bluuebunny/crossref_metadata_2025 huggingface dataset:
The hydrogen sulfide donor, GYY4137, exhibits anti‐atherosclerotic activity in high fat fed apolipoprotein E−/− mice
Authors: Liu Zhen , Han Yi , Li Ling , Lu Hui , Meng Guoliang , Li Xiaozhen , Shirhan Mohammed , Peh Meng Teng , Xie Liping , Zhou Suming , Wang Xiaowei , Chen Qi , Dai Weilu , Tan Choon‐Hong , Pan Shiyang , Moore Philip K , Ji Yong
Published: May 2013

Background and Purpose

Atherosclerosis is associated with reduced vascular hydrogen sulfide (H2S) biosynthesis. GYY4137 is a novel slow‐releasing H2S compound that may effectively mimic the time course of H2S release in vivo. However, it is not known whether GYY4137 affects atherosclerosis.

Experimental Approach

RAW 264.7 cells and human blood monocyte‐derived macrophages were incubated with oxidized low density lipoprotein (ox‐LDL) with/without GYY4137. ApoE−/− mice were fed a high‐fat diet for 4 weeks and administered GYY4137 for 30 days. Lipid and atherosclerotic lesions were measured by oil red O staining. Endothelium‐dependent relaxation was assessed in response to acetylcholine. Superoxide production was detected by dihydroethidium staining. Expression of mRNA and protein were evaluated by quantitative real‐time PCR and Western blot.

Key Results

GYY4137 inhibited ox‐LDL‐induced foam cell formation and cholesterol esterification in cultured cells. GYY4137 decreased the expression of lectin‐like ox‐LDL receptor‐1, iNOS, phosphorylated IκBα, NF‐κB, ICAM‐1, VCAM‐1 and chemokines, including CXCL2, CXCR4, CXCL10 and CCL17, but increased the scavenger protein CD36, in ox‐LDL‐treated RAW 264.7 cells. In vivo, GYY4137 decreased aortic atherosclerotic plaque formation and partially restored aortic endothelium‐dependent relaxation in apoE−/− mice. GYY4137 decreased ICAM‐1, TNF‐α and IL‐6 mRNA expression as well as superoxide (O2−) generation in aorta. In addition, GYY4137 increased aortic eNOS phosphorylation and expression of PI3K, enhanced Akt Ser473 phosphorylation and down‐regulated the expression of LOX‐1.

Conclusion and Implications

GYY4137 inhibits lipid accumulation induced by ox‐LDL in RAW 264.7 cells. In vivo, GYY4137 decreased vascular inflammation and oxidative stress, improved endothelial function and reduced atherosclerotic plaque formation in apoE−/− mice.
A structural chemogenomics analysis of aminergic GPCRs: lessons for histamine receptor ligand design
Authors: Kooistra A J , Kuhne S , de Esch I J P , Leurs R , de Graaf C
Published: May 2013

Background and Purpose

Chemogenomics focuses on the discovery of new connections between chemical and biological space leading to the discovery of new protein targets and biologically active molecules. G‐protein coupled receptors (GPCRs) are a particularly interesting protein family for chemogenomics studies because there is an overwhelming amount of ligand binding affinity data available. The increasing number of aminergic GPCR crystal structures now for the first time allows the integration of chemogenomics studies with high‐resolution structural analyses of GPCR‐ligand complexes.

Experimental Approach

In this study, we have combined ligand affinity data, receptor mutagenesis studies, and amino acid sequence analyses to high‐resolution structural analyses of (hist)aminergic GPCR‐ligand interactions. This integrated structural chemogenomics analysis is used to more accurately describe the molecular and structural determinants of ligand affinity and selectivity in different key binding regions of the crystallized aminergic GPCRs, and histamine receptors in particular.

Key Results

Our investigations highlight interesting correlations and differences between ligand similarity and ligand binding site similarity of different aminergic receptors. Apparent discrepancies can be explained by combining detailed analysis of crystallized or predicted protein‐ligand binding modes, receptor mutation studies, and ligand structure‐selectivity relationships that identify local differences in essential pharmacophore features in the ligand binding sites of different receptors.

Conclusions and Implications

We have performed structural chemogenomics studies that identify links between (hist)aminergic receptor ligands and their binding sites and binding modes. This knowledge can be used to identify structure‐selectivity relationships that increase our understanding of ligand binding to (hist)aminergic receptors and hence can be used in future GPCR ligand discovery and design.

Linked Articles

This article is part of a themed issue on Histamine Pharmacology Update. To view the other articles in this issue visit http://dx.doi.org/
10.1111/bph.2013.170.issue‐1
Feasibility of targeting ischaemia‐related ventricular arrhythmias by mimicry of endogenous protection by endocannabinoids
Authors: Andrag Ellen , Curtis Michael J
Published: May 2013

Background and Purpose

The hypothesis that endocannabinoids protect hearts against ventricular fibrillation (VF) induced by myocardial ischaemia and reperfusion was examined, and the concept that cannabinoids may represent a new class of anti‐VF drug was tested.

Experimental Approach

In rat isolated hearts (Langendorff perfusion), VF evoked by reperfusion after 60 min regional ischaemia is known to be exacerbated by inhibitors of endogenous protectants such as nitric oxide. This preparation was used to assay the effects of cannabinoid agonists and antagonists, and the protocols were varied to examine mechanisms.

