The role of 25-hydroxyvitamin D deficiency in promoting insulin resistance and inflammation in patients with chronic kidney disease: A randomised controlled trial

BACKGROUND Approximately 50% of patients with stage 3 Chronic Kidney Disease are 25-hydroxyvitamin D insufficient, and this prevalence increases with falling glomerular filtration rate. Vitamin D is now recognised as having pleiotropic roles beyond bone and mineral homeostasis, with the vitamin D receptor and metabolising machinery identified in multiple tissues. Worryingly, recent observational data has highlighted an association between hypovitaminosis D and increased cardiovascular mortality, possibly mediated via vitamin D effects on insulin resistance and inflammation. The main hypothesis of this study is that oral Vitamin D supplementation will ameliorate insulin resistance in patients with Chronic Kidney Disease stage 3 when compared to placebo. Secondary hypotheses will test whether this is associated with decreased inflammation and bone/adipocyte-endocrine dysregulation. METHODS/DESIGN This study is a single-centre, double-blinded, randomised, placebo-controlled trial. Inclusion criteria include; estimated glomerular filtration rate 30-59 ml/min/1.73 m(2); aged >or=18 on entry to study; and serum 25-hydroxyvitamin D levels <75 nmol/L. Patients will be randomised 1:1 to receive either oral cholecalciferol 2000IU/day or placebo for 6 months. The primary outcome will be an improvement in insulin sensitivity, measured by hyperinsulinaemic euglycaemic clamp. Secondary outcome measures will include serum parathyroid hormone, cytokines (Interleukin-1beta, Interleukin-6, Tumour Necrosis Factor alpha), adiponectin (total and High Molecular Weight), osteocalcin (carboxylated and under-carboxylated), peripheral blood mononuclear cell Nuclear Factor Kappa-B p65 binding activity, brachial artery reactivity, aortic pulse wave velocity and waveform analysis, and indirect calorimetry. All outcome measures will be performed at baseline and end of study. DISCUSSION To date, no randomised controlled trial has been performed in pre-dialysis CKD patients to study the correlation between vitamin D status with supplementation, insulin resistance and markers of adverse cardiovascular risk. We remain hopeful that cholecalciferol may be a safe intervention, with health benefits beyond those related to bone-mineral homeostasis. TRIAL REGISTRATION Australian and New Zealand Clinical Trials Registry ACTRN12609000246280.

Flow-mediated dilatation of the brachial artery is a poorly reproducible indicator of microvascular function in Type I diabetes mellitus

Aim: Two Type I diabetes and control group comparator studies were conducted to assess the reproducibility of FMD and to analyse blood flow data normally discarded during FMD measurement.

Design: The studies were sequential and differed only with regard to operator and ultrasound machine. Seventy-two subjects with diabetes and 71 controls were studied in total.

Methods: Subjects had FMD measured conventionally. Blood velocity waveforms were averaged over 10 pulses post forearm ischaemia and their component frequencies analysed using the wavelet transform, a mathematical tool for waveform analysis. The component frequencies were grouped into 11 bands to facilitate analysis.

Results: Subjects were well-matched between studies. In Study 1, FMD was significantly impaired in subjects with Type I diabetes vs. controls (median 4.35%, interquartile range 3.10-4.80 vs. 6.50, 4.79-9.42, P < 0.001). No differences were detected between groups in Study 2, however. However, analysis of blood velocity waveforms yielded significant differences between groups in two frequency bands in each study.

Conclusions: This report highlights concerns over the reproducibility of FMD measures. Further work is required to fully elucidate the role of analysing velocity waveforms after forearm ischaemia.

