Exercise, Shear Stress, and Flow-Mediated Dilation of Human Conduit Arteries

Flow-mediated dilation (FMD) refers to the relaxation of vascular smooth muscle and the subsequent dilation of the vessel in response to increases in shear stress on the endothelial lining accompanying increases in blood flow. The phenomenon has been shown to be endothelium dependent and as such is used clinically and experimentally as an index of endothelial health. FMD can be assessed by imaging a conduit artery with ultrasound during a period of reactive hyperaemia, typically following a period of prior blood flow occlusion achieved by the inflation of a pneumatic cuff around the limb distal to the imaging site. Previous studies have shown that the health of the endothelium is predictive of the health of the cardiovascular system as a whole. This thesis set out to scrutinize the FMD test as a marker for endothelial health by testing the following five hypotheses: 1. A short burst of high shear is not adequate to elicit the FMD response. 2. Brachial artery dilation following 15 minutes of occlusion is a clearer indicator of endothelium dependent FMD than 5 minutes of occlusion with exercise. 3. Oscillating the post occlusion shear stress will decrease FMD compared to unidirectional shear). 4. Heavy dynamic hand grip exercise 6 minutes before an occlusion-only FMD protocol will result in an enhanced FMD response. 5. Long term bed-rest inactivity will attenuate the FMD response and an exercise program will preserve endothelial function. The experiments documented in Chapter 2 found that a 20-s shear stress stimulus following 15 min of forearm circulatory occlusion was not adequate to induce an FMD response compared to longer durations of shear and there was a progressive reduction in FMD when the magnitude of the initial peak shear was reduced by limiting the duration of prior occlusion. Also, the FMD response was correlated with the total shear to time of peak diameter for all shear durations and peaks that were studied while the same was not true of peak shear. In Chapter 3 it was revealed that an uncoupling of the shear-to-dilation ratio occurred when dynamic exercise was added to the FMD test as both 15 min of occlusion (15OC) and 5 min of occlusion with 1 min of exercise (1EXin5OC) yielded similar FMD responses, even though the shear stimulus was increased with the addition of exercise. Increased plasma nitrite during hyperaemia was observed only in the 15OC protocol, suggesting that the exercise in the 1EXin5OC protocol initiates dilatory mechanisms that are not as heavily reliant on the shear sensitive nitric oxide pathway . In Chapter 4 it was shown that 5 min of intense dynamic hand grip exercise (5EX) produced a greater dilation than either continuous (15OC) or intermittent (IO) shear following 15OC. Total shear to the time of peak diameter (AUCshear) and peak shear were both correlated to %dilation following 15OC; however this relationship was lost during 5EX and IO. The results of this study echoed the suggestion in Chapter 3 that there was an uncoupling of the intensity of the shear stimulus and the magnitude of vasodilatation when exercise was introduced, and adds that it may be in part due to the oscillatory nature of the shear profile during exercise. The acute effects of local exercise on the FMD response following 15OC were examined in Chapter 5. FMD in the brachial artery was blunted following dynamic hand grip exercise, even though the shear stimulus was greater during PostEX. Nitrite was significantly elevated in CON at 15s while PostEX nitrite was significantly elevated at 30s post cuff release but not different from CON at 15s. The results of this study suggested that prior exercise had a negative effect on FMD which may be related to exercise blunting post occlusion endothelial N ̇O production. Chapter 6 examined the effect of 56 days of head-down tilt bed rest (HDBR) and an exercise countermeasure on conduit artery FMD following release of distal limb ischemia and NMD following sublingual administration of 0.3 mg of nitroglycerin. HDBR without EX decreased the resting diameter of the popliteal artery while EX increased the diameter. HDBR had no effect on the resting diameter of the brachial artery. FMD was elevated in all groups for the brachial but only in the non-exercisers for the popliteal. When change in resting diameter was taken into account the preserved FMD in EX was removed. NMD was not altered by HDBR in any group. There was enhanced endothelial function relative to intrinsic dilatory capacity in both the brachial and popliteal arteries post HDBR. The results from Chapter 2 support hypothesis 1, showing that a 20 second burst of high shear stimulus was not adequate to elicit the FMD response during reactive hyperaemia. It is not clear whether hypothesis 2 was supported or not given that the results from Chapter 3 showed on the one hand that the %FMD did not change with the addition of exercise in the occlusion but on the other hand the shear to dilation ratio was altered. The finding, in Chapter 4, that FMD was not reduced when the hyperaemia was intermittent does not support hypothesis 3. In opposition to hypothesis 4, Chapter 5 showed that %FMD was reduced following bouts of heavy hand grip exercise; however the absolute magnitude of vessel diameter was similar in both post exercise and control tests. Finally, hypothesis 5 was also contradicted, with Chapter 6 showing that long term bed-rest enhanced rather than attenuated the FMD response in both arm and leg arteries, while an exercise countermeasure preserved pre-bed-rest FMD in the legs only. In addition to the specific hypotheses tested, there was evidence that acute exercise evoked dilatory mechanisms in the conduit arteries that were not shear/endothelium dependent given that the shear to dilation relationship was uncoupled during, following, and in occlusion protocols that include exercise. The precise mechanisms by which this is achieved are still unknown, but it may be partially due to the oscillatory nature of the elevated blood flow during exercise. I conclude that inference of cardiovascular health from endothelial function by the evaluation of %FMD should be approached with caution, especially in the event that physical activity is involved