Key Results

Reperfusion‐induced VF was not facilitated by relatively selective CB1 (1 μM AM251) or CB2 (1 μM AM630) antagonists. VF evoked during early (30 min) acute ischaemia was also unaffected. However, AM251 significantly increased the incidence of VF and the duration of VF episodes occurring during the later stage of acute ischaemia (30–60 min). AM630 had no such effects. In a separate study, cannabinoid perfusion (anandamide or 2‐arachidonoylglycerol, both 0.01‐1 μM) failed to reduce VF incidence concentration‐dependently during 30 min ischaemia. In all these studies, changes in ancillary variables (QT, PR, heart rate) were unrelated to changes in VF.

Conclusions and Implications

Endocannabinoids are not endogenous anti‐VF mediators during reperfusion, but may have a weak protective effect during the late stages of ischaemia, mediated via CB1 agonism. This does not suggest endocannabinoids are important endogenous protectants in these settings, or that CB1 (or CB2) receptors are useful novel targets for developing drugs for VF.
Solid lipid nanoparticles of cholesteryl butyrate inhibit the proliferation of cancer cells in vitro and in vivo models
Authors: Minelli R , Occhipinti S , Gigliotti C L , Barrera G , Gasco P , Conti L , Chiocchetti A , Zara G P , Fantozzi R , Giovarelli M , Dianzani U , Dianzani C
Published: May 2013

Background and Purpose

Solid lipid nanoparticles containing cholesteryl butyrate (cholbut SLN) can be a delivery system for the anti‐cancer drug butyrate. These nanoparticles inhibit adhesion of polymorphonuclear and tumour cells to endothelial cells and migration of tumour cells, suggesting that they may act as anti‐inflammatory and anti‐tumour agents. Here we have evaluated the effects of cholbut SLN on tumour cell growth using in vitro and in vivo models.

Experimental Approach

Cholbut SLNs were incubated with cultures of four tumour cell lines, and cell growth was analysed by assessing viability, clonogenic capacity and cell cycle. Effects on intracellular signalling was assessed by Western blot analysis of Akt expression. The in vivo anti‐tumour activity was measured in two models of PC‐3 cell xenografts in SCID/Beige mice.

Key Results

Cholbut SLN inhibited tumour cell line viability, clonogenic activity, Akt phosphorylation and cell cycle progression. In mice injected i.v. with PC3‐Luc cells and treated with cholbut SLN, . in vivo optical imaging and histological analysis showed no metastases in the lungs of the treated mice. In another set of mice injected s.c. with PC‐3 cells and treated with cholbut SLN when the tumour diameter reached 2 mm, analysis of the tumour dimensions showed that treatment with cholbut SLN substantially delayed tumour growth.

Conclusion and Implications

Cholbut SLN were effective in inhibiting tumour growth in vitro and in vivo. These effects may involve, in part, inhibition of Akt phosphorylation, which adds another mechanism to the activity of this multipotent drug.
A single‐point mutation (Ala280Val) in the third intracellular loop alters the signalling properties of the human histamine H3 receptor stably expressed in CHO‐K1 cells
Authors: Flores‐Clemente Cecilia , Osorio‐Espinoza Angélica , Escamilla‐Sánchez Juan , Leurs Rob , Arias Juan‐Manuel , Arias‐Montaño José‐Antonio
Published: May 2013

Background and Purpose

An alanine to valine exchange at amino acid position 280 (A280V) in the third intracellular loop of the human histamine H3 receptor was first identified in a patient suffering from Shy–Drager syndrome and later reported as a risk factor for migraine. Here, we have compared the pharmacological and signalling properties of wild‐type (hH3RWT) and A280V mutant (hH3RA280V) receptors stably expressed in CHO‐K1 cells.

Experimental Approach

The hH3RA280V cDNA was created by overlapping extension PCR amplification. Receptor expression and affinity were assessed by radioligand (N‐α‐[methyl‐3H]‐histamine) binding to cell membranes, and receptor function by the inhibition of forskolin‐induced cAMP accumulation and stimulation of ERK1/2 phosphorylation in intact cells, as well as stimulation of [35S]‐GTPγS binding to cell membranes.

Key Results

Both receptors were expressed at similar levels with no significant differences in their affinities for H3 receptor ligands. Upon activation the hH3RWT was significantly more efficacious to inhibit forskolin‐induced cAMP accumulation and to stimulate [35S]‐GTPγS binding, with no difference in pEC50 estimates. The hH3RWT was also more efficacious to stimulate ERK1/2 phosphorylation, but this difference was not significant. The inverse agonist ciproxifan was more efficacious at hH3RWT to reduce [35S]‐GTPγS binding but, for both receptors, failed to enhance forskolin‐induced cAMP accumulation.

Conclusions and Implications

The A280V mutation reduces the signalling efficacy of the human H3 receptor. This effect may be relevant to the pathophysiology of disorders associated with the mutation.

Linked Articles

This article is part of a themed issue on Histamine Pharmacology Update. To view the other articles in this issue visit http://dx.doi.org/
10.1111/bph.2013.170.issue‐1
High salt‐induced hypertension in B2 knockout mice is corrected by the ETA antagonist, A127722
Authors: Brochu I , Houde M , Desbiens L , Simard E , Gobeil F , Semaan W , Bkaily G , D'Orléans‐Juste P
Published: May 2013

Background and Purpose

The contribution of endothelin‐1 (ET‐1) in a B2KO mouse model of a high salt‐induced arterial hypertension was investigated.