Colour Doppler ultrasound of the ocular circulation in patients with systemic lupus erythematosus identifies altered microcirculatory haemodynamics

We assessed whether quantitative analysis of Doppler flow velocity waveforms is able to identify subclinical microvascular abnormalities in SLE and whether eigenvector analysis can detect changes not detectable using the resistive index (RI). Fifty-four SLE patients with no conventional cardiovascular risk factors, major organ involvement or retinopathy were compared to 32 controls. Flow velocity waveforms were obtained from the ophthalmic artery (OA), central retinal artery (CRA) and common carotid artery (CA). The waveforms were analysed using eigenvector decomposition and compared between groups at each arterial site. The RI was also determined. The RI was comparable between groups. In the OA and CRA, there were significant differences in the lower frequency sinusoidal components (P <0.05 for each component). No differences were apparent in the CA between groups. Eigenvector analysis of Doppler flow waveforms, recorded in proximity of the terminal vascular bed, identified altered ocular microvascular haemodynamics in SLE. Altered waveform structure could not be identified by changes in RI, the traditional measure of downstream vascular resistance. This analytical approach to waveform analysis is more sensitive in detecting preclinical microvascular abnormalities in SLE. It may hold potential as a useful tool for assessing disease activity, response to treatment, and predicting future vascular complications.

Ultrasound entropy may be a new non-invasive measure of pre-clinical vascular damage in young hypertensive patients

Background: The identification of pre-clinical microvascular damage in hypertension by non-invasive techniques has proved frustrating for clinicians. This proof of concept study investigated whether entropy, a novel summary measure for characterizing blood velocity waveforms, is altered in participants with hypertension and may therefore be useful in risk stratification.

Methods: Doppler ultrasound waveforms were obtained from the carotid and retrobulbar circulation in 42 participants with uncomplicated grade 1 hypertension (mean systolic/diastolic blood pressure (BP) 142/92 mmHg), and 26 healthy controls (mean systolic/diastolic BP 116/69 mmHg). Mean wavelet entropy was derived from flow-velocity data and compared with traditional haemodynamic measures of microvascular function, namely the resistive and pulsatility indices.

Results: Entropy, was significantly higher in control participants in the central retinal artery (CRA) (differential mean 0.11 (standard error 0.05 cms(-1)), CI 0.009 to 0.219, p 0.017) and ophthalmic artery (0.12 (0.05), CI 0.004 to 0.215, p 0.04). In comparison, the resistive index (0.12 (0.05), CI 0.005 to 0.226, p 0.029) and pulsatility index (0.96 (0.38), CI 0.19 to 1.72, p 0.015) showed significant differences between groups in the CRA alone. Regression analysis indicated that entropy was significantly influenced by age and systolic blood pressure (r values 0.4-0.6). None of the measures were significantly altered in the larger conduit vessel.

Conclusion: This is the first application of entropy to human blood velocity waveform analysis and shows that this new technique has the ability to discriminate health from early hypertensive disease, thereby promoting the early identification of cardiovascular disease in a young hypertensive population.

Wavelet entropy of Doppler ultrasound blood velocity flow waveforms distinguishes nitric oxide-modulated states

Wavelet entropy assesses the degree of order or disorder in signals and presents this complex information in a simple metric. Relative wavelet entropy assesses the similarity between the spectral distributions of two signals, again in a simple metric. Wavelet entropy is therefore potentially a very attractive tool for waveform analysis. The ability of this method to track the effects of pharmacologic modulation of vascular function on Doppler blood velocity waveforms was assessed. Waveforms were captured from ophthalmic arteries of 10 healthy subjects at baseline, after the administration of glyceryl trinitrate (GTN) and after two doses of N(G)-nitro-L-arginine-methyl ester (L-NAME) to produce vasodilation and vasoconstriction, respectively. Wavelet entropy had a tendency to decrease from baseline in response to GTN, but significantly increased after the administration of L-NAME (mean: 1.60 ± 0.07 after 0.25 mg/kg and 1.72 ± 0.13 after 0.5 mg/kg vs. 1.50 ± 0.10 at baseline, p < 0.05). Relative wavelet entropy had a spectral distribution from increasing doses of L-NAME comparable to baseline, 0.07 ± 0.04 and 0.08 ± 0.03, respectively, whereas GTN had the most dissimilar spectral distribution compared with baseline (0.17 ± 0.08, p = 0.002). Wavelet entropy can detect subtle changes in Doppler blood velocity waveform structure in response to nitric-oxide-mediated changes in arteriolar smooth muscle tone.

