Identifying Pathogenic Epitopes and Autoreactive Cells in ANCA Vasculitis

This dissertation is focused on the interaction between the humoral (B cell) and cellular (T cell) arms of the adaptive immune system, and known autoantigens in patients with anti-neutrophil cytoplasmic autoantibody (ANCA) vasculitis. ANCA vasculitis is characterized by vascular inflammation that leads to organ damage. Current treatment involves medications designed to induce disease remission, but many patients suffer from side effects including severe infection. We hypothesized that elucidating specific interactions between autoreactive lymphocytes and known autoantigens in patients would reveal targets for novel therapies that could halt the autoimmune response without side effects. In Chapter 1, I use high-resolution human leukocyte antigen (HLA) typing to identify alleles prevalent in our patients and demonstrate using Kaplan Meier estimates that carriage of HLA-DPB1*04:01 does not increase risk of relapse, contrary to previous results (1). Based on our independent serotype analysis, we hypothesize that carriage of HLA-DPB1*04:01 is a risk factor for patients with PR3-ANCA vasculitis (not MPO-ANCA vasculitis). Also addressed are significant differences between patients with MPO- and PR3-ANCA vasculitis, to clarify the rationale for focusing exclusively on MPO-ANCA vasculitis for the remainder of this dissertation. Chapter 2 focuses on potentially immunopathogenic regions of MPO. Patient autoantibody reactivity was assessed by enzyme-linked immunosorbent assay (ELISA) and anti-MPO447-461 antibodies were detected in 53% of patients. Epitopes were characterized using alanine scanning, circular dichroism, and solvent exposure experiments. Finally, in silico and in vitro binding studies confirmed the ability of MPO epitopes to bind patient HLA. In Chapter 3, I assess patient CD4+ T cell recognition of MPO epitopes. MHC II tetramers were created with patient HLA alleles and MPO epitopes, and used to stain patient cells. Patients demonstrated specific CD4+CD25intermediate T cell binding to tetramers and these cells secreted the pro-inflammatory cytokine IL-17A. TCR sequencing studies revealed clonally expanded autoreactive cells compared to controls, and some public TCR clones. Elucidation of these specific immune interactions will allow for new antigen-specific treatments using a variety of emerging techniques including chimeric antigen receptor (CAR) T cells, tolerogenic dendritic cells (DC), nanoparticle presentation of antigens, gene therapy, or removal of pathogenic T cells by apheresis.Doctor of Philosoph

Analisis struktur lirik lagu Ebiet G. Ade dalam album "Kupu-kupu kertas"

Puisi merupakan karya sastra dengan struktur yang khas, yang berisi hasil penghayatan penyair tentang kehidupan, dinyatakan secara indah, impresif, dan efektif. Lirik lagu pada hakekatnya adalah puisi. Hal ini ditegaskan dengan pengertian lirik sebagai sajak yang merupakan susunan kata sebuah nyanyian; karya sastra yang berisi curahan perasaan pribadi, yang diutamakan ialah lukisan perasaannya Tujuan yang ingin dicapai dalam penelitian ini adalah ingin mengetahui tema, diksi, gaya bahasa, serta persajakan yang terdapat dalam lirik lagu ebiet G.ade. untuk mencapai tujuan tersebut, diperlukan metode penelitian. Metode penelitian yang digunakan dalam penelitian kualitatif yang bersifat deskriptif. Adaupun prosedur penelitian yang dilakukan peneliti adalah sebagai berikut : membaca dan mendengar lirik lagu melalui kaset dengan bantuan tape recorder, menganalisis tema, diksi, gaya bahasa, dan persajakan yang terdapat dalam lirik lagu ebiet G. Ade dalam album “kupu-kupu ketas”, serta merangkum hasil pemahaman pokok pikiran yang meliputi tema, diksi, gaya bahasa, dan persajakan. Sedangkan data dalam penelitian ini berupa lirik lagu-lagu ebiet G. ade yang berjumlah Sembilan buah, yaitu kupu-kupu kertas, ketika duka menyeruak, hidupkku milik-mu, kosong, apakah mungkin, biarkanlah hati yang berbicara, Rinduku mengumpal, rembulan menangis, dan inginku petik bintang kejora yang diperoleh dari sumber berupa kaset. Berdasarkan hasil analisis, lagu yang diciptakan : Ebiet G Ade dalam album kumpulan lagu “ kupu-kupu” bertemakan: harapan seorang untuk kembali ke jalan yang benar, perasaan duka atas kepergian seseorang, hidup semata-mata hanya untuk tuhan, sepi karena ditinggalkan seseorang, perasaan seseorang tentang rindu dan cintanya, peran suara hati dalam menghadapi masalah, kerinduan untuk bertemu kembali, perasaan duka atas kepergian seseorang, dan kekecewaan karena cinta tak terbalas. Lirik lagu Ebiet G. Ade banyak menggunakan kata-kata yang merupakan simbol maksud tertentu yang dirangkai dari kata-kata sehari-hari, sehingga menghasilkan lambang tertentu pula Gaya bahasa yang digunakan ialah personifikasi, klimaks, epitet, asyndeton, epizeukin, tautotes, anaphora, dan mesodilopsis. Persajakan atau rima yang digunakan antara lain rima berpeluk, rima datar, rima aliterasi, rima asonansi, rima patah, rima rangkai, rima awal, rima tengah, rima akhir, rima mutlak, dan rima kembar Dari hasil analisis dapat disimpulkan bahwa lirik lagu Ebiet G. Ade yang terdapat dalam album kumpulan lagu” kupu-kupu ketas” memiliki tema untuk setiap judul lagu, menggunakan diksi, menggunakan gaya bahasa, serta menggunakan persajakan atau rima Penulis menyarankan bagi guru bahasa dan sastra Indonesia agar lirik lagu dapat dijadikan sebagai alternative bahan pengajaran apresiasi puisi disekolah. Bagi pembaca atau khalayak umum, terutama penggemar music penulis menyarankan agar dalam menilai lirik lagu sebuah lagu, hendaknya tidak hanya menilai dari segi luar atau segi musiknya saja, tetapi perlu juga diperhatikan unsur-unsur yang membangun lirik lagu tersebut seperti hanya puisi. Bagi peneliti lanjut, penulis menyarankan agar dapat meneliti unsur-unsur yang masih perlu diteliti dan dianalisi

