Assoziation der dilatativen Kardiomyopathie mit den CTLA-4-Polymorphismen CT60 und CT42

Infektionen mit kardiotropen Viren sind oft begleitet von anhaltenden Autoimmunreaktionen im Myokardgewebe und führen gelegentlich zum Übergang einer chronischen Myokarditis zur dilatativen Kardiomyopathie (DCM), einer Herzerkrankung charakterisiert durch vergrößerte Ventrikel und eine reduzierte systolische Funktion. Das cytotoxische T-Lymphozyten-Antigen-4 (CTLA-4) ist ein inhibitorischer, auf der Oberfläche von aktivierten T-Zellen exprimierter Rezeptor, welcher mit kostimulatorischem CD28 um die Bindung an B7-Rezeptoren auf Antigen-präsentierenden Zellen kompetiert. Das Ziel der vorliegenden epidemiologischen Studie war es zu untersuchen, ob Einzelnukleotid-Polymorphismen (SNPs) im CTLA-4-Gen mit der Diagnose und dem klinischen Verlauf der DCM assoziiert sind. Insgesamt wurden 152 Patienten mit DCM und als Kontrollkollektiv 221 gesunde Blutspender auf die Präsenz des bekannten +49-(CT42)-Polymorphismus im CTLA-4-Gene mittels denaturierender Gradientengelelelektrophorese (DGGE) getestet. Hierbei ergab sich, dass der G/G- Genotyp des CT42-Polymorphismus signifikant häufiger bei DCM-Patienten auftrat als bei den Kontrollen (24 von 152 Patienten (16%) versus 16 von 221 Kontrollen (7%), p=0.029). In der Nachbeobachtung ein Jahr nach Studieneinschluss hatten sich die linksventrikuläre Ejektionsfraktion und der enddiastolische Durchmesser des linken Ventrikels generell verbessert, doch war kein Unterschied zwischen den DCM- Patienten mit dem G/G-Genotyp und den anderen Genotypen zu verzeichnen. Im Gegensatz zum CT42-SNP fand sich keine statistisch signifikante Assoziation zwischen dem CT60-Polymorphismus in der 3 ́-untranslatierten Region in Exon 4 des CTLA-4-Gens und der Diagnose einer DCM. Zusammenfassend belegen diese Daten, dass der CTLA-4-Polymorphismus CT42 auf eine erhöhte Prädisposition für die Entstehung einer DCM verweist, aber den Verlauf der Erkrankung im ersten Jahr nach Diagnosestellung wohl nicht zu beeinflussen vermag. Der G/G-Genotyp kodiert für eine Thr17Ala-Variante in der amino-terminalen Signalpeptid-Sequenz des CTLA-4-Moleküls. Die Substitution eines singulären Aminosäurerestes von Threonin nach Alanin in dieser Position könnte mit dysregulierten Autoimmunreaktionen gegen Myokardgewebe verbunden sein, die mit fortschreitender Zerstörung von kardialen Myozyten und der Entwicklung einer dilatativen Kardiomyopathie assoziiert sind

Versorgungsforschung bei Demenz

Background: In the last few years, health services research has become an important field of research and has attracted higher attention than ever before. As the so called last mile of the health care System the field is supposed to analyze complex and conflicting problems of health care and eventually develop and evaluate measures to improve health care. The aim of the present endeavor is to integrate three conducted research studies on specific questions in dementia care into the current health services research activities in dementia. It provides an overview of the current care situation, examined topics and used methods. Methodology: In the present study, a systematic literature search has been conducted investigating the health care situation of persons with dementia in Germany between 2011 and 2016. Current research activities are presented as well as the actual health care situation of dementia patients, including the used methods and data sources. The cumulative dissertation at hand includes the author s studies investigating and analyzing trends in the use of antipsychotics, time until nursing home admission and feeding tube provision in dementia patients. Results: An increase of research activities in the field of health care research in dementia could be observed during the past five years. The identified studies reveal a very broad thematic variety. The research landscape is characterized by quantitative studies, mainly in outpatient settings and by observational studies. Mostly, a connection between primary and secondary data is not established. In some areas of pharmaceutical supply deficits have been revealed. In addition, an examination of the care situation is often independent of the stage of the disease and the palliative phase of dementia is frequently not considered. A clear research gap can also be shown for inpatient hospital care. Conclusion: Over the last few years, health care research has evolved into an important discipline and will continue to grow due to current policy measures in Germany. Also, an increase in studies in health services research investigating dementia could be identified in recent years. The wide range of topics covered by the fielda s research reveals deficits. The author s three pioneering studies provide information on specific care situations and the status quo of the care of dementia patients for the first time