Confinement, chiral symmetry, and the lattice

Two crucial properties of QCD, confinement and chiral symmetry breaking, cannot be understood within the context of conventional Feynman perturbation theory. Non-perturbative phenomena enter the theory in a fundamental way at both the classical and quantum level. Over the years a coherent qualitative picture of the interplay between chiral symmetry, quantum mechanical anomalies, and the lattice has emerged and is reviewed here.Comment: 126 pages, 36 figures. Revision corrects additional typos and renumbers equations to be more consistent with the published versio

Challenging Varieties of Capitalism's Account of Business Interests: The New Social Market Initiative and German Employers' Quest for Liberalization, 2000-2014

Do employers in coordinated market economies (CME's) actively defend the non-liberal, market- constraining institutions upon which their strategic coordination and competitive success depends? This paper revisits the debate over firms' employer preferences with an in-depth examination of employers in Germany - a paradigmatic CME and crucial "test case" for Varieties of Capitalism. It is based on interviews with key officials and an in-depth examination of a large-scale campaign - the New Social Market Initiative or INMS - founded and funded by German metalworking employers to shape public opinion. The paper argues that German employers have a strong preference for liberalization: they have pushed hard for the liberalization of labor markets, the reduction of government expenditures, the expansion of market-oriented freedoms, and cuts to social protection, employment protection and benefit entitlements. I find no empirical support for the claim that the INSM is an attempt to appease discontented firms within employers' associations. On the contrary: for many employers, the Agenda 2010 reforms did not go far enough. Following the discrediting of the Anglo-American model in the financial crisis, far-reaching concessions by employees, and the unexpected revitalization of the German economy, employers have moderated their demands - but liberalization remains their default preference. This paper also addresses the role of ideas and the conditions under which employer campaigns can influence policy.Verteidigen Arbeitgeber in koordinierten Marktwirtschaften aktiv die nichtliberalen, marktbeschränkenden Institutionen, von denen ihre Möglichkeiten zur strategischen Koordination und ihr Erfolg im Wettbewerb abhängen? Mit einer umfassenden Untersuchung der Präferenzen von Arbeitgebern in Deutschland, das als typisches Beispiel einer koordinierten Marktwirtschaft und wegweisender "Testfall" für die Theorie über Spielarten des Kapitalismus gilt, greift dieses Discussion Paper die Debatte über die Präferenzen von Unternehmen in ihrer Eigenschaft als Arbeitgeber auf. Es basiert auf Interviews mit führenden Arbeitgeberfunktionären sowie einer detaillierten Untersuchung der Initiative Neue Soziale Marktwirtschaft (INSM): einer groß angelegten, von deutschen Metallarbeitgebern initiierten und finanzierten Kampagne zur öffentlichen Meinungsbildung. Der Beitrag belegt eine deutliche Präferenz deutscher Arbeitgeber für die Liberalisierung. Mit Nachdruck haben sie sich für eine Liberalisierung der Arbeitsmärkte, eine Senkung der Staatsausgaben und eine Ausweitung marktorientierter Gestaltungsfreiheiten ebenso eingesetzt wie für Einschnitte bei der sozialen Sicherung, dem Kündigungsschutz und den Versorgungsansprüchen. Die Behauptung, die INSM sei ein Versuch, unzufriedene Unternehmen innerhalb der Arbeitgeberverbände zu beschwichtigen, lässt sich durch die empirischen Befunde nicht stützen. Im Gegenteil: Vielen Arbeitgebern gingen die Reformen im Zuge der Agenda 2010 nicht weit genug. Zwar haben die deutschen Arbeitgeber nach der Diskreditierung des angloamerikanischen Modells während der Finanzkrise, weitreichenden Zugeständnissen seitens der Arbeitnehmer sowie der unerwarteten Wiederbelebung der deutschen Wirtschaft ihre Forderungen gemäßigt - doch bleibt ihre grundlegende Präferenz für die Liberalisierung bestehen. Dieser Beitrag befasst sich außerdem mit der Rolle von Ideen sowie den Bedingungen, unter denen Arbeitgeberkampagnen politische Maßnahmen beeinflussen können

