Human placental villi are covered by a layer of trophoblast epithelia in direct contact with maternal blood, which exist in a constant steady-state of turnover and renewal ensuring both maternal and fetal health. The process of trophoblast turnover involves proliferation, differentiation and fusion of cytotrophoblast cells to form a terminally differentiated outer syncytiotrophoblast layer which functions as the active transport compartment between mother and fetus. Alterations in the balance between these three processes are thought to diminish both the structural and functional integrity of the syncytiotrophoblast, potentially leading to placental insufficiency associated with severe complications of pregnancy such as pre-eclampsia (PET), intrauterine growth restriction (IUGR) and sudden infant death syndrome (SIDS). Placentas from early (<32 weeks) and late-onset (>33 weeks) pregnancies complicated by PET, IUGR, SIDS and gestational age-matched controls were systematically uniform randomly sampled to assess the morphological basis of placental villous structure and trophoblast turnover (villi, cytotrophoblast, syncytiotrophoblast, apoptotic syncytial knots) using unbiased stereological techniques (volumes and numbers). Villous cytotrophoblast proliferation was assessed using double immunohistochemistry for Ki67 and cytokeratin 7 (CK-7). Severe early-onset IUGR placentas (n=5) were smaller displaying significant reductions in the total number of CT cells, within which the density of proliferating CT was further reduced by 50%. Syncytiotrophoblast volume and number was significantly reduced with an increase in apoptotic syncytial knots. Late-onset IUGR placentas (n=4) also displayed significant reductions in the total number of CT and proliferating CT, but were not associated with changes in the density of proliferating CT. SCT numbers were significantly reduced with an increase in apoptotic knots. Placentas from severe early-onset PET (n=11) were similar to preterm controls, except for a significant increase in apoptotic syncytial knots. However, late-onset PET (n=6) displayed a significant decrease in total CT number, the percentage of which undergoing proliferation was significantly increased for structural villi. There were increased numbers of apoptotic syncytial knots in peripheral villi.

No description available.

published_or_final_version / Medicine / Master / Doctor of Medicine

Purposes: The purpose of this study was threefold. First, to examine how both the effectiveness of valsartan centric regimens and the patient-related factors affect the control rates of the Systolic Blood Pressure (SBP), Diastolic Blood Pressure (DBP) and combined SBP/DBP; specifically for Belgian patients with a history of failed or intolerant anti-hypertensive treatment. Secondly, to assess the effectiveness of valsartan treatment groups and the related factors concerning a patients' total cardiovascular risk (TCVR) residuals. Lastly, to attempt to estimate the cost avoidance factor associated with taking varying levels of valsartan treatment doses. Methodology: This research took the form of a secondary-data analysis study, focusing on the analysis of data collected primarily from seven prospective studies conducted between 2004 and 2009, covering different regimens of valsartan. The variants of valsartan doses given to patients included: valsartan monotherapy (80mg or 160 mg); a combination of valsartan with hydrochlorothiazide (HCTZ) (80 mg and 12.5mg, 160mg and 12.5 mg, or 160mg and 25mg); and a combination of valsartan with amlodipine (80mg and 5mg, 160mg and 5mg, or 160mg and 10mg). We applied Bailey's approach, using Kaplan-Meier curves to estimate the distribution of treatment intensity at which the target rates of SBP, DBP and SBP/DBP were achieved. The treatment intensity was calculated by dividing the daily dose prescribed to a patient by the maximum daily recommended dose of that particular drug variant. The outcomes provided by Bailey's approach included the control rates of SBP, DBP and combined SBP/DBP, in addition to the reduction in TCVR residuals. Another aspect of our methodology was the use of a simulation method to estimate the cost avoidance by using valsartan treatment groups. We used OCED data to compare health indicators between the US and Belgium in order to estimate the ratio enabling us to calculate the cost of hypertension per patient per year. This cost was then used in the simulation method to calculate the cost avoidance of using varying levels of the treatment intensity of valsartan regimens. Results: A total of 17,683 patients were included in this study, contributed to by 3,434 physician-investigators. The mean age of the population was 63.63 + 11.83 years, with a mean BMI of 28.45 + 3.13 kg/m^2 and 47.7% of the population was male and the vast majority of the total population was Caucasian (98%). As a baseline the total population who had controlled SBP, DBP and combined SBP/DBP were 1358, 5301 and 1091 respectively. The total population who were categorized as low added risk TCVR, moderate added risk TCVR, high added risk TCVR, and very high added risk TCVR were 192; 3,721; 3,888 and 9,362 respectively. Overall, there was a statistically significant increase in the proportion of patients with controlled SBP, DBP and combined SBP/DBP after 90 days of starting on valsartan-centric regimens (p<0.001). Both older age and the presence of diabetes were associated with a lower control rate of SBP, DBP and combined SBP/DBP (P<0.05). High adherence to valsartan-centric regimens was associated with an increase in the control rates of blood pressure. Substantial reductions in total cardiovascular risk, particularly in the very high added-risk category was observed 5,852 times (33.1%) (P<0.001) and an increase in the low added risk TCVR 3,331 times (18.9%) (p<0.001). The associated cost avoidance with varying levels of treatment intensity were dose related. The cost avoidance associated with the treatment intensity levels of 0.25, 0.5, 0.75, 1.0 and 1.5 were $261,164; $2,403,188; $6,384,142; $8,702,272 and $10,230,321, respectively. Conclusion: The different levels of the treatment intensity of valsartan-centric regimens were effective in increasing the control rates of SBP, DBP and combined SBP/DBP in the real practice for patients whose prior treatment failed. Not only did valsartan regimens improve the BP control rate, they also reduced the TCVR residuals. Additionally, substantial cost avoidance was found to be associated with the use of higher levels of treatment intensity. These results may support the idea that intensive anti-hypertensive treatment may be associated with higher clinical and economic benefits for both patients and payers. However, more research might be needed to validate our results and to address the questions of adverse effects that may be associated with intensive anti-hypertensive therapy and the economic consequences of treating any such effects.