Experimental Approach

Wild‐type (WT) or B2KO mice receiving a normal diet (ND) or a high‐salt diet (HSD) were monitored by radiotelemetry up to a maximum of 18 weeks. At the 12th week of diet, subgroups under ND or HSD received by gavage the ETA antagonist A127722 during 5 days. In addition, blood samples were collected and, following euthanasia, the lungs, heart and kidneys were extracted, homogenized and assayed for ET‐1 by RIA. In a separate series of experiments, the ETA antagonist, BQ123 was tested against the pressor responses to a NOS inhibitor L‐NG‐nitroarginine methyl ester (L‐NAME) in anaesthetized WT and B2KO mice.

Key Results

In B2KO, but not WT mice, 12 weeks of HSD triggered a maximal increase of the mean arterial pressure (MAP) of 19.1 ± 2.8 mmHg, which was corrected by A127722 to MAP levels found in B2KO mice under ND. Significant increases in immunoreactive ET‐1 were detected only in the lungs of B2KO mice under HSD. On the other hand, metabolic studies showed that sodium urinary excretion was markedly reduced in B2KO compared with WT mice under ND. Finally, BQ123 (2 mg·kg−1) reduced by 50% the pressor response to L‐NAME (2 mg·kg−1) in B2KO, but not WT mice under anaesthesia.

Conclusions and Implications

Our results support the concept that functional B2 receptors oppose high salt‐induced increments in MAP, which are corrected by an ETA receptor antagonist in this mouse model of experimental hypertension.
Association between pretreatment haemoglobin levels and morphometric characteristics of the tumour, response to neoadjuvant treatment and long‐term outcomes in patients with locally advanced rectal cancers
Authors: Khan A. A. , Klonizakis M. , Shabaan A. , Glynne‐Jones R.
Published: May 2013

Aim

The study was carried out to investigate whether pretreatment haemoglobin (Hb) levels act as a biomarker in the management of patients with locally advanced rectal cancer.

Method

We prospectively collected data on all patients within our cancer network with localized low rectal cancer treated with preoperative radiotherapy/chemoradiotherapy at Mount Vernon Centre for Cancer Treatment between March 1994 and July 2008. Pretreatment Hb level was assessed as an independent variable for the whole study sample and dichotomised at a value of 12 g/dl. A multivariate analysis of covariance (MANCOVA) was conducted on parameters that had significant association on univariate analysis of covariance (ANCOVA) and correlational (Kendall tau/Pearson) analyses. Kaplan–Meier survival analysis and Cox proportional hazard models were used to determine significant prognostic markers. Statistical significance was set at 0.05.

Results

463 patients (male/female 2:1; median age = 66 years, interquartile range = 56.5–73.0) were included in the analysis. There was significant tumour response of T stage (P < 0.001) and N stage (P < 0.001), with 17.6% of patients achieving a pathological complete response. Pretreatment Hb value was inversely related to the craniocaudal vertical tumour length (P = 0.02) and pretreatment T stage of the tumour (P = 0.01). Patients with Hb levels of < 12 g/dl and moderately differentiated adenocarcinoma were less responsive. Local recurrence was more common in patients with a pretreatment Hb of < 12 g/dl (hazard ratio = 1.78) over a median follow up of 24 months, but this was not statistically significant (P = 0.08).

Conclusion

The pretreatment Hb level might be used as a biomarker of rectal tumour morphology, response to neoadjuvant chemoradiation and risk of local recurrence.
Learning to look: probabilistic variation and noise guide infants' eye movements
Authors: Tummeltshammer Kristen Swan , Kirkham Natasha Z.
Published: May 2013

Young infants have demonstrated a remarkable sensitivity to probabilistic relations among visual features (Fiser & Aslin, 2002; Kirkham et al., 2002). Previous research has raised important questions regarding the usefulness of statistical learning in an environment filled with variability and noise, such as an infant's natural world. In an eye‐tracking experiment, 8‐month‐old infants viewed sequences of spatio‐temporal events with three different transitional probabilities (1.0‐Deterministic, 0.75‐High probability, and 0.5‐Low probability). Across two between‐subjects conditions, the sequences were presented with or without competing visual distracters. Results show that as transitional probability decreased, infants distributed less attention to the predictable locations and their anticipations were less often correct. With no distraction, infants had faster saccadic latencies to the high probability events; however, with distracters present in the stimulus environment, infants' eye movements shifted to favour the deterministic relations. These findings suggest that infants integrate multiple sources of variability to guide visual attention and facilitate the detection and learning of statistically reliable events.
Domain‐specific impulsivity in school‐age children
Authors: Tsukayama Eli , Duckworth Angela Lee , Kim Betty
Published: May 2013

Impulsivity is a salient individual difference in children with well‐established predictive validity for life outcomes. The current investigation proposes that impulsive behaviors vary systematically by domain. In a series of studies with ethnically and socioeconomically diverse samples of middle school students, we find that schoolwork‐related and interpersonal‐related impulsivity, as observed by teachers, parents, and the students themselves, are distinct, moderately correlated behavioral tendencies. Each demonstrates differentiated relationships with dimensions of childhood temperament, Big Five personality factors, and outcomes, such as report card grades. Implications for theoretical conceptions of impulsivity as well as for practical applications (e.g. domain‐specific interventions) are discussed.
Diabetes Attitudes, Wishes and Needs second study (DAWN2™): Cross‐national benchmarking of diabetes‐related psychosocial outcomes for people with diabetes
Authors: Nicolucci A. , Kovacs Burns K. , Holt R. I. G. , Comaschi M. , Hermanns N. , Ishii H. , Kokoszka A. , Pouwer F. , Skovlund S. E. , Stuckey H. , Tarkun I. , Vallis M. , Wens J. , Peyrot M. ,   the DAWN2 Study Group
Published: May 2013

Aims

The second Diabetes Attitudes, Wishes and Needs (DAWN2) study aimed to assess psychosocial outcomes in people with diabetes across countries for benchmarking.

