New Product Innovation with Multiple Features and Technology Constraints

We model a firm\u27s decisions about product innovation, focusing on the extent to which features should be improved or changed in the succession of models that comprise a life cycle. We show that the structure of the internal and external environment in which a firm operates suggests when to innovate to the technology frontier. The criterion is maximization of the expected present value of products during the life cycle. Computational studies complement the theoretical results and lead to insights about when to bundle innovations across features. The formalization was influenced by extensive interviews with managers in a high-technology firm that dominates its industry

Importance of highly selective LC–MS/MS analysis for the accurate quantification of tamoxifen and its metabolites: focus on endoxifen and 4-hydroxytamoxifen

The antiestrogenic effect of tamoxifen is mainly attributable to the active metabolites endoxifen and 4-hydroxytamoxifen. This effect is assumed to be concentration-dependent and therefore quantitative analysis of tamoxifen and metabolites for clinical studies and therapeutic drug monitoring is increasing. We investigated the large discrepancies in reported mean endoxifen and 4-hydroxytamoxifen concentrations. Two published LC–MS/MS methods are used to analyse a set of 75 serum samples from patients treated with tamoxifen. The method from Teunissen et al. (J Chrom B, 879:1677–1685, 2011) separates endoxifen and 4-hydroxytamoxifen from other tamoxifen metabolites with similar masses and fragmentation patterns. The second method, published by Gjerde et al. (J Chrom A, 1082:6–14, 2005) however lacks selectivity, resulting in a factor 2–3 overestimation of the endoxifen and 4-hydroxytamoxifen levels, respectively. We emphasize the use of highly selective LC–MS/MS methods for the quantification of tamoxifen and its metabolites in biological samples

The first report of Aelurostrongylus falciformis in Norwegian badgers (Meles meles)

The first report of Aelurostrongylus falciformis (Schlegel 1933) in Fennoscandian badgers is described. Routine parasitological examination of nine Norwegian badgers, at the National Veterinary Institute during 2004 and 2005, identified A. falciformis in the terminal airways of five of the animals. The first stage larvae (L1) closely resembled, in size and morphology, those of Angiostrongylus vasorum (Baillet 1866). The diagnosis for both A. falciformis and A. vasorum is frequently based on the identification of L1 in faeces or sputum. The potential for misclassification of an A. falciformis infection as A. vasorum, where larval identification is the only diagnostic method used, is discussed

Matrilineal diversity and population history of Norwegians

Background While well known for its Viking past, Norway's population history and the influences that have shaped its genetic diversity are less well understood. This is particularly true with respect to its demography, migration patterns, and dialectal regions, despite there being curated historical records for the past several centuries. In this study, we undertook an analysis of mitochondrial DNA (mtDNA) diversity within the country to elaborate this history from a matrilineal genetic perspective. Methods We aggregated 1174 partial modern Norwegian mtDNA sequences from the published literature and subjected them to detailed statistical and phylogenetic analysis by dialectal regions and localities. We further contextualized the matrilineal ancestry of modern Norwegians with data from Mesolithic, Iron Age, and historic period populations. Results Modern Norwegian mtDNAs fell into eight West Eurasian (N, HV, JT, I, U, K, X, W), five East Eurasian (A, F, G, N11, Z), and one African (L2) haplogroups. Pairwise analysis of molecular variance (AMOVA) estimates for all Norwegians indicated they were differentiated from each other at 1.68% (p < 0.001). Norwegians within the same dialectal region also showed genetic similarities to each other, although differences between subpopulations within dialectal regions were also observed. In addition, certain mtDNA lineages in modern Norwegians were also found among prehistoric and historic period populations, suggesting some level of genetic continuity over hundreds to many thousands of years. Conclusions This analysis of mtDNA diversity provides a detailed picture of the genetic variation within Norway in light of its topography, settlement history, and historical migrations over the past several centuries.publishedVersio

Дослідження «великого терору» у науково-документальній серії книг «Реабілітовані історією»

У статті автор аналізує результати дослідження «великого терору» 1937–1938 рр. у контексті реалізації Державної програми науково-документальної серії книг «Реабілітовані історією».В статье автор анализирует результаты исследования «большого террора» 1937–1938 гг. в контексте реализации Государственной программы научно-документальной серии книг «Реабилитированные историей».The author analyzes the results of a study of the «great terror» 1937–1938 in the context of implementing the State Program for Research, a documentary series of books «Rehabilitated history»

The regulatory subunit of PKA-I remains partially structured and undergoes β-aggregation upon thermal denaturation