No description available.

Die Arterielle Hypertonie zählt neben Hypercholesterinämie, Diabetes mellitus, Übergewicht, Rauchen und Bewegungsmangel als Risikofaktor für Erkrankungen des Kreislaufsystems. Die in vielen Leitlinien geforderte Behandlungsqualität bei arterieller Hypertonie soll sowohl in der hausärztlichen und fachärztlichen Praxis als auch in der stationären Behandlung optimal erreicht werden. In der vorliegenden Arbeit wird untersucht, ob der Anteil der stationär behandelten Patienten, die insgesamt einen Zielblutdruck unterhalb von 140 mmHg erreichen, höher ist als der Anteil derselben Patienten in der hausärztlichen Versorgung. Durch die retrospektive Auswertung der Daten von Patienten mit Hypertonie in der Abteilung Nephrologie und Rheumatologie der Medizinischen Fakultät der Georg-August-Universität Göttingen wurden die Informationen für die Analyse erfasst und statistisch ausgewertet. Es wird die Frage erörtert, inwiefern die medikamentöse Behandlung im stationären Aufenthalt zu einer signifikanten Verbesserung der Blutdruckwerte, insbesondere bei Patienten mit manifesten Vorerkrankungen und mit Vormedikation gegen Bluthochdruck, führt. Darüber hinaus wurde dem Problem nachgegangen, inwieweit die medikamentöse Behandlung nach dem Krankenhausaufenthalt fortgesetzt wird. Hierzu wurde zunächst ein Fragebogen entwickelt, um folgende Kategorien aus den Krankenakten der ausgewählten Patienten einheitlich erfassen zu können: persönliche Daten, Vorerkrankungen, Familien¬anamnese, Risikofaktoren, Vormedikation, Anamnese am Tag der Aufnahme, Nachmedi-kation, Diagnostik während des stationären Aufenthalts, Daten am Tag der Entlassung. Diese Informationen wurden im Anschluss statistisch ausgewertet und zur Einschätzung der aufgestellten Hypothesen herangezogen. Die Untersuchungen belegen, dass in der stationären Behandlung insgesamt für mehr Patienten Erfolge bezüglich der medikamentösen Therapie erzielt wurden. Die Ergebnisse dokumentieren eine Gleichberechtigung der von der Deutschen Hochdruckliga empfohlenen Therapieformen, sei es die Monotherapie oder die primäre Kombinationstherapie. Alle durchgeführten Medikationen führen gleichermaßen zu signifikanten Verbesserungen der Blutdruckwerte.

Hypertension is associated with a reduction in sensitivity to pain in both animals and humans. Changes in nociception pre-date elevations in blood pressure in animals genetically predisposed to hypertension, and preliminary findings with male offspring of hypertensives indicate that genetic risk for hypertension is related to decreased pain sensitivity in humans. Sensitivity to naturalistic and laboratory pain stimuli was compared in normotensive females with and without a parental history of hypertension in three studies. Genetic risk for hypertension was associated with decreased sensitivity for blood donation venipuncture pain and electric shock, but not for menstrual pain or the cold pressor test. These findings provide modest support for the notion that hypoalgesia is present in females at risk for hypertension. Issues for future research include extension of these findings to other pain stimuli, use of multiple indices of risk, assessment of the effects of cyclic hormonal changes on the relationship between pain sensitivity and risk for hypertension, and further study of the mechanisms and pathophysiological implications of this effect.