Methods

Surveys included new and adapted questions from validated questionnaires that assess health‐related quality of life, self‐management, attitudes/beliefs, social support and priorities for improving diabetes care. Questionnaires were conducted online, by telephone or in person.

Results

Participants were 8596 adults with diabetes across 17 countries. There were significant between‐country differences for all benchmarking indicators; no one country's outcomes were consistently better or worse than others. The proportion with likely depression [WHO‐5 Well‐Being Index (WHO‐5) score ≤ 28] was 13.8% (country range 6.5–24.1%). Diabetes‐related distress [Problem Areas in Diabetes Scale 5 (PAID‐5) score ≥ 40] was reported by 44.6% of participants (17.2–67.6%). Overall quality of life was rated ‘poor’ or ‘very poor’ by 12.2% of participants (7.6–26.1%). Diabetes had a negative impact on all aspects investigated, ranging from 20.5% on relationship with family/friends to 62.2% on physical health. Approximately 40% of participants (18.6–64.9%) reported that their medication interfered with their ability to live a normal life. The availability of person‐centred chronic illness care and support for active involvement was rated as low. Following self‐care advice for medication and diet was most common, and least common for glucose monitoring and foot examination, with marked country variation. Only 48.8% of respondents had participated in diabetes educational programmes/activities to help manage their diabetes.

Conclusions

Cross‐national benchmarking using psychometrically validated indicators can help identify areas for improvement and best practices to drive changes that improve outcomes for people with diabetes.
The Moral Economy Is a Double‐edged Sword: Explaining Farmers’ Earnings and Self‐exploitation in Community‐Supported Agriculture
Authors: Galt Ryan E.
Published: May 2013

In this articleIdevelop a political economic understanding of community‐supported agriculture (CSA). I first develop the relevance of three concepts—economic rents, self‐exploitation, and social embeddedness—toCSAand then introduce a framework that relatesCSAfarmers’ earnings to the average rate of profit, economic rents, and self‐exploitation. I then examine qualitative and quantitative data from a study of 54CSAsin California's Central Valley and surrounding foothills to explain the wide range of farmers’ earnings in relation to the characteristics of production ofCSAs, the social embeddedness ofCSAs, and the farmers’ motivations and rationalities. Qualitative data from interviews are used to interpret the results of an ordinary least squares regression analysis showing that (1) farmers’ age, number of employees, and type ofCSAstrongly shape farmers' earnings; (2) the moral economy ofCSAcuts both ways economically, allowing for the capture of economic rents but more often resulting in self‐exploitation because of farmers’ strong sense of obligation to their members; and (3) farmers’ motivations are diverse, but tend toward low and moderate instrumentalism, meaning that earning an income is often not a high priority relative to other values. The conclusion recommends the need to recognize alternative rationalities but also to discuss and confront strong self‐exploitation in alternative food networks because of the broader political economic context in which they exist.
Differential sources of host species heterogeneity influence the transmission and control of multihost parasites
Authors: Streicker Daniel G. , Fenton Andy , Pedersen Amy B.
Published: May 2013

Controlling parasites that infect multiple host species often requires targeting single species that dominate transmission. Yet, it is rarely recognised that such ‘key hosts’ can arise through disparate mechanisms, potentially requiring different approaches for control. We identify three distinct, but not mutually exclusive, processes that underlie host species heterogeneity: infection prevalence, population abundance and infectiousness. We construct a theoretical framework to isolate the role of each process from ecological data and to explore the outcome of different control approaches. Applying this framework to data on 11 gastrointestinal parasites in small mammal communities across the eastern United States reveals variation not only in the magnitude of transmission asymmetries among host species but also in the processes driving heterogeneity. These differences influence the efficiency by which different control strategies reduce transmission. Identifying and tailoring interventions to a specific type of key host may therefore enable more effective management of multihost parasites.
Relationship between natural teeth and memory in a healthy elderly population
Authors: Hansson Patrik , Sunnegårdh‐Grönberg Karin , Bergdahl Jan , Bergdahl Maud , Nyberg Lars , Nilsson Lars‐Göran
Published: May 2013

The relationship between mastication and cognitive function remains unclear, but both animal and experimental human studies suggest a possible causal relationship. In the present study it was hypothesized that natural teeth are of importance for hippocampus‐based cognitive processes, such as episodic long‐term memory. A population‐based sample of 273 participants (55–80 yr of age; 145 women) was investigated in a cross‐sectional study. The participants underwent health assessment, completed a battery of cognitive tests, and took part in an extensive clinical oral examination. The number of natural teeth contributed uniquely and significantly to explaining variance (3–4%) in performance on measures of episodic memory and semantic memory over and above individual differences in age, years of education, gender, occupation, living conditions, and medical history. The number of natural teeth did not have an influence on the performance of measures of working memory, visuospatial ability, or processing speed. Within the limitations of the current study, a small, but significant, relationship between episodic memory and number of natural teeth is evident.
Future sea ice conditions in Western Hudson Bay and consequences for polar bears in the 21st century
Authors: Castro de la Guardia Laura , Derocher Andrew E. , Myers Paul G. , Terwisscha van Scheltinga Arjen D. , Lunn Nick J.
Published: May 2013

