise from the GC pool, as they seem to be distinctly 'programmed' on the basis of their antigen receptor affinity to enter the long-lived memory pool.

Germinal center B and follicular helper T cells: siblings, cousins or just good friends?

Nutt Stephen L , Tarlinton David M
Nat Immunol.2011 Jun ; 12(6):472-7.
PMID: 21739669[]

先週： 64位 1view,1users 保存 要約 閉じる

Humoral immunity requires interaction between specialized populations of B cells and CD4(+) T cells, called follicular helper T cells (T(FH) cells), in the germinal center (GC) to produce memory B cells and long-lived plasma cells. Molecular crosstalk between GC B cells and T(FH) cells influences the survival, proliferation and differentiation of each cell type. This pairing of GC B cells and T(FH) cells also occurs at the transcriptional level as the Bcl-6–IRF4–Blimp-1 axis, which is crucial for B cell differentiation, is also essential for the T(FH) cell identity. Less is known about the memory B cells that arise from the GC pool, as they seem to be distinctly 'programmed' on the basis of their antigen receptor affinity to enter the long-lived memory pool.

A fine romance: T follicular helper cells and B cells.

King Cecile
Immunity.2011 Jun 24 ; 34(6):827-9.
PMID: 21703537[]

先週： 65位 678view,1users 保存 要約 閉じる

T follicular helper (Tfh) cells help B cells to generate affinity-matured antibodies. Three papers in this issue of Immunity (Choi et al., 2011; Kerfoot et al., 2011; Kitano et al., 2011) provide information about the reciprocal relationship between B cells and Tfh cells.

Programmed Cell Death 1 Suppresses B-1b Cell Expansion and Long-Lived IgG Production in Response to T Cell-Independent Type 2 Antigens.

Haas Karen M
J Immunol.2011 Oct 14 ; ():.
PMID: 22003198[]

先週： 66位 790view,1users 保存 要約 閉じる

B-1b cells play a key role in producing Abs against T cell-independent type 2 Ags. However, the factors regulating Ab production by this unique B cell subset are not well understood. In this study, a detailed analysis of the B cell response to 2,4,6-trinitrophenol (TNP)-Ficoll was performed using normal mice. TNP-Ficoll delivered i.p. or i.v. induced rapid Ag-specific B-1b cell activation, expansion, isotype switching, and plasmablast/plasma cell differentiation. Ag-specific B-1b cell numbers peaked at day 5 and then gradually declined in the spleen but remained elevated in the peritoneal cavity beyond 40 d postimmunization. In addition to expressing CD43, CD44, and CD86, Ag-activated B-1b cells transiently expressed programmed cell death 1 (PD-1), which functionally suppressed BCR-induced B-1b cell in vitro proliferation when additional costimulatory signals were lacking. Inhibiting PD-1:PD-1 ligand interactions during TNP-Ficoll immunization significantly enhanced Ag-specific B-1b cell expansion and the frequency of IgG isotype switching and plasmablast/plasma cell differentiation. Remarkably, PD-1 mAb blockade during the first week following immunization resulted in significantly increased numbers of both splenic and bone marrow Ag-specific IgG3-secreting cells, but not IgM-secreting cells, at both early (day 5) and late (week 6) time points. Moreover, Ag-specific serum IgG3 levels, as well as IgG2c, IgG2b, and IgA levels, remained significantly elevated in PD-1 mAb-treated mice relative to control Ab-treated mice for ≥6 wk postimmunization. Thus, PD-1:PD-1 ligand interactions occurring shortly after initial T cell-independent type 2 Ag encounter play a critical role in suppressing Ag-specific B-1b cell expansion and the development of long-term IgG-producing bone marrow and spleen cells.

Immunization induces activation of bone marrow eosinophils required for plasma cell survival.

