PCN1 COST ANALYSIS OF HLA-IDENTICAL SIBLING AND VOLUNTARY UNRELATED ALLOGENEIC BONE MARROW AND PERIPHERAL BLOOD STEM CELL TRANSPLANTATION IN ADULTS WITH ACUTE MYELOCYTIC LEUKAEMIA OR ACUTE LYMPHOBLASTIC LEUKAEMIA

Item does not contain fulltextAllogeneic stem cell transplantation (SCT) is one of the most expensive medical procedures. However, only a few studies to date have addressed the costs of HLA-identical sibling transplantation and only one study has reported costs of unrelated transplantation. No recent cost analysis with a proper follow-up period and donor identification expenses is available on related or voluntary matched unrelated donor (MUD) SCT for adult AML or ALL. Therefore, we calculated direct medical (hospital) costs based on 97 adults who underwent HLA-identical sibling bone marrow transplantation (BMT) or peripheral blood stem cell transplantation (PBSCT), and patients who received a graft from a MUD between 1994 and 1999. The average costs per transplanted patient were Euro 98,334 (BMT), Euro 151,754 (MUD), and Euro 98,977 (PBSCT), including donor identification expenses, 2 years follow-up and costs of patients who were not transplanted after they had been planned to receive an allograft. The majority of these costs was generated during the hospitalisation for graft infusion. For MUD transplants, nearly one-third of these costs was spent on the search for a suitable donor. For patients who were alive after 2 years, cumulative expenses were calculated to be Euro 103,509 (BMT), Euro 173,587 (MUD), and Euro 105,906 (PBSCT)

A new ultrafast and high-throughput mass spectrometric approach for the therapeutic drug monitoring of the multi-targeted anti-folate pemetrexed in plasma from lung cancer patients

An analytical assay has been developed and validated for ultrafast and high-throughput mass spectrometric determination of pemetrexed concentrations in plasma using matrix assisted laser desorption/ionization–triple quadrupole–tandem mass spectrometry. Patient plasma samples spiked with the internal standard methotrexate were measured by multiple reaction monitoring. The detection limit was 0.4 fmol/μL, lower limit of quantification was 0.9 fmol/μL, and upper limit of quantification was 60 fmol/μL, respectively. Overall observed pemetrexed concentrations in patient samples ranged between 8.7 (1.4) and 142.7 (20.3) pmol/μL (SD). The newly developed mass spectrometric assay is applicable for (routine) therapeutic drug monitoring of pemetrexed concentrations in plasma from non-small cell lung cancer patients

Phase I/II study of the deacetylase inhibitor panobinostat after allogeneic stem cell transplantation in patients with high-risk MDS or AML (PANOBEST trial)

Maintenance therapy after allogeneic hematopoietic stem cell transplantation (HSCT) for acute myeloid leukemia (AML) or myelodysplastic syndrome (MDS) is conceptually attractive to prevent relapse, but has been hampered by the limited number of suitable anti-leukemic agents. The deacetylase inhibitor (DACi) panobinostat demonstrated moderate anti-leukemic activity in a small subset of patients with advanced AML and high-risk MDS in phase I/II trials.1, 2 It also displays immunomodulatory activity3 that may enhance leukemia-specific cytotoxicity4 and mitigate graft versus host disease (GvHD), but conversely could impair T- and NK cell function.5, 6 We conducted this open-label, multi-center phase I/II trial (NCT01451268) to assess the feasibility and preliminary efficacy of prolonged prophylactic administration of panobinostat after HSCT for AML or MDS. The study protocol was approved by an independent ethics committee and conducted in compliance with the Declaration of Helsinki. All patients provided written informed consent. ..