The primary habitat of polar bears is sea ice, but in Western Hudson Bay (WH), the seasonal ice cycle forces polar bears ashore each summer. Survival of bears on land in WH is correlated with breakup and the ice‐free season length, and studies suggest that exceeding thresholds in these variables will lead to large declines in the WH population. To estimate when anthropogenic warming may have progressed sufficiently to threaten the persistence of polar bears in WH, we predict changes in the ice cycle and the sea ice concentration (SIC) in spring (the primary feeding period of polar bears) with a high‐resolution sea ice‐ocean model and warming forced with 21st century IPCC greenhouse gas (GHG) emission scenarios: B1 (low), A1B (medium), and A2 (high). We define critical years for polar bears based on proposed thresholds in breakup and ice‐free season and we assess when ice‐cycle conditions cross these thresholds. In the three scenarios, critical years occur more commonly after 2050. From 2001 to 2050, 2 critical years occur under B1 and A2, and 4 under A1B; from 2051 to 2100, 8 critical years occur under B1, 35 under A1B and 41 under A2. Spring SIC in WH is high (>90%) in all three scenarios between 2001 and 2050, but declines rapidly after 2050 in A1B and A2. From 2090 to 2100, the mean spring SIC is 84 (±7)% in B1, 56 (±26)% in A1B and 20 (±13)% in A2. Our predictions suggest that the habitat of polar bears in WH will deteriorate in the 21st century. Ice predictions in A1B and A2 suggest that the polar bear population may struggle to persist after ca. 2050. Predictions under B1 suggest that reducing GHG emissions could allow polar bears to persist in WH throughout the 21st century.
Factor VIII mutation and desmopressin‐responsiveness in 62 patients with mild haemophilia A
Authors: Nance D. , Fletcher S. N. , Bolgiano D. C. , Thompson A. R. , Josephson N. C. , Konkle B. A.
Published: May 2013

Utilization of the synthetic vasopressin analogue (1‐deamino‐8‐D‐arginine‐vasopressin, DDAVP) in treatment of mild haemophilia A (MHA, specific clotting factor VIII activity level 0.05–0.4 IU mL−1) is convenient and effective for many but not all patients. Genetic testing for patients with MHA is increasingly recognized as providing valuable information for patient care beyond informing reproductive decisions, and as more patients are genotyped, mutation data can be utilized to individualize treatment decisions. To determine if genetic information informs response to DDAVP, a retrospective chart review was performed under Institutional Review Board approval to extract patient data with MHA, genetic mutation results, and response to DDAVP challenge. 62 patients met inclusion criteria. Complete responses (C) presented in mean value IU mL−1 (range), were recorded for 32 of 62(52%) subjects: pre 0.19(0.04–0.45) and post 0.78(0.5–1.95); partial responses (P) were recorded for 15 of 62(24%) subjects: pre 0.1(0.06–0.15) and post 0.4(0.3–0.47); responses that were not clinically significant (N) were recorded for 15 of 62(24%) subjects: pre 0.17(0.02–0.34) and post 0.25(0.03–0.44). Subjects (related and unrelated) with the same mutation showed a trend towards a similar response to DDAVP. Eight genotypes were common to two or more subjects (n = 26). Two genotypes were concordant in all subjects [p.Ser2192Ile n = 3(C), p.Ala2220Pro n = 2(P)]. Of mutations in the C1 or C2 domains, 13 of 15(87%) subjects responded to DDAVP [C = 9(60%); P = 4(27%); n = 2(13%)]. Baseline FVIII:C did not predict magnitude of response to DDAVP. Genetic mutation results can assist with predicting DDAVP responsiveness, but baseline FVIII:C may not.
Quantification of perioperative changes in von Willebrand factor and factor VIII during elective orthopaedic surgery in normal individuals
Authors: Kahlon A. , Grabell J. , Tuttle A. , Engen D. , Hopman W. , Lillicrap D. , James P.
Published: May 2013

von Willebrand's disease (VWD) patients undergoing major surgery are prophylactically treated to promote haemostasis. There is variability in perioperative clinical practice; however, most guidelines suggest replacing the deficient factor to a level of 1.0 IU mL−1 (or 100%). A review of the literature reveals a paucity of well constructed descriptive data quantifying the changes in coagulation that occur in response to surgical stress. The aim of this study was to quantify the changes in haemostatic variables occurring in response to elective orthopaedic surgery in normal individuals. Eligible subjects >18 years of age undergoing total hip or knee replacement were recruited. Blood samples were drawn at five time points: baseline, preoperatively, 30 min after surgical incision, 30 min postoperatively, postoperative day (POD) 1. Analyses included t‐tests and repeated measures anova. Overall 30 patients, 21 women and 9 men, with a mean age of 65 were included in the final analysis. All von Willebrand factor (VWF) variables were seen to significantly decrease intraoperatively and increase postoperatively. VWF multimers showed a statistically significant decrease in high molecular weight multimers intraoperatively and an increase postoperatively. On subgroup analysis, age, gender and anaesthesia type were significantly correlated with changes in VWF parameters. Data presented in the current study establish a physiological baseline for VWF parameters in the normal population and demonstrate mean VWF/factor VIII levels greater than 1.0 IU mL−1 intraoperatively. As such, current management in VWD patients does not appear to mimic the normal physiological response to surgery.
Do patients’ information requirements for choice in health care vary with their socio‐demographic characteristics?
Authors: Laverty Anthony A. , Dixon Anna , Millett Christopher
Published: May 2013

Objectives

This study examines whether the information used to inform hospital choice, and the sources of that information, varies with patients’ socio‐demographic characteristics. It also examines whether information used by patients to inform choice is associated with attending their local hospital.

