Asymmetric Synthesis and Biological Screening of Quinoxaline-Containing Synthetic Lipoxin A₄ Mimetics (QNX-sLXms)

Failure to resolve inflammation underlies many prevalent pathologies. Recent insights have identified lipid mediators, typified by lipoxins (LXs), as drivers of inflammation resolution, suggesting potential therapeutic benefit. We report the asymmetric preparation of novel quinoxaline-containing synthetic-LXA4-mimetics (QNX-sLXms). Eight novel compounds were screened for their impact on inflammatory responses. Structure–activity relationship (SAR) studies showed that (R)-6 (also referred to as AT-02-CT) was the most efficacious and potent anti-inflammatory compound of those tested. (R)-6 significantly attenuated lipopolysaccharide (LPS)- and tumor-necrosis-factor-α (TNF-α)-induced NF-κB activity in monocytes and vascular smooth muscle cells. The molecular target of (R)-6 was investigated. (R)-6 activated the endogenous LX receptor formyl peptide receptor 2 (ALX/FPR2). The anti-inflammatory properties of (R)-6 were further investigated in vivo in murine models of acute inflammation. Consistent with in vitro observations, (R)-6 attenuated inflammatory responses. These results support the therapeutic potential of the lead QNX-sLXm (R)-6 in the context of novel inflammatory regulators

Asymmetric Synthesis and Biological Screening of Quinoxaline-Containing Synthetic Lipoxin A4 Mimetics (QNX-sLXms)

Failure to resolve inflammation underlies many prevalent pathologies. Recent insights have identified lipid mediators, typified by lipoxins (LXs), as drivers of inflammation resolution, suggesting potential therapeutic benefit. We report the asymmetric preparation of novel quinoxaline-containing syntheticLXA4-mimetics (QNX-sLXms). Eight novel compounds were screened for their impact on inflammatory responses. Structure− activity relationship (SAR) studies showed that (R)-6 (also referred to as AT-02-CT) was the most efficacious and potent anti-inflammatory compound of those tested. (R)-6 significantly attenuated lipopolysaccharide (LPS)- and tumor-necrosis-factor-α (TNF-α)-induced NF-κB activity in monocytes and vascular smooth muscle cells. The molecular target of (R)-6 was investigated. (R)-6 activated the endogenous LX receptor formyl peptide receptor 2 (ALX/FPR2). The anti-inflammatory properties of (R)-6 were further investigated in vivo in murine models of acute inflammation. Consistent with in vitro observations, (R)-6 attenuated inflammatory responses. These results support the therapeutic potential of the lead QNX-sLXm (R)-6 in the context of novel inflammatory regulators

Hepatitis B immunity in teenagers vaccinated as infants: an Italian 17-year follow-up study

AbstractWe assessed the persistence of hepatitis B surface antigen antibody (anti-HBs) and immune memory in a cohort of 571 teenagers vaccinated against hepatitis B as infants, 17 years earlier. Vaccinees were followed-up in 2003 and in 2010 (i.e. 10 years and 17 years after primary vaccination, respectively). When tested in 2003, 199 vaccinees (group A) had anti-HBs <10 mIU/mL and were boosted, 372 (group B) were not boosted because they had anti-HBs ≥10 mIU/mL (n = 344) or refused booster (n = 28) despite anti-HBs <10 mIU/mL. In 2010, 72.9% (416/571) of participants had anti-HBs ≥10 mIU/mL (67.3% in group A vs. 75.8% in group B; p 0.03). The geometric mean concentrations (GMCs) were similar in both groups. Between 2003 and 2010, anti-HBs concentrations in previously boosted individuals markedly declined with GMC dropping from 486 to 27.7 mIU/mL (p <0.001). Fifteen vaccinees showed a marked increase of antibody, possibly due to natural booster. In 2010, 96 individuals (37 of group A and 59 of group B) with anti-HBs <10 mIU/mL were boosted; all vaccinees of the former group and all but two of the latter had an anamnestic response. Post-booster GMC was higher in group B (895.6 vs. 492.2 mIU/mL; p 0.039). This finding shows that the immune memory for HBsAg persists beyond the time at which anti-HBs disappears, conferring long-term protection

