Fibroblast growth factor 23 and markers of mineral metabolism in individuals with preserved renal function

Fibroblast growth factor 23 (FGF23) is a bone-derived hormone that regulates phosphate homeostasis. Circulating FGF23 is elevated in chronic kidney disease (CKD) and independently associated with poor renal and cardiovascular outcomes and mortality. Because the study of FGF23 in individuals with normal renal function has received little attention, we examined in a large, population based study of 1128 participants the associations of FGF23 with markers of mineral metabolism and renal function. The median estimated glomerular filtration rate (eGFR) of the cohort was 105 ml/min per 1.73 m2, and the median plasma FGF23 was 78.5 RU/ml. FGF23 increased and plasma 1,25-dihydroxyvitamin D3 decreased significantly below an eGFR threshold of 102 and 99 ml/min per 1.73 m2, respectively. In contrast, plasma parathyroid hormone increased continuously with decreasing eGFR and was first significantly elevated at an eGFR of 126 ml/min per 1.73 m2. On multivariable analysis adjusting for sex, age, body mass index, and GFR, FGF23 was negatively associated with 1,25-dihydroxyvitamin D3, and urinary absolute and fractional calcium excretion but not with serum calcium or parathyroid hormone. We found a positive association of FGF23 with plasma phosphate, but no association with urinary absolute or fractional phosphate excretion and, unexpectedly, a positive association with tubular maximum phosphate reabsorption/GFR. Thus, in the absence of CKD, parathyroid hormone increases earlier than FGF23 when the eGFR decreases. The increase in FGF23 occurs at a higher eGFR threshold than previously reported and is closely associated with a decrease in 1,25-dihydroxyvitamin D3. We speculate that the main demonstrable effect of FGF23 in the setting of preserved renal function is suppression of 1,25-dihydroxyvitamin D3 rather than stimulation of renal phosphate excretion.

Response of B-type natriuretic pepticle to exercise in hypertensive patients with suspected diastolic heart failure: Correlation with cardiac function, hemodynamics, and workload

Background Diastolic heart failure (DHF) is characterized by dyspnea due to increased left ventricular (LV) filling pressures during stress. We sought the relationship of exercise-induced increases in B-type natriuretic peptide (BNP) to LV filling pressures and parameters of cardiovascular performance in suspected DHF. Methods Twenty-six treated hypertensive patients with suspected DHF (exertional dyspnea, LV ejection fraction >50%, and diastolic dysfunction) underwent maximal exercise echocardiography using the Bruce protocol. BNP, transmitral Doppler, and tissue Doppler for systolic (So) and early (Ea) and late (Aa) diastolic mitral annular velocities were obtained at rest and peak stress. LV filling pressures were estimated with E/Ea ratios. Results Resting BNP correlated with resting pulse pressure (r=0.45, P=0.02). Maximal exercise performance (4.6 +/- 2.5min) was limited by dyspnea. Blood pressure increased with exercise (from 143 +/- 19/88 +/- 8 to 191 +/- 22/90 +/- 10 mm Hg); 13 patients (50%) had a hypertensive response. Peak exercise BNP correlated with peak transmitral E velocity (r = 0.41, P <.05) and peak heart rate (r = -0.40, P <.05). BNP increased with exercise (from 48 57 to 74 97 pg/mL, P =.007), and the increment of BNP with exercise was associated with maximal workload and peak exercise So, Ea, and Aa (P <.01 for all). Filling pressures, approximated by lateral E/Ea ratio, increased with exercise (7.7 +/- 2.0 to 10.0 +/- 4.8, P <.01). BNP was higher in patients with possibly elevated filling pressures at peak exercise (E/Ea >10) compared to those with normal pressures (123 +/- 124 vs 45 +/- 71 pg/mL, P =.027). Conclusions Augmentation of BNP with exercise in hypertensive patients with suspected DHF is associated with better exercise capacity, LV systolic and diastolic function, and left atrial function. Peak exercise BNP levels may identify exercise-induced elevation of filling pressures in DHF.