Background: The regulatory subunit (R) of cAMP-dependent protein kinase (PKA) is a modular flexible protein that responds with large conformational changes to the binding of the effector cAMP. Considering its highly dynamic nature, the protein is rather stable. We studied the thermal denaturation of full-length RIα and a truncated RIα(92-381) that contains the tandem cyclic nucleotide binding (CNB) domains A and B. Methodology/Principal Findings: As revealed by circular dichroism (CD) and differential scanning calorimetry, both RIα proteins contain significant residual structure in the heat-denatured state. As evidenced by CD, the predominantly α-helical spectrum at 25°C with double negative peaks at 209 and 222 nm changes to a spectrum with a single negative peak at 212-216 nm, characteristic of β-structure. A similar α→β transition occurs at higher temperature in the presence of cAMP. Thioflavin T fluorescence and atomic force microscopy studies support the notion that the structural transition is associated with cross-β-intermolecular aggregation and formation of non-fibrillar oligomers. Conclusions/Significance: Thermal denaturation of RIα leads to partial loss of native packing with exposure of aggregation-prone motifs, such as the B' helices in the phosphate-binding cassettes of both CNB domains. The topology of the β-sandwiches in these domains favors inter-molecular β-aggregation, which is suppressed in the ligand-bound states of RIα under physiological conditions. Moreover, our results reveal that the CNB domains persist as structural cores through heat-denaturation. © 2011 Dao et al

Associations between tamoxifen, estrogens, and FSH serum levels during steady state tamoxifen treatment of postmenopausal women with breast cancer

<p>Abstract</p> <p>Background</p> <p>The cytochrome P450 (CYP) enzymes 2C19, 2D6, and 3A5 are responsible for converting the selective estrogen receptor modulator (SERM), tamoxifen to its active metabolites 4-hydroxy-tamoxifen (4OHtam) and 4-hydroxy-<it>N</it>-demethyltamoxifen (4OHNDtam, endoxifen). Inter-individual variations of the activity of these enzymes due to polymorphisms may be predictors of outcome of breast cancer patients during tamoxifen treatment. Since tamoxifen and estrogens are both partly metabolized by these enzymes we hypothesize that a correlation between serum tamoxifen and estrogen levels exists, which in turn may interact with tamoxifen on treatment outcome. Here we examined relationships between the serum levels of tamoxifen, estrogens, follicle-stimulating hormone (FSH), and also determined the genotypes of CYP2C19, 2D6, 3A5, and SULT1A1 in 90 postmenopausal breast cancer patients.</p> <p>Methods</p> <p>Tamoxifen and its metabolites were measured by liquid chromatography-tandem mass spectrometry. Estrogen and FSH levels were determined using a sensitive radio- and chemiluminescent immunoassay, respectively.</p> <p>Results</p> <p>We observed significant correlations between the serum concentrations of tamoxifen, <it>N</it>-dedimethyltamoxifen, and tamoxifen-<it>N</it>-oxide and estrogens (p < 0.05). The genotype predicted CYP2C19 activity influenced the levels of both tamoxifen metabolites and E1.</p> <p>Conclusions</p> <p>We have shown an association between tamoxifen and its metabolites and estrogen serum levels. An impact of CYP2C19 predicted activity on tamoxifen, as well as estrogen kinetics may partly explain the observed association between tamoxifen and its metabolites and estrogen serum levels. Since the role of estrogen levels during tamoxifen therapy is still a matter of debate further prospective studies to examine the effect of tamoxifen and estrogen kinetics on treatment outcome are warranted.</p

Improving education in primary care: development of an online curriculum using the blended learning model

<p>Abstract</p> <p>Background</p> <p>Standardizing the experiences of medical students in a community preceptorship where clinical sites vary by geography and discipline can be challenging. Computer-assisted learning is prevalent in medical education and can help standardize experiences, but often is not used to its fullest advantage. A blended learning curriculum combining web-based modules with face-to-face learning can ensure students obtain core curricular principles.</p> <p>Methods</p> <p>This course was developed and used at The Case Western Reserve University School of Medicine and its associated preceptorship sites in the greater Cleveland area. Leaders of a two-year elective continuity experience at the Case Western Reserve School of Medicine used adult learning principles to develop four interactive online modules presenting basics of office practice, difficult patient interviews, common primary care diagnoses, and disease prevention. They can be viewed at <url>http://casemed.case.edu/cpcp/curriculum</url>. Students completed surveys rating the content and technical performance of each module and completed a Generalist OSCE exam at the end of the course.</p> <p>Results</p> <p>Participating students rated all aspects of the course highly; particularly those related to charting and direct patient care. Additionally, they scored very well on the Generalist OSCE exam.</p> <p>Conclusion</p> <p>Students found the web-based modules to be valuable and to enhance their clinical learning. The blended learning model is a useful tool in designing web-based curriculum for enhancing the clinical curriculum of medical students.</p