Increased risk of cardiovascular disease (CVD) with age in HIV-positive men : a comparison of the D:A:D CVD risk equation and general population CVD risk equations

OBJECTIVES: The aim of the study was to statistically model the relative increased risk of cardiovascular disease (CVD) per year older in Data collection on Adverse events of anti-HIV Drugs (D:A:D) and to compare this with the relative increased risk of CVD per year older in general population risk equations. METHODS: We analysed three endpoints: myocardial infarction (MI), coronary heart disease (CHD: MI or invasive coronary procedure) and CVD (CHD or stroke). We fitted a number of parametric age effects, adjusting for known risk factors and antiretroviral therapy (ART) use. The best-fitting age effect was determined using the Akaike information criterion. We compared the ageing effect from D:A:D with that from the general population risk equations: the Framingham Heart Study, CUORE and ASSIGN risk scores. RESULTS: A total of 24 323 men were included in analyses. Crude MI, CHD and CVD event rates per 1000 person-years increased from 2.29, 3.11 and 3.65 in those aged 40-45 years to 6.53, 11.91 and 15.89 in those aged 60-65 years, respectively. The best-fitting models included inverse age for MI and age + age(2) for CHD and CVD. In D:A:D there was a slowly accelerating increased risk of CHD and CVD per year older, which appeared to be only modest yet was consistently raised compared with the risk in the general population. The relative risk of MI with age was not different between D:A:D and the general population. CONCLUSIONS: We found only limited evidence of accelerating increased risk of CVD with age in D:A:D compared with the general population. The absolute risk of CVD associated with HIV infection remains uncertain.

Role of vitamin D deficiency in extraskeletal complications : predictor of health outcome or marker of health status?

The relationship of vitamin D with extraskeletal complications, such as cardiovascular disease, cancer, and autoimmune disease, is of major interest considering its roles in key biological processes and the worldwide high prevalence of vitamin D deficiency. However, the causal relationships between vitamin D and most extraskeletal complications are weak. Currently, a heated debate over vitamin D is being conducted according to two hypotheses. In this review, we first present the different arguments that suggest a major role of vitamin D in a very broad type of extraskeletal complications (hypothesis #1). We then present results from recent meta-analyses of randomized controlled trials indicating a lack of association of vitamin D with major extraskeletal complications (hypothesis #2). We discuss different issues (e.g., causality, confounding, reverse causation, misclassification, and Mendelian randomization) that contribute to the favoring of one hypothesis over the other. While ultimately only one hypothesis is correct, we anticipate that the results from the ongoing randomized controlled trials will be unlikely to reconcile the divided experts.

Interplay of vitamin D, erythropoiesis, and the renin-angiotensin system.

For many years deficiency of vitamin D was merely identified and assimilated to the presence of bone rickets. It is now clear that suboptimal vitamin D status may be correlated with several disorders and that the expression of 1-α-hydroxylase in tissues other than the kidney is widespread and of clinical relevance. Recently, evidence has been collected to suggest that, beyond the traditional involvement in mineral metabolism, vitamin D may interact with other kidney hormones such as renin and erythropoietin. This interaction would be responsible for some of the systemic and renal effects evoked for the therapy with vitamin D. The administration of analogues of vitamin D has been associated with an improvement of anaemia and reduction in ESA requirements. Moreover, vitamin D deficiency could contribute to an inappropriately activated or unsuppressed RAS, as a mechanism for progression of CKD and/or cardiovascular disease. Experimental data on the anti-RAS and anti-inflammatory effects treatment with active vitamin D analogues suggest a therapeutic option particularly in proteinuric CKD patients. This option should be considered for those subjects that are intolerant to anti-RAS agents or, as add-on therapy, in those already treated with anti-RAS but not reaching the safe threshold level of proteinuria.

Ten years of R&D and full automation in molecular diagnosis.

A 10-year experience of our automated molecular diagnostic platform that carries out 91 different real-time PCR is described. Progresses and future perspectives in molecular diagnostic microbiology are reviewed: why automation is important; how our platform was implemented; how homemade PCRs were developed; the advantages/disadvantages of homemade PCRs, including the critical aspects of troubleshooting and the need to further reduce the turnaround time for specific samples, at least for defined clinical settings such as emergencies. The future of molecular diagnosis depends on automation, and in a novel perspective, it is time now to fully acknowledge the true contribution of molecular diagnostic and to reconsider the indication for PCR, by also using these tests as first-line assays.

