京都大学 / 新制・課程博士 / 博士(工学) / 甲第25273号 / 工博第5232号 / 京都大学大学院工学研究科建築学専攻 / (主査)教授 小椋 大輔, 教授 原田 和典, 教授 石田 泰一郎 / 学位規則第4条第1項該当 / Doctor of Philosophy (Engineering) / Kyoto University / DFAM

Motivation In the black population of South Africa, cardiovascular disease (CVD) is rapidly increasing due to urbanisation. Stroke is usually accompanied by a prothrombotic haemostatic profile. Changing lifestyle factors that accompany the urbanisation process could have a negative impact on the haemostatic profile of black South Africans. Elevated levels of pro-coagulant factors, von Willebrand factor (vWF), fibrinogen and fibrin D-dimer have been reported in the black population, which could increase the black population’s susceptibility to CVD. However, low levels of plasminogen activator inhibitor-1 (PAI-1) previously reported in the black population could contribute towards a pro-fibrinolytic state, which may counteract the hypercoagulant state. This may have a beneficial effect on the haemostatic profile of the black population. More investigation into the haemostatic profile of black South Africans is therefore needed to determine if an altered haemostatic profile exists in this group, and if so, to what extent these alterations may relate to cardiovascular dysfunction. This study included markers of both the coagulation (vWF, fibrinogen, fibrin D-dimer) and fibrinolytic (PAI-1, fibrin D-dimer and fibrinolytic potential) systems in an attempt to investigate the haemostatic profile of the black population of South Africa, and for comparison purposes that of the white population as well. The relationship of these markers’ with selected markers of cardiovascular function was also examined to determine if they could possibly contribute to an increase in cardiovascular risk, especially in the black population. Aims The aims of this study were to first compare coagulation and fibrinolysis markers in the black and white populations of South Africa. Furthermore, to determine if associations exist between the selected components of the haemostatic system and markers of cardiovascular function, especially in the black population of South Africa, who tends to be at a higher cardiovascular risk due to altered metabolic and haemostatic profiles. Methodology The Sympathetic activity and Ambulatory Blood Pressure in Africans (SABPA) study was a prospective cohort study that consisted of 409 participants at baseline (2008-2009) that were equally distributed according to both ethnicity (200 black; 209 white) and gender (black, 101 men, 99 women; white, 101 men, 108 women). At follow-up (2011/2012) the cohort totalled 359 participants (170 black, 88 men and 82 women; 189 white, 93 men and 96 women). Data from baseline measurements were used for the first two manuscripts (chapters 2 and 3), while followup data was used for the third manuscript (chapter 4). vWF, fibrinogen, PAI-1, fibrin D-dimer, CLT, serum peroxides, glutathione, glutathione peroxidase and reductase activity were determined, and ambulatory blood pressure and the retinal vessel calibres were measured. The groups were stratified by ethnicity as specified by statistical interaction terms. T-tests and chi-square tests were used to compare means and proportions, respectively. Pearson and partial regression analyses were used to determine correlations between the components of the haemostatic system and cardiovascular function markers. This was followed by multiple linear regression analyses to investigate whether independent associations exist between the variables in both ethnic groups. P-values ≤0.050 were deemed significant. Results and conclusion of each manuscript The first manuscript (chapter 2) compares the haemostatic profiles of the black and white population to determine whether ambulatory blood pressure is related to components of the haemostatic system. The black participants displayed a prothrombotic profile with significantly higher vWF, fibrinogen, PAI-1, fibrin D-dimer and a longer CLT than their white counterparts. Furthermore, partial and multiple linear regression analyses showed a positive association of systolic and diastolic blood pressure with fibrin D-dimer in the black population, while a negative association existed between ambulatory blood pressure and CLT in the white population. These associations suggest that fibrin D-dimer may contribute, at least in part, to the high prevalence of hypertension in the black population. The second manuscript (chapter 3) determined associations between markers of the haemostatic and oxidant-antioxidant systems in the black and white populations. In addition to the prothrombotic profile that exists in the black population, this group also had significantly higher serum peroxides (oxidative stress) and lower glutathione peroxidase activity (antioxidant) levels. Multiple linear regression analyses indicated positive associations between fibrinogen and serum peroxides in both populations. In the white population, an additional positive association was found between serum peroxide and CLT. In the black population, vWF and CLT were negatively associated with GPx