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The Mediterranean Diet, characterized by higher intakes of plant foods including plant proteins, monounsaturated fat, fish, and lower consumption of animal products and saturated fat, has long been associated with reduced cardiovascular risk, but the molecular mechanisms underlying these associations have not been fully elucidated. We conducted a pilot study to evaluate associations of an Alternate Mediterranean Diet Score, reflective of adherence to this diet pattern and adapted for US populations, and its components, with markers of endothelial inflammation directly measured in endothelial cells harvested from a diverse sample of women (n = 25, mean ± SD age 33 ± 10.5y, 68% racial/ethnic minorities). Cardiovascular risk markers including nuclear factor kappa B (NF-κB)—a marker of inflammation, as well as oxidative stress and endothelial nitric oxide synthase (eNOS) gene expression-markers of endothelial function, were evaluated in harvested endothelial cells. We hypothesized that the Mediterranean diet pattern would be associated with lower inflammation and oxidative stress and higher eNOS expression in endothelial cells. Results showed that lower oxidative stress was associated with higher plant-based protein (Exp(β) = 0.96; P = .007), overall protein (Exp(β) = 0.99; P = .007), and red and processed meat intake (Exp(β) = 0.93; P = .012). Lower NF-κB was associated with higher legume (Exp(β) = 0.79; P = .045) intake, and higher eNOS was associated with higher red and processed meat intake (Exp(β) = 1.13; P = .005). Our findings suggest potential novel mechanisms through which certain Mediterranean dietary components may influence pre-clinical vascular alterations that may be associated with cardiovascular risk through lower endothelial oxidative stress, lower inflammation, and greater endothelial functioning. These findings warrant confirmation, prospectively in a larger sample.

Background Insufficient sleep increases blood pressure. However, the effects of milder, highly prevalent but frequently neglected sleep disturbances, including poor sleep quality and insomnia, on vascular health in women are unclear. We investigated whether poor sleep patterns are associated with blood pressure and endothelial inflammation in a diverse sample of women. Methods and Results Women who participated in the ongoing American Heart Association Go Red for Women Strategically Focused Research Network were studied (n=323, 57% minority, mean age=39±17 years, range=20–79 years). Sleep duration, sleep quality, and time to sleep onset were assessed using the Pittsburgh Sleep Quality Index (score ≥5=poor sleep quality). Risk for obstructive sleep apnea was evaluated using the Berlin questionnaire, and insomnia was assessed using the Insomnia Severity Index. In a subset of women who participated in the basic study (n=26), sleep duration was assessed objectively using actigraphy, and endothelial inflammation was assessed directly in harvested endothelial cells by measuring nuclear translocation of nuclear factor kappa B. Vascular reactivity was measured by brachial artery flow‐mediated dilation (n=26). Systolic and diastolic blood pressure were measured by trained personnel (n=323). Multivariable linear regressions were used to evaluate associations between sleep patterns and blood pressure, nuclear factor kappa B, and flow‐mediated dilation. Mean sleep duration was 6.8±1.3 hours/night in the population study and 7.5±1.1 hour/night in the basic study. In the population study sample, 50% had poor sleep quality versus 23% in the basic study, and 37% had some level of insomnia versus 15% in the basic study. Systolic blood pressure was associated directly with poor sleep quality, and diastolic blood pressure was of borderline significance with obstructive sleep apnea risk after adjusting for confounders ( P =0.04 and P =0.08, respectively). Poor sleep quality was associated with endothelial nuclear factor kappa B activation (β=30.6; P =0.03). Insomnia and longer sleep onset latency were also associated with endothelial nuclear factor kappa B activation (β=27.6; P =0.002 and β=8.26; P =0.02, respectively). No evidence was found for an association between sleep and flow‐mediated dilation. Conclusions These findings provide direct evidence that common but frequently neglected sleep disturbances such as poor sleep quality and insomnia are associated with increased blood pressure and vascular inflammation even in the absence of inadequate sleep duration in women. Clinical Trial Registration URL : https://www.clinicaltrials.gov . Unique identifier: NCT 02835261.