Variación de volumen sistólico como predictor de hipovolemia en pacientes pediátricos con choque séptico

El compromiso del sistema cardiovascular es frecuente en los pacientes en estado crítico, por tanto la monitorización hemodinámica es esencial para un tratamiento apropiado dirigido a objetivos terapéuticos en este grupo de pacientes. La monitorización hemodinámica del gasto cardíaco y la estimación del volumen intravascular son fundamentales para el manejo de los pacientes pediátricos en estado crítico, la medición del gasto cardíaco es uno de los principales elementos para evaluar la situación hemodinámica y la perfusión tisular de un paciente ayudando a dirigir el tratamiento y a monitorizar la respuesta clínica en pacientes con choque séptico. La hipovolemia es una causa común para la falla circulatoria en pacientes en condición crítica, el encontrar un método confiable para medición de precarga es importante para guiar la administración de líquidos. Tradicionalmente se han utilizado medidas de la volemia asociadas como la presión venosa central (PVC), frecuencia cardiaca (FC), presión arterial (PA) y el gasto urinario. Estos indicadores tienen grandes factores de distracción que hacen que su valor sea limitado y por tanto se tengan que buscar alternativas más confiables. En años recientes se han postulado parámetros dinámicos para la evaluación de la precarga, entre ellos uno de los mas ampliamente estudiado es la medición de la variabilidad de Volumen sistólico (VVS); Este valor se basa en el concepto de que durante la inspiración, la disminución del retorno venoso produce una disminución del Volumen sistólico, lo cual se manifiesta como una disminución en la onda de pulso; Por tanto en una situación de hipovolemia esta diferencia será mayor, dado que será más evidente la disminución del volumen al final de la diástole. En adultos este parámetro se ha convertido en una herramienta útil para evaluar estado de volumen de los pacientes que se encuentran en estado crítico y ha demostrado su utilidad para predecir respuesta a administración de fluidos en diferentes poblaciones de pacientes. En la actualidad no hay estudios en niños que comparen la medición de VVS contra dichas medidas tradicionales de volemia.

On optimizing micropower MOS regulated cascode circuits on switched current techniques

Trade-off between settling time and micropower consumption in MOS regulated cascode current sources as building parts in high-accuracy, current-switching D/A converters is analyzed. The regulation-loop frequency characteristic is obtained and difficulties to impose a dominant-pole condition to the resulting 2nd-order system are discussed. Raising pole frequencies while meeting consumption requirements is basically limited by parasitic capacitances. An alternative is found by imposing a twin-pole system in which design constraints are somewhat relaxed and settling slightly faster. Relationships between pole frequencies, transistor geometry and bias are established. Simulated waveforms obtained with PSpice of designed circuits following a voltage perturbation suggest a good agreement with theory. The proposed approach applied to the design of a micropower current-mode D/A converter improves its simulated settling performance.

Discrete generator coordinate: Symmetry restoration in finite-dimensional spaces

Group theoretical-based techniques and fundamental results from number theory are used in order to allow for the construction of exact projectors in finite-dimensional spaces. These operators are shown to make use only of discrete variables, which play the role of discrete generator coordinates, and their application in the number symmetry restoration is carried out in a nuclear BCS wave function which explicitly violates that symmetry. © 1999 Published by Elsevier Science B.V. All rights reserved.

Evaluation and identification of lightning models by artificial neural networks

This paper describes a novel approach for mapping lightning models using artificial neural networks. The networks acts as identifier of structural features of the lightning models so that output parameters can be estimated and generalized from an input parameter set. Simulation examples are presented to validate the proposed approach. More specifically, the neural networks are used to compute electrical field intensity and critical disruptive voltage taking into account several atmospheric and structural factors, such as pressure, temperature, humidity, distance between phases, height of bus bars, and wave forms. A comparative analysis with other approaches is also provided to illustrate this new methodology.

