A monoclonal antibody which blocks the function of factor D of human complement.

Factor D is an essential enzyme for activation of complement by the alternative pathway (AP). It has been difficult to obtain mouse monoclonal antibodies (Mabs) which block the function of factor D. We have developed a strategy to obtain such Mabs using a double screening procedure of the initial clones. We selected the clone whose supernatant had the lowest level of anti-factor D Ab by ELISA and abolished factor D haemolytic activity. Addition of this Mab to human serum was shown to abolish conversion of C3 by cobra venom factor, haemolysis of rabbit erythrocytes, and activation of C3 and C5 by cuprophane dialysis membranes.

Analysis and quantification of vitamin D metabolites in serum by ultra-performance liquid chromatography coupled to tandem mass spectrometry and high-resolution mass spectrometry: a method comparison and validation.

RATIONALE: The aim of the work was to develop and validate a method for the quantification of vitamin D metabolites in serum using ultra-high-pressure liquid chromatography coupled to mass spectrometry (LC/MS), and to validate a high-resolution mass spectrometry (LC/HRMS) approach against a tandem mass spectrometry (LC/MS/MS) approach using a large clinical sample set. METHODS: A fast, accurate and reliable method for the quantification of the vitamin D metabolites, 25-hydroxyvitamin D2 (25OH-D2) and 25-hydroxyvitamin D3 (25OH-D3), in human serum was developed and validated. The C3 epimer of 25OH-D3 (3-epi-25OH-D3) was also separated from 25OH-D3. The samples were rapidly prepared via a protein precipitation step followed by solid-phase extraction (SPE) using an HLB μelution plate. Quantification was performed using both LC/MS/MS and LC/HRMS systems. RESULTS: Recovery, matrix effect, inter- and intra-day reproducibility were assessed. Lower limits of quantification (LLOQs) were determined for both 25OH-D2 and 25OH-D3 for the LC/MS/MS approach (6.2 and 3.4 µg/L, respectively) and the LC/HRMS approach (2.1 and 1.7 µg/L, respectively). A Passing & Bablok fit was determined between both approaches for 25OH-D3 on 662 clinical samples (1.11 + 1.06x). It was also shown that results can be affected by the inclusion of the isomer 3-epi-25OH-D3. CONCLUSIONS: Quantification of the relevant vitamin D metabolites was successfully developed and validated here. It was shown that LC/HRMS is an accurate, powerful and easy to use approach for quantification within clinical laboratories. Finally, the results here suggest that it is important to separate 3-epi-25OH-D3 from 25OH-D3. Copyright © 2012 John Wiley & Sons, Ltd.

[Archives de la Parole]. , La parabole de l'enfant prodigue : récit (dravidien, canara, province de Madras) / [Sir George Grierson], éd. ; Linguistic survey of India ; [D. Narayana Batt], voix

[Traditions. Asie. Inde. Province de Madras [i.e. Chennai]. Etat du Karnara]

A Genetic Validation Study Reveals a Role of Vitamin D Metabolism in the Response to Interferon-Alfa-Based Therapy of Chronic Hepatitis C.

BACKGROUND: To perform a comprehensive study on the relationship between vitamin D metabolism and the response to interferon-α-based therapy of chronic hepatitis C. METHODOLOGY/PRINCIPAL FINDINGS: Associations between a functionally relevant polymorphism in the gene encoding the vitamin D 1α-hydroxylase (CYP27B1-1260 rs10877012) and the response to treatment with pegylated interferon-α (PEG-IFN-α) and ribavirin were determined in 701 patients with chronic hepatitis C. In addition, associations between serum concentrations of 25-hydroxyvitamin D(3) (25[OH]D(3)) and treatment outcome were analysed. CYP27B1-1260 rs10877012 was found to be an independent predictor of sustained virologic response (SVR) in patients with poor-response IL28B genotypes (15% difference in SVR for rs10877012 genotype AA vs. CC, p = 0.02, OR = 1.52, 95% CI = 1.061-2.188), but not in patients with favourable IL28B genotype. Patients with chronic hepatitis C showed a high prevalence of vitamin D insufficiency (25[OH]D(3)<20 ng/mL) during all seasons, but 25(OH)D(3) serum levels were not associated with treatment outcome. CONCLUSIONS/SIGNIFICANCE: Our study suggests a role of bioactive vitamin D (1,25[OH](2)D(3), calcitriol) in the response to treatment of chronic hepatitis C. However, serum concentration of the calcitriol precursor 25(OH)D(3) is not a suitable predictor of treatment outcome.

