Myeloperoxidase in vascular disease and autoimmunity

This dissertation defines mechanisms whereby myeloperoxidase (MPO) can mediate vascular damage when released into the vessel, and explores the pathogenesis of an autoimmune disease targeting MPO. The most abundant neutrophil granule protein, MPO generates powerful oxidants that contribute to innate host defense. However, these same oxidants cause host injury; the release of MPO into the vessel correlates with the impairment of vasoregulatory processes and cellular injury. Herein, we report that cytokeratin 1, an endothelial protein, mediates MPO binding and internalization. Cytokeratin 1 also functions as a scaffolding protein for the vasoregulatory plasma kallikrein-kinin system. This system produces bradykinin, a potent inducer of endothelial nitric oxide synthesis. Our investigations revealed that MPO bound and co-localized with high molecular weight kininogen on endothelial cells, and this interaction interfered with bradykinin cleavage by plasma kallikrein. Further, MPO oxidized and inactivated both kininogen and kallikrein, thus preventing bradykinin release. This work identified cytokeratin 1 as a facilitator of MPO-mediated responses, and provided a new paradigm by which MPO affects vasoregulatory processes during inflammation. One disease characterized by excess intravascular neutrophil degranulation is antineutrophil cytoplasmic autoantibody (ANCA)-mediated vasculitis. One major ANCA specificity is for MPO (MPO-ANCA). The origin of these pathogenic autoantibodies is unknown, though our group previously published studies implicating proteins complementary in sequence to autoantigens as the inciting elements of autoimmune disease in patients with proteinase 3-specific ANCA. In chapter 2, we demonstrated the presence of anti-complementary MPO antibodies in patients; this implied that the development of MPO-specific antibodies was a result of an anti-idiotypic response against the anti-complementary protein antibody, and in this way normal tolerogenic mechanisms were bypassed. For this dissertation, we tested the hypothesis that complementary proteins could cause disease in an MPO-ANCA mouse model. While results were not as we predicted, the work revealed the importance of identifying a pathogenic epitope. An epitope mapping study was carried out using a mass spectrometry-based technique, a tool that may generate powerful data for us in the near future. While the human data suggests a role for complementary proteins in MPO-ANCA disease, proving causation in an animal model remains an elusive goal

HUBUNGAN ANTARA PRESTASI REMAJA SMA YANG DIKONSULKAN KE BIMBINGAN DAN KONSELING DENGAN TINGKAT DEPRESI

Background Inability teenagers survive in the face of excessive problems can be a stressor. Thus, decrease and failure of academic achievement in teenagers high school grade 10, 11, and 12 which are in a transitional period of life can make them fall in a state of depression. Goal To prove that there is a relation between Senior High School teenagers’ achievement that is consulted at Guide and Counseling with the level of depression. Method Method of this research is analytical observational with cross sectional design. There are 69 teenager respondents from Tritunggal Senior High School students’ grade 10, 11, and 12 that is consulted in Guide and Counseling. The achievement is measured by using the academic result of student. While, the depression level is measured by Beck Depression Inventory-II questionnaire. Result The result of depression level are 69,6 % do not experiencing depression; 21,7 % experiencing mild depression; 5,8 % experiencing moderate depression; dan 2,9 % experiencing severe depression. In Kolmogorov-Smirnov test finds that there is no significant relation between Senior High School teenagers’ achievement that is consulted at Guide and Counseling with the level of depression. Conclusion There is no significant relation between Senior High School teenagers’ achievement that is consulted at Guide and Counseling with the level of depression because on the attitude itself becomes the reason teenagers have to be consulted, and they are still active doing hobbies affected lowering depression. Moreover, Guide and Counseling has an important roles in handling students. Keywords Achievement, Senior High School teenagers’ that is consulted at Guide and Counseling, depression level

Myeloperoxidase Interacts with Endothelial Cell-Surface Cytokeratin 1 and Modulates Bradykinin Production by the Plasma Kallikrein-Kinin System