Impact of pallidotomy on physiological articulation function and speech intelligibility in Parkinsons disease

The objective of this study was to evaluate the effects of posteroventral pallidotomy on perceptual and physiological measures of articulatory function and speech intelligibility in Parkinson disease (M). The study examined 11 participants with M who underwent posteroventral pallidotomy Physiological measures of hp and tongue function. and perceptual measures of speech intelligibility were obtained prepallidotomy and 3 months postpallidotomy. The participants with PD were also assessed on the Unified Parkinsons Disease Rating Scale (UPDRS Part III) In addition, the study included a group of 16 participants with PD who did not undergo pallidotomy and a group of 30 nonneurologically impaired participants. Analyses of physiological articulatory function and speech intelligibility did not reveal corresponding improvements in motor speech function as observed in general limb motor function postpallidotomy. Overall, individual reliable change analyses revealed that the majority of surgical PD participants demonstrated no reliable change on perceptual and physiological measures of articulation. The cur rent study revealed preliminary evidence that articulatury function and speech intelligibility did not change following posteroventral pallidotomy in a group of individuals with PD.

The 2dF-SDSS LRG and QSO (2SLAQ) survey: the z < 2.1 quasar luminosity function from 5645 quasars to g=21.85

We have used the Two-Degree Field (2dF) instrument on the Anglo-Australian Telescope (AAT) to obtain redshifts of a sample of z < 3 and 18.0 < g < 21.85 quasars selected from Sloan Digital Sky Survey (SDSS) imaging. These data are part of a larger joint programme between the SDSS and 2dF communities to obtain spectra of faint quasars and luminous red galaxies, namely the 2dF-SDSS LRG and QSO (2SLAQ) Survey. We describe the quasar selection algorithm and present the resulting number counts and luminosity function of 5645 quasars in 105.7 deg(2). The bright-end number counts and luminosity functions agree well with determinations from the 2dF QSO Redshift Survey (2QZ) data to g similar to 20.2. However, at the faint end, the 2SLAQ number counts and luminosity functions are steeper (i.e. require more faint quasars) than the final 2QZ results from Croom et al., but are consistent with the preliminary 2QZ results from Boyle et al. Using the functional form adopted for the 2QZ analysis ( a double power law with pure luminosity evolution characterized by a second-order polynomial in redshift), we find a faint-end slope of beta =-1.78 +/- 0.03 if we allow all of the parameters to vary, and beta =-1.45 +/- 0.03 if we allow only the faint-end slope and normalization to vary (holding all other parameters equal to the final 2QZ values). Over the magnitude range covered by the 2SLAQ survey, our maximum-likelihood fit to the data yields 32 per cent more quasars than the final 2QZ parametrization, but is not inconsistent with other g > 21 deep surveys for quasars. The 2SLAQ data exhibit no well-defined 'break' in the number counts or luminosity function, but do clearly flatten with increasing magnitude. Finally, we find that the shape of the quasar luminosity function derived from 2SLAQ is in good agreement with that derived from Type I quasars found in hard X-ray surveys.

Articulatory function following traumatic brain injury in childhood: A perceptual and instrumental analysis

Primary objective: To investigate the articulatory function of a group of children with traumatic brain injury (TBI), using both perceptual and instrumental techniques. Research design: The performance of 24 children with TBI was assessed on a battery of perceptual (Frenchay Dysarthria Assessment, Assessment of Intelligibility of Dysarthric Speech and speech sample analysis) and instrumental ( lip and tongue pressure transduction systems) assessments and compared with that of 24 non-neurologically impaired children matched for age and sex. Main outcomes: Perceptual assessment identified consonant and vowel imprecision, increased length of phonemes and overall reduction in speech intelligibility, while instrumental assessment revealed significant impairment in lip and tongue function in the TBI group, with rate and pressure in repetitive lip and tongue tasks particularly impaired. Significant negative correlations were identified between the degree of deviance of perceptual articulatory features and decreased function on many non-speech measures of lip function, as well as maximum tongue pressure and fine force tongue control at 20% of maximum tongue pressure. Additionally, sub-clinical articulatory deficits were identified in the children with TBI who were non-dysarthric. Conclusion: The results of the instrumental assessment of lip and tongue function support the finding of substantial articulatory dysfunction in this group of children following TBI. Hence, remediation of articulatory function should be a therapeutic priority in these children.

