bluuebunny/crossref_metadata_2025_split huggingface dataset:
Structure‐Activity Relationships for a Series of Compounds that Inhibit Aggregation of the Alzheimer's Peptide, Aβ42
Authors: McKoy Angela F. , Chen Jermont , Schupbach Trudi , Hecht Michael H. 
Published: April 2014

Inhibiting aggregation of the amyloid‐beta (Aβ) peptide may be an effective strategy for combating Alzheimer's disease. As the high‐resolution structure of the toxic Aβ aggregate is unknown, rational design of small molecule inhibitors is not possible, and inhibitors are best isolated by high‐throughput screening. We applied high‐throughput screening to a collection of 65 000 compounds to identify compound D737 as an inhibitor of Aβ aggregation. D737 diminished the formation of oligomers and fibrils, and reduced Aβ42‐induced cytotoxicity. Most importantly, D737 increased the life span and locomotive ability of transgenic flies in a Drosophila melanogaster model of Alzheimer's disease (J Biol Chem, 287, 2012, 38992). To explore the chemical features that make D737 an effective inhibitor of Aβ42 aggregation and toxicity, we tested a small collection of eleven analogues of D737. Overall, the ability of a compound to inhibit Aβ aggregation was a good predictor of its efficacy in prolonging the life span and locomotive ability of transgenic flies expressing human Aβ42 in the central nervous system. Two compounds (D744 and D830) with fluorine substitutions on an aromatic ring were effective inhibitors of Aβ42 aggregation and increased the longevity of transgenic flies beyond that observed for the parent compound, D737.
Design, Synthesis and Biological Evaluation of Peptidyl Epoxyketone Proteasome Inhibitors Composed of β‐amino Acids
Authors: Zhang Jiankang , Han Mengmeng , Ma Xiaodong , Xu Lei , Cao Jiayi , Zhou Yubo , Li Jia , Liu Tao , Hu Yongzhou 
Published: April 2014

A series of novel di‐ and tripeptidyl epoxyketone derivatives composed of β‐amino acids were designed, synthesized and evaluated for their proteasome inhibitory activities and anti‐proliferation activities against two multiple myeloma cell lines RPMI 8226 and NCI‐H929 and normal cells (peripheral blood mononucleated cells). Among these tested compounds, tripeptidyl analogues showed much more potent activities than dipeptides, and four tripeptidyl compounds exhibited proteasome inhibitory activities with IC50 values ranging from 0.97 ± 0.05 to 1.85 ± 0.11 μm. In addition, all the four compounds showed anti‐proliferation activities with IC50 values at low micromolar levels against two multiple myeloma cell lines and weak activities against normal cells. Furthermore, Western blot analysis was performed to verify the proteasome inhibition induced by compounds 21d and 21e. All the experimental results validated that the β‐amino acid building block has the potential for the development of proteasome inhibitors.
Distinct Age‐Related Differences in Temporal Discounting and Risk Taking in Adolescents and Young Adults
Authors: de Water Erik , Cillessen Antonius H. N. , Scheres Anouk 
Published: April 2014

Age‐related differences in temporal discounting (TD) and risk taking, and their association, were examined in adolescents and young adults (n = 337) aged 12–27 years. Since monetary rewards are typically used in TD and risk‐taking tasks, the association between monetary reward valuation and age and decision making in these tasks was explored as well. TD declined linearly with age, with a particularly sharp decline from 15 to 16 years. In contrast, risk taking was not correlated with age and TD. Reward valuation was not associated with TD and risk taking, and age‐related differences in TD remained significant after controlling for reward valuation. Together, these findings suggest that risk taking and TD are two separate constructs with distinct age‐related differences in adolescence and young adulthood.
IgE antibodies to alpha‐gal in the general adult population: relationship with tick bites, atopy, and cat ownership
Authors: Gonzalez‐Quintela A. , Dam Laursen A. S. , Vidal C. , Skaaby T. , Gude F. , Linneberg A. 
Published: April 2014