Platelets of patients with chronic kidney disease demonstrate deficient platelet reactivity in vitro

<p>Abstract</p> <p>Background</p> <p>In patients with chronic kidney disease studies focusing on platelet function and properties often are non-conclusive whereas only few studies use functional platelet tests. In this study we evaluated a recently developed functional flow cytometry based assay for the analysis of platelet function in chronic kidney disease.</p> <p>Methods</p> <p>Platelet reactivity was measured using flow cytometric analysis. Platelets in whole blood were triggered with different concentrations of agonists (TRAP, ADP, CRP). Platelet activation was quantified with staining for P-selectin, measuring the mean fluorescence intensity. Area under the curve and the concentration of half-maximal response were determined.</p> <p>Results</p> <p>We studied 23 patients with chronic kidney disease (9 patients with cardiorenal failure and 14 patients with end stage renal disease) and 19 healthy controls. Expression of P-selectin on the platelet surface measured as mean fluorescence intensity was significantly less in chronic kidney disease patients compared to controls after maximal stimulation with TRAP (9.7 (7.9-10.8) vs. 11.4 (9.2-12.2), P = 0.032), ADP (1.6 (1.2-2.1) vs. 2.6 (1.9-3.5), P = 0.002) and CRP (9.2 (8.5-10.8) vs. 11.5 (9.5-12.9), P = 0.004). Also the area under the curve was significantly different. There was no significant difference in half-maximal response between both groups.</p> <p>Conclusion</p> <p>In this study we found that patients with chronic kidney disease show reduced platelet reactivity in response of ADP, TRAP and CRP compared to controls. These results contribute to our understanding of the aberrant platelet function observed in patients with chronic kidney disease and emphasize the significance of using functional whole blood platelet activation assays.</p

Comparison of hemodynamic and nutritional parameters between older persons practicing regular physical activity, nonsmokers and ex-smokers

<p>Abstract</p> <p>Background</p> <p>Sedentary lifestyle combined with smoking, contributes to the development of a set of chronic diseases and to accelerating the course of aging. The aim of the study was to compare the hemodynamic and nutritional parameters between elderly persons practicing regular physical activity, nonsmokers and ex-smokers.</p> <p>Methods</p> <p>The sample was comprised of 40 elderly people practicing regular physical activity for 12 months, divided into a Nonsmoker Group and an Ex-smoker Group. During a year four trimestrial evaluations were performed, in which the hemodynamic (blood pressure, heart rate- HR and VO₂) and nutritional status (measured by body mass index) data were collected. The paired t-test and t-test for independent samples were applied in the intragroup and intergroup analysis, respectively.</p> <p>Results</p> <p>The mean age of the groups was 68.35 years, with the majority of individuals in the Nonsmoker Group being women (n = 15) and the Ex-smoker Group composed of men (n = 11). In both groups the variables studied were within the limits of normality for the age. HR was diminished in the Nonsmoker Group in comparison with the Ex-smoker Group (p = 0.045) between the first and last evaluation. In the intragroup analysis it was verified that after one year of exercise, there was significant reduction in the HR in the Nonsmoker Group (p = 0.002) and a significant increase in VO₂for the Ex-smoker Group (p = 0.010). There are no significant differences between the hemodynamic and nutritional conditions in both groups.</p> <p>Conclusion</p> <p>In elderly persons practicing regular physical activity, it was observed that the studied variables were maintained over the course of a year, and there was no association with the history of smoking, except for HR and VO₂.</p

A Rapid Flp-In System for Expression of Secreted H5N1 Influenza Hemagglutinin Vaccine Immunogen in Mammalian Cells

Continuing transmissions of highly pathogenic H5N1 viruses in poultry and humans underscores the need for a rapid response to potential pandemic in the form of vaccine. Recombinant technologies for production of immunogenic hemagglutinin (HA) could provide an advantage over the traditional inactivated vaccine manufacturing process. Generation of stably transfected mammalian cells secreting properly folded HA proteins is important for scalable controlled manufacturing.We have developed a Flp-In based 293 stable cell lines through targeted site-specific recombination for expression of secreted hemagglutinin (HA) proteins and evaluated their immunogenicity. H5N1 globular domain HA1(1-330) and HA0(1-500) proteins were purified from the supernatants of 293 Flp-In stable cell lines. Both proteins were properly folded as confirmed by binding to H5N1-neutralizing conformation-dependent human monoclonal antibodies. The HA0 (with unmodified cleavage site) was monomeric, while the HA1 contained oligomeric forms. Upon rabbit immunization, both HA proteins elicited neutralizing antibodies against the homologous virus (A/Vietnam/1203/2004, clade 1) as well as cross-neutralizing antibodies against heterologous H5N1 clade 2 strains, including A/Indonesia/5/2005. These results exceeded the human antibody responses against the inactivated sub-virion H5N1 vaccine.Our data suggest that the 293 Flp-In system could serve as a platform for rapid expression of HA immunogens in mammalian cells from emerging influenza strains

