Adiponectin in health and disease

The incidence of diseases associated with the metabolic syndrome has rapidly increased in recent years. The most common of these diseases is Type 2 Diabetes. Research into ways of alleviating the pathogenicity of Diabetes is ongoing, and the increase in diagnosis in recent years has motivated scientists to investigate novel risk markers to help predict and prevent Type 2 Diabetes Mellitus and the diseases associated with it. Adiponectin has become an important molecule in this search. Despite being released from adipose tissue, adiponectin correlates inversely with body fat in humans and animals. It also exhibits important metabolic regulatory functions such as glucose regulation and fatty acid catabolism and has been suggested to have anti-inflammatory properties. This thesis reviews literature on the adiponectin molecule and aims to explore the complex functioning of this adipokine and its relationship to Cardiovascular Disease (CVD) and Diabetes. The methodological considerations chapters focus on pre-analytical and analytical variables that may affect the collection of blood and the measurement of the molecule. We observed the molecule to be very stable. The measurement of both the high molecular weight (HMW) and total adiponectin species were not affected by up to 7 freeze thaw cycles. Furthermore, blood processing times and temperatures did not significantly alter results. Although the R&D systems adiponectin kits do not advise the use of citrated plasma, we validated its use in these kits and although absolute concentrations were lower than with EDTA plasma, they were consistently lower throughout the measured sample set. Two other commercial kits (Mercodia and ALPCO diagnostics) were tested for performance against the R&D systems Enzyme-Linked Immunosorbent Assay (ELISA) kit. Although there were differences between absolute values in each kit, the overall performance of the kits were satisfactory as judged by Bland-Altman plots. In the first of the two clinical associations chapters, we report, from a prospective study of older British women, no evidence of any association of HMW adiponectin (or its ratio to total adiponectin) with incident vascular events and suggest that circulating concentrations of adiponectin (and its fractions) may be more strongly aligned to the risk for Diabetes than to vascular events. The final study investigates the relationship between B-type natriuretic peptide (BNP) and adiponectin in Acute Coronary Syndrome (ACS) patients. Adiponectin and BNP are both known to be positively associated with risk of poor outcome, and with each other, in cross-sectional studies. However, serial changes in these parameters, following ACS, have not previously been measured. In this study, adiponectin and BNP positively correlated at baseline, 7 weeks, and importantly, change over 7 weeks in both parameters was significantly correlated. We reported that increases in plasma adiponectin (rather than absolute levels) after ACS are related to risk of adverse outcome, but that this relationship is not independent of BNP levels. Our results allude to a potential direct or indirect effect of BNP on adiponectin levels, post-ACS; an observation that requires further investigation. In summary, this thesis has shown adiponectin to be a very stable and robust analyte in plasma or serum, with good reproducibility within persons and broadly between differing assays. Whilst there are clear data linking low adiponectin with incident diabetes, our clinical studies show adiponectin has more complex associations with vascular disease, perhaps mediated in part by a complex interaction with BNP. Further genetic studies are needed to elaborate causal association for this complex molecule

Linking Learners for Life Where They Live (L4): Developing a Global Health Initiative for Student Engagement

This article describes a graduate student learning experience as part of an international nursing collaborative working together to develop an academic partnership for global health education in the circumpolar north. The experience provided an opportunity to conduct a pilot project in a rural, remote, northern community using an indigenous, global context. Building on the Canadian–Siberian collaboration, the graduate student attended an academic institution in Siberia, where she focused on the sharing of expertise, knowledge, and insights in order to address the challenges facing indigenous people in achieving optimal health and well-being in the circumpolar north. The goal was to create a foundation for “putting health into place” in a northern context, with the hope of creating shared learning opportunities for undergraduate students between the 2 countries.The intent is to share the approach used by the graduate student to use a conceptual model to assess the feasibility of creating a context-relevant global health experience for northern nursing education

The Concept of Divergent Targeting through the Activation and Inhibition of Receptors as a Novel Chemotherapeutic Strategy: Signaling Responses to Strong DNA-Reactive Combinatorial Mimicries