Chu Van Trung , Berek Claudia
Eur J Immunol.2011 Nov 7 ; ():.
PMID: 22057654[]

先週： 67位 482view,1users 保存 要約 閉じる

Eosinophils have multiple functions as effector cells of the innate immune system but also as modulators of immune responses. As producers of cytokines required for plasma cell survival, they are essential for the long-term maintenance of plasma cells in the bone marrow (BM). Here we show that activation of eosinophils both in vitro and in vivo enhances expression of the plasma cell survival factors APRIL, IL-6, IL-4, IL-10 and TNF-α. The in vivo activation of eosinophils is independent of the type of adjuvant used for primary immunization. Although eosinophils are activated by adjuvant itself, a stable activation and a constant increase in BM eosinophils is observed only in the presence of antigen. Thus, the numbers and the quality of eosinophils are dependent on priming the adaptive immune system. With secondary immunization and re-activation of antigen dependent memory cells, the ability of eosinophils to promote plasma cell survival is further increased. These findings suggest that in T cell-dependent immune responses eosinophils are conditioned so as to support the long-term survival of plasma cells in the BM. It implies that through accelerated numbers of eosinophils stable plasma cell survival niches are established and the long term survival of plasma cells is ensured.

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[]

先週： 68位 1,554view,1users 保存 要約 閉じる

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.

In vitro cell quality of buffy coat platelets in additive solution treated with pathogen reduction technology.

Ostrowski Sisse R , Bochsen Louise , Salado-Jimena José A , Ullum Henrik , Reynaerts Inge , Goodrich Raymond P , Johansson Pär I
Transfusion.2010 Oct ; 50(10):2210-9.
PMID: 20456708[]

先週： 69位 4,302view,1users 保存 要約 閉じる

BACKGROUND: Pathogen reduction technologies (PRTs) may induce storage lesion in platelet (PLT) concentrates. To investigate this, buffy coat PLTs (BCPs) in PLT additive solution (AS; SSP+) with or without Mirasol PRT (CaridianBCT Biotechnologies) were assessed by quality control tests and four-color flow cytometry. STUDY DESIGN AND METHODS: In vitro comparison of PRT and control pooled-and-split BCPs after 2, 3, 6, 7, and 8 days of storage was made. PLT concentration, count per unit, swirl, metabolism, activation (CD62P, PAC1, CD42b/GPIb, CD63, CD40L/CD154, CD40, annexin V), and microparticle, sCD40L, and sCD62P release were evaluated. RESULTS: PRT induced a minor initial PLT loss (Day 2 [mean±SD], 302×10(9) ±44×10(9) PLTs/unit vs. 325× 10(9) ±46×10(9) PLTs/unit; p<0.001) but the decline was comparable to control BCP. Swirling was comparable and declined with similar rates in PRT-treated and control BCPs during storage. PRT enhanced PLT metabolism and activation, evidenced by lower pH(22) ; increased glucose consumption and lactate production rates (p<0.01); early increases in CD62P-, PAC1-, CD63-, CD40L-, CD40-, and annexin V-positive PLTs; reduced GPIb expression; and enhanced release of PLT-derived MPs and sCD40L (all p<0.05). CD62P and PAC1 expression changed with different kinetics during storage and varying GPIb expression was displayed within the CD62P/PAC1-positive PLT subsets. CONCLUSION: PRT treatment of BCP in AS induced a minor initial PLT loss and enhanced metabolism and PLT activation. The clinical relevance for PLT function in vivo of these findings will be investigated in a clinical trial.

Origins of CD4(+) effector and central memory T cells.

Pepper Marion , Jenkins Marc K
Nat Immunol.2011 Jun ; 12(6):467-71.
PMID: 21739668[]

先週： 70位 913view,1users 保存 要約 閉じる

Lineage-committed effector CD4(+) T cells are generated at the peak of the primary response and are followed by heterogeneous populations of central and effector memory cells. Here we review the evidence that T helper type 1 (T(H)1) effector cells survive the contraction phase of the primary response and become effector memory cells. We discuss the applicability of this idea to the T(H)2 cell, T(H)17 helper T cell, follicular helper T cell (T(FH) cell) and induced regulatory T cell lineages. We also discuss how central memory cells are formed, with an emphasis on the role of B cells in this process.