activity. The results suggest that there are ethnic-specific relationships between the haemostatic and oxidant-antioxidant systems. The third manuscript (chapter 4) investigated the relationships between the retinal vessel calibres and components of the haemostatic system in the black and white population. The investigation focussed specifically on arteriolar diameters in the lower median, since a narrow arteriolar diameter is known to be associated with elevated blood pressure. In both ethnic groups, a narrower arteriolar calibre was accompanied by narrower venular calibres. Independent positive associations were found between the central retinal vein equivalent (CRVE) and fibrinogen in the black population, as well as vWF and CLT in the white population. In addition, independent negative associations were found between the central retinal artery equivalent and CLT in the black population and with vWF in the white population. The results suggest that haemostatic alterations are linked to early vascular changes that may differ between ethnicities. General conclusion Ethnic-specific relationships between the components of the haemostatic system and measures of cardiovascular function are evident. The prothrombotic profile that is observed in the black population, together with the adverse associations of the haemostatic components with blood pressure, a compromised oxidant-antioxidant profile, and retinal vessel calibres may contribute, at least in part, to the high cardiovascular and cerebrovascular risk evident in this population group. / PhD (Physiology), North-West University, Potchefstroom Campus, 2015

Motivation In the black population of South Africa, cardiovascular disease (CVD) is rapidly increasing due to urbanisation. Stroke is usually accompanied by a prothrombotic haemostatic profile. Changing lifestyle factors that accompany the urbanisation process could have a negative impact on the haemostatic profile of black South Africans. Elevated levels of pro-coagulant factors, von Willebrand factor (vWF), fibrinogen and fibrin D-dimer have been reported in the black population, which could increase the black population’s susceptibility to CVD. However, low levels of plasminogen activator inhibitor-1 (PAI-1) previously reported in the black population could contribute towards a pro-fibrinolytic state, which may counteract the hypercoagulant state. This may have a beneficial effect on the haemostatic profile of the black population. More investigation into the haemostatic profile of black South Africans is therefore needed to determine if an altered haemostatic profile exists in this group, and if so, to what extent these alterations may relate to cardiovascular dysfunction. This study included markers of both the coagulation (vWF, fibrinogen, fibrin D-dimer) and fibrinolytic (PAI-1, fibrin D-dimer and fibrinolytic potential) systems in an attempt to investigate the haemostatic profile of the black population of South Africa, and for comparison purposes that of the white population as well. The relationship of these markers’ with selected markers of cardiovascular function was also examined to determine if they could possibly contribute to an increase in cardiovascular risk, especially in the black population. Aims The aims of this study were to first compare coagulation and fibrinolysis markers in the black and white populations of South Africa. Furthermore, to determine if associations exist between the selected components of the haemostatic system and markers of cardiovascular function, especially in the black population of South Africa, who tends to be at a higher cardiovascular risk due to altered metabolic and haemostatic profiles. Methodology The Sympathetic activity and Ambulatory Blood Pressure in Africans (SABPA) study was a prospective cohort study that consisted of 409 participants at baseline (2008-2009) that were equally distributed according to both ethnicity (200 black; 209 white) and gender (black, 101 men, 99 women; white, 101 men, 108 women). At follow-up (2011/2012) the cohort totalled 359 participants (170 black, 88 men and 82 women; 189 white, 93 men and 96 women). Data from baseline measurements were used for the first two manuscripts (chapters 2 and 3), while followup data was used for the third manuscript (chapter 4). vWF, fibrinogen, PAI-1, fibrin D-dimer, CLT, serum peroxides, glutathione, glutathione peroxidase and reductase activity were determined, and ambulatory blood pressure and the retinal vessel calibres were measured. The groups were stratified by ethnicity as specified by statistical interaction terms. T-tests and chi-square tests were used to compare means and proportions, respectively. Pearson and partial regression analyses were used to determine correlations between the components of the haemostatic system and cardiovascular function markers. This was followed by multiple linear regression analyses to investigate whether independent associations exist between the variables in both ethnic groups. P-values ≤0.050 were deemed significant. Results and conclusion of each manuscript The first manuscript (chapter 