ABSTRACT
Optimising the roles played by both generalists and specialists in the diagnosis and treatment of Alzheimer's disease (AD) could have a major impact on the quality and cost of patient care. Therefore, one aim of the IMPACT survey was to characterise the similarities and differences between these 2 categories of physicians, in 5 different European countries, across a number of domains relevant to the medical care of people at risk for AD and those with the disease. Physician respondents comprised 250 generalists and 250 specialists from 5 European countries--France, Germany, Italy, Spain, and the United Kingdom. A substantial majority of generalists were either general practitioners or family physicians; the majority of specialists were neurologists. In April and May 2009, physician respondents completed a 30-minute, Web-based questionnaire during which they were presented with a number of multiple-choice-type questions concerning their knowledge of AD, approach to diagnosis and treatment of AD and experience of providing care for people with dementia. Generalists reported that 45% of their AD patients had mild symptoms at the initial visit compared with 60% for specialists (P < 0.001). Specialists claimed that they diagnose patients with AD themselves in 65% of cases versus 33% for generalists (P < 0.001). The main prescription treatment options employed were AD-specific medication (90%) and medication for mood or behaviour (78%). A similar percentage of generalists and specialists (77% and 75%) initiate drug treatment within 1 month of diagnosis. Overall, there were more similarities than differences between specialists and generalists regarding a broad spectrum of issues relating to AD; differences between countries appear to be greater than differences between physician groups.
Subject(s)
Alzheimer Disease/diagnosis , Alzheimer Disease/drug therapy , Clinical Competence , Family Practice , Neurology , Practice Patterns, Physicians'/statistics & numerical data , Specialization , Central Nervous System Agents/therapeutic use , Data Collection , Europe , Humans , Internet , Surveys and QuestionnairesABSTRACT
Two crystal structures of Oct-1 POU domain bound to DNA provide a rationale for differential, conformation-dependent recruitment of transcription cofactors. The POU-homeo and POU-specific subdomains of Oct-1 contain two different nonoverlapping pairs of surface patches that are capable of forming unrelated protein-protein interfaces. Members of the POU factor family contain one or two conserved sequence motifs in the interface that are known to be phosphorylated, as noted for Oct-1 and Pit-1. Modeling of Oct-4 reveals the unique case where the same conserved sequence is located in both interfaces. Our studies provide the basis for two distinct dimeric POU factor arrangements that are dictated by the architecture of each DNA response element. We suggest interface swapping in dimers could be a general mechanism of modulating the activity of transcription factors.
Subject(s)
DNA-Binding Proteins/metabolism , DNA/metabolism , Protein Structure, Tertiary , Transcription Factors/metabolism , Amino Acid Sequence , Binding Sites , Crystallography, X-Ray , DNA-Binding Proteins/chemistry , Dimerization , Host Cell Factor C1 , Models, Molecular , Molecular Sequence Data , Mutagenesis, Site-Directed , Nucleic Acid Conformation , Octamer Transcription Factor-1 , Octamer Transcription Factor-3 , Protein Binding , Protein Conformation , Sequence Alignment , Transcription Factors/chemistryABSTRACT
POU domain proteins contain a bipartite DNA binding domain divided by a flexible linker that enables them to adopt various monomer configurations on DNA. The versatility of POU protein operation is additionally conferred at the dimerization level. The POU dimer formed on the PORE (ATTTGAAATGCAAAT) can recruit the transcriptional coactivator OBF-1, whereas POU dimers formed on the consensus MORE (ATGCATATGCAT) or on MOREs from immunoglobulin heavy chain promoters (AT[G/A][C/A]ATATGCAA) fail to interact. An interaction with OBF-1 is precluded since the same Oct-1 residues that form the MORE dimerization interface are also used for OBF-1/Oct-1 interactions on the PORE. Our findings provide a paradigm of how specific POU dimer assemblies can differentially recruit a coregulatory activity with distinct transcriptional readouts.
Subject(s)
DNA-Binding Proteins/metabolism , Oligonucleotides/metabolism , Trans-Activators/metabolism , Transcription Factors/metabolism , Amino Acid Motifs , Animals , Base Sequence , Cell Line , DNA-Binding Proteins/chemistry , DNA-Binding Proteins/genetics , Dimerization , Gene Expression Regulation , Genes, Reporter , Host Cell Factor C1 , Humans , Mice , Models, Molecular , Molecular Sequence Data , Octamer Transcription Factor-1 , Octamer Transcription Factor-2 , Octamer Transcription Factor-3 , Octamer Transcription Factor-6 , Oligonucleotides/genetics , Promoter Regions, Genetic , Protein Binding/genetics , Protein Structure, Tertiary , Sequence Analysis , Trans-Activators/genetics , Transcription Factor Pit-1 , Transcription Factors/chemistry , Transcription Factors/genetics , Transcription, Genetic , TransfectionSubject(s)
Condylomata Acuminata/complications , Dyspareunia/etiology , Vaginal Neoplasms/complications , Adult , Female , HumansABSTRACT
Pharmacological properties of a substance extracted from the roots of Miconia sp. (Herb. I.A.U.F.Pe-1903) named as primin (2-metoxi-6-n-pentil-benzoquinone), are described. Median lethal dose was evaluated in 12.78 mg/kg, intraperitoneally, by Thompson and Weil method. Local irritation on rat skin and rabbit vascular endothelium, were positive. In doses up to 8 mg/kg it did not affect rat respiratory mechanism. Primin (1 mg) induced to decrease the dropping of a nutrient flux through isolated peribronchial tissue. Normal flux was obtained when adrenalin (100 mcg) was administered. Urinary excretion and blood level of this substance, was detected by microbiological method, after the fourth and the fifth hour of the drug application. Doses of 1 and 3 mg/kg i.p. were tested.