Recently, we reported the combination of multitargeted ErbB1 inhibitor–DNA damage combi-molecules with OCT in order to downregulate ErbB1 and activate SSTRs. Absence of translation to cell kill was believed to be partially due to insufficient ErbB1 blockage and DNA damage. In this study, we evaluated cell response to molecules that damage DNA more aggressively and induce stronger attenuation of ErbB1 phosphorylation. We used three cell lines expressing low levels (U87MG) or transfected to overexpress wildtype (U87/EGFR) or a variant (U87/EGFRvIII) of ErbB1. The results showed that Iressa ± HN2 and the combi-molecules, ZRBA4 and ZR2003, significantly blocked ErbB1 phosphorylation in U87MG cells. Addition of OCT significantly altered cell cycle distribution. Analysis of the DNA damage response pathway revealed strong upregulation of p53 by HN2 and the combi-molecules. Apoptosis was only induced by a 48 h exposure to HN2. All other treatments resulted in cell necrosis. This is in agreement with Akt-Bad pathway activation and survivin upregulation. Despite strong DNA damaging properties and downregulation of ErbB1 phosphorylation by these molecules, the strongest effect of SSTR activation was on cell cycle distribution. Therefore, any enhanced antiproliferative effects of combining ErbB1 inhibition with SSTR activation must be addressed in the context of cell cycle arrest

Prediction of cardiovascular disease risk by cardiac biomarkers in 2 United Kingdom cohort studies: does utility depend on risk thresholds for treatment?

We tested the predictive ability of cardiac biomarkers N-terminal pro B-type natriuretic peptide (NT-proBNP), high-sensitivity troponin T, and midregional pro adrenomedullin for cardiovascular disease (CVD) events using the British Regional Heart Study (BRHS) of men aged 60 to 79 years, and the MIDSPAN Family Study (MFS) of men and women aged 30 to 59 years. They included 3757 and 2226 participants, respectively, and during median 13.0 and 17.3 years follow-up the primary CVD event rates were 16.6 and 5.3 per 1000 patient-years, respectively. In Cox models adjusted for basic classical risk factors, 1 SD increases in log-transformed NT-proBNP, high-sensitivity troponin T, and midregional pro adrenomedullin were generally associated with increased primary CVD risk in both the studies (P<0.006) except midregional pro adrenomedullin in MFS (P=0.10). In BRHS, QRISK2 risk factors yielded a C-index of 0.657, which was improved by 0.017 (P=0.005) by NT-proBNP, but not by other biomarkers. Using 28% 14-year risk as a proxy for 20% 10-year risk, NT-proBNP improved risk classification for primary CVD cases (case net reclassification index, 5.9%; 95% confidence interval, 2.8%–9.2%), but only improved classification of noncases at a 14% 14-year risk threshold (4.6%; 2.9%–6.3%). In MFS, ASSIGN risk factors yielded a C-index of 0.752 for primary CVD; none of the cardiac biomarkers improved the C-index. Improvements in risk classification were only seen using NT-proBNP and high-sensitivity troponin T among cases using the 28% 14-year risk threshold (4.7%; 1.0%–9.2% and 2.6%; 0.0%–5.8%, respectively). In conclusion, the improvement in treatment allocation gained by adding cardiac biomarkers to risk scores seems to depend on the risk threshold chosen for commencing preventative treatments

Using e-mail recruitment and an online questionnaire to establish effect size: A worked example

