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Obesity is a serious health problem worldwide. Consumption of fat rich food is a common cause of obesity. Some of the food components (i.e. saturated free fatty acids (SFAs)) have been identified as inflammatory inducers (Egger G at al., 2010). After a meal, absorbed free fatty acids (FFAs) will be stored in the liver and adipose tissue. On the luminal surfaces of endothelium in adipose tissue microcirculation, lipoprotein lipase hydrolyses absorbed triglycerides into FFAs. Then, in order to be available for adipocyte storage, FFAs have to cross the capillary endothelium barrier, which connected by tight junctions (Stremmel W et al., 2001). Increased leukocyte infiltration is a featured sign of adipose tissue inflammation found in obesity. Endothelial adhesion molecules up-regulation contributes to leukocyte infiltration during inflammation. Some clinical data suggested an increase of leukocyte-endothelium interaction in healthy volunteers after ingestion of high-fat meals (Shimabukuro M et al., 2007). Other lab results also showed that neutrophil infiltration occurred at a very early stage with high-fat feeding in mice (Talukdar S et al., 2012). However, the detailed mechanism of the above phenomena is still unknown. This thesis provides exciting preliminary data which will guide the further study in this area. First of all, we successfully established a stable protocol that CD31 antibody conjugated microbeads were used to isolate primary microvascular endothelial cells from fresh mice lung tissue. After second sorting, CD31+ cells reach 83.3% by FACS analysis. Previous literatures showed that FFAs activate recruitment of inflammatory cells through up-regulation of endothelial adhesion molecules via reduced eNOS derived eNO production (Rizzo NO et al., 2010; Davenpeck KL et al., 1994; Ahluwalia A et al., 2004). In this thesis, it was found that SFAs palmitate exposure dose dependently reduced endothelial AMPK thr172 and eNOS ser1177 phosphorylation by western blot. Moreover, our study demonstrated that endothelial calpain, a calcium dependent protease associated with endothelial dysfunction, was activated by palmitate, specifically its μ-calpain isoform. Altogether, these data suggested that a new role of calpain as a key mediator of palmitate induced endothelial dysfunction and indicated both AMPK and eNOS1177 phosphorylation contribute to this pathological process. Further investigations are still needed to explore connections among those molecules. This thesis may also lead to a novel way of clinical treatment for the obese related vascular diseases. / Physiology

Background: Peripartum cardiomyopathy (PPCM) is an incompletely understood disease that causes significant morbidity and mortality in many parts of the world, including Northern Nigeria. The aims of this Thesis were: [1] to determine if selenium deficiency, serum ceruloplasmin and traditional birth practices are risk factors for PPCM, in Kano, Nigeria; [2] to describe the one year survival and left ventricular reverse remodeling (LVRR) in a group of patients with PPCM from three referral hospitals in Kano, Nigeria; [3] to identify potential electrocardiographic (ECG) predictors of PPCM; and [4] to assess right ventricular systolic dysfunction (RVSD) and remodelling in a cohort of PPCM patients in Kano, Nigeria. Materials and Methods: The studies were carried out in 3 referral hospitals in Kano, Nigeria. Study 1: This was a case-control study. Critically low serum selenium concentration was defined as <70μg/L. Study 2: This was a longitudinal study. LVRR was defined as absolute increase in LV ejection fraction (LVEF) by ≥10.0% and decrease in LV end-diastolic dimension indexed to body surface area (LVEDDi) ≤33.0 mm/m2, while recovered LV systolic function as LVEF ≥55%, at 12 months follow-up. Study 3: This was a case-control study. Logistic regression models and a risk score were developed to determine ECG predictors of PPCM. Study 4: This was a longitudinal study and patients were followed up for 12 months. RVSD was defined as the presence of either tricuspid annular plane systolic excursion (TAPSE) <16mm or peak systolic wave (S’) tissue Doppler velocity of RV free wall <10cm/s. Recovery of RV systolic function was defined as an improvement of reduced TAPSE to ≥16mm or S’ to ≥10cm/s, without falling to reduced levels again, during follow-up. Results: Study 1: Total of 39 PPCM patients and 50 controls were consecutively recruited after satisfying the inclusion criteria. Mean serum selenium in patients (61.7±14.9μg/L) was significantly lower than in controls (118.4±45.6μg/L) (p<0.001). The prevalence of serum selenium <70μg/L was