Suppression of Plant Resistance Gene-Based Immunity by a Fungal Effector

The innate immune system of plants consists of two layers. The first layer, called basal resistance, governs recognition of conserved microbial molecules and fends off most attempted invasions. The second layer is based on Resistance (R) genes that mediate recognition of effectors, proteins secreted by pathogens to suppress or evade basal resistance. Here, we show that a plant-pathogenic fungus secretes an effector that can both trigger and suppress R gene-based immunity. This effector, Avr1, is secreted by the xylem-invading fungus Fusarium oxysporum f.sp. lycopersici (Fol) and triggers disease resistance when the host plant, tomato, carries a matching R gene (I or I-1). At the same time, Avr1 suppresses the protective effect of two other R genes, I-2 and I-3. Based on these observations, we tentatively reconstruct the evolutionary arms race that has taken place between tomato R genes and effectors of Fol. This molecular analysis has revealed a hitherto unpredicted strategy for durable disease control based on resistance gene combinations

Systemic virus distribution and host responses in brain and intestine of chickens infected with low pathogenic or high pathogenic avian influenza virus

<p>Abstract</p> <p>Background</p> <p>Avian influenza virus (AIV) is classified into two pathotypes, low pathogenic (LP) and high pathogenic (HP), based on virulence in chickens.</p> <p>Differences in pathogenicity between HPAIV and LPAIV might eventually be related to specific characteristics of strains, tissue tropism and host responses.</p> <p>Methods</p> <p>To study differences in disease development between HPAIV and LPAIV, we examined the first appearance and eventual load of viral RNA in multiple organs as well as host responses in brain and intestine of chickens infected with two closely related H7N1 HPAIV or LPAIV strains.</p> <p>Results</p> <p>Both H7N1 HPAIV and LPAIV spread systemically in chickens after a combined intranasal/intratracheal inoculation. In brain, large differences in viral RNA load and host gene expression were found between H7N1 HPAIV and LPAIV infected chickens. Chicken embryo brain cell culture studies revealed that both HPAIV and LPAIV could infect cultivated embryonic brain cells, but in accordance with the absence of the necessary proteases, replication of LPAIV was limited. Furthermore, TUNEL assay indicated apoptosis in brain of HPAIV infected chickens only. In intestine, where endoproteases that cleave HA of LPAIV are available, we found minimal differences in the amount of viral RNA and a large overlap in the transcriptional responses between HPAIV and LPAIV infected chickens. Interestingly, brain and ileum differed clearly in the cellular pathways that were regulated upon an AI infection.</p> <p>Conclusions</p> <p>Although both H7N1 HPAIV and LPAIV RNA was detected in a broad range of tissues beyond the respiratory and gastrointestinal tract, our observations indicate that differences in pathogenicity and mortality between HPAIV and LPAIV could originate from differences in virus replication and the resulting host responses in vital organs like the brain.</p

Dog Bites in Humans and Estimating Human Rabies Mortality in Rabies Endemic Areas of Bhutan

Dog bites in humans are a public health problem worldwide. We conducted a hospital based questionnaire survey and described the incidence and risk factors for human dog bites in Bhutan. We also estimated the human death rate attributable to rabies in two rabies endemic areas of south Bhutan. Our study shows that dog bites incidents in humans are common in the survey areas. There were significant gender and age differences in bite incidents; males and the children are affected the most. The majority of the victims were bitten by stray dogs, increasing the risk of rabies infection if not treated in time. Our decision tree model predicted 2.23 (95% CI: 1.20–3.59) human deaths from rabies/year, equivalent to an annual incidence of 4.67 (95% CI: 2.53–7.53) deaths/100,000 in the two rabies endemic areas of south Bhutan. In the absence of post exposure prophylaxis, the model predicted 19.24 (95% CI: 13.69–25.14) deaths/year in these two areas. The public should be encouraged to visit hospitals for post exposure prophylaxis following dog bite injury in south Bhutan