Identification of \u3ci\u3eFrancisella tularensis\u3c/i\u3e subsp. \u3ci\u3etularensis \u3c/i\u3eA1 and A2 Infections by Real-Time Polymerase Chain Reaction

Francisella tularensis subsp. tularensis (type A) is subdivided into clades A1 and A2. Human tularemia infections caused by A1 and A2 differ with respect to clinical outcome; A1 infections are associated with a higher case fatality rate. In this study, we develop and evaluate TaqMan polymerase chain reaction (PCR) assays for identification of A1 and A2. Both assays were shown to be specific to either A1 or A2, with sensitivities of 10 genomic equivalents. Real-time PCR results for identification of A1 and A2 were in complete agreement with results obtained by pulsed field gel electrophoresis analysis or conventional PCR when specimens from sporadic tularemia cases and a tularemia outbreak involving both A1 and A2 were tested. In addition, outbreak samples not previously typed to the clade level could be classified as A1 or A2. The assays described here provide new diagnostic tools with a level of sensitivity not previously available for identification of A1 and A2 infections

Identification of \u3ci\u3eFrancisella tularensis\u3c/i\u3e subsp. \u3ci\u3etularensis \u3c/i\u3eA1 and A2 Infections by Real-Time Polymerase Chain Reaction

Francisella tularensis subsp. tularensis (type A) is subdivided into clades A1 and A2. Human tularemia infections caused by A1 and A2 differ with respect to clinical outcome; A1 infections are associated with a higher case fatality rate. In this study, we develop and evaluate TaqMan polymerase chain reaction (PCR) assays for identification of A1 and A2. Both assays were shown to be specific to either A1 or A2, with sensitivities of 10 genomic equivalents. Real-time PCR results for identification of A1 and A2 were in complete agreement with results obtained by pulsed field gel electrophoresis analysis or conventional PCR when specimens from sporadic tularemia cases and a tularemia outbreak involving both A1 and A2 were tested. In addition, outbreak samples not previously typed to the clade level could be classified as A1 or A2. The assays described here provide new diagnostic tools with a level of sensitivity not previously available for identification of A1 and A2 infections

African American community of southeast Rocky Mount, North Carolina : an action-oriented community diagnosis final report

During the fall of 2007 and spring of 2008, a team of five graduate students from the University of North Carolina at Chapel Hill’s School of Public Health conducted an Action-Oriented Community Diagnosis (AOCD) of the community in Southeast Rocky Mount. AOCD is a component of the curriculum for graduate students in the Department of Health Behavior and Health Education. Historically, the teaching team has been approached by community members seeking an assessment of their community. These community members then act as preceptors to student teams, introducing them to the community and aiding in our AOCD process. The process itself involves interacting with community members and service providers to systematically collect information about community strengths and challenges. The student team in Rocky Mount interviewed 19 service providers and 14 community members, conducted 2 focus groups and attended 12 community events. On April 12, the team hosted a community forum in Southeast Rocky Mount (SERM), at which findings were presented back to the community. Through break-out groups focused on discussing particular emerging themes, community members and service providers created action steps to address these themes. Hence, the AOCD process transformed from a diagnosis made by outsiders to a series of commitments by community participants to addressing their collective needs. At the beginning of the AOCD process, the student team conducted a secondary data review to learn more about Southeast Rocky Mount’s health, economics, crime and education status. The team then compared this data to that of the city of Rocky Mount, Edgecombe County and/or North Carolina depending upon the sources of data available. Rocky Mount is divided between two counties, Nash and Edgecombe, which at times affected the availability of data. The team also collected primary data through interviews and focus groups, which were guided by a predetermined set of questions. These discussions with community members and service providers provided much richer qualitative information. Team members transcribed and coded this data to determine which themes occurred most frequently. Identified strengths of the community included the people within the community and the history of a strong, thriving African American community in the area, among others. Meanwhile, challenges identified included: disparities between resources available in Nash County and Edgecombe County; lack of reliable public transportation; limited educational opportunities for youth and young adults; limited recreational and enrichment activities for youth; limited employment opportunities; dilapidated and sub-standard housing conditions; crime due to drugs and gang violence; and limited collaboration between community resources. Through consideration of these strengths and challenges, along with the coded interview data, the student team developed a list of emerging themes. These themes were presented to the eight community members and service providers that made up the forum planning committee. These members helped select the final themes to be used at the April forum. The initial list included: Youth, Education, Employment, Transportation, Crime, Housing/Cost of living, Parenting, and Communication between existing community resources. These eight preliminary themes were then narrowed down to the final five themes that we presented at the community form. The final themes selected for presentation to the community were: Youth, Employment, Connecting Community Resources, Crime, Housing. Approximately 65 individuals attended the community forum. Overall, participants were enthusiastic and optimistic when discussing the selected themes. At the end of the day, action steps were created for each theme and individuals personally committed to completing those steps. A future date was set for the community members and service providers to meet, without the student team, so that the AOCD process could continue within and among the community.Master of Public Healt