2) compares the haemostatic profiles of the black and white population to determine whether ambulatory blood pressure is related to components of the haemostatic system. The black participants displayed a prothrombotic profile with significantly higher vWF, fibrinogen, PAI-1, fibrin D-dimer and a longer CLT than their white counterparts. Furthermore, partial and multiple linear regression analyses showed a positive association of systolic and diastolic blood pressure with fibrin D-dimer in the black population, while a negative association existed between ambulatory blood pressure and CLT in the white population. These associations suggest that fibrin D-dimer may contribute, at least in part, to the high prevalence of hypertension in the black population. The second manuscript (chapter 3) determined associations between markers of the haemostatic and oxidant-antioxidant systems in the black and white populations. In addition to the prothrombotic profile that exists in the black population, this group also had significantly higher serum peroxides (oxidative stress) and lower glutathione peroxidase activity (antioxidant) levels. Multiple linear regression analyses indicated positive associations between fibrinogen and serum peroxides in both populations. In the white population, an additional positive association was found between serum peroxide and CLT. In the black population, vWF and CLT were negatively associated with GPx activity. The results suggest that there are ethnic-specific relationships between the haemostatic and oxidant-antioxidant systems. The third manuscript (chapter 4) investigated the relationships between the retinal vessel calibres and components of the haemostatic system in the black and white population. The investigation focussed specifically on arteriolar diameters in the lower median, since a narrow arteriolar diameter is known to be associated with elevated blood pressure. In both ethnic groups, a narrower arteriolar calibre was accompanied by narrower venular calibres. Independent positive associations were found between the central retinal vein equivalent (CRVE) and fibrinogen in the black population, as well as vWF and CLT in the white population. In addition, independent negative associations were found between the central retinal artery equivalent and CLT in the black population and with vWF in the white population. The results suggest that haemostatic alterations are linked to early vascular changes that may differ between ethnicities. General conclusion Ethnic-specific relationships between the components of the haemostatic system and measures of cardiovascular function are evident. The prothrombotic profile that is observed in the black population, together with the adverse associations of the haemostatic components with blood pressure, a compromised oxidant-antioxidant profile, and retinal vessel calibres may contribute, at least in part, to the high cardiovascular and cerebrovascular risk evident in this population group. / PhD (Physiology), North-West University, Potchefstroom Campus, 2015

Deep brain stimulation (DBS) is a neurosurgical intervention now established for the treatment of movement disorders. For the treatment of chronic pain refractory to medical therapies, several prospective case series have been reported, but few centres worldwide have published findings from patients treated during the last decade using current standards of technology. This thesis seeks to survey the current clinical status of DBS for pain, investigate its mechanisms and their interactions with autonomic function, its clinical limitations and ablative alternatives. Presented first is a review of the current status of analgesic DBS including contemporary clinical studies. The historical background, scientific rationale, patient selection and assessment methods, surgical techniques and results are described. The clinical outcomes of DBS of the sensory thalamus and periventricular / periaqueductal grey (PAVG) matter in two centres are presented including results from several pain and quality of life measures. A series of translational investigations in human subjects receiving DBS for pain elucidating mechanisms of analgesic DBS and its effects upon autonomic function are then presented. Single photon emission tomography comparing PAVG, VP thalamus and dual target stimulation is described. Somatosensory and local field potential (LFP) recordings suggesting PAVG somatotopy are shown. ABPM results demonstrating changes with PAVG DBS are given and Portapres studies into heart rate variability changes with ventral PAVG DBS are detailed. Investigations using naloxone are then shown to hypothesise separate dorsal opioidergic and ventral parasympathetic analgesic streams in the PAVG. Finally, cingulotomy in lung cancer to relieve pain and dyspnoea results are discussed in the context of altering pain and autonomic function by functional neurosurgery. Pain and autonomic interactions and mechanisms in deep brain surgery for pain are then discussed alongside its limitations with proposals made for optimising treatment and improving outcomes.

