bluuebunny/crossref_metadata_2025 huggingface dataset:
Long‐term follow‐up and second malignancies in 487 patients with hairy cell leukaemia
Authors: Cornet Edouard , Tomowiak Cécile , Tanguy‐Schmidt Aline , Lepretre Stéphane , Dupuis Jehan , Feugier Pierre , Devidas Alain , Mariette Clara , Leblond Véronique , Thiéblemont Catherine , Validire‐Charpy Patricia , Sutton Laurent , Gyan Emmanuel , Eisenmann Jean‐Claude , Cony‐Makhoul Pascale , Ysebaert Loïc , Troussard Xavier ,   the Société Française d'Hématologie
Published: April 2014

A large, multicentre, retrospective survey of patients with hairy cell leukaemia (HCL) was conducted in France to determine the frequency of second malignancies and to analyse the long‐term effects of the established purine nucleoside analogues (PNAs), cladribine and pentostatin. The survey retrospectively reviewed the medical history of patients and their immediate family, clinical and biological presentation at the time of HCL diagnosis, treatment choice, response to treatment, time to relapse and cause of death. Data were collected for 487 patients with HCL. Of the patients included in the survey, 18% (88/487) had a familial history of cancers, 8% (41/487) presented with malignancies before HCL diagnosis and 10% (48/487) developed second malignancies after HCL was diagnosed. An excess incidence of second malignancies was observed, with a standardized incidence ratio (SIR) of 1·86 (95% confidence interval (CI): 1·34–2·51), with no significant difference between PNAs. For second haematological malignancies alone, the SIR was markedly increased at 5·32 (95% CI: 2·90–8·92). This study highlights the high frequency of cancers in HCL patients and their family members. The frequency of second malignancies is notably increased, particularly for haematological malignancies. The respective role of pentostatin and cladribine in the development of second malignancies is debatable.
A search for meaning: telling your life with learning disabilities
Authors: Horn Jaime Helena , Moss Duncan
Published: April 2014

Accessible summary

This article describes one woman's experience of living life with a learning disability.

It gives a summary of research into this area.

It describes a narrative approach.

This research is important as it helps us to understand the experiences of people with learning disabilities.

Research has identified the collective experiences of oppression, stigma and isolation in the lives of people with learning disabilities. Against the backdrop of social and cultural processes that shape and limit the life experiences of people with learning disabilities, the authors are interested in how the individual develops a sense of self and identity. The aim is to further understand the subjective world of one woman with learning disabilities, drawing attention to how meaning about herself and her world has been constructed. The authors present and analyse one woman's life story, adopting a narrative and participatory research approach, with its focus on personal experience, whilst making links between the individual and social world.
Inhibition of proteasome‐mediated glucocorticoid receptor degradation restores nitric oxide bioavailability in myocardial endothelial cells in vitro
Authors: Blecharz Kinga G. , Burek Malgorzata , Bauersachs Johann , Thum Thomas , Tsikas Dimitrios , Widder Julian , Roewer Norbert , Förster Carola Y.
Published: April 2014

Background Information

Glucocorticoids (GCs), including the synthetic GC derivate dexamethasone, are widely used as immunomodulators. One of the numerous side effects of dexamethasone therapy is hypertension arising from reduced release of the endothelium‐derived vasodilator nitric oxide (NO).

Results

Herein, we described the role of dexamethasone and its glucocorticoid receptor (GR) in the regulation of NO synthesis in vitro using the mouse myocardial microvascular endothelial cell line, MyEND. GC treatment caused a firm decrease of extracellular NO levels, whereas the expression of endothelial NO synthase (eNOS) was not affected. However, GC application induced an impairment of tetrahydrobiopterin (BH4) concentrations as well as GTP cyclohydrolase‐1 (GTPCH‐1) expression, both essential factors for NO production upstream of eNOS. Moreover, dexamethasone stimulation resulted in a substantially decreased GR gene and protein expression in MyEND cells. Importantly, inhibition of proteasome‐mediated proteolysis of the GR or overexpression of an ubiquitination‐defective GR construct improved the bioavailability of BH4 and strengthened GTPCH‐1 expression and eNOS activity.