SummaryBackgroundThe carbohydrate alpha‐gal epitope is present in many animal proteins, including those of red meat and animal immunoglobulins, such as cat IgA. Systemic anaphylaxis to the alpha‐gal epitope has recently been described.ObjectiveTo investigate and compare the prevalence of alpha‐gal‐specific (s)IgE and its associated factors in the general adult population from two separated (Northern and Southern) European regions (Denmark and Spain, respectively).MethodsCross‐sectional study of 2297 and 444 randomly selected adults from 11 municipalities in Denmark and one in Spain. Alpha‐gal sIgE was assessed by ImmunoCAP to bovine thyroglobulin. Additional assessments included a panel of skin prick test (SPT) to common aeroallergens and epidemiological factors, including the history of tick bites in the Danish series.ResultsThe prevalence of positive (≥ 0.1 kUA/L) sIgE to alpha‐gal was 5.5% and 8.1% in the Danish and Spanish series, respectively. The prevalence of sIgE ≥ 0.35 kUA/L was 1.8% and 2.2% in Denmark and Spain, respectively. Alpha‐gal sIgE positivity was associated with pet ownership in both series and, particularly, cat ownership (data available in the Danish series). Alpha‐gal sIgE positivity was associated with atopy (SPT positivity) in both series, although it was not associated with SPT positivity to cat or dog dander. Alpha‐gal sIgE positivity was strongly associated with a history of tick bites.Conclusions and Clinical RelevanceThe prevalence of alpha‐gal sIgE antibodies in these general adult European populations is similarly low. The presence of alpha‐gal sIgE antibodies is associated with a history of tick bites, atopy, and cat ownership.
Post-traumatic immunosuppression is reversed by anti-coagulated salvaged blood transfusion: deductions from studying immune status after knee arthroplasty
Authors: Islam N , Whitehouse M , Mehendale S , Hall M , Tierney J , O'Connell E , Blom A , Bannister G , Hinde J , Ceredig R , Bradley B A 
Published: April 2014

Summary
Major trauma increases vulnerability to systemic infections due to poorly defined immunosuppressive mechanisms. It confers no evolutionary advantage. Our objective was to develop better biomarkers of post-traumatic immunosuppression (PTI) and to extend our observation that PTI was reversed by anti-coagulated salvaged blood transfusion, in the knowledge that others have shown that non-anti-coagulated (fibrinolysed) salvaged blood was immunosuppressive.
A prospective non-randomized cohort study of patients undergoing primary total knee arthroplasty included 25 who received salvaged blood transfusions collected post-operatively into acid–citrate–dextrose anti-coagulant (ASBT cohort), and 18 non-transfused patients (NSBT cohort). Biomarkers of sterile trauma included haematological values, damage-associated molecular patterns (DAMPs), cytokines and chemokines. Salvaged blood was analysed within 1 and 6 h after commencing collection. Biomarkers were expressed as fold-changes over preoperative values. Certain biomarkers of sterile trauma were common to all 43 patients, including supranormal levels of: interleukin (IL)-6, IL-1-receptor-antagonist, IL-8, heat shock protein-70 and calgranulin-S100-A8/9. Other proinflammatory biomarkers which were subnormal in NSBT became supranormal in ASBT patients, including IL-1β, IL-2, IL-17A, interferon (IFN)-γ, tumour necrosis factor (TNF)-α and annexin-A2. Furthermore, ASBT exhibited subnormal levels of anti-inflammatory biomarkers: IL-4, IL-5, IL-10 and IL-13. Salvaged blood analyses revealed sustained high levels of IL-9, IL-10 and certain DAMPs, including calgranulin-S100-A8/9, alpha-defensin and heat shock proteins 27, 60 and 70. Active synthesis during salvaged blood collection yielded increasingly elevated levels of annexin-A2, IL-1β, Il-1-receptor-antagonist, IL-2, IL-4, IL-6, IL-8, IL-10, IL-12p70, IL-17A, IFN-γ, TNF-α, transforming growth factor (TGF)-β1, monocyte chemotactic protein-1 and macrophage inflammatory protein-1α. Elevated levels of high-mobility group-box protein-1 decreased. In conclusion, we demonstrated that anti-coagulated salvaged blood reversed PTI, and was attributed to immune stimulants generated during salvaged blood collection.
Activation of the aryl hydrocarbon receptor affects activation and function of human monocyte-derived dendritic cells
Authors: Wang C , Ye Z , Kijlstra A , Zhou Y , Yang P 
Published: April 2014