Pseudotumoural soft tissue lesions of the foot and ankle: a pictorial review

In the foot and ankle region, benign neoplasms and pseudotumoural soft tissue lesions are significantly more frequent than malignant tumours. The pseudotumoural lesions constitute a heterogeneous group, with highly varied aetiology and histopathology. This article reviews the imaging features of the most common pseudotumours of the soft tissues in the foot and ankle. Although the imaging characteristics of several of the lesions discussed are non-specific, combining them with lesion location and clinical features allows the radiologist to suggest a specific diagnosis in most cases

Research protocol of the NeedYD-study (Needs in Young onset Dementia): a prospective cohort study on the needs and course of early onset dementia

Contains fulltext : 89407.pdf (publisher's version ) (Open Access)BACKGROUND: Early onset dementia has serious consequences for patients and their family members. Although there has been growing attention for this patient group, health care services are still mainly targeted at the elderly. Specific knowledge of the needs of early onset dementia patients and their families is limited but necessary for the development of adequate health care services and specific guidelines. This research project is mainly targeted at delineating the course of early onset dementia, the functional characteristics and needs of early onset dementia patients and their caregivers, the risk factors for institutionalization and the interaction with the caring environment. METHODS/DESIGN: The NeedYD-study (Needs in Young Onset Dementia) is a longitudinal observational study investigating early onset dementia patients and their caregivers (n = 217). Assessments are performed every six months over two years and consist of interviews and questionnaires with patients and caregivers. The main outcomes are (1) the needs of patients and caregivers, as measured by the Camberwell Assessment of Needs for the Elderly (CANE) and (2) neuropsychiatric symptoms, as measured by the NeuroPsychiatric Inventory (NPI). Qualitative analyses will be performed in order to obtain more in-depth information on the experiences of EOD patients and their family members. The results of this study will be compared with comparable data on late onset dementia from a historical cohort. DISCUSSION: The study protocol of the NeedYD-study is presented here. To our knowledge, this study is the first prospective cohort study in this research area. Although some limitations exist, these do not outweigh the strong points of this study design

The association between timed up and go test and history of falls: The Tromsø study

BACKGROUND: Fall-related injuries in older adults are a major health problem. Although the aetiology of falls is multifactorial, physical factors are assumed to contribute significantly. The "Timed up and go test" (TUG) is designed to measure basic mobility function. This report evaluates the association between TUG times and history of falls. METHODS: A retrospective, observational, population-based study was conducted on 414 men and 560 women with mean age 77.5 (SD 2.3). TUG time and falls during the previous 12 months were recorded. Covariates were age, sex, medical history and health-related mobility problems. Means, confidence intervals and test characteristics for TUG were calculated. Odds ratios and influence of covariates were examined by logistic regression. RESULTS: The mean TUG time was 11.1s (SD 2.5) among male non-fallers and 13.0s (SD 7.8) among fallers. The difference was 1.9s (95%CI 0.9–3.0). The odds ratio for fallers being in the upper quartile was 2.1 (95%CI 1.4–3.3). Adjusted for covariates, the odds ratio was (OR = 1.8, 95%CI 1.1–2.9). The corresponding mean was 13.0s (SD 5.74) among female non-fallers and 13.9s (SD 8.5) among fallers. The difference was 0.9 (95%CI -0.3–2.1). The odds ratio for fallers being in upper quartile was 1.0 (95%CI 0.7–1.4). The area under the ROC curve was 0.50 (95%CI 0.45–0.55) in women and 0.56 (95%CI 0.50–0.62) in men. CONCLUSION: TUG is statistically associated with a history of falls in men but not in women. The ability to classify fallers is poor, and the clinical value of the association is therefore limited