significantly higher among patients (76.9%) than controls (22.0%) (p<0.001). The mean ceruloplasmin and prevalence of socio-economic indices, multiparity, pregnancy-induced hypertension, obesity and twin pregnancy were not different between the groups (p>0.05). Logistic regression showed that rural residency significantly increased the odds for serum selenium <70μg/L by 2.773 fold (p=0.037). Study 2: A total of 33 patients were followed-up. Of the 17 survivors at 12 months, 8 patients (47.1%) satisfied the criteria for LVRR, of whom 5 (29.4%) had recovered LV systolic function, but LVRR was not predicted by any variable in the regression models. The prevalence of normal LV diastolic function increased from 11.1% at baseline to 35.3% at twelve months (p=0.02). At one year follow-up, 41.4% of patients had died (two thirds of them within the first 6 months), but mortality wasn’t predicted by any variable including LVRR. Study 3: A total of 54 PPCM and 77 controls were studied. A rise in heart rate by 1 beat/minute increased the odds of PPCM by 6.4% (p=0.001), while presence of ST-T-wave changes increased the odds of PPCM by 12.06 fold (p<0.001). In patients, QRS duration modestly correlated (r=0.4; p<0.003) with LV dimensions and end-systolic volume index (LVESVI), and was responsible for 19.9% of the variability of the latter (R2 = 0.199; p=0.003). A risk score of ≥2 had a sensitivity of 85.2%, specificity of 64.9%, negative predictive value of 86.2% and area under the curve of 83.8% (p<0.0001) for potentially predicting PPCM. Study 4: A total of 45 patients were studied. RV systolic function recovery occurred in a total of 8 patients (8/45; 17.8%), of whom 6 (75.0%) recovered in 6 months after diagnosis. The prevalence of RVSD fell from 71.1% at baseline to 36.4% at 6 months (p=0.007) and 18.8% at one year (p=0.0008 vs baseline; p=0.41 vs 6 month). Although 83.3% of the deceased had RVSD, it didn’t predict mortality in the regression models (p>0.05). Conclusion: These studies have shown that selenium deficiency seems to be a risk factor for PPCM in Kano, Nigeria, related to rural residency. However, serum ceruloplasmin, customary birth practices and some other characteristics were not associated with PPCM in the study area. They have also shown that PPCM patients had modest LVRR but high mortality at one year. In addition, using the ECG risk score could help to streamline the diagnosis of PPCM with significant accuracy, prior to confirmatory investigations in postpartum women. Finally, RVSD and reverse remodelling were common in Nigerians with PPCM, in whom the first 6 months after diagnosis seem to be critical for RV recovery and survival. / Summary

Purpose: The purpose of this study was to assess whether the factors historically presented in the literature to differentiate vocal cord dysfunction (VCD) from breathing difficulties of other etiologies accurately predict and identify patients who have VCD. The researchers were also interested in whether patients with VCD have a higher risk of misdiagnosis than patients with breathing difficulties of other etiologies. Finally, the present study investigated whether patients with VCD were more likely to have their symptoms attributed to psychological factors than patients with breathing difficulties of other etiologies. Method: A survey comprised of 23 questions regarding the participants’ previous and current diagnoses, triggers that precede breathing difficulty, and whether or not the participants have ever been misdiagnosed was posted to internet support groups, websites, blogs, and forums. The final participant pool included 20 participants with VCD and 25 participants with asthma. Results: None of the factors investigated accurately differentiated participants with asthma from participants with VCD one hundred percent of the time. However, participants with VCD were more likely to report throat tightness during an attack, association of an attack with symptoms of acid reflux, and rapid resolution of symptoms without treatment. Conversely, participants with asthma were more likely to report expiratory stridor and chest tightness, full resolution of symptoms with use of asthma medications, nocturnal symptoms or symptoms just after waking, and symptoms that seemed to be triggered by environmental agents or allergens. Preliminary findings from the present study suggest that patients with VCD are both more likely to receive a misdiagnosis and have their symptoms attributed to psychological factors than participants with asthma. Conclusion: A diagnosis of VCD must be made very carefully, ideally with instrumental evaluation of the vocal mechanism during an acute “attack” of breathing difficulty. The factors identified in the literature to differentially diagnose patients with asthma from patients with VCD do not accurately differentiate these populations. These findings suggest that continued education about the nature of VCD and differential diagnosis should be paramount to medical professionals. / text