Socioeconomic position, cognitive function, and clustering of cardiovascular risk factors in adolescence: Findings from the Mater University Study of Pregnancy and its outcomes

Objectives: The objectives of this study were to examine the extent of clustering of smoking, high levels of television watching, overweight, and high blood pressure among adolescents and whether this clustering varies by socioeconomic position and Cognitive function. Methods: This study was a cross-sectional analysis of 3613 (1742 females) participants of an Australian birth cohort who were examined at age 14. Results: Three hundred fifty-three (9.8%) of the participants had co-occurrence of three or four risk factors. Risk factors clustered in these adolescents with a greater number of participants than would be predicted by assumptions of independence having no risk factors and three or four risk factors. The extent of clustering tended to be greater in those from lower-income families and among those with lower cognitive function. The age-adjusted ratio of observed to expected cooccurrence of three or four risk factors was 2.70 (95% confidence interval [Cl], 1.80-4.06) among those from low-income families and 1.70 (95% Cl, 1.34-2.16) among those from more affluent families. The ratio among those with low Raven's scores (nonverbal reasoning) was 2.36 (95% Cl, 1.69-3.30) and among those with higher scores was 1.51 (95% Cl, 1.19-1.92); similar results for the WRAT 3 score (reading ability) were 2.69 (95% Cl, 1.85-3.94) and 1.68 (95% Cl, 1.34-2.11). Clustering did not differ by sex. Conclusion: Among adolescents, coronary heart disease risk factors cluster, and there is some evidence that this clustering is greater among those from families with low income and those who have lower cognitive function.

Ocular and systemic markers for vascular function in those at risk of type 2 diabetes mellitus and cardiovascular disease

The devastating impact of Type 2 Diabetes Mellitus (T2DM) -related morbidity and mortality on global healthcare is escalating with higher prevalences of obesity, poor diet, and sedentary lifestyles. Therefore, the clinical need for early diagnosis and prevention in groups of high-risk individuals is necessary. The purpose of this thesis was to investigate the use of surrogate markers, namely retinal vascular function, to determine future vascular endothelial dysfunction, atherosclerosis, large vessel disease and cardiovascular risk in certain groups. This namely covered normoglycaemic and normotensive South Asians (SAs), those with Impaired-Glucose Tolerance (IGT) and individuals with a familial history (FH) of T2DM. Additionally the effect of overweight and obesity was studied. The techniques and modified protocols adopted for this thesis involved the investigation of endothelial function by means of vascular reactivity at the ocular and systemic level. Furthermore, the relationships between retinal and systemic function with circulating markers for endothelial cell function and cardiovascular risk markers were explored. The principal studies and findings of the research were: Vascular Function in Normoglycaemic Individuals with and without a FH of T2DM WE FH individuals exhibited higher levels of total cholesterol levels that correlated well with the retinal arterial dilation amplitude to flicker light stimulus. However this did not extend to noticeable differences in markers for endothelial cell damage and impaired retinal and systemic function. Vascular Function in Normoglycaemic South-Asians vs. White-Europeans without a FH and Vascular Disturbances Compared to healthy WEs (normo -glycaemic and -tensive), SA participants exhibited levels of dyslipidaemia and a state of oxidative stress that extended to impaired vascular function as detected by reduced brachial artery flow-mediated dilation, slower retinal arterial vessel dilation reaction times (Appendix 3) and steeper constriction profiles. Furthermore, gender sub-group analysis presented in a sub-chapter shows that SA males demonstrated 24-hour systemic blood pressure (BP) and heart rate variability (HRV) abnormalities and heightened cardiovascular disease (CVD) risk. Vascular Function in Individuals Newly Diagnosed with IGT as compared to Normoglycaemic Healthy Controls Newly-diagnosed WE and SA IGT patients showed a greater risk for CVD and T2DM progression by means of 24-hour BP abnormalities, dyslipidaemia, increased carotid artery intimal-media thickness (c-IMT), Framingham scores and cholesterol ratios. Additionally, pre-clinical markers for oxidative stress and endothelial dysfunction, as evident by significantly lower levels of plasma glutathione and increased levels of von-Willebrand factor in IGT individuals, extended to impaired vascular systemic and retinal function compared to normal controls. This originally shows retinal, systemic and biochemical disturbances in newly-diagnosed IGT not previously reported before. Vascular Function in Normal, Overweight and Obese Individuals of SA and WE Ethnicity In addition to the intended study chapters, the thesis also investigated the influence of obesity and overweight on vascular function. Most importantly, it was found for the first time that compared to lean individuals it was overweight and not obese individuals that exhibited signs of vascular systemic and ocular dysfunction that was evident alongside markers of atherosclerosis, CVD risk and endothelial damage.