Background: Insufficient sleep impairs blood pressure regulation. However, the effects of milder, highly prevalent but frequently neglected sleep disturbances, including poor sleep quality and insomnia, on vascular health in women are unclear. We investigated whether poor sleep patterns are associated with blood pressure and endothelial inflammation in a diverse sample of women. Methods: Women who participated in the ongoing AHA Go Red for Women Strategically Focused Research Network population project were studied (n=323, 57% minority, mean age=39 + 17 y, range=20-79 y). Sleep duration, sleep quality, and time to sleep onset were assessed using the Pittsburgh Sleep Quality Index (score > 5=poor sleep quality). Risk for obstructive sleep apnea (OSA) was evaluated using the Berlin questionnaire, and insomnia was assessed using the Insomnia Severity Index (ISI). In a subset of women who participated in the basic study (n=28), sleep duration was assessed objectively using actigraphy and endothelial inflammation was assessed directly in harvested endothelial cells by measuring nuclear translocation of nuclear factor kappa B (NFκB). Vascular reactivity was measured by brachial artery flow-mediated dilation (FMD). Systolic and diastolic blood pressure (SBP and DPB) were measured by trained personnel. Multivariate linear regressions were used to evaluate associations between sleep patterns and blood pressure, NFκB and FMD. Results: Mean sleep duration was 6.8 ± 1.3 h/night in the population study and 7.5 ± 1.1 h/night in the basic study. In the population study sample, 50% had poor sleep quality (25% in the basic study), and 37% had some level of insomnia (15% in the basic study). SBP was associated directly with poor sleep quality, and DBP with OSA risk after adjusting for confounders (p=0.04 and p=0.08, respectively). Poor sleep quality was associated with endothelial NFκB activation (β=30.6; p=0.03). Insomnia and longer time to sleep onset were also associated with endothelial NFκB activation (β=27.6; p=0.002 and β=8.26; p=0.02, respectively). Sleep patterns were not associated with FMD. Conclusions: These findings provide direct evidence that common but frequently neglected sleep disturbances such as poor sleep quality and insomnia are associated with increased blood pressure and vascular inflammation even in the absence of sleep deprivation in women.