Summary
Aryl hydrocarbon receptor (AhR) is well known for mediating the toxic effects of dioxin-containing pollutants, but has also been shown to be involved in the natural regulation of the immune response. In this study, we investigated the effect of AhR activation by its endogenous ligands 6-formylindolo[3,2-b]carbazole (FICZ) and 2-(1′H-indole-3′-carbonyl)-thiazole-4-carboxylic acid methyl ester (ITE) on the differentiation, maturation and function of monocyte-derived DCs in Behçet's disease (BD) patients. In this study, we showed that AhR activation by FICZ and ITE down-regulated the expression of co-stimulatory molecules including human leucocyte antigen D-related (HLA-DR), CD80 and CD86, while it had no effect on the expression of CD83 and CD40 on DCs derived from BD patients and normal controls. Lipopolysaccharide (LPS)-treated dendritic cells (DCs) from active BD patients showed a higher level of interleukin (IL)-1β, IL-6, IL-23 and tumour necrosis factor (TNF)-α production. FICZ or ITE significantly inhibited the production of IL-1β, IL-6, IL-23 and TNF-α, but induced IL-10 production by DCs derived from active BD patients and normal controls. FICZ or ITE-treated DCs significantly inhibited the T helper type 17 (Th17) and Th1 cell response. Activation of AhR either by FICZ or ITE inhibits DC differentiation, maturation and function. Further studies are needed to investigate whether manipulation of the AhR pathway may be used to treat BD or other autoimmune diseases.
Helminths in the hygiene hypothesis: sooner or later?
Authors: Maizels R M , McSorley H J , Smyth D J 
Published: April 2014

SummaryThere is increasing recognition that exposures to infectious agents evoke fundamental effects on the development and behaviour of the immune system. Moreover, where infections (especially parasitic infections) have declined, immune responses appear to be increasingly prone to hyperactivity. For example, epidemiological studies of parasite-endemic areas indicate that prenatal or early-life experience of infections can imprint an individual's immunological reactivity. However, the ability of helminths to dampen pathology in established inflammatory diseases implies that they can have therapeutic effects even if the immune system has developed in a low-infection setting. With recent investigations of how parasites are able to modulate host immune pathology at the level of individual parasite molecules and host cell populations, we are now able to dissect the nature of the host–parasite interaction at both the initiation and recall phases of the immune response. Thus the question remains – is the influence of parasites on immunity one that acts primarily in early life, and at initiation of the immune response, or in adulthood and when recall responses occur? In short, parasite immunosuppression – sooner or later?
Human CD4+CD39+ regulatory T cells produce adenosine upon co-expression of surface CD73 or contact with CD73+ exosomes or CD73+ cells
Authors: Schuler P J , Saze Z , Hong C-S , Muller L , Gillespie D G , Cheng D , Harasymczuk M , Mandapathil M , Lang S , Jackson E K , Whiteside T L 
Published: April 2014

SummaryWhile murine CD4+CD39+ regulatory T cells (Treg) co-express CD73 and hydrolyze exogenous (e) adenosine triphosphate (ATP) to immunosuppressive adenosine (ADO), surface co-expression of CD73 on human circulating CD4+CD39+Treg is rare. Therefore, the ability of human Treg to produce and utilize ADO for suppression remains unclear. Using mass spectrometry, we measured nucleoside production by subsets of human CD4+CD39+ and CD4+CD39(–)CD73+T cells or CD19+B cells isolated from blood of 30 volunteers and 14 cancer patients. CD39 and CD73 expression was evaluated by flow cytometry, Western blots, confocal microscopy or reverse transcription–polymerase chain reaction (RT–PCR). Circulating CD4+CD39+Treg which hydrolyzed eATP to 5′-AMP contained few intracytoplasmic granules and had low CD73 mRNA levels. Only ∼1% of these Treg were CD39+CD73+. In contrast, CD4+CD39negCD73+T cells contained numerous CD73+ granules in the cytoplasm and strongly expressed surface CD73. In vitro-generated Treg (Tr1) and most B cells were CD39+CD73+. All these CD73+T cell subsets and B cells hydrolyzed 5′-AMP to ADO. Exosomes isolated from plasma of normal control (NC) or cancer patients carried enzymatically active CD39 and CD73+ and, when supplied with eATP, hydrolyzed it to ADO. Only CD4+CD39+Treg co-incubated with CD4+CD73+T cells, B cells or CD39+CD73+ exosomes produced ADO. Thus, contact with membrane-tethered CD73 was sufficient for ADO production by CD4+CD39+Treg. In microenvironments containing CD4+CD73+T cells, B cells or CD39+CD73+ exosomes, CD73 is readily available to CD4+CD39+CD73negTreg for the production of immunosuppressive ADO.
Rebamipide attenuates autoimmune arthritis severity in SKG mice via regulation of B cell and antibody production
Authors: Byun J-K , Moon S-J , Jhun J-Y , Kim E-K , Park J-S , Youn J , Min J-K , Park S-H , Kim H-Y , Cho M-L 
Published: April 2014