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[The antiviral activity of diphenyl derivatives in different model systems].

Fiziol Zh.2012 ; 58(1):36-42.
PMID: 22590736[]

2012/05/16 保存 要約 閉じる

In experiments on two model systems L929/VSV and RF/ HSV-1 in vitro we have studied the antiviral activity of new structural analogues of tilorone--4,4'-bis[2-(diethyl-amino)ethoxy]diphenyl dihydrochloride and 2-methoxy-carbonyl-4-4'-bis[2-(diethylamino)ethoxy]diphenyl dihydrochloride. In experiments the tested substances were administered in preventive and therapeutic schemes. The preventive scheme confirms the existence of a correlation between IFN production under the influence of tested substances and their antiviral activity. It is shown that diphenyls are able to inhibit the development of viral cytopathic effect induced by DNA- and RNA-containing viruses. Diphenyl derivatives are less toxic than tilorone and could be considered as promising substances for further research to develop new antiviral drugs.

[The changes of metabolism in myocardium at ischemia-reperfusion and activating of the ATP-sensitive potassium channels].

Fiziol Zh.2012 ; 58(1):13-26.
PMID: 22590734[]

2012/05/16 保存 要約 閉じる

In experiments on the anaesthetized dogs with modeling of experimental ischemia (90 min) and reperfusion (180 min) it was investigated the changes of biochemical processes in the different areas of heart (intact, risk and necrotic zone) during intragastric introduction of medicinal form (tablets) of flocalin (the fluorine-containing opener of ATP-sensitive potassium channels) in a dose 2,2 mg/kg. The data analysis allowed to define a few possible cardioprotective mechanisms of flocalin action at ischemia-reperfusion conditions: the preservation of sufficient levels of de novo (by cNOS) NO synthesis, an inhibition of de novo (by iNOS) and salvage (by NADH-dependent nitratreductase) NO synthesis, an inhibition of L-arginine degradation by arginase, an inhibition of oxidizing metabolism due to limitation of ROS and RNS generation, inhibition of free arachidonic acid and eicosanoids synthesis, inhibition of ATP and GTP degradations and, possibly, stimulation of protective haem degradation. These changes may prevent formation of toxic peroxynitrite and suggest the possibility of participating in flocalin-mediated cardioprotective effects of warning a mitochondrial permeability transition pore (MPTP) opening and inhibition of apoptosis and/or necrosis of cardiomyocytes induced by it.

Sensitive fluorescence biosensor for folate receptor based on terminal protection of small-molecule-linked DNA.

Wei Xiaofeng , Lin Wenlie , Ma Na , Luo Fang , Lin Zhenyu , Guo Longhua , Qiu Bin , Chen Guonan
Chem Commun (Camb).2012 May 16 ; ():.
PMID: 22590712[]

2012/05/16 保存 要約 閉じる

Based on the specific folic acid-folate receptor (FA-FR) interaction, macromolecular FR can bind with FA-linked DNA-small molecule chimeras, which can prevent enzymolysis by exonuclease III (Exo III), enabling a novel fluorescence biosensor for FR to be developed using quinaldine red as a G-quadruplex-binding probe.

Recoverable organorhodium-functionalized polyhedral oligomeric silsesquioxane: a bifunctional heterogeneous catalyst for asymmetric transfer hydrogenation of aromatic ketones in aqueous medium.

Tang Shuang , Jin Ronghua , Zhang Huaisheng , Yao Hui , Zhuang Jinglan , Liu Guohua , Li Hexing
Chem Commun (Camb).2012 May 16 ; ():.
PMID: 22590711[]

2012/05/16 保存 要約 閉じる

A bifuctional heterogeneous chiral rhodium catalyst exhibited excellent catalytic activity and enantioselectivity in asymmetric transfer hydrogenation of aromatic ketones and their analogues in aqueous medium, which could be recovered easily and used repetitively without affecting obviously its enantioselectivity.

Stimuli-responsive 2D polyelectrolyte photonic crystals for optically encoded pH sensing.