Çalışma giriş, dört bölüm ve sonuçtan oluşmaktadır. Girişte araştırmanın konusu, amacı, yöntemi, sınırlılıkları ve kaynaklar ele alındı. Burada ayrıca Zerdüştîliğin İran'daki tarihsel gelişimi üzerine değerlendirme yapıldı. Tezin birinci bölümünde, İran'daki Zerdüştîlerin demografik yapı, etnik aidiyet, kültür, gelenek ve görenekler, ahlâkî kurallar, kadının konumu, eğitim, kurumlar, devlet-Müslüman toplumla ve farklı coğrafyalardaki dindaşlarıyla ilişkileri gibi toplumsal hayatla ilgili konulara değinildi. Ayrıca Zerdüştîlerin yoğun olarak kullandıkları bazı dini semboller ve dini takvim konuları açıklandı. Tezin ikinci bölümünde, inanç konularına yer verildi. Tanrı, kutsal kitap, peygamber, ahiret ve kurtarıcı inancı konuları üzerinde duruldu. Özellikle Tanrı ve kurtarıcı inancı konularındaki geleneksel inançtaki değişimlere vurgu yapıldı. Tezin üçüncü bölümünde, dini uygulamalar açıklandı. Bölümün başında ateş kültü, din adamları ve mabet gibi konulara değinildi. Bundan sonra bölümün asıl konusu olan namaz, nebûr/perhiz, kutsal yerleri ziyaret, kurban, bayramlar, törenler ve önemli günler konusu açıklandı. Konular hakkında yazılı kaynaklara dayalı bilgiler vermekle birlikte, Zerdüştîlerin bunları nasıl pratize ettikleri üzerinde duruldu. Tezin dördüncü bölümünde, geçiş mensekleri başlığı altında Zerdüştîlerin dine giriş töreni, doğum, evlilik ve ölümle ilgili durumları hakkında bilgiler sunuldu. Yazılı kaynaklarda ve alan araştırmasında doğum konusuyla ilgili yeterli bilgiye ulaşılamadığından özellikle dine giriş töreni, evlilik ve ölüm konuları hakkında bilgi verildi. Bu bölümde son olarak ölü için yapılan törenlere yer verildi. Sonuçta, Zerdüştî toplumun günümüz ve gelecekteki durumlarıyla ilgili tespitler ele alındı. Onların devlet ve Müslümanlarla ilişkilerinin genel bir değerlendirilmesi yapıldı. Ekler başlığında, alan araştırması sırasında sorulan sorular, bazı konularla ilgili fotoğraflar verildi. This study consists of introduction, four parts and the conclusion. In the introduction part the subject, aim, method, sources and limitation of the study have been dealt. Additionally, the historical development of the Zoroastrianism in Iran has been evaluated in this part. In the first part of the study, the issues related to Zoroastrians' social life such as, their demographic structure, ethnical belongingness, culture, customs, moral principles, position of woman among them, education, institutions and also their relations with government, Muslim society, and co-religionists in other parts of the world have been mentioned. Furthermore, some of the religious symbols and religious calendars have also been explained. The second part of the thesis includes issues on believes. God, holy writ, prophet, after-life and the savior faith have been discoursed. Especially, the changes in the traditional belief of the God and the savior faith have been emphasized. In the third part of the thesis, the religious practices have been explained. In the beginning of the part, it has been mentioned about cult of the fire, reverend and chapel. Then, the main subjects of the part have been explained such as prayer, fasting, visiting sanctums, sacrifice, festivals, ceremonies and occasions. It has been focused on how Zoroastrian practiced them by giving information based on written sources. In the fourth part of the thesis, information has been given about entrance to the religion, birth, marriage and death under the title of rituals. Especially, entrance to the religion, marriage and death have been widely studied as researcher has not found enough information about birth in written sources and his field research this issue has not been studied in details. There is also some information about rites for death in this part. In conclusion part, the determinations on the today and future of Zoroastrian society have been discussed. Their relation with the government and Muslims has been evaluated. In appendix, the questions which were asked during the field research, and some important pictures related to topics has been given. 294

BACKGROUND The relative risk for cardiovascular diseases in passive smokers is similar to that of active smokers despite almost a 100-fold lower dose of inhaled cigarette smoke. However, the mechanisms underlying the surprising susceptibility of the vascular tissue to the toxins in secondhand smoke (SHS) have not been directly investigated. The aim of this study was to investigate directly vascular endothelial cell function in passive smokers. METHODS Using a minimally invasive method of endothelial biopsy, we investigated directly the vascular endothelium in 23 healthy passive smokers, 25 healthy active smokers, and 23 healthy control subjects who had never smoked and had no regular exposure to SHS. Endothelial nitric oxide synthase (eNOS) function (expression of basal eNOS and activated eNOS [phosphorylated eNOS at serine1177 (P-eNOS)]) and expression of markers of inflammation (nuclear factor-κB [NF-κB]) and oxidative stress (nitrotyrosine) were assessed in freshly harvested venous endothelial cells by quantitative immunofluorescence. RESULTS Expression of eNOS and P-eNOS was similarly reduced and expression of NF-κB was similarly increased in passive and active smokers compared with control subjects. Expression of nitrotyrosine was greater in active smokers than control subjects and similar in passive and active smokers. Brachial artery flow-mediated dilation was similarly reduced in passive and active smokers compared with control subjects, consistent with reduced endothelial NO bioavailability. CONCLUSIONS Secondhand smoking increases vascular endothelial inflammation and reduces active eNOS to a similar extent as active cigarette smoking, indicating direct toxic effects of SHS on the vasculature.