Conclusions

Summarising our results, we propose a new mechanism involved in the regulation of NO signalling by GCs in myocardial endothelial cells. We suggest that a sufficient GR protein expression plays a crucial role for the management of GC‐induced harmful adverse effects, including deregulations of vasorelaxation arising from disturbed NO biosynthesis.
Role of cues and contexts on drug‐seeking behaviour
Authors: Perry Christina J , Zbukvic Isabel , Kim Jee Hyun , Lawrence Andrew J
Published: April 2014

Environmental stimuli are powerful mediators of craving and relapse in substance‐abuse disorders. This review examined how animal models have been used to investigate the cognitive mechanisms through which cues are able to affect drug‐seeking behaviour. We address how animal models can describe the way drug‐associated cues come to facilitate the development and persistence of drug taking, as well as how these cues are critical to the tendency to relapse that characterizes substance‐abuse disorders. Drug‐associated cues acquire properties of conditioned reinforcement, incentive motivation and discriminative control, which allow them to influence drug‐seeking behaviour. Using these models, researchers have been able to investigate the pharmacology subserving the behavioural impact of environmental stimuli, some of which we highlight. Subsequently, we examine whether the impact of drug‐associated stimuli can be attenuated via a process of extinction, and how this question is addressed in the laboratory. We discuss how preclinical research has been translated into behavioural therapies targeting substance abuse, as well as highlight potential developments to therapies that might produce more enduring changes in behaviour.

Linked Articles

This article is part of a themed section on Animal Models in Psychiatry Research. To view the other articles in this section visithttp://dx.doi.org/10.1111/bph.2014.171.issue‐20
Olmesartan prevents cardiac rupture in mice with myocardial infarction by modulating growth differentiation factor 15 and p53
Authors: Chen Baihe , Lu Di , Fu Yujuan , Zhang Jingwen , Huang Xiaobo , Cao Shiping , Xu Dingli , Bin Jianping , Kitakaze Masafumi , Huang Qiaobing , Liao Yulin
Published: April 2014

Background and Purpose

Cardiac rupture is a catastrophic complication that occurs after acute myocardial infarction (MI) and, at present, there are no effective pharmacological strategies for preventing this condition. Here we investigated the effect of the angiotensin II receptor blocker olmesartan (Olm) on post‐infarct cardiac rupture and its underlying mechanisms of action.

Experimental Approach

C57Bl/6 mice with MI were treated with Olm, aldosterone (Aldo) or vehicle. Cultured neonatal cardiomyocytes and fibroblasts were exposed to normoxia or anoxia and treated with angiotensin II (Ang II), RNH6270 (active ingredient of Olm) or Aldo.

Key Results

The mortality rate and incidence of cardiac rupture in MI mice during the first week in the Olm‐treated group were significantly lower than in the vehicle‐treated group. Olm or RNH6270 reduced myeloperoxidase staining in the infarcted myocardium, decreased apoptosis in cultured cardiomyocytes and fibroblasts, as assessed by Hoechst staining and TUNEL assay, attenuated the accumulation of p53 and phosphorylated p53 and cleaved caspase 3 induced by MI or Ang II, as assessed by Western blotting, and up‐regulated growth differentiation factor‐15 (GDF‐15). In cultured cardiomyocytes and fibroblasts, treatment with Ang II, Aldo or anoxia significantly down‐regulated the expression of GDF‐15.

Conclusions and Implications

Olm prevents cardiac rupture through inhibition of apoptosis and inflammation, which is attributable to the down‐regulation of p53 activity and up‐regulation of GDF‐15. Our findings suggest that early administration of an AT1 receptor anatagonist to patients with acute MI is a potential preventive approach for cardiac rupture.
Nonsuicidal self‐injury as an affect‐regulation strategy and the moderating role of impulsivity
Authors: Di Pierro Rossella , Sarno Irene , Gallucci Marcello , Madeddu Fabio
Published: April 2014

Background

Nonsuicidal self‐injury (NSSI) is used to cope with negative affect states. We investigated the association between impulsivity and this affect‐regulation process.