Thesis (MPhil)--Stellenbosch University, 2014. / ENGLISH ABSTRACT: Pre-eclampsia is a common and dangerous condition of pregnancy. During clinical care the sensitive obstetrician will frequently recognise moral ambiguity and ethical conflicts. It is important to understand the pertinent issues and find ways of resolving them. Counselling is an important element of modern medicine. In deciding which counselling model to apply, clinicians must consider many variables including the particular clinical scenario, strength of evidence, and the justifiable limits of paternalism and autonomy in a position of shared responsibility. Couples have a moral right to procreate even when the pursuit of pregnancy involves significant risks. However, with their understanding of care ethics as well as rights ethics, informed women are well placed to negotiate the extremes of these positions when deciding whether to risk a pregnancy or not. The concept of the “fetal patient” is a helpful one. An autonomous woman may choose to confer or deny this status to her previable fetus, while obstetricians must balance autonomy- and beneficence-based obligations to the pregnant woman with beneficence-based obligations to her fetus. Maternal behaviour that harms the fetus and future child is categorised as maternal-fetal conflict. However, any pregnant woman is morally required to avoid harming the fetus, if this can be done without sacrificing her own important interests. The term non-compliance implies a hierarchical nature in the doctor-patient relationship. This reduces patient agency, erodes trust and conflicts with informed choice. Although sometimes justified, this “label” generally does more harm than good. Expectant management of early pre-eclampsia recognises that neonatal intensive care is an expensive and limited resource. The ultimate goal of expectant management remains the safety of the mother and the delivery of a live infant who will not require intensive and prolonged neonatal care. This judicious use of neonatal intensive care improves distributive justice but by consenting to expectant management as an inpatient, the pregnant woman voluntarily restricts her freedom. The decision is morally undergirded by the value accorded to the viable fetus and the scientific evidence informing the decision. When an extremely preterm, growth restricted fetus requires delivery, resuscitation may become an issue for consideration. The distinction between withholding resuscitation in such cases, or initiating but later withdrawing care is morally irrelevant. Categories of optional and obligatory treatments are more helpful, but perinatologists must determine treatment thresholds through understanding the relevant data and ethics issues. Finally, women do not lose their rights when they become terminally ill. When an undelivered woman is declared brain dead following complications of pre-eclampsia, her doctors and family must formulate clear plans for her and her living fetus. She must still be treated with respect and her right to die with dignity not forgotten. Extension of somatic support to optimise the outcome of her fetus can be supported ethically provided that the fetus is at the threshold of viability, the support is not prolonged (distributive justice), advanced level support is available with a successful outcome likely, and that doctors and family are in clear agreement. / AFRIKAANSE OPSOMMING: Pre-eklampsie is ‘n algemene en gevaarlike toestand van swangerskap. Die verloskundige met ‘n fyn waarnemingsvermoë sal dikwels morele dubbelsinnigheid en etiese konflik tydens kliniese sorg erken. Dit