Class Frizzled GPCRs in GtoPdb v.2021.3

Receptors of the Class Frizzled (FZD, nomenclature as agreed by the NC-IUPHAR subcommittee on the Class Frizzled GPCRs [175]), are GPCRs originally identified in Drosophila [19], which are highly conserved across species. While SMO shows structural resemblance to the 10 FZDs, it is functionally separated as it mediates effects in the Hedgehog signaling pathway [175]. FZDs are activated by WNTs, which are cysteine-rich lipoglycoproteins with fundamental functions in ontogeny and tissue homeostasis. FZD signalling was initially divided into two pathways, being either dependent on the accumulation of the transcription regulator β-catenin or being β-catenin-independent (often referred to as canonical vs. non-canonical WNT/FZD signalling, respectively). WNT stimulation of FZDs can, in cooperation with the low density lipoprotein receptors LRP5 (O75197) and LRP6 (O75581), lead to the inhibition of a constitutively active destruction complex, which results in the accumulation of β-catenin and subsequently its translocation to the nucleus. β-catenin, in turn, modifies gene transcription by interacting with TCF/LEF transcription factors. WNT/β-catenin-independent signalling can also be activated by FZD subtype-specific WNT surrogates [133]. β-catenin-independent FZD signalling is far more complex with regard to the diversity of the activated pathways. WNT/FZD signalling can lead to the activation of heterotrimeric G proteins [33, 178, 150], the elevation of intracellular calcium [184], activation of cGMP-specific PDE6 [2] and elevation of cAMP as well as RAC-1, JNK, Rho and Rho kinase signalling [56]. Novel resonance energy transfer-based tools have allowed the study of the GPCR-like nature of FZDs in greater detail. Upon ligand stimulation, FZDs undergo conformational changes and signal via heterotrimeric G proteins [239, 240, 102, 174]. Furthermore, the phosphoprotein Dishevelled constitutes a key player in WNT/FZD signalling towards planar-cell-polarity-like pathways. Importantly, FZDs exist in at least two distinct conformational states that regulate pathway selection [240]. As with other GPCRs, members of the Frizzled family are functionally dependent on the arrestin scaffolding protein for internalization [22], as well as for β-catenin-dependent [13] and -independent [89, 14] signalling. The pattern of cell signalling is complicated by the presence of additional ligands, which can enhance or inhibit FZD signalling (secreted Frizzled-related proteins (sFRP), Wnt-inhibitory factor (WIF), sclerostin or Dickkopf (DKK)), as well as modulatory (co)-receptors with Ryk, ROR1, ROR2 and Kremen, which may also function as independent signalling proteins

Multiple Francisella tularensis Subspecies and Clades, Tularemia Outbreak, Utah

In July 2007, a deer fly–associated outbreak of tularemia occurred in Utah. Human infections were caused by 2 clades (A1 and A2) of Francisella tularensis subsp. tularensis. Lagomorph carcasses from the area yielded evidence of infection with A1 and A2, as well as F. tularensis subsp. holarctica. These findings indicate that multiple subspecies and clades can cause disease in a localized outbreak of tularemia

Class Frizzled GPCRs (version 2019.4) in the IUPHAR/BPS Guide to Pharmacology Database