Zoroastrianism is a religionwith a long historical background. The founder of this religion is Zoroasterwho is regarded as prophet by his members. Nowadays, Zoroastrians live in aminority status with a tendency of population decrease in Iran. In this study,the different forms of burials applied by Iran Zoroastrians are examined. Themost familiar of these is the method that Zoroastrians calls as dakhma, westerners calls as tower of silence. In this method, thecorpses were left for the vultures to come and eat in places where called as dahme.Because of various reasons in the recent period, Zoroastrians have had toabandon this method. Nowadays they are burying their dead., Zerdüştîlik uzun tarihî geçmişe sahip bir dindir. Budinin kurucusu, mensupları tarafından peygamber olarak kabul edilenZerdüşt’tür. Günümüzde Zerdüştîler, İran’da azalma trendinde olan nüfuslarıyla azınlıkstatüsünde yaşamaktadırlar. Bu çalışmada İran Zerdüştîlerinde geçmiştengünümüze uygulanan farklı defin şekilleri incelenmiştir. Bunların en bilineni Zerdüştîlerindahme, (دخمه) batılıların tower of silence dediği yöntemdir.Bu yöntemde cesetler, akbabaların gelip yemesi için dahme denilen yapılarabırakılırdı. Yakın dönemde çeşitli sebeplerden dolayı Zerdüştîler bunu terketmek zorunda kalmışlardır. Günümüzde artık ölülerini gömmektedirler.

Obstructive sleep apnea (OSA), characterized by intermittent hypoxia (IH) during transient cessation of breathing, triples the risk for cardiovascular diseases. We used a phage display peptide library as an unbiased approach to investigate whether IH, which is specific to OSA, activates endothelial cells (ECs) in a distinctive manner. The target of a differentially bound peptide on ECs collected from OSA patients was identified as CD59, a major complement inhibitor that protects ECs from the membrane attack complex (MAC). A decreased proportion of CD59 is located on the EC surface in OSA patients compared with controls, suggesting reduced protection against complement attack. In vitro, IH promoted endothelial inflammation predominantly via augmented internalization of CD59 and consequent MAC deposition. Increased internalization of endothelial CD59 in IH appeared to be cholesterol-dependent and was reversed by statins in a CD59-dependent manner. These studies suggest that reduced complement inhibition may mediate endothelial inflammation and increase vascular risk in OSA patients.

Shedding of the extracellular domain of cytokine receptors allows the diffusion of soluble receptors into the extracellular space; these then bind and neutralize their cytokine ligands, thus dampening inflammatory responses. The molecular mechanisms that control this process, and the extent to which shedding regulates cytokine-induced microvascular inflammation, are not well defined. Here, we used real-time confocal microscopy of mouse lung microvascular endothelium to demonstrate that mitochondria are key regulators of this process. The proinflammatory cytokine soluble TNF-α (sTNF-α) increased mitochondrial Ca2+, and the purinergic receptor P2Y2 prolonged the response. Concomitantly, the proinflammatory receptor TNF-α receptor-1 (TNFR1) was shed from the endothelial surface. Inhibiting the mitochondrial Ca2+ increase blocked the shedding and augmented inflammation, as denoted by increases in endothelial expression of the leukocyte adhesion receptor E-selectin and in microvascular leukocyte recruitment. The shedding was also blocked in microvessels after knockdown of a complex III component and after mitochondria-targeted catalase overexpression. Endothelial deletion of the TNF-α converting enzyme (TACE) prevented the TNF-α receptor shedding response, which suggests that exposure of microvascular endothelium to sTNF-α induced a Ca2+-dependent increase of mitochondrial H2O2 that caused TNFR1 shedding through TACE activation. These findings provide what we believe to be the first evidence that endothelial mitochondria regulate TNFR1 shedding and thereby determine the severity of sTNF-α-induced microvascular inflammation.