Malmquist indexes using a geometric distance function (GDF)

Traditional approaches to calculate total factor productivity change through Malmquist indexes rely on distance functions. In this paper we show that the use of distance functions as a means to calculate total factor productivity change may introduce some bias in the analysis, and therefore we propose a procedure that calculates total factor productivity change through observed values only. Our total factor productivity change is then decomposed into efficiency change, technological change, and a residual effect. This decomposition makes use of a non-oriented measure in order to avoid problems associated with the traditional use of radial oriented measures, especially when variable returns to scale technologies are to be compared.

Ocular and systemic vascular function in human ageing

The importance of vascular risk factors in various age-related pathologies has been extensively researched. Nevertheless, the haemodynamic disturbance occurring in various ocular and systemic vascular beds to impact upon ocular function remained largely unknown. The purpose of the following studies was to explore the presence and impact of both ocular and systemic vascular dysregulation as well as biochemical vascular risk factors in healthy elderly individuals and patients with age-related macular degeneration. Furthermore, the possible role was played by circulatory oxidative stress and its relationship with endothelial dysfunction at both ocular and systemic levels has also been investigated. There were four principal sections to the present work: 1. To assess the relationship between ocular and systemic anti-oxidative defence in healthy individuals The principal findings of this work were: -It has been shown that MPOD significantly and positively related with circulatory GSH levels. 2. To investigate macro- and microcirculation and oxidative stress in early AMD patients without overt systemic disease The principal findings of this work were: -AMD patients exhibit abnormal macrocirculation compared to the controls. -Blood GSSG level was significantly higher in early AMD patients than controls. -AMD patients showed abnormal microcirculation at retinal level compared. -In early AMD patients, retinal venous RT positively correlated with blood GSSG levels. 3. To assess the relationship between ocular vascular function and circulatory markers of endothelial dysfunction and CVD risk The principal findings of this work were: -Age had a positive effect on ET-1, vWF and slope of retinal arterial constriction in otherwise healthy individuals. -Even in otherwise healthy individuals, retinal arterial vascular function showed a significant correlation with circulatory markers of endothelial dysfunction and CVD risk. 4. To assess age-related changes in ANS and vascular function, and their relationship to retinal vascular function parameters The principal findings of this work were: -Elderly individuals demonstrated abnormal circadian changes of PSNS activity compared to middle-aged group. -Elderly groups showed higher ET-1 and vWF level as well as C-IMT and AIx, and also impaired retinal vascular function compared to the middle-aged group. -In the elderly group, impaired retinal vascular function significantly correlated with the dysregulation of PSNS activity.

Extracellular loops 1 and 3 and their associated transmembrane regions of the calcitonin receptor-like receptor are needed for CGRP receptor function

The first and third extracellular loops (ECL) of G protein-coupled receptors (GPCRs) have been implicated in ligand binding and receptor function. This study describes the results of an alanine/leucine scan of ECLs 1 and 3 and loop-associated transmembrane (TM) domains of the secretin-like GPCR calcitonin receptor-like receptor which associates with receptor activity modifying protein 1 to form the CGRP receptor. Leu195Ala, Val198Ala and Ala199Leu at the top of TM2 all reduced aCGRP-mediated cAMP production and internalization; Leu195Ala and Ala199Leu also reduced aCGRP binding. These residues form a hydrophobic cluster within an area defined as the "minor groove" of rhodopsin-like GPCRs. Within ECL1, Ala203Leu and Ala206Leu influenced the ability of aCGRP to stimulate adenylate cyclase. In TM3, His219Ala, Leu220Ala and Leu222Ala have influences on aCGRP binding and cAMP production; they are likely to indirectly influence the binding site for aCGRP as well as having an involvement in signal transduction. On the exofacial surfaces of TMs 6 and 7, a number of residues were identified that reduced cell surface receptor expression, most noticeably Leu351Ala and Glu357Ala in TM6. The residues may contribute to the RAMP1 binding interface. Ile360Ala impaired aCGRP-mediated cAMP production. Ile360 is predicted to be located close to ECL2 and may facilitate receptor activation. Identification of several crucial functional loci gives further insight into the activation mechanism of this complex receptor system and may aid rational drug design.