Global urban environmental change drives adaptation in white clover

Urbanization transforms environments in ways that alter biological evolution. We examined whether urban environmental change drives parallel evolution by sampling 110,019 white clover plants from 6169 populations in 160 cities globally. Plants were assayed for a Mendelian antiherbivore defense that also affects tolerance to abiotic stressors. Urban-rural gradients were associated with the evolution of clines in defense in 47% of cities throughout the world. Variation in the strength of clines was explained by environmental changes in drought stress and vegetation cover that varied among cities. Sequencing 2074 genomes from 26 cities revealed that the evolution of urban-rural clines was best explained by adaptive evolution, but the degree of parallel adaptation varied among cities. Our results demonstrate that urbanization leads to adaptation at a global scale

31st Annual Meeting and Associated Programs of the Society for Immunotherapy of Cancer (SITC 2016) : part two

Background The immunological escape of tumors represents one of the main ob- stacles to the treatment of malignancies. The blockade of PD-1 or CTLA-4 receptors represented a milestone in the history of immunotherapy. However, immune checkpoint inhibitors seem to be effective in specific cohorts of patients. It has been proposed that their efficacy relies on the presence of an immunological response. Thus, we hypothesized that disruption of the PD-L1/PD-1 axis would synergize with our oncolytic vaccine platform PeptiCRAd. Methods We used murine B16OVA in vivo tumor models and flow cytometry analysis to investigate the immunological background. Results First, we found that high-burden B16OVA tumors were refractory to combination immunotherapy. However, with a more aggressive schedule, tumors with a lower burden were more susceptible to the combination of PeptiCRAd and PD-L1 blockade. The therapy signifi- cantly increased the median survival of mice (Fig. 7). Interestingly, the reduced growth of contralaterally injected B16F10 cells sug- gested the presence of a long lasting immunological memory also against non-targeted antigens. Concerning the functional state of tumor infiltrating lymphocytes (TILs), we found that all the immune therapies would enhance the percentage of activated (PD-1pos TIM- 3neg) T lymphocytes and reduce the amount of exhausted (PD-1pos TIM-3pos) cells compared to placebo. As expected, we found that PeptiCRAd monotherapy could increase the number of antigen spe- cific CD8+ T cells compared to other treatments. However, only the combination with PD-L1 blockade could significantly increase the ra- tio between activated and exhausted pentamer positive cells (p= 0.0058), suggesting that by disrupting the PD-1/PD-L1 axis we could decrease the amount of dysfunctional antigen specific T cells. We ob- served that the anatomical location deeply influenced the state of CD4+ and CD8+ T lymphocytes. In fact, TIM-3 expression was in- creased by 2 fold on TILs compared to splenic and lymphoid T cells. In the CD8+ compartment, the expression of PD-1 on the surface seemed to be restricted to the tumor micro-environment, while CD4 + T cells had a high expression of PD-1 also in lymphoid organs. Interestingly, we found that the levels of PD-1 were significantly higher on CD8+ T cells than on CD4+ T cells into the tumor micro- environment (p < 0.0001). Conclusions In conclusion, we demonstrated that the efficacy of immune check- point inhibitors might be strongly enhanced by their combination with cancer vaccines. PeptiCRAd was able to increase the number of antigen-specific T cells and PD-L1 blockade prevented their exhaus- tion, resulting in long-lasting immunological memory and increased median survival