Projektbericht E-Government-Modellkommunen

PROJEKTBERICHT E-GOVERNMENT-MODELLKOMMUNEN Projektbericht E-Government-Modellkommunen / Stember, Jürgen (Rights reserved) ( -

Electronic Medical Record Cancer Incidence over Six Years Comparing New Users of Glargine with New Users of NPH Insulin

Background: Recent studies suggested that insulin glargine use could be associated with increased risk of cancer. We compared the incidence of cancer in new users of glargine versus new users of NPH in a longitudinal clinical cohort with diabetes for up to 6 years. Methods and Findings: From all patients who had been regularly followed at Massachusetts General Hospital from 1/01/2005 to 12/31/2010, 3,680 patients who had a medication record for glargine or NPH usage were obtained from the electronic medical record (EMR). From those we selected 539 new glargine users (age: 60.1±13.6 years, BMI: 32.7±7.5 kg/m2) and 343 new NPH users (61.5±14.1 years, 32.7±8.3 kg/m2) who had no prevalent cancer during 19 months prior to glargine or NPH initiation. All incident cancer cases were ascertained from the EMR requiring at least 2 ICD-9 codes within a 2 month period. Insulin exposure time and cumulative dose were validated. The statistical analysis compared the rates of cancer in new glargine vs. new NPH users while on treatment, adjusted for the propensity to receive one or the other insulin. There were 26 and 28 new cancer cases in new glargine and new NPH users for 1559 and 1126 person-years follow-up, respectively. There were no differences in the propensity-adjusted clinical characteristics between groups. The adjusted hazard ratio for the cancer incidence comparing glargine vs. NPH use was 0.65 (95% CI: 0.36–1.19). Conclusions: Insulin glargine is not associated with development of cancers when compared with NPH in this longitudinal and carefully retrieved EMR data

Personalized Genetic Risk Counseling to Motivate Diabetes Prevention: A randomized trial

OBJECTIVE To examine whether diabetes genetic risk testing and counseling can improve diabetes prevention behaviors. RESEARCH DESIGN AND METHODS We conducted a randomized trial of diabetes genetic risk counseling among overweight patients at increased phenotypic risk for type 2 diabetes. Participants were randomly allocated to genetic testing versus no testing. Genetic risk was calculated by summing 36 single nucleotide polymorphisms associated with type 2 diabetes. Participants in the top and bottom score quartiles received individual genetic counseling before being enrolled with untested control participants in a 12-week, validated, diabetes prevention program. Middle-risk quartile participants were not studied further. We examined the effect of this genetic counseling intervention on patient self-reported attitudes, program attendance, and weight loss, separately comparing higher-risk and lower-risk result recipients with control participants. RESULTS The 108 participants enrolled in the diabetes prevention program included 42 participants at higher diabetes genetic risk, 32 at lower diabetes genetic risk, and 34 untested control subjects. Mean age was 57.9 ± 10.6 years, 61% were men, and average BMI was 34.8 kg/m2, with no differences among randomization groups. Participants attended 6.8 ± 4.3 group sessions and lost 8.5 ± 10.1 pounds, with 33 of 108 (30.6%) losing ≥5% body weight. There were few statistically significant differences in self-reported motivation, program attendance, or mean weight loss when higher-risk recipients and lower-risk recipients were compared with control subjects (P > 0.05 for all but one comparison). CONCLUSIONS Diabetes genetic risk counseling with currently available variants does not significantly alter self-reported motivation or prevention program adherence for overweight individuals at risk for diabetes