Method

Affect states associated with NSSI and impulsivity traits were evaluated in 30 Italian adolescent self‐injurers (63.3% female, mean age = 16.63, SD = 0.56).

Results

Nonsuicidal self‐injury was associated with decreases in affective arousal, but impulsivity moderated other affective changes. High impulsivity was associated with increases in negative high‐arousal affects after NSSI, whereas low impulsivity was associated with increases in positive affects after NSSI.

Conclusion

Impulsivity traits influenced the success or failure of the NSSI affect‐regulation process.
Synthesis and Antitubercular Screening of [(2‐Chloroquinolin‐3‐yl)methyl] Thiocarbamide Derivatives
Authors: Kumar Suresh , Upmanyu Neeraj , Afzal Obaid , Bawa Sandhya
Published: April 2014

A series of 1‐(substituted‐phenyl)‐1‐[(2‐chloroquinolin‐3‐yl)methyl]thiocarbamide and 1‐(substituted‐phenyl)‐1‐[(2‐chloroquinolin‐3‐yl)methyl]methylthiocarbamide derivatives was synthesized as antitubercular agent. The structure of quinolinyl amines and their thiocarbamide derivatives were established on the basis of IR, 1H and 13C‐NMR and mass spectral data. All the compounds were tested in vitro for antimycobacterial activity against Mycobacterium tuberculosis (ATCC‐25177) in Lowenstein‐Jensen medium by well diffusion method and MIC by twofold serial dilution method. Results of the antitubercular screening revealed that compounds showed moderate to good antitubercular activity. Compound having two halogens in the phenyl rings viz. 3g, 3h, 4g, and 4h exhibited MIC of 50 μg/mL. The computational parameters relevant to absorption and permeation of target compounds were also calculated and found to be well correlated with antitubercular activity.
Design, Synthesis, Anti‐Tobacco Mosaic Virus (TMV) Activity, and SARs of 7‐Methoxycryptopleurine Derivatives
Authors: Wang Ziwen , Feng Anzheng , Cui Mingbo , Liu Yuxiu , Wang Lizhong , Wang Qingmin
Published: April 2014

A series of 7‐methoxycryptopleurine derivatives 2–23 were prepared and evaluated for their antiviral activity against tobacco mosaic virus (TMV) for the first time. The bioassay results showed that most of these compounds exhibited excellent in vivo anti‐TMV activity, of which 7‐methoxycryptopleurine salt derivatives 16, 19, and 23 displayed significantly higher activity than 7‐methoxycryptopleurine (1) and commercial ribavirin and ningnanmycin. Salification, the most commonly employed method for modifying physical‐chemical properties, did significantly increase antiviral activity, and different salt forms displayed different antiviral effect. This study provides fundamental support for development and optimization of phenanthroquinolizidine alkaloids as potential inhibitors of plant virus.
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.
Infants Segment Continuous Events Using Transitional Probabilities
Authors: Stahl Aimee E. , Romberg Alexa R. , Roseberry Sarah , Golinkoff Roberta Michnick , Hirsh‐Pasek Kathryn
Published: April 2014

Throughout their 1st year, infants adeptly detect statistical structure in their environment. However, little is known about whether statistical learning is a primary mechanism for event segmentation. This study directly tests whether statistical learning alone is sufficient to segment continuous events. Twenty‐eight 7‐ to 9‐month‐old infants viewed a sequence of continuous actions performed by a novel agent in which there were no transitional movements that could have constrained the possible upcoming actions. At test, infants distinguished statistically intact units from less predictable ones. The ability to segment events using statistical structure may help infants discover other cues to event boundaries, such as intentions, and carve up the world of continuous motion in meaningful ways.
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

Background

The 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.

Objective

To 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).