is belangrik om die kernaspekte te verstaan en maniere te vind om dit op te los. Berading is ‘n belangrike komponent van moderne geneeskunde. Tydens besluitneming oor watter model van berading toegepas moet word, moet klinici ‘n aantal veranderlikes teen mekaar opweeg insluitend die spesifieke kliniese senario, sterkte van die getuienis, die geregverdigde perke van paternalisme en outonomie in ‘n posisie van gedeelde verantwoordelikheid. Die egpare het ‘n morele reg om voort te plant selfs wanneer die verlange na swangerskap betekenisvolle risiko’s inhou. Vrouens wat goed ingelig is, het die vermoë om die uiterstes van etiek van sorg en regte teen mekaar op te weeg wanneer hulle besluit om die risiko van swangerskap te loop. Die konsep van “fetus as pasiënt” kan wel tot verdere besluitneming bydra. Die outonome vrou mag self besluit of die fetus daardie status het. Aan die ander kant moet die verloskundige outonomie en goedwilligheid- (“beneficence”) gebasseerde verpligtinge teenoor die swanger vrou opweeg teen die goedwilligheid-gebasseerde verpligting teenoor haar fetus. Moederlike gedrag wat die fetus en toekomstige kind skend, word as ‘n moeder-fetus konflik beskou. Enige swanger vrou is egter moreel verplig om nie die fetus skade te berokken nie, mits dit gedoen kan word sonder die prysgawe van haar eie noodsaaklike belange. Die term “nie-inskiklikheid” (“non-compliance”) impliseer hiërargie in die dokter-pasiëntverhouding. Hierdie hiërargie doen afbreuk aan die besluitneming van die pasiënt, ondermyn vertroue en bots met ingeligte keuses. Alhoewel besluitneming op grond van hiërargies-gebaseerde gesag soms geregverdig is, veroorsaak hierdie kategorisering gewoonlik meer kwaad as goed. Afwagtende hantering van vroeë pre-eklampsie gaan van die standpunt uit dat neonatale intensiewe sorg ‘n duur en skaars hulpbron is. Die uiteindelike doel van afwagtende hantering bly die veiligheid en gesondheid van die ma en die verlossing van ‘n lewendige baba wat nie verlengde intensiewe- en neonatale sorg benodig nie. Hierdie oordeelkundige gebruik van neonatale sorg bevorder distributiewe geregtigheid, maar wanneer sy toestemming gee tot afwagtende behandeling as binnepasiënt, beperk die swanger vrou vrywilliglik haar vryheid. Hierdie besluit word moreel ondersteun deur die waarde wat aan die lewensvatbare fetus toegevoeg word en die wetenskaplike gronde waarop die besluit berus. Wanneer ‘n erge voortydse, groeivertraagde fetus verlossing benodig, word ressussitasie soms iets wat oorweeg moet word. Die onderskeid tussen die weerhouding van ressussitasie in sulke gevalle en die onttrekking van sorg waar dit aanvanklik begin is, is moreel irrelevant. Kategorieë van opsionele en verpligte behandelings is meer behulpsaam, maar perinatoloë moet die behandelingsdrempels bepaal deur die relevante data en etiek te verstaan. Laastens, vroue verloor nie hul regte wanneer hulle terminaal siek word nie. Wanneer die komplikasies van pre-eklampsie breindood van die vrou veroorsaak voor die verlossing van haar baba, moet haar dokters en familie duidelike planne vir die hantering van haar en haar fetus ontwikkel. Sy moet nogsteeds met respek behandel word en haar reg om met waardigheid te sterf, mag nie uit die oog verloor word nie. Verlenging van die ondersteuning van lewensfunksies om die uitkoms van haar fetus te verbeter, kan eties ondersteun word, mits die fetus na aan lewensvatbaarheid is, die ondersteuning nie te lank duur nie (distributiewe geregtigheid), gevorderde ondersteuning beskikbaar is met ‘n goeie kans vir suksesvolle uitkoms en dat die dokters en familie ten volle saamstem.