Summary
Oxidative stress is involved in the pathophysiology of rheumatoid arthritis (RA). We investigated the therapeutic potential of rebamipide, a gastroprotective agent with a property of reactive oxygen species scavenger, on the development of inflammatory polyarthritis and the pathophysiological mechanisms by which rebamipide might confer anti-arthritic effects in SKG mice, an animal model of RA. Intraperitoneal (i.p.) injection of rebamipide attenuated the severity of clinical and histological arthritis. Rebampide treatment reduced the number of T helper type 1 (Th1), Th2, Th17, inducible T cell co-stimulator (ICOS)+ follicular helper T (Tfh) transitional type (T2) and mature B cells in the spleen, but increased the number of regulatory T (Treg), CD19+ CD1dhigh CD5high, CD19+ CD25high forkhead box protein 3 (FoxP3)+ regulatory B (Breg) cells, memory B cells, and transitional type 1 (T1) B cells. In addition, flow cytometric analysis revealed significantly decreased populations of FAS+ GL-7+ germinal centre B cells and B220− CD138+ plasma cells in the spleens of rebamipide-treated SKG mice compared to controls. Rebamipide decreased germinal centre B cells and reciprocally induced Breg cells in a dose-dependent manner in vitro. Rebamipide-induced Breg cells had more suppressive capacity in relation to T cell proliferation and also inhibited Th17 differentiation from murine CD4+ T cells. Together, these data show that i.p. administration of rebamipide suppresses arthritis severity by inducing Breg and Treg cells and suppressing Tfh and Th17 cells in a murine model of RA.
Differentiating the location of cervical lymph node metastasis is very useful for estimating the risk of distant metastases in papillary thyroid carcinoma
Authors: Jeon Min Ji , Kim Tae Yong , Kim Won Gu , Han Ji Min , Jang Eun Kyung , Choi Yun Mi , Song Dong Eun , Yoon Jong Ho , Chung Ki‐Wook , Hong Suck Joon , Shong Young Kee , Kim Won Bae 
Published: April 2014

SummaryObjectiveA larger primary tumour size, greater numbers of cervical lymph node (LN) metastasis are associated with a higher risk of distant metastases in papillary thyroid carcinoma (PTC). However, the impact of the location of cervical LN metastasis on distant metastasis is controversial. The aim of this study was to evaluate the risk of distant metastases according to the tumour size and LN status in PTC patients, with special consideration of the LN metastasis pattern.PatientsThis retrospective cohort study reviewed 1700 classical PTC patients who underwent initial thyroid surgery at Asan Medical Center between 2000 and 2004.ResultsThe cumulative risk of distant metastases was increased with the increase in tumour size and was significantly different according to the location of involved LNs by the tumour node metastasis (TNM) staging. The cumulative risk in pN1b group showed the steepest increasing pattern with the increase in tumour size compared with pN1a and pN0/Nx group. When we analysed the cumulative risk of distant metastases according to the number of involved LNs, patients with more than 20 involved LNs also had the steepest increase in the risk of distant metastases with the increase in tumour size. However, only the location of involved LNs, not the number of involved LNs, was associated with distant metastases in multivariate analysis.ConclusionsWe confirm that the location of involved LNs categories based on the TNM staging system is more useful than the number of involved LNs categories for estimating the risk of distant metastasis in PTC. Differentiating N1a disease from N1b disease is important for the follow‐up and management of patients with PTC.
Preclinic investigations accelerate decision‐making, reduce delays in treatment and are highly popular with endocrinology patients and staff
Authors: Srinivas V. , Gomez J. , Kerry S. , Swords F.M. 
Published: April 2014

SummaryObjectiveEndocrine diagnosis relies on a thorough history, examination and confirmatory biochemical tests. Previously, in our unit, tests were performed after new patients attended clinic. We proposed that diagnosis and management would be improved if this system was inverted.DesignClinicians and chemical pathologists reviewed available guidance and local practice to determine the key tests to confirm or refute most common endocrine disorders. A system was developed for clinicians to categorize new referrals into diagnostic groups: for example, nodular thyroid disease or possible polycystic ovarian syndrome. Standard letters were developed and sent to patients explaining the requirement for tests to be performed prior to first hospital appointment. The letters and requests for investigation sets were standardized for each diagnostic group and generated via a one‐click automated method.After one year, clinical outcomes were audited and patients and staff surveyed.ResultsThe time from referral to confirming diagnosis and starting treatment was halved: mean 11·8–5·7 weeks (P < 0·001). Acute patients were also discharged from clinic earlier: mean 17 to 10·3 weeks (P < 0·005).Ninety four percent patients surveyed had their tests performed easily prior to attending their appointment. Hundred per cent of patients, 100% of hospital staff and 93% referring general practitioners who responded felt the system improved patient care and should continue.ConclusionsPerforming investigations prior to new patient appointments is practical, popular with staff and patients and has dramatically improved our referral to treatment statistics by reducing delays prior to diagnosis. This system could be used as a model for other departments.
Metabolic and hormonal contributors to survival in the participants of the Mataró Ageing Study at 8 years follow‐up
Authors: Mora Mireia , Serra‐Prat Mateu , Palomera Elisabet , Puig‐Domingo Manel 
Published: April 2014

