CD28/CTLA4 double deficient mice demonstrate crucial role for B7 co-stimulation in the induction of allergic lower airways disease

Background The existence of a third B7-1/B7-2 receptor was postulated in a recent study using a novel mouse strain lacking both CD28 and CTLA4 (CD28/CTLA4(-/-)).Objective In the present study, it was investigated if T cell co-stimulation via the putative B7-1/B7-2 receptor plays a role in the induction of Th2-mediated asthma manifestations in mice.Methods BALB/c wild-type, CD28/CTLA4(-/-) and B7-1/B7-2(-/-) mice were sensitized and aerosol challenged with ovalbumin (OVA).Results At 24 h after the last aerosol, wild-type mice showed airway hyper-responsiveness in vivo and up-regulated levels of serum OVA-specific IgE compared with the situation shortly before OVA challenge. In addition, eosinophil numbers and IL-5 levels in the broncho-alveolar lavage fluid and Th2 cytokine production by lung cells upon OVA re-stimulation in vitro were observed. In agreement with an earlier study, we failed to induce any of the asthma manifestations in B7-1/B7-2(-/-) mice. Importantly, also CD28/CTLA4(-/-) mice showed no asthma manifestations upon OVA sensitization and challenge.Conclusion These data clearly demonstrate that T cell co-stimulation via the putative B7-1/B7-2 receptor appears to have no role in the induction of Th2-mediated asthma manifestations in this murine model and, conversely, that CD28 signalling is crucial.</p

HURUF AL JAR FI QISHAH ANA AL MAUT AL QASIRAH LI TAUFIQ AL HAKIM : DIRASAH TAHLILIYAH NAHWIYAH

Dalam tata bahasa Arab, kata (kalimat dalam bahasa Arab) sebagai satuan terkecil bahasa, sebagaimana dalam bahasa yang lain dapat dikelompokkan menjadi tiga macam; pertama isim, fi’il dan huruf. Yang kemudian dapat lebih mudah untuk dipelajari namun, penulis dalam hal ini hanya akan sedikit membahas bagian yang terakhir yang berkaitan dengan huruf khusunya huruf jer. Pembahasan dalam skripsi ini mengkaji tentang Huruf Jer dalam cerpen “Akulah Kematian” karya Taufiq Hakim, dengan pendekatan ilmu Nahwu. Masalah yang dikemukakan dalam rumusan masalah ini meliputi dua hal yaitu; huruf jer apa saja yang terdapat dalam cerpen “Akulah Kematian” karya Taufiq Hakim dan apa saja makna huruf jer yang terdapat dalam cerpen “Akulah Kematian” karya Taufiq Hakim. Dalam pembahasan skripsi ini peneliti menggunakan ilmu nahwu sebagai pisau analisis dan ilmu kebahasaan sebagai pendekatannya. Peneliti mengambil beberapa teori nahwu dari buku-buku yang mudah dimengerti dalam penjelasannya seperti kitab Jamiud Durus. Adapun tujuan pembahasan ini adalah untuk mengungkap ilmu kebahasan yang terdapat dalam cerpen “Akulah Kematian” karya Taufiq Hakim, sedangkan metode penelitian yang dipakai adalah metode penelitian deskriptif kualitatif. Huruf Jer secara umum yang banyak dikemukakan oleh ahli nahwu berjumlah 20 huruf, sedangkan dalam cerpen “Akulah Kematian” karya Taufiq Hakim berjumlah 9 huruf yang terdiri dari (الباء، من، إلى، حتى، على، الكاف، عن، اللام، في) Adapun kesimpulan dalam penelitian ini bahwa di dalam cerpen “Akulah Kematian” terdapat 395 huruf jer, pertama: huruf jer berbentuk ba’ dengan makna ilshoq, mushohabah, as-sababiyyah wa at-ta’lil, at-ta’diyah, al-ist’la’, al-isti’anah, adz-dzhorfiyah, al-badal, al-‘iwadh. Harfu min dengan makna al-ibtida’ at-tab’iid, at-ta’kid, adz-dzorfiyah, dan makna ‘an. Harfu ila dengan makna al-intiha’, al-mushohabah, makna ‘inda. Huruf jer hatta dengan makna lil intiha’ ka ila. Huruf jer ‘an dengan makna almujawazah wal bu’du, makna min, dan makna ‘ala. Huruf jer ‘ala dengan makna al-isti’la’, makna min, makna ba’, makna ‘an, makna fi. Huruf jer fi dengan makna adz-dzorfiyah, al-muhohabah, al-isti’la’, dan makna ba. Huruf jer kaf dengan makna at-ta’lil, as-sababiyah, dan makna ‘ala. Huruf jer lam dengan makna al-isti’la’, al-milku, lamul-ikhtishah, as-sababiyah wat-ta’lil, sibhul-miku, dan taukid