Ocular and systemic endothelial function in the off spring of diabetics:a pilot study

Purpose To investigate ocular and systemic correlates of endothelial function in the normoglycaemic offspring of Type 2 Diabetics (T2DM). Methods Healthy participants aged between 25-65 with (n=30) and without (n=39) a family history were recruited. Retinal vessel reactivity was assessed by using the Retinal Vessel Analyser (RVA, Imedos GmBH). In addition, systemic endothelial function was assessed by using the flow mediated dilation (FMD) technique. Results Parametric testing showed no significant differences in anthropometric, blood assay or ocular and systemic function between both groups (p>0.05). The average maximum dilation in the measured retinal artery correlated significantly with the maximum dilation of the measured brachial artery (p=0.002 R=0.55) in healthy controls; however, this was not true for subjects with family history of T2DM. Conclusion Subjects with family history of T2DM show possibly early signs of endothelial dysfunction that, in certain conditions, could contribute to the higher risk of this group of developing similar pathology to their parents.

Productivity change using growth accounting and frontier-based approaches:evidence from a Monte Carlo analysis

This study presents some quantitative evidence from a number of simulation experiments on the accuracy of the productivitygrowth estimates derived from growthaccounting (GA) and frontier-based methods (namely data envelopment analysis-, corrected ordinary least squares-, and stochastic frontier analysis-based malmquist indices) under various conditions. These include the presence of technical inefficiency, measurement error, misspecification of the production function (for the GA and parametric approaches) and increased input and price volatility from one period to the next. The study finds that the frontier-based methods usually outperform GA, but the overall performance varies by experiment. Parametric approaches generally perform best when there is no functional form misspecification, but their accuracy greatly diminishes otherwise. The results also show that the deterministic approaches perform adequately even under conditions of (modest) measurement error and when measurement error becomes larger, the accuracy of all approaches (including stochastic approaches) deteriorates rapidly, to the point that their estimates could be considered unreliable for policy purposes.

Effect of medications with anti-cholinergic properties on cognitive function, delirium, physical function and mortality:a systematic review

Objectives: to determine the effect of drugs with anti-cholinergic properties on relevant health outcomes.Design: electronic published and unpublished literature/trial registries were systematically reviewed. Studies evaluating medications with anti-cholinergic activity on cognitive function, delirium, physical function or mortality were eligible.Results: forty-six studies including 60,944 participants were included. Seventy-seven percent of included studies evaluating cognitive function (n = 33) reported a significant decline in cognitive ability with increasing anti-cholinergic load (P < 0.05). Four of five included studies reported no association with delirium and increasing anti-cholinergic drug load (P > 0.05). Five of the eight included studies reported a decline in physical function in users of anti-cholinergics (P < 0.05). Three of nine studies evaluating mortality reported that the use of drugs with anti-cholinergic properties was associated with a trend towards increased mortality, but this was not statistically significant. The methodological quality of the evidence-base ranged from poor to very good.Conclusion: medicines with anti-cholinergic properties have a significant adverse effect on cognitive and physical function, but limited evidence exists for delirium or mortality outcomes. © The Author 2014. Published by Oxford University Press on behalf of the British Geriatrics Society. All rights reserved.