Methods

Cross‐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.

Results

The 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 Relevance

The 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

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

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

There 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

While 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

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

Objective

A 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.

Patients

This retrospective cohort study reviewed 1700 classical PTC patients who underwent initial thyroid surgery at Asan Medical Center between 2000 and 2004.

Results

The 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.

Conclusions

We 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

Objective

Endocrine 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.

Design

Clinicians 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.

Results

The 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.

Conclusions

Performing 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

Objective

Ageing 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 methods

313 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.

Results

At 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).

Conclusions

Waist 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

Introduction

Evidence of crosstalk between bone and insulin metabolism has been identified. In primary hyperparathyroidism (PHPT), scant data exist on this relationship.

Aim

To evaluate the relationship between insulin levels or sensitivity and bone mineral density (BMD) in PHPT.

Subject and Methods

Two 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).

Results

In 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.

Conclusions

Our 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.
Occurrence of giant focal forms of congenital hyperinsulinism with incorrect visualization by 18F DOPA‐PET/CT scanning
Authors: Kühnen Peter , Matthae Ritana , Arya Ved , Hauptmann Kathrin , Rothe Karin , Wächter Simon , Singer Michael , Mohnike Wolfgang , Eberhard Traugott , Raile Klemens , Lauffer Lina M. , Iakoubov Roman , Hussain Khalid , Blankenstein Oliver
Published: April 2014

Context

Congenital hyperinsulinism (CHI) is a rare disease characterized by severe hypoglycaemic episodes due to pathologically increased insulin secretion from the pancreatic beta cells. When untreated, CHI might result in irreversible brain damage and death. Currently, two major subtypes of CHI are known: a focal form, associated with local distribution of affected beta cells and a nonfocal form, affecting every single beta cell. The identification of focal forms is important, as the patients can be cured by limited surgery. 18F DOPA‐PET/CT is an established non‐invasive approach to differentiate focal from nonfocal CHI.

Objective

The purpose of this study was to identify possible limitations of 18F DOPA‐PET/CT scan in patients with focal forms nonfocal CHI.

Design

A retrospective chart review of 32 patients (from 2008 through 2013) who underwent 18F DOPA‐PET/CT and partial pancreatectomy for focal CHI at the reference centres in Berlin, Germany and London, UK.

Results

In most cases (n = 29, 90·7%), 18F DOPA‐PET/CT was sufficient to localize the complete focal lesion. However, in some patients (n = 3, 9·3%), 18F DOPA‐PET/CT wrongly visualized only a small portion of the focal lesion. In this group of patients, a so‐called ‘giant focus’ was detected in histopathological analysis during the surgery.

Conclusions

Our data show that in most patients with focal CHI 18F DOPA‐PET/CT correctly predicts the size and anatomical localisation of the lesion. However, in those patients with a ‘giant focal’ lesion 18F DOPA‐PET/CT is unreliable for correct identification of ‘giant focus’ cases.
Current concepts in the diagnosis and management of type 1 gastric neuroendocrine neoplasms
Authors: Kaltsas Gregory , Grozinsky‐Glasberg Simona , Alexandraki Krystallenia I. , Thomas Dimitrios , Tsolakis Apostolos V. , Gross David , Grossman Ashley B.
Published: April 2014

The vast majority of gastrin‐related gastrointestinal neuroendocrine neoplasms (GI‐NENs) develop in the context of chronic atrophic gastritis (type 1), a condition closely related to autoimmune thyroid diseases. These neoplasms are defined as gastricNENs type 1 (GNEN1) and have recently been shown to constitute the commonestGI‐NENs in a prospective study. GNEN1s are usually multiple and follow a relative indolent course, raising questions regarding the extent that such patients should be investigated and the appropriate therapeutic interventions needed. Recently, a number of consensus statements and guidelines have been published from various societies dealing with the diagnosis and management ofGI‐NENs. Endocrinologists are among the many different medical specialties involved in GNEN1s diagnosis and management. However, despite recent advances, few randomized trials are available, and thus existing evidence remains relatively weak compared to other malignancies. The purpose of this review is to provide recent evidence along with currently employed modalities addressing the diagnosis, management, long‐term follow‐up and potential comorbidities ofGNEN1s.
Efficacy and safety of growth hormone treatment in adults with growth hormone deficiency: a systematic review of studies on morbidity
Authors: van Bunderen Christa C. , van Varsseveld Nadège C. , Erfurth Eva Marie , Ket Johannes C.F. , Drent Madeleine L.
Published: April 2014