The thesis offers the following contributions to the epidemiology of hypertension in Canada: 1.The first manuscript uses cross-sectional data from the 2007-2009 Canadian Health Measures Survey (CHMS) to compare the prevalence of controlled hypertension between people with and without diabetes. Of the 74% of Canadians with diabetes who had hypertension, 56% (95% CI: 45%-66%) had controlled blood pressure compared to 64% (95% CI: 58%-69%) of Canadians without diabetes. Among people taking medication, individuals with diabetes were less likely to have controlled hypertension (ORadjusted: 0.3; 95% CI: 0.2-0.6). 2.The objective of the second manuscript was to determine, among Canadians with hypertension, whether individuals with diabetes were less likely than those without to recall health professional advice for healthy behaviours and whether receipt of such advice influences behaviour, using cross-sectional data from the 2009 Survey on Living with Chronic Diseases in Canada (SLCDC). Canadians with diabetes were more likely than those without to recall advice to control/lose weight (81% vs. 66%), exercise (79% vs. 68%), limit alcohol (78% vs. 55%) and modify diet (70% vs. 61%) but not limit salt (65% vs. 64%). Both groups were equally likely to report following advice, with receipt of advice positively associated with engagement in healthy behaviours. 3. The third manuscript describes knowledge of blood pressure targets in Canadians with hypertension using cross-sectional data from the 2009 SLCDC. Knowledge of blood pressure targets was low, with 28% and 32% of Canadians with and without diabetes reporting having discussed a blood pressure target and reporting a target in line with clinical practice guidelines. 4.The fourth manuscript validates an existing self-reported blood pressure control question in a sample of 161 patients with hypertension in Kingston. In people with and without diabetes, the question had sensitivities of 83% ± 11% and 78% ± 10% and specificities of 30% ±19% and 58% ± 21%, respectively. 5.The final manuscript tests a method designed to account for misclassification in epidemiologic studies, using data from the CHMS. The method was found to perform inconsistently in multivariate contexts and introduced bias when minor differential misclassification was ignored. / Thesis (Ph.D, Community Health & Epidemiology) -- Queen's University, 2013-11-14 09:55:12.161

Introduction: Developmental origins of disease refers to the theory that adverse maternal environments influence fetal development and the risk of cardiovascular disease (CVD) in adulthood. To test the hypothesis that gestational hypertension influences the development of CVD in offspring, a novel experimental paradigm was developed using atrial natriuretic peptide gene disrupted mice (ANP-/-). The objective of this thesis was to determine the effect of gestational hypertension on cardio-renal function in offspring. Methods: ANP+/+ females were crossed with ANP-/- males (yielding ANP+/-WT offspring) and ANP-/- females with ANP+/+ males (yielding ANP+/-KO offspring). Previous work has established that ANP-/- dams are hypertensive during pregnancy. Offspring gene expression was measured using qPCR. Offspring arterial blood pressure (BP) was measured with a non-invasive tail cuff system. Offspring left ventricular (LV) function was examined using echocardiography (ECHO). Offspring were treated with normal salt (NS) or high salt (HS) chow for five weeks to assess salt-sensitivity. Daily injections of isoproterenol (ISO) were used to induce cardiac stress in offspring. Collagen deposition was assessed using Masson’s trichrome and picrosirius red staining. Results: Absence of maternal ANP had no effect on either litter size or offspring growth, but caused significant LV hypertrophy in offspring, with no change in LV function. Treatment with ISO resulted in myocardial fibrosis and significant LV diastolic dysfunction with a restrictive filling pattern (increased E/A ratio and E/e’) only in ANP+/-KO offspring. Furthermore, absence of maternal ANP was associated with salt-resistant BP in offspring. Conclusions: Gestational hypertension using the ANP-/- mouse model results in a salt-resistant phenotype in offspring, as well as significant cardiac hypertrophy and an adverse response to activation of the sympathetic nervous system in adult offspring. These data suggest that adverse maternal environments may increase the risk of cardiovascular disease in offspring later in life. / Thesis (Ph.D, Anatomy & Cell Biology) -- Queen's University, 2012-09-18 16:12:01.147

Psychological stress may be a risk factor for essential hypertension. While several variables have been implicated as mediators or moderators of the relationship between stress and high blood pressure, their exact roles and level of importance remain to be elucidated. A key moderating variable may be family history of hypertension. A series of five studies examined the cardiovascular and emotional reactions to stress of normotensive individuals with and without a parental history of hypertension. In an attempt to facilitate the generalizability of the results, the studies used stressors with greater ecological validity than those used in most previous studies of this topic. This aspect of the research aided the examination of a possible mediator of group differences in cardiovascular reactivity, i.e., emotionality. Several studies observed significant group differences in cardiovascular reactivity to stress, suggesting that stress may be more likely to contribute to the development of hypertension in those with a genetic predisposition for the disorder. However, the exaggerated cardiovascular responsivity of individuals with a parental history of hypertension did not appear to be mediated by greater trait or state emotionality.