Enhancement of R&D project management system

Stora Enso has research centres in Finland, Sweden and Germany. The research centres use PIMS as a research project invoicing and monitoring system. Possible reorganization and new financing model for R&D functions have been considered and the project management system should be developed to support the new operation model. The objective of this thesis is to find a model for R&D project management, and to present the project management system of Stora Enso, and to discuss if the current system could be developed to respond to the new needs or should it be replaced with another system. The theoretical part of the study describes challenges in R&D project management, and presents different project characteristics, and methods for managing R&D project portfolio. It is also described how the project management system can support project monitoring and controlling, and how inter-project learning can be enhanced. The empirical part of the study presents the current project management system of Stora Enso and how the system should be developed to support Stora Enso’s R&D functions better. In conclusion, it is stated that there is no relevant reason to replace PIMS with another system, because PIMS can be developed to support R&D project management better with a hybrid system. It is also suggested that the new financing model should not be implemented before more comprehensive analysis of its effects is conducted.

Total synthesis of lamellarin D and analogs library

Larnellarins are a group of marine natural products isolated from the prosobranch mollusc Lamellaria sp., the ascidian Didemnum sp., and the sponge Dendrilla Cactos. Several of them exhibit interesting biological activities. Natural as well as synthetic lamellarins should be excellent candidates for the development of new drugs due to their unique skeletal structure and their important biological activities especially as antitumor agents. Lamelarin O has been recently characterized as a topoisomerase 1-targeted anti tumor agent. A variety of synthetic approaches have been developed for this family of alkaloids. Herein we describe a new route to the synthesis of Lamellarin D, from a methyl 2-pyrrolecarboxylate. Transformation of the starting material into the scaffold, a substituted 5,6-dihydropyrrolo (2,l ­a)isoquinoline (5,6-DHPl), was afforded by N-alkylation followed by intramolecular Heck cyclization. From this scaffold the synthetic strategy is based on two sequential regioselective bromination!Suzuki cross-coupling reactions which permitted the introduction of differently substituted aryl groups on positions 1 and 2 followed by oxidation, deprotection, and lactonization.

Strategic outsourcing of R&D: The location-specific advantages of India to the pharmaceutical industry

Companies are increasingly under pressure to be more efficient both in terms of costs and overall performance and thus, they seek new ways to develop their products and innovate. For pharmaceutical industry it can take several decades to launch a new drug to the markets. Since pharmaceutical industry is one of the most research-intensive industries, is outsourcing one way to enhance the R&D processes of such companies. It is said that outsourcing to offshore locations is vastly more challenging and complicated than any other exporting activity or inter-company relationship that has evoked a lot of discussion. By outsourcing strategically, companies must also thoroughly focus on transaction costs and core competences. Today, the suppliers are looked for beyond national boundaries and furthermore, the location of the outsourcing activity must also be thoroughly considered. Consequently, the purpose of this study is to analyze what is known of strategic outsourcing of pharmaceutical R&D to India. In order to meet the purpose of the study, this study tries to answer three sub-questions set to it: first, what is strategic outsourcing, second, why pharmaceutical companies utilize strategic outsourcing of R&D and last, why pharmaceutical companies select India as the location for outsourcing their R&D. The study is a qualitative study. The purpose of the study was approached by a literature review with systematic elements and sub-questions were analyzed through different relevant theories, such as theory of transaction costs, core competences and location advantages. Applicable academic journal articles were comprehensively included in the study. The data was collected from electronic journal article databases using key words and almost only peer-reviewed, as new as possible articles were included. Also both the reference list of the included articles and article recommendations from professionals generated more articles for inclusion. The data was analyzed through thematization that resulted in themes that illuminate the purpose of the study and sub-questions. As an outcome of the analysis, each of the theory chapters in the study represents one sub-question. The literature used in this study revealed that strategic outsourcing of R&D is increasingly used in pharmaceutical industry and the major motives to practice it has to do with lowering costs, accessing skilled labor, resources and knowledge and enhancing their quality while speeding up the introduction of new drugs. Mainly for the above-mentioned motives India is frequently chosen as the target location for pharma outsourcers. Still, the literature is somewhat incomplete in this complex phenomenon and more research is needed.