Due to the positive effects demonstrated in randomized clinical trials on cardiovascular surrogate markers and bone metabolism, a positive effect of growth hormone (GH) treatment on clinically relevant end‐points seems feasible. In this review, we discuss the long‐term efficacy and safety of GH treatment in adult patients with growth hormone deficiency (GHD) with emphasis on morbidity: fatal and nonfatal cardiovascular disease (CVD) and stroke, fractures, fatal and nonfatal malignancies and recurrences, and diabetes mellitus. A positive effect of GH treatment on CVD and fracture risk could be concluded, but study design limitations have to be considered. Stroke and secondary brain tumours remained more prevalent. However, other contributing factors have to be taken into account. Regrowth and recurrences of (peri)pituitary tumours were not increased in patients with GH treatment compared to similar patients without GH treatment. All fatal and nonfatal malignancies were not more prevalent in GH‐treated adults compared to the general population. However, follow‐up time is still relatively short. The studies on diabetes are difficult to interpret, and more evidence is awaited. In clinical practice, a more individualized assessment seems appropriate, taking into consideration the underlying diagnosis of GHD, other treatment regimens, metabolic profile and the additional beneficial effects of GH set against the possible risks. Large and thoroughly conducted observational studies are needed and seem the only feasible way to inform the ongoing debate on health care costs, drug safety and clinical outcomes.
Innovative personalized medicine in gastric cancer: time to move forward
Authors: Lee J. , Kim K.‐M. , Kang W.K. , Ou S.‐H.I.
Published: April 2014

Globally, gastric cancer (GC) is the second leading cancer cause of death. To date, only one targeted therapy trial generated positive survival outcomes in a selected population among many targeted therapy trials. This trial showed the addition of trastuzumab to fluoropyrimidine/platinum chemotherapy as first‐line chemotherapy for human epidermal growth factor receptor 2 (HER2)‐positive GC that resulted in an overall survival (OS) benefit. The increasing use of next generation sequencing approach to genomically profile GC patients allows the identification of many more GC patients who could benefit from specific targeted agents. Here we provide a comprehensive review of targeted therapy trials in GC and discuss future potential actionable driver mutations in GC.
Quality of total mesorectal excision and depth of circumferential resection margin in rectal cancer: a matched comparison of the first 20 robotic cases
Authors: Barnajian M. , Pettet D. , Kazi E. , Foppa C. , Bergamaschi R.
Published: April 2014

Aim

There are concerns about the impact of robotic proctectomy on the quality of total mesorectal excision (TME) and the impact of laparoscopic proctectomy on the depth of the circumferential resection margin (CRM). The aim of this study was to compare the first 20 consecutive robotic proctectomies performed in our unit with matched series of open and laparoscopic proctocolectomy performed by the same surgeon.

Method

Data on the first 20 consecutive patients treated with robotic proctectomy for rectal cancer, <12 cm from the anal verge, by the senior author (RB) were extracted from a prospectively maintained database. Groups of patients treated with open and laparoscopic proctectomy, matched for age, gender and body mass index (BMI) with those undergoing robotic proctectomy, were selected. The quality of the TME was judged as complete, nearly complete or incomplete. CRM clearance was reported in millimetres. Physiological parameters and operative severity were assessed.