During an inflammatory state, functional myeloperoxidase (MPO) is released into the vessel as a result of intravascular neutrophil degradation. One mechanism of resulting cellular injury involves endothelial internalization of MPO, which causes oxidative damage and impairs endothelial signaling. We report the discovery of a protein that facilitates MPO internalization, cytokeratin 1 (CK1), identified using affinity chromatography and mass spectrometry. CK1 interacts with MPO in vitro, even in the presence of 100% human plasma, thus substantiating biological relevance. Immunofluorescent microscopy confirmed that MPO added to endothelial cells can co-localize with endogenously expressed CK1. CK1 acts as a scaffolding protein for the assembly of the vasoregulatory plasma kallikrein-kinin system; thus we explored whether MPO and high molecular weight kininogen (HK) reside on CK1 together or whether they compete for binding. The data support cooperative binding of MPO and HK on cells such that MPO masked the plasma kallikrein cleavage site on HK, and MPO-generated oxidants caused inactivation of both HK and kallikrein. Collectively, interactions between MPO and the components of the plasma kallikrein-kinin system resulted in decreased bradykinin production. This study identifies CK1 as a facilitator of MPO-mediated vascular responses and thus provides a new paradigm by which MPO affects vasoregulatory systems

Corkscrew

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Placental telomere length shortening is not associated with preeclampsia but the gestational age

STRUCTURED ABSTRACTBackgroundPreeclampsia is a severe pregnancy complication that affects about 2-8% of pregnant women globally and is one of the leading causes of maternal and fetal mortality and morbidity. Telomere length change has been associated with aging, environmental stress, and various diseases. Studying the telomere length change in preeclampsia complicated placentas may shed light on the pathophysiology of preeclampsia.ObjectivesIn this study, we aimed to explore if associations exist between placental telomere length and preeclampsia, gestational age, and other demographic, clinical and physiological factors related to pregnancy.Study DesignWe collected placentas samples from 120 severe preeclamptic deliveries and 129 healthy full-term deliveries in Hawaii between year 2006 and 2013 and measured the average absolute placental telomeres with quantitative polymerase chain reaction (qPCR). We retrieved their pre-recorded demographic, clinical and physiological data and conducted multiple linear regressions to associate placental telomeres with preeclampsia and other variables.ResultsPlacental telomere length of severe preeclampsia cases showed no significant difference (P=0.20) from healthy controls after controlling for gestational age difference. Instead, we identified that placental telomere length consistently decreases as gestation progresses (P=6.10e-05). Male babies have shorter placental telomere than female babies in the early trimester (p = 0.024), but the placentas of male babies have a reduced rate of telomere shortening along pregnancies, compared to those of female babies (p = 0.029). Latino mothers show longer placenta telomeres than other ethnicities (P=0.012), whereas mothers of blood type O have shorter placenta telomeres than those of other blood types (P=0.039).ConclusionsUsing the largest multiethnic cohort to date, we showed the lack of association between preeclampsia and placental telomere length. Rather, gestational age is the most dominant variable associated with placental telomere shortening.CondensationPlacental telomere length shows no significant association with preeclampsia but significantly shortens with the progressing gestational age at different rates for male and female babies.AJOG At A GlanceA.Why was this study conducted?Understanding the TL change in healthy and preeclampsia complicated placenta may help us better understand the physio-pathological impact of preeclampsia.B.What are the key findings?We found no significant association between severe preeclampsia and placental TL in the largest multi-ethnic cohort to date.Placental TL shortens consistently largely due to gestational age increase.Placentas of male babies have shorter TLs at the early third trimester but slower TL shortening compared to those of female babies.Latino mothers have longer placental TL compared to non-Latino mothers.Mothers of blood type O have shorter placenta TL than others.C.What does this study add to what is already known?We showed that placental telomere length shortening is not associated with preeclampsia but the gestational age in a large multi-ethnical cohort.</jats:sec