Harmonics filtering and detection of disturbances using wavelets

Traditional mathematical tools, like Fourier Analysis, have proven to be efficient when analyzing steady-state distortions; however, the growing utilization of electronically controlled loads and the generation of a new dynamics in industrial environments signals have suggested the need of a powerful tool to perform the analysis of non-stationary distortions, overcoming limitations of frequency techniques. Wavelet Theory provides a new approach to harmonic analysis, focusing the decomposition of a signal into non-sinusoidal components, which are translated and scaled in time, generating a time-frequency basis. The correct choice of the waveshape to be used in decomposition is very important and discussed in this work. A brief theoretical introduction on Wavelet Transform is presented and some cases (practical and simulated) are discussed. Distortions commonly found in industrial environments, such as the current waveform of a Switched-Mode Power Supply and the input phase voltage waveform of motor fed by inverter are analyzed using Wavelet Theory. Applications such as extracting the fundamental frequency of a non-sinusoidal current signal, or using the ability of compact representation to detect non-repetitive disturbances are presented.

An AC voltage regulator with high-power-factor, and control using a FPGA device

This paper presents the analysis, design, simulation, and experimental results for a high frequency high Power-Factor (PF) AC (Alternate Current) voltage regulator, using a Sepic converter as power stage. The control technique employed to impose a sinusoidal input current waveform, with low Total Harmonic Distortion (THD), is the sinusoidal variable hysteresis control. The control technique was implemented in a FPGA (Field Programmable Gate Array) device, using a Hardware Description Language (VHDL). Through the use of the proposed control technique, the AC voltage regulator performs active power-factor correction, and low THD in the input current, for linear and non-linear loads, satisfying the requirements of the EEC61000-3-2 standards. Experimental results from an example prototype, designed for 300W of nominal output power, 50kHz (switching frequency), and 127Vrms of nominal input and output voltages, are presented in order to validate the proposed AC regulator. © 2005 IEEE.

Programmable PFC based hybrid multipulse power rectifier for utility interface of power electronic converters

In this paper it is proposed a novel hybrid three-phase rectifier capable to achieve high input power factor (PF), and low total harmonic distortion in the input currents (THDI). The proposed hybrid high power rectifier is composed by a standard three-phase 6-pulses diode rectifier (Graetz bridge) with a parallel connection of single-phase Boost rectifiers in each three-phase rectifier leg. Such topology results in a structure capable of programming the input current waveform and providing conditions for obtaining high input power factor and low harmonic current distortion. In order to validate the proposed hybrid rectifier, this paper describes its principles of operation, with detailed experimental results and discussions on power rating of the required Boost converters as related to the desired total harmonic current distortion. It is demonstrated that only a fraction of the output power is processed through the Boost converters, making the proposed solution economically viable for very high power installations, with fast pay back of the investment. Moreover, retrofitting to existing installations is also feasible since the parallel path can be easily controlled by integration with the existing de-link. A prototype rated at 6 kW has been implemented in laboratory and fully demonstrated its operation, performance and feasibility to high power applications. © 2005 IEEE.

Sonographic Assessment of the Umbilical Cord

The umbilical cord is not an inert structure, suspended between the fetus and placenta, but it plays an active role and it is involved in several processes afflicting the feto-placental unit. Its study has to be regarding not only its morphology and morphometry, and the impendance of blood flow by Doppler waveform analysis, but it includes also an analysis of the coiling type and the amount of the Wharton Jelly. The umbilical cord has been considered like an important and huge source of informations, useful to assess the well-being of the fetus and the outcome of pregnancy. The standardization of ultrasound techniques is the first step to speak the same language and make the study of this structure a fundamental part of well-being fetus assessment. This article is carefully focused on morphologic, morphometric and functional ultrasound examination of umbilical cord and suggests that any anomaly detected should provide an indication for an intense fetal follow-up, useful for early helpful therapy, preventing serious complication for the pregnancy.