Results

Age (P = 0.619), Physiological and Operative Severity Score for the Enumeration of Morbidity and Mortality (POSSUM) score (P = 0.657), operative severity score (P = 0.977), predicted mortality (P = 0.758), comorbidities (P = 0.427), previous abdominal surgery (P = 0.941), tumour height (P = 0.912), location (P = 0.876), stage (P = 0.984), neoadjuvant chemoradiation (P = 0.625), operating time (P = 0.066), blood loss (P = 0.356), ileostomy (P = 0.934), conversion (P = 0.362), resection type (P = 1.000), flatus (P = 0.437), diet (P = 0.439), length of hospital stay (P = 0.978), complications (P = 0.671), reoperations (P = 0.804), reinterventions (P = 0.612), readmissions (P = 0.349), tumour size (P = 0.542; P = 0.532; P = 0.238), distal margin (P = 0.790), nodes harvested (P = 0.338) and pathology stage (P = 0.623) did not differ among the three groups. The quality of TME showed a trend to be lower following robotic surgery, although this was not statistically significant [open 95/5/15 (complete/nearly complete/incompete) vs laparoscopic 95/5/15 vs robotic 80/5/15; P = 0.235], but the degree of clearance at the CRM was significantly greater in robotic patients [open 8 (0–30) mm vs laparoscopic 4 (0–30) mm vs robotic 10.5 (1–30) mm; P = 0.02].

Conclusion

The study reports no statistically significant difference between open and laparoscopic techniques in the quality of TME during the learning curve of robotic proctectomy for rectal cancer and demonstrates an improved CRM.
Foam properties and application in dyeing cotton fabrics with reactive dyes
Authors: Yu Hong , Wang Yuanfeng , Zhong Yi , Mao Zhiping , Tan Sisi
Published: April 2014

The foam dyeing of cotton fabric with CI Reactive Red 120 has been studied as a low‐add‐on technology. The foamability of different types of foaming agent and the stability of foam stabilisers were compared. Factors influencing foam dyeing, including wet pick‐up, fixation agent, foam stabiliser, and blow ratio, were evaluated by colour strength and dye fixation rate. Wet pick‐up, fixation agent, and foam stabiliser were found to be the main factors in the foam dyeing process. The comparative build‐up properties, dyeing properties, and total consumption between foam dyeing and conventional dyeing were assessed. The results indicate that, in foam dyeing, the dyestuff has a better build‐up property, the dyed fabric has excellent wash and rub fastness, and large amounts of water and energy are saved. Moreover, foam dyeing requires smaller dosages of chemical agents and reduces the difficulty of effluent treatment.
Treatment of textile dyeing wastewater by electrocoagulation using Fe and Al electrodes: optimisation of operating parameters using central composite design
Authors: Kobya Mehmet , Gengec Erhan , Sensoy Mehmet Tonay , Demirbas Erhan
Published: April 2014

Textile dyeing wastewater was treated by electrocoagulation using aluminium and iron plate electrodes. Response surface methodology and central composite design were applied in the experiments and in statistical data analysis. A current density of 30–100 A m−2, an initial pH of 4–8, and an operating time of 10–40 min were chosen as independent variables, and the chemical oxygen demand, total organic carbon, and turbidity removal efficiencies and the operating cost were selected as responses in the electrocoagulation process. The developed quadratic models for the responses and the experimental data were in good agreement with model predictions statistically (R2 ≥ 0.92, Adj R2 ≥ 0.82, and Prob > F < 0.004). The optimised operating variables (initial pH, current density, and operating time) and the maximum total organic carbon, chemical oxygen demand, and turbidity removal efficiencies for textile dyeing wastewater were 5.5, 63.2 A m−2, 30.4 min, 77%, 82%, and 94% for the iron electrode and 5.6, 52.5 A m−2, 33.9 min, 68%, 69% and 99% for the aluminium electrode respectively. Minimum operating costs for the iron and aluminium electrodes under optimum conditions were €2.1 m−3 (€1.0 kg−1 COD) and €2.4 m−3 (€1.6 kg−1 COD). The iron electrode was found to be superior to the aluminium electrode in terms of removal efficiencies and operating cost for the treatment of textile dyeing wastewater.