Thesis (MScSportSc)--Stellenbosch University, 2013. / ENGLISH ABSTRACT: There are extensive literature on the PEH response after acute and chronic aerobic and resistance exercise, as well as a few studies on concurrent and water exercise. However, there is comparatively little evidence that high intensity interval training (HIIT) elicits similar post exercise blood pressure reductions (PEH) compared to other types of exercise. Furthermore, it is difficult to quantify the magnitude of the hypotensive response following these exercises, due to variations in exercise protocols in terms of intensity and duration. Both these training variables are considered important determinants of the magnitude and duration of the PEH response. The current study determined the magnitude of the PEH response after an acute bout and six sessions of HIIT, and the effects after two weeks of detraining in overweight/obese young women. Twenty young women (aged 21 ± 2 years) volunteered for the study. All the subjects were normotensive (SBP: 119.2 ± 5.6 mmHg and DBP: 78.8 ± 4.1 mmHg). Subjects performed six sessions of HIIT within two weeks and detrained for two weeks. SBP, DBP, MAP and HR were monitored during seated recovery after exercise for 60 min to determine the change from resting values. The overall outcome showed that an acute HIIT session resulted in a reduction of 2.9 mmHg in SBP which approached near clinical significance, while six sessions of HIIT caused a clinically significant reduction of 5.3 mmHg; this response was almost totally reversed after detraining. There were no clinically significant reductions in DBP after the acute or six sessions of HIIT (1.7 and 2.7 mmHg, respectively). However, a clinically significant hypotensive response of 3.9 mmHg was sustained after detraining following the maximal exercise capacity test. MAP also reduced by a magnitude of 2.3 and 5.6 mmHg, respectively, after the acute bout and six sessions of HIIT, and detraining values were still 2.9 mmHg lower than resting values and approached near clinical significance. The results indicate that both an acute bout and six sessions of HIIT elicited a meaningful PEH response. However, the six sessions of HIIT caused a clinically significant reduction which was approximately twice the acute session. Likewise, detraining showed clinically significant effects in DBP and MAP, but SBP returned to near baseline values. This suggests that in only two weeks, the accumulated effects of six sessions of HIIT elicited a greater hypotensive response than after an acute session of HIIT. / AFRIKAANSE OPSOMMING: Daar is omvattende literatuur oor die post-oefening hipotensie (POH) na afloop van akute en kroniese aërobiese en weerstandsoefeninge, asook enkele studies oor gelyktydige krag- en uithouvermoë- en wateroefeninge. Daar is egter relatief min bewyse dat hoë intensiteit interval oefening (HIIO) soortgelyke post-oefening afnames in bloeddruk (POH) in vergelyking met ander tipes oefening veroorsaak. Voorts is dit moeilik om die omvang van die hipotensiewe respons na afloop van oefening te kwantifiseer, hoofsaaklik as gevolg van die variasies in oefeningprotokolle in terme van intensiteit en tydsduur. Beide hierdie inoefeningveranderlikes word as belangrike determinante van die omvang en die tydsduur van die POH respons beskou. Die huidige studie het die omvang van die POH respons na ʼn akute sessie en ses sessies HIIO, en die gevolge na afloop van twee weke se nie-inoefening (“detraining”) by oorgewig/vetsugtige jong dames, bepaal. Twintig jong dames (ouderdom 21 ± 2 jaar) het vrywillig ingestem om aan die studie deel te neem. Al die deelnemers was normotensief (SBD: 119.2 ± 5.6 mmHg en DBD: 78.8 ± 4.1 mmHg). Die deelnemers het ses sessies HIIO binne twee weke voltooi en het daarna vir twee weke geen inoefeningsessies gehad nie. SBD, DBD, GAD en HS is tydens ʼn sittende herstelfase vir 60 minute gemonitor om die verandering vanaf rustende waardes te bepaal. Die algehele uitkoms toon dat ʼn akute HIIO sessie ʼn afname van 2.9 mmHg in SBD tot gevolg gehad het wat aan kliniese betekenisvolheid grens, terwyl ses sessies van HIIO ʼn klinies betekenisvolle afname van 5.3 mmHg veroorsaak het; hierdie respons wat bykans volledige omgekeerd na die twee weke met geen inoefening. DBD het geen kliniese betekenisvolle afname na afloop van die akute of ses sessies van HIIO getoon nie (1.7 en 2.7 mmHg, respektiewelik). ʼn Klinies betekenisvolle hipotensiewe respons van 3.9 mmHg is egter gevind na die geen inoefeningsperiodes. GAD het ook met ʼn omvang van 2.3 en 5.6 mmHg, respektiewelik, verminder na afloop van die akute sessie en ses sessies van HIIO. Die geen inoefening waardes was steeds 2.9 mmHg laer as die rustende waardes en het aan kliniese betekenisvolheid gegrens. Die resultate toon dat beide ʼn akute sessie en ses sessies van HIIO ʼn betekenisvolle POH respons ontlok het. Ses sessies van HIIO het egter ʼn klinies betekenisvolle afname, wat ongeveer twee keer soveel as die afname van die akute sessie was, veroorsaak. In dieselde lig het ʼn twee weke geen inoefeningsperiode steeds klinies betekenisvolle veranderinge in DBD en GAD getoon, maar SBD het tot naby aan die basislyn waardes teruggekeer. Hierdie resultate suggereer dat in slegs twee weke die geakkumuleerde effekte van ses sessies van HIIO ʼn groter hipotensiewe respons as na ʼn akute sessie van HIIO ontlok het.