Methods

A survey of 1033 patients who were offered a choice of hospital provider for elective treatment in England. Logistic regression was used to examine associations between patient characteristics and information used to inform choice of a hospital provider and sources of information used.

Results

Factors most important to patients in choosing a hospital were quality of care, cleanliness, standard of facilities and reputation. While quality of care and related factors are important to the majority of patients, those with lower levels of education were more likely to report that location and appointment times were important. Those who thought quality important were more likely to attend their local hospital provider. The main sources of information used to inform choice of hospital were own experience, family and friends and the general practitioner (GP). Patients who sought advice from their GP or booking advisors were less likely to attend their local hospitals.

Conclusions

Differences among patients as to what factors are important when choosing a hospital provider and what information and support they access suggest there needs to be a variety of information sources and support available to promote choice. Greater shared decision making through active involvement and support by GPs or booking advisors may be required if they are to make choices in line with their preferences.
HLA class II allele polymorphism in an outbreak of chikungunya fever in Middle Andaman, India
Authors: Chaaithanya Itta Krishna , Muruganandam Nagarajan , Anwesh Maile , Rajesh Reesu , Ghosal Sruti R. , Kartick Chinnaiah , Prasad Kadiyala Nageswara , Muthumani Karuppiah , Vijayachari Paluru
Published: May 2013

A sudden upsurge of fever cases with joint pain was observed in the outpatient department, Community Health Centre, Rangat during July–August 2010 in Rangat Middle Andaman, India. The aetiological agent responsible for the outbreak was identified as chikungunya virus (CHIKV), by using RT‐PCR and IgM ELISA. The study investigated the association of polymorphisms in the human leucocyte antigen class II genes with susceptibility or protection against CHIKV. One hundred and one patients with clinical features suggestive of CHIKV infection and 104 healthy subjects were included in the study. DNA was extracted and typed for HLA‐DRB1 and DQB1 alleles. Based on the amino acid sequences of HLA‐DQB1 retrieved from the IMGT/HLA database, critical amino acid differences in the specific peptide‐binding pockets of HLA‐DQB1 molecules were investigated. The frequencies of HLA‐DRB1 alleles were not significantly different, whereas lower frequency of HLA‐DQB1*03:03 was observed in CHIKV patients compared with the control population [P = 0·001, corrected P = 0·024; odds ratio (OR)  = 0, 95% confidence interval (95% CI) 0·0–0·331; Peto's OR = 0·1317, 95% CI 0·0428–0·405). Significantly lower frequency of glutamic acid at position 86 of peptide‐binding pocket 1 coding HLA‐DQB1 genotypes was observed in CHIKV patients compared with healthy controls (P = 0·004, OR = 0·307, 95% CI 0·125–0·707). Computational binding predictions of CD4 epitopes of CHIKV by NetMHCII revealed that HLA‐DQ molecules are known to bind more CHIKV peptides than HLA‐DRB1 molecules. The results suggest that HLA‐DQB1 alleles and critical amino acid differences in the peptide‐binding pockets of HLA‐DQB1 alleles might have role in influencing infection and pathogenesis of CHIKV.
Fat tails in marine microbial population fluctuations
Authors: Segura A. M. , Calliari D. , Fort H. , Lan B. L.
Published: May 2013

The fluctuations of natural populations have deep impact on important ecological issues, such as pest outbreaks, fisheries or the formation of harmful algal blooms (HABs). However, consensus on the appropriate descriptor of such fluctuations is still lacking. Here, using 16 to 20 years of weekly data on marine microbial population abundance comprising more than 200 species, we analysed the distribution of the population fluctuations. We found that population fluctuations of all groups and in 12 out of 17 species were not Gaussian (D’Agostino test p < 0.05) but instead were adequately described by Levy‐stable distributions (LSD). Consistent with ecological theories, the LSD characteristic parameter (α) characterizes as highly volatile those groups known to form HABs, such as dinoflagellates (α= 1.48), and as lowly volatile, nanoflagellates (α= 1.92), a group which can be subjected to predatory control. Moreover, zooplankton groups composed of species with sexual reproduction and complex life cycles such as crustacean and Appendicullaria also showed departures from Gaussian population fluctuations and adequate fits to LSD. Our results suggest that heavy‐tailed population fluctuations are widespread, implying that extreme population fluctuations are more likely than previously expected, a fact that has important consequences for the predictability of population outbreaks.
High‐Pressure Behavior and Phase Stability of Al5BO9, a Mullite‐Type Ceramic Material
Authors: Gatta G. Diego , Lotti Paolo , Merlini Marco , Liermann Hanns‐Peter , Fisch Martin
Published: May 2013

Phase stability, elastic behavior, and pressure‐induced structural evolution of synthetic boron‐mullite Al5BO9 (a = 5.6780(7), b = 15.035(6), and c =7.698(3) Å, space group Cmc21, Z = 4) were investigated up to 25.6(1) GPa by in situ single‐crystal synchrotron X‐ray diffraction with a diamond anvil cell (DAC) under hydrostatic conditions. No evidence of phase transition was observed up to 21.7(1) GPa. At 25.6(1) GPa, the refined unit‐cell parameters deviated significantly from the compressional trend, and the diffraction peaks appeared broader than at lower pressure. At 26.7(1) GPa, the diffraction pattern was not indexable, suggesting amorphization of the material or a phase transition to a high‐pressure polymorph. Fitting the P–V data up to 21.7(1) GPa with a second‐order Birch–Murnaghan Equation‐of‐State, we obtained a bulk modulus KT0 = 164(1) GPa. The axial compressibilities, here described as linearized bulk moduli, are as follows: KT0(a) = 244(9), KT0(b) = 120(4), and KT0(c) = 166(11) GPa (KT0(a):KT0(b):KT0(c) = 2.03:1:1.38). The structure refinements allowed a description of the main deformation mechanisms in response to the applied pressure. The stiffer crystallographic direction appears to be controlled by the infinite chains of edge‐sharing octahedra running along [100], making the structure less compressible along the a‐axis than along the b‐ and c‐axis.
Identification of periodontitis associated changes in the proteome of whole human saliva by mass spectrometric analysis
Authors: Salazar Manuela Gesell , Jehmlich Nico , Murr Annette , Dhople Vishnu M. , Holtfreter Birte , Hammer Elke , Völker Uwe , Kocher Thomas
Published: May 2013

