Influence of HAART on Alternative Reading Frame Immune Responses over the Course of HIV-1 Infection

Background: Translational errors can result in bypassing of the main viral protein reading frames and the production of alternate reading frame (ARF) or cryptic peptides. Within HIV, there are many such ARFs in both sense and the antisense directions of transcription. These ARFs have the potential to generate immunogenic peptides called cryptic epitopes (CE). Both antiretroviral drug therapy and the immune system exert a mutational pressure on HIV-1. Immune pressure exerted by ARF CD8(+) T cells on the virus has already been observed in vitro. HAART has also been described to select HIV-1 variants for drug escape mutations. Since the mutational pressure exerted on one location of the HIV-1 genome can potentially affect the 3 reading frames, we hypothesized that ARF responses would be affected by this drug pressure in vivo. Methodology/Principal findings: In this study we identified new ARFs derived from sense and antisense transcription of HIV-1. Many of these ARFs are detectable in circulating viral proteins. They are predominantly found in the HIV-1 env nucleotide region. We measured T cell responses to 199 HIV-1 CE encoded within 13 sense and 34 antisense HIV-1 ARFs. We were able to observe that these ARF responses are more frequent and of greater magnitude in chronically infected individuals compared to acutely infected patients, and in patients on HAART, the breadth of ARF responses increased. Conclusions/Significance: These results have implications for vaccine design and unveil the existence of potential new epitopes that could be included as vaccine targets.

Sein, Identität und Kultur: Versuch einer strukturhermeneutischen Anthropologie im Anschluss an Martin Heidegger und Jean-Paul Sartre

Mit dem vorliegenden Buch verfolgt der Autor vor allem drei Ziele: Das erste besteht darin, die anthropologischen Überlegungen, die sich in konzentrierter Form vor allem in den frühen Hauptwerken von Martin Heidegger und Jean-Paul Sartre finden, herauszulösen, zu systematisieren und zu einem einheitlichen anthropologischen Gedankengefüge zu vernetzen. In einem zweiten Schritt soll dieses Gefüge durch eigene Überlegungen ergänzt und in Auseinandersetzung mit Helmuth Plessner und Karl Jaspers weiterentwickelt werden. Drittens schließlich sollen vor diesem Hintergrund Grundlagen einer »strukturhermeneutischen Anthropologie« ausgearbeitet werden, die ein hermeneutisches Instrumentarium für die Aufklärung der unbedingten persönlichen Geltung kultureller Bindung bereitstellen können und von eigenen identitätstheoretischen Grundüberlegungen getragen werden. Da im fokussierten Zusammenhang kultureller Bindung und interkultureller Auseinandersetzung die Fragen nach dem menschlichen Selbstverhältnis und den Möglichkeiten sowie Bedingungen des Fremdverstehens eine wichtige Rolle spielen, sollen dabei nicht nur die hermeneutischen Aspekte der erörterten anthropologischen Positionen in den Blick genommen werden, sondern auch die damit unmittelbar verknüpften Fragen der Sinn- und Identitätsbildung. In kulturphilosophischer Hinsicht soll ein zentrales Ergebnis der Arbeit sein, anthropologische Eckpunkte menschlichen Entwerfens und Mechanismen der kulturellen Sinn- und Identitätsstiftung herauszuarbeiten, um der Analyse kultureller Bindung sowohl ein anthropologisches als auch ein hermeneutisches Fundament zu geben.

Early loading after 21 days of healing of nonsubmerged titanium implants with a chemically modified sandblasted and acid-etched surface: two-year results of a prospective two-center study

PURPOSE: The aim of this two-center study was to evaluate screw-type titanium implants with a chemically modified, sandblasted and acid-etched surface when placed in the posterior maxilla or mandible, and loaded 21 days after placement. MATERIAL AND METHODS: All 56 patients met strict inclusion criteria and provided informed consent. Each patient displayed either a single-tooth gap, an extended edentulous space, or a distal extension situation in the posterior mandible or maxilla. Eighty-nine dental implants (SLActive, Institut Straumann AG, Basel, Switzerland) were inserted according to an established nonsubmerged protocol and underwent undisturbed healing for a period of 21 days. Where appropriate, the implants were loaded after 21 days of healing with provisional restorations in full occlusion. Definitive metal ceramic restorations were fabricated and positioned on each implant after 6 months of healing. Clinical measurements regarding soft tissue parameters and radiographs were obtained at different time points up to 24 months after implant placement. RESULTS: Of the 89 inserted implants, two (2.2%) implants failed to integrate and were removed during healing, and two (2.2%) additional implants required a prolonged healing time. A total of 85 (95.6%) implants were therefore loaded without incident after 21 days of healing. No additional implant was lost throughout the study period, whereas one implant was lost to follow-up and therefore left unaccounted for further analysis. The remaining 86 implants all exhibited favorable radiographic and clinical findings. Based on strict success criteria, these implants were considered successfully integrated 2 years after insertion, resulting in a 2-year success rate of 97.7%. CONCLUSION: The results of this prospective two-center study demonstrate that titanium implants with a modified SLA surface can predictably achieve successful tissue integration when loaded in full occlusion 21 days after placement. Integration could be maintained without incident for at least 2 years of follow-up.

T-cell recognition of chemicals, protein allergens and drugs: towards the development of in vitro assays

Chemicals can elicit T-cell-mediated diseases such as allergic contact dermatitis and adverse drug reactions. Therefore, testing of chemicals, drugs and protein allergens for hazard identification and risk assessment is essential in regulatory toxicology. The seventh amendment of the EU Cosmetics Directive now prohibits the testing of cosmetic ingredients in mice, guinea pigs and other animal species to assess their sensitizing potential. In addition, the EU Chemicals Directive REACh requires the retesting of more than 30,000 chemicals for different toxicological endpoints, including sensitization, requiring vast numbers of animals. Therefore, alternative methods are urgently needed to eventually replace animal testing. Here, we summarize the outcome of an expert meeting in Rome on 7 November 2009 on the development of T-cell-based in vitro assays as tools in immunotoxicology to identify hazardous chemicals and drugs. In addition, we provide an overview of the development of the field over the last two decades.