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Objective:  Obesity has become the leading cause of mortality worldwide; however, the fundamental pathophysiology underlying this association remains unclear. The discovery of adipokines, i.e., cytokines produced by adipose cells (adipocytes), revealed that adipose tissue is a highly endocrine organ, thus opening new lines of investigation. The prototypical adipokine leptin increases in obesity, and leptin receptors are found in vascular cells. However, results are contradictory regarding the role of leptin in vascular and endothelial functions. Leptin has been shown to elicit vasodilatation, but has also been linked with atherosclerotic and thrombotic disease. The main aim of the present thesis was to study the association of circulating levels of leptin with markers of endothelial function, and to analyze the effects of leptin infusion in vivo  on vasomotor function and endogenous fibrinolysis. Material:  Four associative studies and two interventional studies were conducted. The former included DISARM (studies 1 and 2), the PIVUS study (study 3), and the Scottish post-infarction study (study 4). The DISARM studies and study 4, respectively, recruited 20 men and 83 men and women with stable ischemic heart disease. Study 3 included a random sample of 1016 subjects (54% women, 70 years old) living in the community of Uppsala, Sweden. For the interventional studies (studies 5 and 6), 10 healthy men were recruited for each study. Methods:  In all studies, endothelial function was estimated based on forearm blood flow (FBF) as measured by strain-gauge venous occlusion plethysmography, at rest or during infusion of vasodilators. In study 3, additional measurement techniques were used, such as brachial ultrasound flow-mediated dilation (FMD) and the aortic augmentation index (AoAIx) by tonometry in the radial artery. Fibrinolytic status was estimated based on basal and stimulated levels of tissue plasminogen activator antigen (t-PA), and by assessment of the endothelial release of t-PA (net t-PA release). Plasma leptin levels were measured by radioimmunoassay. In the associative studies, endothelial function and fibrinolytic status were related to circulating plasma leptin levels. In the experimental studies, exogenous leptin was administered in the brachial artery and endothelial function was assessed by strain-gauge plethysmography Results:  In elderly men and women, leptin was independently associated with decreased endothelial-dependent and -independent vasodilatation, reflecting disturbed endothelial function in resistance vessels. This association was attenuated after adjustment for BMI, and when analyzed among subjects with high plasma leptin levels. FMD (a measure of endothelial function in conduit vessels) was not associated with leptin. Exogenous leptin infusion did not alter vasomotor tone, but the endothelium-dependent and -independent vasodilatation was impaired during concomitant infusion of leptin and vasodilators. Infused leptin in the forearm did not affect blood pressure or pulse rate. Chronic hyperleptinemia, but not acutely induced hyperleptinemia, was associated with release of endothelial tissue plasminogen activator (net t-PA). Conclusions:  In humans, leptin was associated with impaired vasodilatation. However, this relationship was blunted after adjustment for BMI, suggesting that leptin could be the mediator between obesity and impaired vascular function. Furthermore, the observed lack of association in hyperleptinemic subjects may reflect a state of leptin resistance. The experimental result showing attenuated vascular reactivity following leptin infusion is in accordance with the results of the associative studies. The augmented net t-PA release in patients with chronic hyperleptinemia may indicate a state of “vascular activation,” which was not observed in healthy endothelium during a short period of leptin infusion. This thesis addresses several controversial issues regarding the action of leptin on vascular tissue in humans. The final results indicate that the in vivo action of leptin on vascularity is complex and mediated by several mechanisms. Our findings suggest that leptin is an important mediator between obesity and endothelial dysfunction, and should stimulate further investigation of this matter. / Manuel Cruz Gonzalez

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