Acute life-threatening presentation of vitamin d deficiency rickets.

Context: Clinical manifestations of vitamin D deficiency rickets are widely described; however cardiorespiratory arrest is an extremely rare presentation. Objective: The aim of this paper is to present the symptoms of severe vitamin D deficiency rickets and to highlight the importance of vitamin D prophylaxis in infants. Results: We report a case of a 16-month-old infant who presented to emergency room with a stridor that evolved into a full cardiorespiratory arrest secondary to hypocalcemia. Medical history revealed that the infant was exclusively breastfed without vitamin D supplementation until the age of 10 months. Due to cultural habits, his diet was also grossly deficient in dairy products. Physical exam revealed clinical signs of rickets. Laboratory test showed severe hypocalcemia, elevated alkaline phosphatase, normal serum phosphorous, decreased 25(OH) cholecalciferol, increased intact parathyroid hormone level, and normal urine calcium excretion. The radiography of the wrist showed evidence of cupping, fraying, metaphyseal widening, and demineralization of the distal radial and ulnar metaphyses. The bone mineral density of the lumbar spine measured by dual x-ray absorptiometry showed a Z-score below -2 SD. His cardiorespiratory arrest secondary to hypocalcemia was therefore attributed to severe nutritional rickets. Conclusion: Vitamin D deficiency rickets can be life threatening. Vitamin D supplementation is therefore crucial, especially in breastfed infants and some ethnic minorities (dark-skinned people, poor sun exposure), more at risk for developing severe rickets if not supplemented.

Aspects thérapeutiques de la vitamine D: quels taux cibler avec quels traitements [Therapeutic goal of vitamin D: optimal serum level and dose requirements].

Therapeutic goal of vitamin D: optimal serum level and dose requirements Results of randomized controlled trials and meta-analyses investigating the effect of vitamin D supplementation on falls and fractures are inconsistent. The optimal serum level 25(OH) vitamin D for musculoskeletal and global health is > or = 30 ng/ml (75 nmol/l) for some experts and 20 ng/ml (50 nmol/l) for some others. A daily dose of vitamin D is better than high intermittent doses to reach this goal. High dose once-yearly vitamin D therapy may increase the incidence of fractures and falls. High serum level of vitamin D is probably harmful for the musculoskeletal system and health at large. The optimal benefits for musculoskeletal health are obtained with an 800 UI daily dose and a serum level of near 30 ng/ml (75 nmol/l).

Endogeneizing know-how flows through the nature of R&D investments

In this paper we carefully link knowledge flows to and from a firm s innovation process with this firm s investment decisions. Three types of investments are considered: investments in applied research, investments in basic research, and investments in intellectual property protection. Only when basic research is performed, can the firm effectively access incoming knowledge flows and these incoming spillovers serve to increase the efficiency of own applied research. The firm can at the same time influence outgoing knowledge flows, improving appropriability of its innovations, by investing in protection. Our results indicate that firms with small budgets for innovation will not invest in basic research. This occurs in the short run, when the budget for know-how creation is restricted, or in the long-run, when market opportunities are low, when legal protection is not very important, or, when the pool of accessible and relevant external know-how is limited. The ratio of basic to applied research is non-decreasing in the size of the pool of accessible external know-how, the size and opportunity of the market, and, the effectiveness of intellectual property rights protection. This indicates the existence of economies of scale in basic research due to external market related factors. Empirical evidence from a sample of innovative manufacturing firms in Belgium confirms the economies of scale in basic research as a consequence of the firm s capacity to access external knowledge flows and to protectintellectual property, as well as the complementarity between legal and strategic investments.