Efficacy of the d-phenothrin/pyriproxyfen association against mites in naturally co-infested rabbits

The aim of the present study was to evaluate the efficacy of the d-phenothrin/pyriproxyfen association against Psoroptes ovis, Cheyletiella parasitivorax, and Leporacarus gibbus infestations in naturally co-infested rabbits. Twenty crossbreed (New Zealand White x California) rabbits concurrently infested by the three mite species were randomly divided in two groups. All rabbits presented with hyperemia, erythema and formation of crusts in the ear canals caused by P. ovis. Infestations by both C. parasitivorax and L. gibbus were considered asymptomatic in all animals.Ten animals were treated with a 4.4% d-phenothrin and 0.148% pyriproxyfen spray formulation until have their body surface uniformly sprayed, including external ear canals. The other ten rabbits remained untreated, serving as control group. Observations were done on days +7, +14, +21, +28, and +35 post-treatment. The d-phenothrin/pyriproxyfen association showed 100% efficacy against the three mite species and was responsible for the remission of psoroptic mange lesions on treated animals. No signs of intoxication were observed. The results indicate that d-phenothrin/pyriproxyfen spray formulation in a single application is an effective and clinically safe option for the control of different mite infestations in rabbits.

pH titration of native and unfolded ß-trypsin: evaluation of the D D G0 titration and the carboxyl pK values

The stabilizing free energy of ß-trypsin was determined by hydrogen ion titration. In the pH range from 3.0 to 7.0, the change in free energy difference for the stabilization of the native protein relative to the unfolded one (D D G0 titration) was 9.51 ± 0.06 kcal/mol. An isoelectric point of 10.0 was determined, allowing us to calculate the Tanford and Kirkwood electrostatic factor w. This factor presented a nonlinear behavior and indicated more than one type of titratable carboxyl groups in ß-trypsin. In fact, one class of carboxyl group with a pK = 3.91 ± 0.01 and another one with a pK = 4.63 ± 0.03 were also found by hydrogen ion titration of the protein in the folded state

Differential regulation of vitamin D receptor expression in distinct leukemic cell lines upon phorbol ester-induced growth arrest

A close correlation between vitamin D receptor (VDR) abundance and cell proliferation rate has been shown in NIH-3T3 fibroblasts, MCF-7 breast cancer and in HL-60 myeloblastic cells. We have now determined if this association occurs in other leukemic cell lines, U937 and K562, and if VDR content is related to c-myc expression, which is also linked to cell growth state. Upon phorbol myristate acetate (PMA) treatment, cells from the three lineages (HL-60, U937 and K562) differentiated and expressed specific surface antigens. All cell lines analyzed were growth inhibited by PMA and the doubling time was increased, mainly due to an increased fraction of cells in the G0/G1 phase, as determined by flow cytometry measurements of incorporated bromodeoxyuridine and cell DNA content. C-myc mRNA expression was down-regulated and closely correlated to cell growth arrest. However, VDR expression in leukemic cell lines, as determined by immunofluorescence and Northern blot assays, was not consistently changed upon inhibition of cell proliferation since VDR levels were down-regulated only in HL-60 cells. Our data suggest that VDR expression cannot be explained simply as a reflection of the leukemic cell growth state.

Effect of actinomycin D on simian rotavirus (SA11) replication in cell culture

Rotaviruses are the major cause of viral diarrhea in humans and animals. Actinomycin D (Act D) is an antibiotic that intercalates DNA and therefore inhibits DNA-dependent transcription. The current study was carried out to assess the influence of Act D on the replication of simian rotavirus (SA11) in cell culture. Virus-infected MA-104 cell cultures were studied in the presence of Act D at concentrations of 1.25 and 2.5 µg/ml. Treatment of rotavirus-infected cells with 2.5 µg/ml Act D 48 h post-infection reduced the cytoplasmic metachromasia after staining with acridine orange by 25%. Viral RNA labeled with ³H-uridine in the presence of the drug was separated by polyacrylamide gel electrophoresis. Viral RNA replication was not affected by Act D, but increased ³H-uridine uptake was demonstrable by infected cells in the presence of the drug. This possibly was due to the inhibition of cellular RNA synthesis by Act D, which thus enhances incorporation of the radionuclide into the viral RNA. Act D reduced the number of infected cells presenting virus-specific fluorescence 48 h post-infection by more than 50%. These data suggest that Act D may have complexed with viral RNA and prevented newly synthesized mRNA from being translated, but may not have prevented early replication.