Low-dose FK506 blocks collar-induced atherosclerotic plaque development and stabilizes plaques in ApoE-/- mice

Since atherosclerosis is a chronic inflammatory disease, we tested the hypothesis that the immunosuppressive drug FK506 would attenuate the development of atherosclerosis using a mouse model of collar-induced atherosclerosis. ApoE-/- mice were treated for 4 weeks with the immunosuppressive drug FK506 (0.05 mg/kg/day), yielding sustained blood levels (approximately 0.2 ng/mL) without systemic side effects. Atherosclerotic plaque development of FK506-treated mice was significantly reduced (63%) while plaque cell density was increased (52%) compared to controls. Importantly, FK506 also blocked progression of pre-existing atherosclerotic plaques. Plaque area of pre-existing plaques was 35% reduced by FK506. Cell density (35%) and collagen content (51%) were significantly increased, whereas necrotic core content was decreased (42%), indicating a more stable plaque morphology. Similar results were found during spontaneous atherosclerotic plaque development in ApoE-/- mice (treatment 17-25 weeks of age). Flow-cytometric analysis showed no peripheral effects on blood cell count or T-cell activation after FK506-treatment. In vitro, FK506 decreased vascular smooth muscle cell (VSMC) apoptosis and inhibited nuclear factor of activated T cells (NFAT)-luciferase reporter activity at concentrations in the range of the in vivo concentration. Low-dose FK506 inhibits collar-induced atherosclerotic plaque development and progression and induces more stable plaque phenotypes in ApoE-/- mice without any peripheral side effect

Prolonged shear stress and KLF2 suppress constitutive proinflammatory transcription through inhibition of ATF2

Absence of shear stress due to disturbed blood flow at arterial bifurcations and curvatures leads to endothelial dysfunction and proinflammatory gene expression, ultimately resulting in atherogenesis. KLF2 has recently been implicated as a transcription factor involved in mediating the anti-inflammatory effects of flow. We investigated the effect of shear on basal and TNF-alpha-induced genomewide expression profiles of human umbilical vein endothelial cells (HUVECs). Cluster analysis confirmed that shear stress induces expression of protective genes including KLF2, eNOS, and thrombomodulin, whereas basal expression of TNF-alpha-responsive genes was moderately decreased. Promoter analysis of these genes showed enrichment of binding sites for ATF transcription factors, whereas TNF-alpha-induced gene expression was mostly NF-kappa B dependent. Furthermore, human endothelial cells overlying atherosclerotic plaques had increased amounts of phosphorylated nuclear ATF2 compared with endothelium at unaffected sites. In HUVECs, a dramatic reduction of nuclear binding activity of ATF2 was observed under shear and appeared to be KLF2 dependent. Reduction of ATF2 with siRNA potently suppressed basal proinflammatory gene expression under no-flow conditions. In conclusion, we demonstrate that shear stress and KLF2 inhibit nuclear activity of ATF2, providing a potential mechanism by which endothelial cells exposed to laminar flow are protected from basal proinflammatory, atherogenic gene expressio

Serine protease inhibitor Serp-1 strongly impairs atherosclerotic lesion formation and induces a stable plaque phenotype in ApoE-/-mice