Antigen Drives Regulatory B10 Cell Development and Function

B cells mediate immune responses via the secretion of antibody and interactions with other immune cell populations through antigen presentation, costimulation, and cytokine secretion. Although B cells are primarily believed to promote immune responses using the mechanisms described above, some unique regulatory B cell populations that negatively influence inflammation have also been described. Among these is a rare interleukin (IL)-10-producing B lymphocyte subset termed “B10 cells.” B cell-derived IL-10 can inhibit various arms of the immune system, including polarization of Th1/Th2 cell subsets, antigen presentation and cytokine production by monocytes and macrophages, and activation of regulatory T cells. Further studies in numerous autoimmune and inflammatory models of disease have confirmed the ability of B10 cells to negatively regulate inflammation in an IL-10-dependent manner. Although IL-10 is indispensable to the effector functions of B10 cells, how this specialized B cell population is selected in vivo to produce IL-10 is unknown. Some studies have demonstrated a link between B cell receptor (BCR)-derived signals and the acquisition of IL-10 competence. Additionally, whether antigen-BCR interactions are required for B cell IL-10 production during homeostasis as well as active immune responses is a matter of debate. Therefore, the goal of this thesis is to determine the importance of antigen-driven signals during B10 cell development in vivo and during B10 cell-mediated immunosuppression.

Chapter 3 of the dissertation explored the BCR repertoire of spleen and peritoneal cavity B10 cells using single-cell sequencing to lay the foundation for studies to understand the full range of antigens that may be involved in B10 cell selection. In both the spleen and peritoneal cavity B10 cells studied, BCR gene utilization was diverse, and the expressed BCR transcripts were largely unmutated. Thus, B10 cells are likely capable of responding to a wide range of foreign and self-antigens in vivo.

Studies in Chapter 4 determined the predominant antigens that drive B cell IL-10 secretion during homeostasis. A novel in vitro B cell expansion system was used to isolate B cells actively expressing IL-10 in vivo and probe the reactivities of their secreted monoclonal antibodies. B10 cells were found to produce polyreactive antibodies that bound multiple self-antigens. Therefore, in the absence of overarching active immune responses, B cell IL-10 is secreted following interactions with self-antigens.

Chapter 5 of this dissertation investigated whether foreign antigens are capable of driving B10 cell expansion and effector activity during an active immune response. In a model of contact-induced hypersensitivity, in vitro B cell expansion was again used to isolate antigen-specific B10 clones, which were required for optimal immunosuppression.

The studies described in this dissertation shed light on the relative contributions of BCR-derived signals during B10 cell development and effector function. Furthermore, these investigations demonstrate that B10 cells respond to both foreign and self-antigens, which has important implications for the potential manipulation of B10 cells for human therapy. Therefore, B10 cells represent a polyreactive B cell population that provides antigen-specific regulation of immune responses via the production of IL-10.

Effects of retirement on cognitive function: A gender and international perspecive

Background: As the global population is ageing, studying cognitive impairments including dementia, one of the leading causes of disability in old age worldwide, is of fundamental importance to public health. As a major transition in older age, a focus on the complex impacts of the duration, timing, and voluntariness of retirement on health is important for policy changes in the future. Longer retirement periods, as well as leaving the workforce early, have been associated with poorer health, including reduced cognitive functioning. These associations are hypothesized to differ based on gender, as well as on pre-retirement educational and occupational experiences, and on post-retirement social factors and health conditions. Methods: A cross-sectional study is conducted to determine the relationship between duration and timing of retirement and cognitive function, using data from the five sites of International Mobility in Aging Study (IMIAS). Cognitive function is assessed using the Leganes Cognitive Test (LCT) scores in 2012. Data are analyzed using multiple linear regressions. Analyses are also done by site/region separately (Canada, Latin America, and Albania). Robustness checks are done with an analysis of cognitive change from 2012 to 2014, the effect of voluntariness of retirement on cognitive function. An instrumental variable (IV) approach is also applied to the cross-sectional and longitudinal analyses as a robustness check to address the potential endogeneity of the retirement variable. Results: Descriptive statistics highlight differences between men and women, as well as between sites. In linear regression analysis, there was no relationship between timing or duration of retirement and cognitive function in 2012, when adjusting for site/region. There was no association between retirement characteristics and cognitive function in site/region/stratified analyses. In IV analysis, longer retirement and on time or late retirement was associated with lower cognitive function among men. In IV analysis, there is no relationship between retirement characteristics and cognitive function among women. Conclusions: While results of the thesis suggest a negative effect of retirement on cognitive function, especially among men, the relationship remains uncertain. A lack of power results in the inability to draw conclusions for site/region-specific analysis and site-adjusted analysis in both linear and IV regressions.