Background\ud Sample size calculations require effect size estimations. Sometimes, effect size estimations and standard deviation may not be readily available, particularly if efficacy is unknown because the intervention is new or developing, or the trial targets a new population. In such cases, one way to estimate the effect size is to gather expert opinion. This paper reports the use of a simple strategy to gather expert opinion to estimate a suitable effect size to use in a sample size calculation.\ud \ud Methods\ud Researchers involved in the design and analysis of clinical trials were identified at the University of Birmingham and via the MRC Hubs for Trials Methodology Research. An email invited them to participate.\ud \ud An online questionnaire was developed using the free online tool 'Survey Monkey©'. The questionnaire described an intervention, an electronic participant information sheet (e-PIS), which may increase recruitment rates to a trial. Respondents were asked how much they would need to see recruitment rates increased by, based on 90%. 70%, 50% and 30% baseline rates, (in a hypothetical study) before they would consider using an e-PIS in their research.\ud \ud Analyses comprised simple descriptive statistics.\ud \ud Results\ud The invitation to participate was sent to 122 people; 7 responded to say they were not involved in trial design and could not complete the questionnaire, 64 attempted it, 26 failed to complete it. Thirty-eight people completed the questionnaire and were included in the analysis (response rate 33%; 38/115). Of those who completed the questionnaire 44.7% (17/38) were at the academic grade of research fellow 26.3% (10/38) senior research fellow, and 28.9% (11/38) professor. Dependent upon the baseline recruitment rates presented in the questionnaire, participants wanted recruitment rate to increase from 6.9% to 28.9% before they would consider using the intervention.\ud \ud Conclusions\ud This paper has shown that in situations where effect size estimations cannot be collected from previous research, opinions from researchers and trialists can be quickly and easily collected by conducting a simple study using email recruitment and an online questionnaire. The results collected from the survey were successfully used in sample size calculations for a PhD research study protocol.\ud \u

Particle-in-cell experiments examine electron diffusion by whistler-mode waves: 1. Benchmarking with a cold plasma

Using a particle-in-cell code, we study the diffusive response of electrons due to wave particle interactions with whistler-mode waves. The relatively simple configuration of field-aligned waves in a cold plasma is used in order to benchmark our novel method, and to compare with previous works that used a different modelling technique. In this boundary-value problem, incoherent whistler-mode waves are excited at the domain boundary, and then propagate through the ambient plasma. Electron diffusion characteristics are directly extracted from particle data across all available energy and pitch-angle space. The ‘nature’ of the diffusive response is itself a function of energy and pitch-angle, such that the rate of diffusion is not always constant in time. However, after an initial transient phase, the rate of diffusion tends to a constant, in a manner that is consistent with the assumptions of quasilinear diffusion theory. This work establishes a framework for future investigations on the nature of diffusion due to whistler-mode wave-particle interactions, using particle-in-cell numerical codes with driven waves as boundary value problems

“The more you know, the more you realise it is really challenging to do”: tensions and uncertainties in person-centred support for people with long-term conditions

ACKNOWLEDGEMENTS We thank the health professionals who participated in this research and shared their experiences and insights. We thank Louise Cotterell and Bev Smith (Health Services Research Unit, University of Aberdeen) for administrative and clerical support, Darshan Patel and colleagues at the Health Foundation for wonderfully facilitative research management, and NJC Secretarial for transcribing services. This study was funded by the Health Foundation (grant reference 7209). Health Foundation staff took part in one of the knowledge exchange discussions at the end of the project, but played no role in the analysis or writing of this manuscript, for which the authors take full responsibility.Peer reviewedPublisher PD

Acute flaccid paralysis with anterior myelitis - California, June 2012-June 2014.

In August 2012, the California Department of Public Health (CDPH) was contacted by a San Francisco Bay area clinician who requested poliovirus testing for an unvaccinated man aged 29 years with acute flaccid paralysis (AFP) associated with anterior myelitis (i.e., evidence of inflammation of the spinal cord involving the grey matter including anterior horn cell bodies) and no history of international travel during the month before symptom onset. Within 2 weeks, CDPH had received reports of two additional cases of AFP with anterior myelitis of unknown etiology. Testing at CDPH's Viral and Rickettsial Disease Laboratory for stool, nasopharyngeal swab, and cerebrospinal fluid (CSF) did not detect the presence of an enterovirus (EV), the genus of the family Picornaviridae that includes poliovirus. Additional laboratory testing for infectious diseases conducted at the CDPH Viral and Rickettsial Disease Laboratory did not identify a causative agent to explain the observed clinical syndrome reported among the patients. To identify other cases of AFP with anterior myelitis and elucidate possible common etiologies, CDPH posted alerts in official communications for California local health departments during December 2012, July 2013, and February 2014. Reports of cases of neurologic illness received by CDPH were investigated throughout this period, and clinicians were encouraged to submit clinical samples for testing. A total of 23 cases of AFP with anterior myelitis of unknown etiology were identified. Epidemiologic and laboratory investigation did not identify poliovirus infection as a possible cause for the observed cases. No common etiology was identified to explain the reported cases, although EV-D68 was identified in upper respiratory tract specimens of two patients. EV infection, including poliovirus infection, should be considered in the differential diagnosis in cases of AFP with anterior myelitis and testing performed per CDC guidelines