SummaryObjectiveAgeing is a physiological process that may be influenced by genetic factors as well as metabolic and hormonal determinants. The aim was to describe metabolic and hormonal factors related to survival in the cohort of non‐institutionalized people aged >70 years old of the Mataró Ageing Study.Design and methods313 individuals were included and followed‐up during 8 years. Metabolic syndrome (MS) parameters by International Diabetes Federation and ATP‐III as well as hormonal factors (TSH, free‐T4, growth hormone, IGF‐I, ghrelin, cortisol, dehidroepiandrosterone –DHEA‐, DHEAs, testosterone, SHBG, estradiol, estrone, cortisol/DHEA and cortisol/DHEAs) were studied and their relationship with survival was assessed.ResultsAt 8 year of follow‐up, 96 out of 313 subjects (30·7%) died. No association between MS and its components and survival was found. However, when abdominal perimeter was analyzed according to distribution in quartiles and categorized by gender, the lowest and highest quartile showed higher mortality (P = 0·009; waist circumference (WC) between 98–102 cm in men and 95–102 cm in women were associated to lower mortality). In men, IGF‐I, estrone, cortisol/DHEA ratio and cortisol/DHEAs ratio were lower in survivors, and in women, growth hormone and ghrelin were higher in survivors and cortisol/DHEAs ratio was lower. When Cox regression was performed for survival analysis of the whole cohort (adjusting by age, gender, tobacco consumption and WC, cortisol (B = 0·036, P = 0·033), estrone (B = 0·014, P = 0·004) and cortisol/DHEA ratio (B = 0·018, P = 0·008) were significantly associated to mortality. Sequential adjustments including additionally in the model Lawton scale, MiniNutritional Assessment and MCE showed significant association to estrone (P = 0·018).ConclusionsWaist circumference in a U‐shaped relationship, together with hormonal factors (adrenal steroids and somatotropic axis) influenced survival in individuals participating in Mataró Ageing Study.
Relationship between insulin sensitivity and bone mineral density in primary hyperparathyroidism
Authors: Gianotti Laura , Tassone Francesco , Baffoni Claudia , Pellegrino Micaela , Cassibba Sara , Castellano Elena , Magro Gianpaolo , Cesario Flora , Visconti Gianluca , Borretta Giorgio 
Published: April 2014

SummaryIntroductionEvidence of crosstalk between bone and insulin metabolism has been identified. In primary hyperparathyroidism (PHPT), scant data exist on this relationship.AimTo evaluate the relationship between insulin levels or sensitivity and bone mineral density (BMD) in PHPT.Subject and MethodsTwo hundred and sixty‐seven patients with PHPT without known diabetes mellitus were studied. Fasting blood glucose and insulin levels as well as BMD at lumbar spine, femoral neck and forearm were measured. Insulin sensitivity was assessed using Quantitative Insulin Sensitivity Check Index (QUICKI). The same parameters were measured 2 years (interquartile range 2·8 years) after surgery (PTX) in a subgroup of patients (n = 51).ResultsIn univariate analysis, a positive relationship between insulin levels and BMD (R = 0·17, P < 0·03) or T‐score (R = 0·20, P < 0·005) was found at femoral neck level. Consequently, a negative relationship between QUICKI and femoral BMD (R = −0·20, P < 0·01) or T‐score (R = −0·21, P < 0·004) was found. In multivariate analysis, when femoral BMD was the dependent variable, age (beta = −0·35, P < 0·000004), BMI (beta = 0·39, P < 0·00001), PTH (beta = −0·18, P < 0·05) and QUICKI (R = −0·15, P < 0·05) had an independent effect (R2 = 0·29). Insulin levels and QUICKI did not change after PTX. No relationship was found between QUICKI or insulin levels at the time of diagnosis and change in BMD at any site at follow‐up.ConclusionsOur data show a weak relationship between insulin levels and/or insulin sensitivity and BMD in PHPT. However, the insulin state does not influence change in bone density after PTX in PHPT.