Receptors of the Class Frizzled (FZD, nomenclature as agreed by the NC-IUPHAR subcommittee on the Class Frizzled GPCRs [156]), are GPCRs originally identified in Drosophila [17], which are highly conserved across species. While SMO shows structural resemblance to the 10 FZDs, it is functionally separated as it mediates effects in the Hedgehog signaling pathway [156]. FZDs are activated by WNTs, which are cysteine-rich lipoglycoproteins with fundamental functions in ontogeny and tissue homeostasis. FZD signalling was initially divided into two pathways, being either dependent on the accumulation of the transcription regulator β-catenin or being β-catenin-independent (often referred to as canonical vs. non-canonical WNT/FZD signalling, respectively). WNT stimulation of FZDs can, in cooperation with the low density lipoprotein receptors LRP5 (O75197) and LRP6 (O75581), lead to the inhibition of a constitutively active destruction complex, which results in the accumulation of β-catenin and subsequently its translocation to the nucleus. β-Catenin, in turn, modifies gene transcription by interacting with TCF/LEF transcription factors. β-Catenin-independent FZD signalling is far more complex with regard to the diversity of the activated pathways. WNT/FZD signalling can lead to the activation of heterotrimeric G proteins [28, 159, 135], the elevation of intracellular calcium [164], activation of cGMP-specific PDE6 [2] and elevation of cAMP as well as RAC-1, JNK, Rho and Rho kinase signalling [48]. Novel resonance energy transfer-based tools have allowed the study of the GPCR-like nature of FZDs in greater detail. Upon ligand stimulation, FZDs undergo conformational changes and signal via heterotrimeric G proteins [213, 214]. Furthermore, the phosphoprotein Dishevelled constitutes a key player in WNT/FZD signalling. Importantly, FZDs exist in at least two distinct conformational states that regulate the pathway selection [214]. As with other GPCRs, members of the Frizzled family are functionally dependent on the arrestin scaffolding protein for internalization [19], as well as for β-catenin-dependent [12] and -independent [80, 13] signalling. The pattern of cell signalling is complicated by the presence of additional ligands, which can enhance or inhibit FZD signalling (secreted Frizzled-related proteins (sFRP), Wnt-inhibitory factor (WIF), sclerostin or Dickkopf (DKK)), as well as modulatory (co)-receptors with Ryk, ROR1, ROR2 and Kremen, which may also function as independent signalling proteins

Class Frizzled GPCRs in GtoPdb v.2023.1

Receptors of the Class Frizzled (FZD, nomenclature as agreed by the NC-IUPHAR subcommittee on the Class Frizzled GPCRs [180]), are GPCRs originally identified in Drosophila [20], which are highly conserved across species. While SMO shows structural resemblance to the 10 FZDs, it is functionally separated as it is involved in the Hedgehog signaling pathway [180]. SMO exerts its effects by activating heterotrimeric G proteins or stabilization of GLI by sequestering catalytic PKA subunits [186, 6, 58]. While SMO itself is bound by sterols and oxysterols [27, 94], FZDs are activated by WNTs, which are cysteine-rich lipoglycoproteins with fundamental functions in ontogeny and tissue homeostasis. FZD signalling was initially divided into two pathways, being either dependent on the accumulation of the transcription regulator β-catenin or being β-catenin-independent (often referred to as canonical vs. non-canonical WNT/FZD signalling, respectively). WNT stimulation of FZDs can, in cooperation with the low density lipoprotein receptors LRP5 (O75197) and LRP6 (O75581), lead to the inhibition of a constitutively active destruction complex, which results in the accumulation of β-catenin and subsequently its translocation to the nucleus. β-catenin, in turn, modifies gene transcription by interacting with TCF/LEF transcription factors. WNT/β-catenin-dependent signalling can also be activated by FZD subtype-specific WNT surrogates [138]. β-catenin-independent FZD signalling is far more complex with regard to the diversity of the activated pathways. WNT/FZD signalling can lead to the activation of heterotrimeric G proteins [34, 183, 155], the elevation of intracellular calcium [189], activation of cGMP-specific PDE6 [2] and elevation of cAMP as well as RAC-1, JNK, Rho and Rho kinase signalling [57]. Novel resonance energy transfer-based tools have allowed the study of the GPCR-like nature of FZDs in greater detail. Upon ligand stimulation, FZDs undergo conformational changes and signal via heterotrimeric G proteins [244, 245, 107, 179, 104]. Furthermore, the phosphoprotein Dishevelled constitutes a key player in WNT/FZD signalling towards planar-cell-polarity-like pathways. Importantly, FZDs exist in at least two distinct conformational states that regulate pathway selection [245]. As with other GPCRs, members of the Frizzled family are functionally dependent on the arrestin scaffolding protein for internalization [23], as well as for β-catenin-dependent [14] and -independent [91, 15] signalling. The pattern of cell signalling is complicated by the presence of additional ligands, which can enhance or inhibit FZD signalling (secreted Frizzled-related proteins (sFRP), Wnt-inhibitory factor (WIF), sclerostin or Dickkopf (DKK)), as well as modulatory (co)-receptors with Ryk, ROR1, ROR2 and Kremen, which may also function as independent signalling proteins