Autophagic Flux Modulation by Wnt/β-Catenin Pathway Inhibition in Hepatocellular Carcinoma

Autophagy targets cellular components for lysosomal-dependent degradation in which the products of degradation may be recycled for protein synthesis and utilized for energy production. Autophagy also plays a critical role in cell homeostasis and the regulation of many physiological and pathological processes and prompts this investigation of new agents to effect abnormal autophagy in hepatocellular carcinoma (HCC). 2,5-Dichloro-N-(2-methyl-4-nitrophenyl) benzenesulfonamide (FH535) is a synthetic inhibitor of the Wnt/β-catenin pathway that exhibits anti-proliferative and anti-angiogenic effects on different types of cancer cells. The combination of FH535 with sorafenib promotes a synergistic inhibition of HCC and liver cancer stem cell proliferation, mediated in part by the simultaneous disruption of mitochondrial respiration and glycolysis. We demonstrated that FH535 decreased HCC tumor progression in a mouse xenograft model. For the first time, we showed the inhibitory effect of an FH535 derivative, FH535-N, alone and in combination with sorafenib on HCC cell proliferation. Our study revealed the contributing effect of Wnt/β-catenin pathway inhibition by FH535 and its derivative (FH535-N) through disruption of the autophagic flux in HCC cells

Changes in HPV prevalence following a national bivalent HPV vaccination programme in Scotland: a 7-year cross-sectional study

Background: On Sept 1, 2008, Scotland launched routine vaccination for human papillomavirus (HPV) types 16 and 18, targeted at 12–13-year-old girls, of whom 92·4% were fully vaccinated in 2008–09. In this study, we report on vaccine effectiveness of the bivalent vaccine in these vaccinated women who attended for routine cervical screening at age 20–21 years. Methods: In this 7-year cross-sectional study (covering birth cohorts 1988–1995), we sampled approximately 1000 samples per year from those attending cervical screening at age 20–21 years and tested each for HPV. By linkage to vaccination records we ascertained prevalence by birth cohort and vaccination status. Estimates of vaccine effectiveness for HPV types 16 and 18, HPV types 31, 33, and 45, other high-risk types, and any HPV were calculated using logistic regression. Findings: In total, 8584 samples were HPV genotyped. Prevalence of HPV types 16 and 18 reduced substantially from 30·0% (95% CI 26·9–33·1) in the 1988 cohort to 4·5% (3·5–5·7) in the 1995 cohort, giving a vaccine effectiveness of 89·1% (85·1–92·3) for those vaccinated at age 12–13 years. All cross-protective types showed significant vaccine effectiveness (HPV type 31, 93·8% [95% CI 83·8–98·5]; HPV type 33, 79·1% [64·2–89·0]; HPV type 45, 82·6% [61·5–93·9]). Unvaccinated individuals born in 1995 had a reduced odds of HPV types 16 and 18 infection compared with those born in 1988 (adjusted odds ratio 0·13 [95% CI 0·06–0·28]) and reduced odds of HPV types 31, 33, and 45 (odds ratio 0·45 [0·23–0·89]). Interpretation: Bivalent vaccination has led to a startling reduction in vaccine and cross-protective HPV types 7 years after vaccination. There is also evidence of herd protection against the vaccine-specific and cross-protective types in unvaccinated individuals born in 1995. These findings should be considered in cost-effectiveness models informing vaccine choice and models to shape the future of cervical screening programmes