RNase 7 Contributes to the Cutaneous Defense against Enterococcus faecium

Background: Human skin is able to mount a fast response against invading microorganisms by the release of antimicrobial proteins such as the ribonuclease RNase 7. Because RNase 7 exhibits high activity against Enterococcus faecium the aim of this study was to further explore the role of RNase 7 in the cutaneous innate defense system against E. faecium. Methodology/Principal Findings: Absolute quantification using real-time PCR and ELISA revealed that primary keratinocytes expressed high levels of RNase 7. Immunohistochemistry showed RNase 7 expression in all epidermal layers of the skin with an intensification in the upper more differentiated layers. Furthermore, RNase 7 was secreted by keratinocytes in vitro and in vivo in a site-dependent way. RNase 7 was still active against E. faecium at low pH (5.5) or high NaCl (150 mM) concentration and the bactericidal activity of RNase 7 against E. faecium required no ribonuclease activity as shown by recombinant RNase 7 lacking enzymatic activity. To further explore the role of RNase 7 in cutaneous defense against E. faecium, we investigated whether RNase 7 contributes to the E. faecium killing activity of skin extracts derived from stratum corneum. Treatment of the skin extract with an RNase 7 specific antibody, which neutralizes the antimicrobial activity of RNase 7, diminished its E. faecium killing activity. Conclusions/Significance: Our data indicate that RNase 7 contributes to the E. faecium-killing activity of skin extracts an

A Study of B0 -> J/psi K(*)0 pi+ pi- Decays with the Collider Detector at Fermilab

We report a study of the decays B0 -> J/psi K(*)0 pi+ pi-, which involve the creation of a u u-bar or d d-bar quark pair in addition to a b-bar -> c-bar(c s-bar) decay. The data sample consists of 110 1/pb of p p-bar collisions at sqrt{s} = 1.8 TeV collected by the CDF detector at the Fermilab Tevatron collider during 1992-1995. We measure the branching ratios to be BR(B0 -> J/psi K*0 pi+ pi-) = (8.0 +- 2.2 +- 1.5) * 10^{-4} and BR(B0 -> J/psi K0 pi+ pi-) = (1.1 +- 0.4 +- 0.2) * 10^{-3}. Contributions to these decays are seen from psi(2S) K(*)0, J/psi K0 rho0, J/psi K*+ pi-, and J/psi K1(1270)

Observation of Bs-Bsbar Oscillations

We report the observation of Bs-Bsbar oscillations from a time-dependent measurement of the Bs-Bsbar oscillation frequency Delta ms. Using a data sample of 1 fb^-1 of p-pbar collisions at sqrt{s}=1.96 TeV collected with the CDF II detector at the Fermilab Tevatron, we find signals of 5600 fully reconstructed hadronic Bs decays, 3100 partially reconstructed hadronic Bs decays, and 61500 partially reconstructed semileptonic Bs decays. We measure the probability as a function of proper decay time that the Bs decays with the same, or opposite, flavor as the flavor at production, and we find a signal for Bs-Bsbar oscillations. The probability that random fluctuations could produce a comparable signal is 8 X 10^-8, which exceeds 5 sigma significance. We measure Delta ms = 17.77 +- 0.10 (stat) +- 0.07 (syst) ps^-1 and extract |Vtd/Vts| = 0.2060 +- 0.0007 (exp) + 0.0081 - 0.0060 (theor).Comment: 9 pages, 5 figures, submitted to Physical Review Letter

Forward-Backward Asymmetry in Top Quark Production in ppbar Collisions at sqrt{s}=1.96 TeV

Reconstructable final state kinematics and charge assignment in the reaction ppbar->ttbar allows tests of discrete strong interaction symmetries at high energy. We define frame dependent forward-backward asymmetries for the outgoing top quark in both the ppbar and ttbar rest frames, correct for experimental distortions, and derive values at the parton-level. Using 1.9/fb of ppbar collisions at sqrt{s}=1.96 TeV recorded with the CDF II detector at the Fermilab Tevatron, we measure forward-backward top quark production asymmetries in the ppbar and ttbar rest frames of A_{FB,pp} = 0.17 +- 0.08 and A_{FB,tt} = 0.24 +- 0.14.Comment: 7 pages, 2 figures, submitted to Phys.Rev.Lett, corrected references and change of tex