Effect of vitamin D on EBV-specific CD8+T cells in patients with early multiple sclerosis

Introduction: Infection with Epstein-Barr Virus (EBV) and a lack invitamin D are emerging as the twomost significant environmental triggersof multiple sclerosis (MS). Sincewe and others have shown that CD8+T cells are important immune mediatorsof the inflammatory response inMS, we examined whether vitamin Ddirectly affects the CD8+ T cell response.We also explored if vitaminDmodulates the EBV-specific CD8+ Tcell response. Methods: PBMC of 10patients with early MS and 10 healthycontrols (HC) were stimulated eitherwith a pool of EBVimmunodominantpeptides or anti-CD3/anti-CD28 beads.Cytokine secretion was assessed witha Cytometric Beads Array (CBA),ELISA and intracellular cytokinestaining. To examine whether vitaminD could directly modulate CD8+ Tcell immune responses, we depletedCD4+ T cells using a negative selection.Results: We found that vitaminD-treated PBMC stimulated eitherwith the EBV peptide pool or anti-CD3/anti-CD28 beads adopted ananti-inflammatory profile: significantdecrease in IFN-and TNF secretion,contrasting with a significant increasein IL-5 and TGF-secretion. At baseline,but also after vitamin D stimulation,IL-5 was significantly less producedby stimulated CD8+ T cells ofearly MS than HC. Finally, using depletionof CD4+ T cells, we couldshow that vitaminDcan directlymodulateCD8+ T cells. Discussion: Ourdata suggest that vitaminDconfers ananti-inflammatory profile to CD8+ Tcells, without the help of CD4+ Tcells. Even if vitamin D has a significanteffect on CD8+ T cells of earlyMS patients, this "rescuing" effect isof smaller magnitude than in HC subjects.Finally, vitamin D does influencethe CD8+ T cell response toEBV in early MS patients, suggestingthat there is an interplay betweenthese two major environmental factorsof MS.

Severe hypercalcemia after a single high dose of vitamin D in a patient with sarcoidosis.

LETTER TO THE EDITOR

Knowledge Licensing in a Model of R&D-driven Endogenous Growth

In this paper I present an endogenous growth model where the engine of growth is in-house R&D performed by high-tech firms. I model knowledge (patent) licensing among high-tech firms. I show that if there is knowledge licensing, high-tech firms innovate more and economic growth is higher than in cases when there are knowledge spillovers or there is no exchange of knowledge among high-tech firms. However, in case when there is knowledge licensing the number of high-tech firms is lower than in cases when there are knowledge spillovers or there is no exchange of knowledge.

Knowledge Licensing in a Model of R&D-driven Endogenous Growth

In this paper I present an endogenous growth model where the engine of growth is in-house R&D performed by high-tech firms. I model knowledge (patent) licensing among high-tech firms. I show that if there is knowledge licensing, high-tech firms innovate more and economic growth is higher than in cases when there are knowledge spillovers or there is no exchange of knowledge among high-tech firms. However, in case when there is knowledge licensing the number of high-tech firms is lower than in cases when there are knowledge spillovers or there is no exchange of knowledge.

Methods to Increase Durability of Reactive ("D" Cracking) Coarse Aggregate in Portland Cement Concrete, MLR-73-01, 1973

The coarse aggregates used for Portland Cement concrete in southwest Iowa have exhibited a poor serviceability. This early failure is attributed to a characteristic commonly referred as "D" cracking. "D" line cracking is a discolored area of concrete caused by many fine, parallel hairline cracks. "D" line cracking is primarily caused by the movement of water in and through coarse aggregate with a unique pore structure. The presence of the water in the aggregates at the time of freezing causes the "D" cracking to occur and early failure. By making the pore structure less permeable to moisture, it is thought the durability factor of the concrete should increase. By drying the aggregate before mixing and then mixing with the cement, the particles of cement should enter the outer pore structure, and upon hydration make the pore structure less permeable to moisture.