Aim

Interest in human saliva proteomics for disease‐specific biomarker screening increased in the last decade. We used whole saliva samples from periodontally healthy and diseased subjects with chronic periodontitis to screen for disease‐associated differences in the protein pattern.

Material and Methods

We selected 20 periodontally healthy and 20 periodontally diseased subjects from the population‐based cross‐sectional Study of Health in Pomerania (SHIP‐2 and SHIP‐Trend). Saliva collection was performed with commercially available Salivette® (Sarstedt, Nümbrecht, Germany). Whole saliva proteins were analysed after trichloroacetic acid (TCA) precipitation and proteolytic digestion with trypsin by LC‐MS/MS. MS‐data were analysed and quantified using the Rosetta Elucidator software package.

Results

In whole saliva we identified 344 human protein groups across all samples. For label free quantitation we only considered 152 proteins identified with more than one unique peptide. In total, 20 proteins showed 1.5‐fold difference in abundance between controls and patients (p < 0.05); the majority of these proteins showed higher abundance in the periodontally diseased subjects. Functional annotation of proteins linked the periodontally diseased status with acute phase response and inflammatory processes.

Conclusion

Label free proteomic analysis of whole saliva is a powerful tool to characterize the periodontal disease status and differentiate between healthy and periodontally diseased subjects.
Mineralization of the vertebral bodies inAtlantic salmon (Salmo salarL.) is initiated segmentally in the form of hydroxyapatite crystal accretions in the notochord sheath
Authors: Wang Shou , Kryvi Harald , Grotmol Sindre , Wargelius Anna , Krossøy Christel , Epple Mattias , Neues Frank , Furmanek Tomasz , Totland Geir K.
Published: May 2013

We performed a sequential morphological and molecular biological study of the development of the vertebral bodies inAtlantic salmon (Salmo salarL.). Mineralization starts in separate bony elements which fuse to form complete segmental rings within the notochord sheath. The nucleation and growth of hydroxyapatite crystals in both the lamellar typeIIcollagen matrix of the notochord sheath and the lamellar typeIcollagen matrix derived from the sclerotome, were highly similar. In both matrices the hydroxyapatite crystals nucleate and accrete on the surface of the collagen fibrils rather than inside the fibrils, a process that may be controlled by a template imposed by the collagen fibrils. Apatite crystal growth starts with the formation of small plate‐like structures, about 5 nm thick, that gradually grow and aggregate to form extensive multi‐branched crystal arborizations, resembling dendritic growth. The hydroxyapatite crystals are always oriented parallel to the long axis of the collagen fibrils, and the lamellar collagen matrices provide oriented support for crystal growth. We demonstrate here for the first time by means of synchroton radiation based on X‐ray diffraction that the chordacentra contain hydroxyapatite. We employed quantitative real‐timePCRto study the expression of key signalling molecule transcripts expressed in the cellular core of the notochord. The results indicate that the notochord not only produces and maintains the notochord sheath but also expresses factors known to regulate skeletogenesis:sonic hedgehog(shh),indian hedgehog homolog b(ihhb),parathyroid hormone 1 receptor(pth1r) andtransforming growth factor beta 1(tgfb1). In conclusion, our study provides evidence for the process of vertebral body development in teleost fishes, which is initially orchestrated by the notochord.
Clinical competence in developmental‐behavioural paediatrics: Raising the bar
Authors: O'Keeffe Mick
Published: May 2013

For our specialist paediatric workforce to be suitably equipped to deal with current childhood morbidity, a high level of competence in developmental‐behavioural paediatrics (DBP) is necessary. New models of training and assessment are required to meet this challenge. An evolution of training in DBP, built around the centrepiece of competency‐based medical education, is proposed. Summative assessment based upon entrustable professional activities, and a menu of formative workplace‐based assessments specific to the DBP context are key components. A pilot project to develop and implement these changes is recommended.
Phthalates in the NICU: Is it safe?
Authors: Fischer Céline J , Bickle Graz Myriam , Muehlethaler Vincent , Palmero David , Tolsa Jean‐François
Published: May 2013

Aims

As growing concerns exist regarding phthalate exposure, which could be teratogenic, carcinogenic or induce reproductive toxicity, we aimed to review the evidence of the risks due to the use of medical devices containing di(2‐ethylhexyl)phthalate in hospitalized neonates.

Methods

We reviewed the literature, searching through medical literature databases (Pubmed, MEDLINE, EBM reviews, Cochrane database, Embase and Google Scholar) using the following keywords: phthalate, di(2‐ethylhexyl)phthalate, newborn and neonate.

Results

We identified several associations with short and long term health dangers, mainly subfertility, broncho‐pulmonary dysplasia, necrotising enterocolitis, parenteral nutrition associated cholestasis and neuro‐developmental disorders. These data are based mainly on animal or observational human studies.

