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Heart rate variability (HRV) analysis is a powerful non-invasive tool used to determine the state of the heart and assess the development of the Autonomic Nervous System (ANS). The reduced HRV has been associated with negative outcome of ANS. This work describes the results obtained by HRV analysis of two groups of children, 41 Intrauterine growth retarded (IUGR) and 34 normal for a period of 24 hours. The main objective of this work was to explore the autonomic control in IUGR children by performing HRV analysis and comparing the results with normal children to find differences in HRV at 10 years of age. Barker theory and hypothesis states that the IUGR can be prone to coronary heart diseases or hypertension in their adulthood. Signal processing was performed on the ECG signal (data) provided which included filtering and detecting the QRS to find the RR segments. In the time domain analysis many parameters were calculated for all 75 children. Several comparisons between IUGR and normal children groups using night time and one hour RR data collected at night using several variables were computed. Frequency domain analysis of RR has been performed by autoregressive model (AR) Fast Fourier Transform (FFT) after re-sampling RR data of all 75 children. Calculation of the frequency components, large frequency, high frequency, and ratio of LF/HF, were obtained using FFT, AR and Lomb periodogram. Statistical analyses were performed to compare between IUGR and normal children. Time and frequency analysis comparison between the two groups of children showed no significant statistical differences, but the analysis has shown significant difference when dividing IUGR into IUGR1 (< 2.5 kg) and IUGR2 (≥ 2.5 kg), and highlighted differences in Respiratory Sinus Arrhythmia (RSA) at night time. QT algorithm was developed to measure HR, QRS, ST and QT. It was found that QT for IUGR children is slightly higher than that of normal children. Using Poincaré plots, significant difference was found between female and male children. Females had low long term variability. The 24 hr and 15 min pre-wake HRV time domain and Frequency domain analysis showed that IUGR children have reduced HRV which is a marker of a negative outcome of the ANS.

Chronic venous insufficiency (CVI) describes diseases of the lower limb veins in which venous return is impaired and varicose veins and skin ulceration may develop. The roles of purinergic signalling in regulation of vascular tone in the long saphenous vein (LSV) and in the trophic changes occurring in LSV muscle cells and epidermal keratinocytes in lower leg skin were studied. The purinergic role in penile blood flow was also studied, where regulation of penile blood flow affects tumescence. Purinergic signalling was studied using immunohistochemistry, organ bath pharmacology and electron microscopy. P2Xj, P2Yi, P2Y2, P2Y4 and P2Y6 receptor immunoreactivity was present on LSV smooth muscle. Purine-mediated muscle contractions were weaker in varicose veins. Electron microscopy and immunohistochemistry findings support the view that smooth muscle cells change from the contractile to the synthetic phenotype in varicose veins, associated with an upregulation of P2Yi and P2Y2 receptors and a down regulation of P2Xi receptors. CVI skin showed a decrease in P2X7 receptor expression and an increase in P2Yj, P2Y2 and P2X5 receptor expression in different epidermal layers. Mean skin epidermal area in CVI was reduced. Immunohistochemistry and RT-PCR techniques were used to study the presence of P2Y6 receptors in corpus cavernosal tissue. Using organ bath pharmacology, P2Y6 receptors on cavernosal tissue mediated relaxation which was diminished by a P2Y6 antagonist. In conclusion it is suggested that the LSV muscle cell phenotype change may be a causal factor in the development of varicose veins. The thinner epidermis found in CVI might be the result of the changes in expression of P2Y and P2X receptors on keratinocytes. Increased keratinocyte P2X5 receptor activity may, in part, be accountable for epidermal thinning in CVI. Purinergic modulation of human cavernosal smooth muscle cells via the P2Y6 receptor subtype might play a physiological role in penile erection.

Plasminogen activator inhibitor type 1 (PAI-1) is the major inhibitor of fibrinolysis. Plasma PAI-1 levels show clear circadian oscillation, peaking in the morning. Expression of the PAI-1 gene may be directly influenced by the –675 4G/5G polymorphism in the PAI-1 promoter. The aim of the present study was to investigate the regulation of PAI-1, using monocytes and platelets as cell models, under conditions that would simulate events occurring within a forming thrombus. Blood from donors genotyped for the 4G/5G polymorphism was used. Direct stimulation of monocyte with lipopolysaccharide (LPS), induced a small increase in Pai-1 expression (710-fold) above baseline, however, monocyte Pai-1 expression was markedly increased (4700-fold) by interaction with platelets activated by cross-linked collagen related peptide (XL-CRP). Furthermore, the induction of monocyte PAI-1 expression by platelets was not dependent upon cell-cell contact, but appeared to be mediated by both exogenous and endogenous release of TGF-β1. The induction of monocyte Pai-1 expression by either LPS or CRP-XL was not associated with the 4G/5G polymorphism, but the amount of PAI-1 released into plasma following stimulation was influenced by the polymorphism. Five peripheral clock genes examined were expressed in monocytes under resting conditions. LPS induced the expression of Dec1 and Bmal2 but rapidly switched off the expression of mPer2 and clock in monocytes, whereas the stimulation of monocytes by CRP-XL did not affect the expression of clock genes, apart from the down-regulation of Clock and up-regulation of mPer2. Therefore, the acute induction of PAI-1 in blood cells does not appear to be dependent on the circadian clock. Platelet count significantly increased during the afternoon compared to the morning. But platelet Pai-1 mRNA abundance did not exhibit significant diurnal variation nor was it influenced by the 4G/5G polymorphism. Although anucleate, platelets appear to retain the ability to synthesise PAI-1, which could be partially inhibited by cycloheximide, both the synthesis of PAI-1, and release from α-granules of activated platelets, was related to the 4G/5G polymorphism, with the highest level of PAI-1 synthesised and released by platelets from 4G homozygous subjects. In conclusion, PAI-1 in circulatory cells is regulated by circadian factors under resting conditions, but circadian influences may be masked following stimulation. The 4G/5G polymorphism regulates the amount of PAI-1 released by both stimulated monocytes and platelets, and may therefore play a role in the formation or resolution of a thrombus.

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