The myxoma virus protein Serp-1 is a member of the serine protease inhibitor superfamily. Serp-1 potently inhibits human serum proteases including plasmin, urokinase-type plasminogen activator (uPA), and tissue-type plasminogen activator (tPA). Serp-1 also displays a high antiinflammatory activity, rendering it a promising candidate for antiatherosclerotic therapy. In this study, we have thus examined the effect of Serp-1 on de novo atherosclerotic plaque formation and on advanced lesions. Perivascular collars were placed around carotid arteries of ApoE-/- mice to induce atherosclerotic plaques and Serp-1 treatment started at week 1 and week 5 after collar placement. Effects of Serp-1 on de novo atherogenesis were characterized by a significantly lower plaque size than that of control mice (18+/-5x10(3) versus 57+/-12x10(3) microm2, respectively; P=0.007). Immunostaining showed a 50% (P=0.004) decrease in the MOMA-2-stained lesion area of Serp-1-treated mice. Treatment of advanced lesions with Serp-1 resulted in a decrease in plaque size and lumen stenosis (P=0.028). Alpha-actin staining of these lesions was significantly increased compared with the control (P=0.017). In both studies, a higher cellularity of the plaque and increased collagen content was observed in Serp-1-treated mice. In vitro studies showed that Serp-1 induces proliferation and migration of vascular smooth muscle cells. In conclusion, Serp-1 inhibits carotid artery plaque growth and progression in ApoE-/- mice. Equally relevant, it enhances cellularity of the plaque core potentially leading to improved plaque stability. The above results indicate that Serp-1 constitutes a promising lead in antiatherosclerotic therap

Hazard Ratios (95% confidence intervals) for a future cardiovascular event¹ during follow-up in patients with the acute coronary syndrome, according to the number of chemokines (CCL3/MIP-1α, CCL5/RANTES and CCL18/PARC) in the highest tertile, Bad Nauheim ACS II registry.

<p>HR: hazard ratio; CI: confidence interval.</p>1<p>A cardiovascular event is defined as the occurrence of death, an acute myocardial infarction or an urgent revascularization procedure.</p>2<p>Adjusted for age, sex, diabetes, smoking, family history of cardiovascular disease and baseline levels of NT-proBNP, CK-MB and TnT.</p>3<p>All three chemokines concentrations in the lowest tertile.</p

Baseline characteristics and biomarker levels of the study population according to the occurrence of a cardiovascular event within six months of follow-up, Bad Nauheim ACS II registry.

<p>CVD: cardiovascular disease; AMI: acute myocardial infarction; TnT: Troponin T; CRP: C-Reactive Protein; NT-proBNP: N-terminal pro-Brain Natriuretic Peptide; CK-MB: Creatinine Kinase-MB; UAP: unstable angina pectoris; STEMI: ST-segment elevated myocardial infarction; NSTEMI: Non-ST-segment elevated myocardial infarction.</p>1<p>Presented as mean ± sd,</p>2<p>Presented as median (interquartile range),</p>3<p>Time of blood drawing since onset of symptoms,</p>4<p>based on values of 513 event free patients and 68 event patients,</p>5<p>based on values of 516 event free patients and 63 event patients,</p>6<p>based on values of 480 event free patients and 53 event patients.</p

Hazard Ratios (95% confidence intervals) for a fatal future cardiovascular event during follow-up in patients with the acute coronary syndrome, according to baseline levels of CCL3/MIP-1α, CCL5/RANTES and CCL18/PARC, Bad Nauheim ACS II registry.

<p>HR: hazard ratio; CI: confidence interval.</p>1<p>Tertile boundaries for CCL3/MIP-1α: 18.7–33.3 pg/ml, CCL5/RANTES: 16.2–134.15 ng/ml, CCL18/PARC: 43.0–70.9 ng/ml.</p>2<p>Adjusted for age, sex, diabetes, smoking, family history of cardiovascular disease and baseline levels of NT-proBNP, CK-MB and TnT.</p