Li Cheng , Lotsch Bettina V
Chem Commun (Camb).2012 May 16 ; ():.
PMID: 22590710[]

2012/05/16 保存 要約 閉じる

A versatile photonic crystal sensing motif based on a two-dimensional (2D) inverse opal monolayer of stimuli-responsive polyelectrolyte gel with tunable optical properties is reported. The photonic membrane shows prompt response to pH and can be readily read out from either its optical spectra or interference colours.

Solution processed high performance pentacene thin-film transistors.

Chao Ting-Han , Chang Ming-Jen , Watanabe Motonori , Luo Ming-Hui , Chang Yuan Jay , Fang Tzu-Chien , Chen Kew-Yu , Chow Tahsin J
Chem Commun (Camb).2012 May 15 ; ():.
PMID: 22590709[]

2012/05/16 保存 要約 閉じる

High performance thin-film transistors were fabricated using a new precursor of pentacene through a multiple spin-heat procedure. High quality pentacene thin films can be prepared by this method and hence a FET device can be made in a top-contact configuration. The device exhibited a remarkable field-effect mobility of 0.38 cm(2) V(-1) s(-1) with an on/off ratio of 10(6).

Phosphine oxide functionalised imidazolium ionic liquids as tuneable ligands for lanthanide complexation.

Vicente Jorge Alvarez , Mlonka Agata , Gunaratne H Q Nimal , Swadźba-Kwaśny Małgorzata , Nockemann Peter
Chem Commun (Camb).2012 May 16 ; ():.
PMID: 22590708[]

2012/05/16 保存 要約 閉じる

A series of novel, phosphine oxide functionalised ionic liquids have been synthesised and their application as tuneable lanthanide complexing agents is demonstrated.

Toward biodegradable nanogel star polymers via organocatalytic ROP.

Appel Eric A , Lee Victor Y , Nguyen Timothy T , McNeil Melanie , Nederberg Frederik , Hedrick James L , Swope William C , Rice Jullia E , Miller Robert D , Sly Joseph
Chem Commun (Camb).2012 May 16 ; ():.
PMID: 22590707[]

2012/05/16 保存 要約 閉じる

Organocatalytic ring opening polymerization (OROP) is used to effect the rapid, scalable, room temperature formation of size-controlled, highly uniform, polyvalent, nanogel star polymer nanoparticles of biodegradable composition.

Insulated donor-π-acceptor systems based on fluorene-phosphine oxide hybrids for non-doped deep-blue electroluminescent devices.

Yu Donghui , Zhao Fangchao , Zhang Zhen , Han Chunmiao , Xu Hui , Li Jing , Ma Dongge , Yan Pengfei
Chem Commun (Camb).2012 May 16 ; ():.
PMID: 22590706[]

2012/05/16 保存 要約 閉じる

An ambipolar ternary deep-blue emitter with CIE coordinates of (0.15, 0.07) and high electroluminescent performance was constructed on the basis of an insulated donor-π-acceptor system through an indirect linkage.

Phthalocyanines: a new class of G-quadruplex-ligands with many potential applications.

Yaku Hidenobu , Fujimoto Takeshi , Murashima Takashi , Miyoshi Daisuke , Sugimoto Naoki
Chem Commun (Camb).2012 May 15 ; ():.
PMID: 22590705[]

2012/05/16 保存 要約 閉じる

A G-quadruplex is a four-stranded DNA structure featuring stacked guanine tetrads, G-quartets. Formation of a G-quadruplex in telomere DNA can inhibit telomerase activity; therefore, development of G-quadruplex-ligands, which induce and/or stabilize G-quadruplexes, has become an area of great interest. Phthalocyanine derivatives have substantial potential as high-affinity G-quadruplex-ligands because these planar chromophores are similar in size and shape to the G-quartets. Here, we focus on the latest findings on phthalocyanine derivatives as G-quadruplex-ligands, and discuss the mechanisms by which phthalocyanines bind to G-quadruplexes with high affinity and selectivity. We also discuss potential biomedical and organic electronic applications of phthalocyanines that are dependent on their photophysical properties.

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