Although exposure to ambient hypoxia is known to cause proinflammatory vascular responses, the mechanisms initiating these responses are not understood. We tested the hypothesis that in systemic hypoxia, erythrocyte-derived H(2)O(2) induces proinflammatory gene transcription in vascular endothelium. We exposed mice or isolated, perfused murine lungs to 4 hours of hypoxia (8% O(2)). Leukocyte counts increased in the bronchoalveolar lavage. The expression of leukocyte adhesion receptors, reactive oxygen species, and protein tyrosine phosphorylation increased in freshly recovered lung endothelial cells (FLECs). These effects were inhibited by extracellular catalase and by the removal of erythrocytes, indicating that the responses were attributable to erythrocyte-derived H(2)O(2). Concomitant nuclear translocation of the p65 subunit of NF-κB and hypoxia-inducible factor-1α stabilization in FLECs occurred only in the presence of erythrocytes. Hemoglobin binding to the erythrocyte membrane protein, band 3, induced the release of H(2)O(2) from erythrocytes and the p65 translocation in FLECs. These data indicate for the first time, to our knowledge, that erythrocytes are responsible for endothelial transcriptional responses in hypoxia.

Although the lung expresses procoagulant proteins under inflammatory conditions, underlying mechanisms remain unclear. Here, we addressed lung endothelial expression of tissue factor (TF), which initiates the coagulation cascade and expression of which signifies development of a procoagulant phenotype in the vasculature. To establish the model of acid-induced acute lung injury (ALI), we intranasally instilled anesthetized mice with saline or acid. Then 2 h later, we isolated pulmonary vascular cells for flow cytometry and confocal microscopy to detect the leukocyte antigen, CD45 and the endothelial markers VE-cadherin and von Willebrand factor (vWf). Acid increased both the number of vWf-expressing cells as well as TF and P-selectin expressions on these cells. All of these effects were markedly inhibited by treating mice with antiplatelet serum, suggesting the involvement of platelets. The increased expressions of TF, vWf, and P-selectin in response to acid also occurred in platelets. Moreover, the effects were replicated in endothelial cells derived from isolated, blood-perfused lungs. However, the effect was inhibited completely in lungs perfused with platelet-depleted and, to a lesser extent, with leukocyte-depleted blood. Acid injury increased endothelial expressions of the platelet proteins, CD41 and CD42b, providing evidence that platelet proteins were transferred to the vascular surface. Reactive oxygen species (ROS) were implicated in these responses, in that the endothelial and platelet protein expressions were inhibited. We conclude that acid-induced ALI causes NOX2-mediated ROS generation that activates platelets, which then generate a procoagulant endothelial surface.

Bone marrow-derived stromal cells (BMSCs) protect against acute lung injury (ALI). To determine the role of BMSC mitochondria in this protection, we airway-instilled mice first with lipopolysaccharide (LPS) and then with either mouse BMSCs (mBMSCs) or human BMSCs (hBMSCs). Live optical studies revealed that the mBMSCs formed connexin 43 (Cx43)-containing gap junctional channels (GJCs) with the alveolar epithelia in these mice, releasing mitochondria-containing microvesicles that the epithelia engulfed. The presence of BMSC-derived mitochondria in the epithelia was evident optically, as well as by the presence of human mitochondrial DNA in mouse lungs instilled with hBMSCs. The mitochondrial transfer resulted in increased alveolar ATP concentrations. LPS-induced ALI, as indicated by alveolar leukocytosis and protein leak, inhibition of surfactant secretion and high mortality, was markedly abrogated by the instillation of wild-type mBMSCs but not of mutant, GJC-incompetent mBMSCs or mBMSCs with dysfunctional mitochondria. This is the first evidence, to our knowledge, that BMSCs protect against ALI by restituting alveolar bioenergetics through Cx43-dependent alveolar attachment and mitochondrial transfer.

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