Conclusion

Clinicians must be aware of the potential risks due to phthalate exposure in the NICU. Di(2‐ethylhexyl)phthalate containing materials should be identified and alternative devices should be considered. There is a need to improve knowledge in this area.
Salivary antioxidants as periodontal biomarkers in evaluation of tissue status and treatment outcome
Authors: Novakovic N. , Todorovic T. , Rakic M. , Milinkovic I. , Dozic I. , Jankovic S. , Aleksic Z. , Cakic S.
Published: May 2013

Background and objective

One of the major pathologic patterns in periodontitis represents an imbalance among the production of free radicals and local antioxidants resulting in periodontal tissue destruction. The objective of the study was to investigate the influence of non‐surgical periodontal treatment on salivary antioxidants and to evaluate their capacity as biomarkers reflecting periodontal tissue condition and therapy outcome.

Material and Methods

Sixty‐three systemically healthy non‐smokers, including 21 periodontally healthy subjects (HC) and 42 patients with current chronic periodontitis fulfilled the inclusion criteria. Half of the patients received scaling and root planing (SRP) and the other half received only oral hygiene instructions. Full mouth clinical measurements, including gingival index (GI), plaque index (PI), periodontal pocket depth, clinical attachment level and saliva sampling were performed at baseline visit and 2 mo after treatment/baseline visit. Total antioxidant capacity (TAOC), albumins (ALB), uric acid (UA), superoxide dismutase (SOD) and glutathione peroxidase (GPX) were evaluated in saliva samples using commercial kits.

Results

All measured antioxidants were affected by treatment resulting in significant increase in TAOC (p < 0.005), ALB (p < 0.001), UA (p < 0.001) and GPX (p < 0.001) and decrease of SOD (p < 0.005) in response to SRP, where no differences were observed for any of parameters in the oral hygiene instructions group. Comparison of antioxidant levels between the HC and SRP group showed that before treatment ALB were significantly higher in HC when compared to the SRP group (p = 0.039), and GXP (p = 0.000) and SOD (p = 0.021) levels were significantly higher in the SRP group. Comparison of values after treatment showed that TAOC was significantly higher in the HC than in the SRP group (p = 0.001), but UA was, inversely, significantly higher in the SRP group (p = 0.034). All clinical parameters except clinical attachment level were significantly decreased after SRP and significant correlations were observed between SOD and GI (p = 0.017), SOD and PI (p = 0.011), GPX and GI (p = 0.003) and GPX and PI (p = 0.008).

Conclusion

Non‐surgical periodontal treatment affected salivary TAOC, ALB, UA, SOD and GPX; moreover, these biochemical parameters convincingly reflected periodontal status and tissue response on treatment.
Clinical significance of microscopic haematuria in diabetic nephropathy in type 2 diabetes patients with overt proteinuria
Authors: Okada Tomonari , Nagao Toshitaka , Matsumoto Hiroshi , Nagaoka Yume , Wada Toshikazu , Nakao Toshiyuki
Published: May 2013

Aim

Although some patients with diabetic nephropathy with overt proteinuria have microscopic haematuria, the pathological characteristics and clinical significance related to microscopic haematuria have not yet been clarified. The aim of the present study was to clarify the pathological characteristics and clinical significance of microscopic haematuria.

Methods

Eighty‐four type 2 diabetes patients with overt proteinuria and biopsy‐confirmed diabetic nephropathy were enrolled. The clinical and histological findings were compated between the patients with persistent haematuria (group 1, n = 25) and those with persistent non‐haematuria (group 2, n = 23) after renal biopsy. The association between persistent haematuria and renal outcome at 5 years was examined. Histological scoring was made according to the original system and that of Tervaert et al.

Results

Thirty‐six patients (43%) had microscopic haematuria at the time of renal biopsy. Age was significantly smaller and blood pressure was significantly greater in group 1 than in group 2 (age: group 1, 56 ± 10 years; group 2, 62 ± 9 years; P = 0.03, systolic blood pressure: group 1, 152 ± 16 mmHg; group 2, 140 ± 16 mmHg; P = 0.01). There were no significant differences in histological parameters between the two groups. A logistic regression model demonstrated that arteriolar hyalinosis was significantly associated with persistent haematuria (OR = 2.81; P = 0.04). There were no significant differences in changes in reciprocal serum creatinine and rates of doubling of serum creatinine after renal biopsy between the two groups.

Conclusion

Although arteriolar hyalinosis was associated with persistent haematuria, the clinical significance of microscopic haematuria was minor in diabetic nephropathy in type 2 diabetes patients with overt proteinuria.
Emerging landscape of non‐codingRNAs in oral health and disease
Authors: Perez P , Jang S‐I , Alevizos I
Published: May 2013

The world of non‐coding RNAs has only recently started being discovered. For the past 40 years, coding genes,mRNA, and proteins have been the center of cellular and molecular biology, and pathologic alterations were attributed to either the aberration of gene sequence or altered promoter activity. It was only after the completion of the human genome sequence that the scientific community started seriously wondering why only a very small portion of the genome corresponded to protein‐coding genes. New technologies such as the whole‐genome and whole‐transcriptome sequencing demonstrated that at least 90% of the genome is actively transcribed. The identification and cataloguing of multiple kinds of non‐coding RNA (ncRNA) have exponentially increased, and it is now widely accepted that ncRNAs play major biological roles in cellular physiology, development, metabolism, and are also implicated in a variety of diseases. The aim of this review is to describe the two major classes (long and short forms) of non‐coding RNAs and describe their subclasses in terms of function and their relevance and potential in oral diseases.