Noninvasive assessment of diabetic cardiovascular autonomic neuropathy (AN): Cardiac and vascular dysfunctions resulting from AN are complications of diabetes, often undiagnosed. Our objectives were to: 1) determine sympathetic and parasympathetic components of compromised blood pressure regulation in patients with polyneuropathy, and 2) rank noninvasive indexes for their sensitivity in diagnosing AN. Continuous 12-lead electrocardiography (ECG), blood pressure (BP), respiration, regional blood flow and bio-impedance were recorded from 12 able-bodied subjects (AB), 7 diabetics without (D0), 7 with possible (D1) and 8 with definite polyneuropathy (D2), during 10 minutes supine control, 30 minutes 70-degree head-up tilt and 5 minutes supine recovery. During the first 3 minutes of tilt, systolic BP decreased in D2 while increased in AB. Parasympathetic control of heart rate, baroreflex sensitivity, and baroreflex effectiveness and sympathetic control of heart rate and vasomotion were reduced in D2, compared with AB. Baroreflex effectiveness index was identified as the most sensitive index to discriminate diabetic AN. Four-dimensional multiscale modeling of ECG indexes of diabetic autonomic neuropathy: QT interval prolongation which predicts long-term mortality in diabetics with AN, is well known. The mechanism of QT interval prolongation is still unknown, but correlation of regional sympathetic denervation of the heart (revealed by cardiac imaging) with QT interval in 12-lead ECG has been proposed. The goal of this study is to 1) reproduce QT interval prolongation seen in diabetics, and 2) develop a computer model to link QT interval prolongation to regional cardiac sympathetic denervation at the cellular level. From the 12-lead ECG acquired in the study above, heart rate-corrected QT interval (QTc) was computed and a reduced ionic whole heart mathematical model was constructed. Twelve-lead ECG was produced as a forward solution from an equivalent cardiac source. Different patterns of regional denervation in cardiac images of diabetic patients guided the simulation of pathological changes. Minimum QTc interval of lateral leads tended to be longer in D2 than in AB. Prolonging action potential duration in the basal septal region in the model produced ECG and QT interval similar to that of D2 subjects, suggesting sympathetic denervation in this region in patients with definite neuropathy.