Use of umbilical artery Doppler velocimetry in the monitoring of pregnancy in women with pre-existing diabetes

Background: The usefulness of umbilical artery Doppler velocimetry for the monitoring of diabetic pregnancies is controversial. The aim of the present study was to assess whether umbilical artery Doppler velocity waveform analysis can predict adverse perinatal outcomes for pregnancies complicated by pre-existing diabetes mellitus. Methods: All diabetic pregnancies (type 1 and 2) delivered at Mater Mothers' Hospital, Queensland, between 1 January 1995 and 31 December 1999 were included. All pregnant diabetic women were monitored with umbilical artery Doppler velocimetry at 28, 32, 36, and 38 weeks' gestation. Adverse perinatal outcome was defined as pregnancies with one or more of the following: small-for-gestational age, Caesarean section for non-reassuring cardiotocography, fetal acidaemia at delivery, 1-min Apgar of 3 or less, 5-min Apgar of less than 7, hypoxic ischaemic encephalopathy or perinatal death. Abnormal umbilical artery Doppler velocimetry was defined as a pulsatility index of 95th centile or higher for gestation. Results: One hundred and four pregnancies in women with pre-existing diabetes had umbilical arterial Doppler studies carried out during the study period. Twenty-three pregnancies (22.1%) had an elevated pulsatility index. If the scans were carried out within 2 weeks of delivery, 71% of pregnancies with abnormal umbilical Doppler had adverse outcomes (P < 0.01; likelihood ratio, 4.2). However, the sensitivity was 35%; specificity was 94%; positive predictive value was 80%; and negative predictive value was 68%. Only 30% of women with adverse perinatal outcomes had abnormal umbilical arterial Doppler flow. Conclusion: Umbilical artery Doppler velocimetry is not a good predictor of adverse perinatal outcomes in diabetic pregnancies.

Physiological and pathological human ocular perfusion characteristics

There were three principle aims to this thesis. Firstly, the acquisition protocols of clinical blood flow apparatus were investigated in order to optimise them for both cross-sectional and longitudinal application. Secondly, the effects of physiological factors including age and systematic circulation on ocular blood flow were investigated. Finally, the ocular perfusion characteristics of patients diagnosed with ocular diseases considered to be of a vascular origin were investigated. The principle findings of this work are:- 1) Optimisation of clinical investigationsPhotodiode sensitivity of the scanning laser Doppler flowmeter should be kept within a range of 70-150 DC when acquiring images of the retina and optic nerve head in order to optimise the reproducibility of capillary blood flow measures. Account of the physiological spatial variation in retinal blood flow measures can be made using standard analysis protocols of the scanning laser Doppler flowmeter combined with a local search strategy. Measurements of pulsatile ocular blood flow using the ocular blood flow analyser are reproducible, however this reproducibility can be improved when consecutive intraocular pressure pulses are used to calculate pulsatile ocular blood flow. Spectral analysis of the intraocular pressure pulse-wave is viable and identifies the first four harmonic components of the waveform. 2) Physiological variation in ocular perfusionAge results in a significant reduction in perfusion of the retinal microcirculation, which is not evident in larger vessel beds such as the choroid. Despite known asymmetry in the systemic vasculature, no evidence of interocular asymmetry in ocular perfusion is apparent. 3) Pathological variation in ocular perfusionIn primary open angle glaucoma, perfusion is reduced in the retinal microcirculation of patients classified as having early to moderate visual field defects. However, ocular pulsatility defects are masked when patients and subjects are matched for systemic variables (pulse rate and mean arterial pressure); differentiation is facilitated by the application of waveform analysis to the continuos intraocular pressure curve even in the early stages of disease. Diabetic patients with adequate glycaemic control, exhibit maintenance of macular blood flow, macular topography and visual function following phacoemulsification.