<p>Hydronephrosis, due to ureteropelvic junction obstruction, is a common condition in infants with an incidence of approximately 0.5-1%. During the last decade, the surgical management of non-symptomatic hydronephrosis has become more conservative, and the long-term physiological consequences of this new policy are unclear. The overall aim of this thesis was to determine whether there is a link between hydronephrosis and the development of hypertension. Hydronephrosis was induced by partial ureteral obstruction in 3-week old rats or mice. In the adult animals, blood pressure was measured telemetrically during different sodium conditions and the renal function was evaluated. Both species developed salt-sensitive hypertension and histopathological changes (i.e. fibrosis, inflammation, glomerular and tubular changes) that correlated with the degree of hydronephrosis. An abnormal renal excretion pattern with increased diuresis and impaired urine concentrating ability was observed in hydronephrosis. The mechanisms were primarily located to the diseased kidney, as relief of the obstruction attenuated blood pressure and salt-sensitivity. Increased renin angiotensin system activity, due to ureteral obstruction, might be involved in the development but not necessary the maintenance of hypertension. Hydronephrotic animals displayed reduced nitric oxide availability, which might be due to increased oxidative stress in the diseased kidney. Renal nitric oxide deficiency and subsequent resetting of the tubuloglomerular feedback mechanism, appeared to have an important role in the development of hypertension. In conclusion, experimental hydronephrosis, induced by partial ureteral obstruction, provides a new model for studies of salt-sensitive hypertension. Furthermore, the new findings imply that the current conservative treatment strategy in hydronephrosis should be reconsidered in favour of treatment that is more active, in order to prevent the development of renal injury and hypertension in later life.</p>

Hypertension, or high blood pressure (BP), is an ever-growing epidemic in the developing world. Understanding the genetics behind essential hypertension (EH), or hypertension with no known cause, is especially important. In this study, three single nucleotide polymorphisms (SNPs) known to be linked to an increase in susceptibility to EH were quantified from a cohort of Kenyans living in the Kasigau region. The SNPs are located in three genes that are part of the renin angiotensin system, the primary regulatory pathway in humans controlling BP. They include: AGT (rs699), AGTR1 (rs5186), and HSD11β2 (rs5479). Overall, by using a fluorescent-based RT-PCR technique, the genotype distribution of AGT (rs699) was 0.63 C/C, 0.34 C/T, and 0.03 T/T. When evaluated as normotensive, prehypertensive, Stage I, or Stage II categories the allele frequencies for f(C)= 0.77,0.85,0.81, 0.77, respectively, and demonstrated Hardy Weinberg Equilibrium (HWE) as assessed by Χ2, p < 0.05. The genotype distribution of AGTR1 (rs5186) was 0.96 A/A, 0.03 A/C, and 0.00 C/C and the genotype distribution of HSD11β2 (rs5479) was 0.46 A/A, 0.46 A/C, and 0.08 C/C. The majority of genotype frequencies for each SNP were in HWE, with the exception of the AGT (rs699) SNP found in the sublocation of Bughuta suggesting other evolutionary selective pressures may be at work in this subpopulation. The high prevalence of the susceptible C allele for AGT (rs699) likely implies it is a critical factor in the high prevalence of EH observed in this population.

<p>Teza istražuje mogućnost kori&scaron;ćenja kopule u finoj analizi međusobne zavisnosti kardiovaskularnih signala. U tu svrhu kori&scaron;ćene su različite GoF (Goodness of Fit) tehnike i matematički alati bazirani na kopuli. Predložena metoda određuje nivo zavisnosti kao funkciju vremenskog ka&scaron;njenja signala pulsnog intervala u odnosu na signal sistoličkog krvnog pritiska i omogućuje uvid u mehanizme otkucaj-po-otkucaj regulacije krvnog pritiska. Farmakolo&scaron;ka validacija je izvedena administracijom lekova koji inhibiraju autonomni nervni sistem, pri čemu su dobijeni rezultati imali jasan fiziolo&scaron;ki odziv.</p> / <p>The thesis investigates a possibility to apply a copula method for a more refined analysis of mutual dependency of cardiovascular signals. Different GoF (Goodness of Fit) techniques and mathematical tools based on copula are applied to prove this possibility. Proposed method determines the level of dependency of the pulse interval response in respect to the systolic blood pressure for different time lags and provides further insight into the beat-to-beat regulation of blood pressure. Pharmacological validation of the method was performed by administration of autonomic blockers drugs, as the obtained copula response was in accordance with the physiological interpretation.</p>