186 research outputs found
Levothyrox® new and old formulations: are they switchable for millions of patients?
International audienceIn France, more than 2.5 million patients are currently treated with levothyroxine, mainly as the marketed product Levothyrox ®. In March 2017, at the request of French authorities, a new formulation of Levothyrox ® was licensed, with the objective of avoiding stability deficiencies of the old formulation. Before launching this new formulation, an average bioequivalence trial, based on European Union recommended guidelines, was performed. The implicit rationale was the assumption that the two products, being bioequivalent, would also be switchable, allowing substitution of the new for the old formulation, thus avoiding the need for individual calibration of the dosage regimen of thyroxine, using the thyroid-stimulating hormone level as the endpoint, as required for a new patient on initiating treatment. Despite the fact that both formulations were shown to be bioequivalent, adverse drug reactions were reported in several thousands of patients after taking the new formulation. In this opinion paper, we report that more than 50% of healthy volunteers enrolled in a successful regulatory average bioequivalence trial were actually outside the a priori bioequivalence range. Therefore, we question the ability of an average bioequivalence trial to guarantee the switchability within patients of the new and old levothyroxine formulations. We further propose an analysis of this problem using the conceptual framework of individual bioequivalence. This involves investigating the bioavailability of the two formulations within a subject, by comparing not only the population means (as established by average bioequivalence) but also by assessing two variance terms, namely the within-subject variance and the variance estimating subject-by-formulation interaction. A higher within individual variability for the new formulation would lead to reconsideration of the appropriateness of the new formulation. Alternatively, a possible subject-by-formulation interaction would allow a judgement on the ability, or not, of doctors to manage patients effectively during transition from the old to the new formulation
Assessment of the In Vivo Toxicity of Gold Nanoparticles
The environmental impact of nanoparticles is evident; however, their toxicity due to their nanosize is rarely discussed. Gold nanoparticles (GNPs) may serve as a promising model to address the size-dependent biological response to nanoparticles because they show good biocompatibility and their size can be controlled with great precision during their chemical synthesis. Naked GNPs ranging from 3 to 100 nm were injected intraperitoneally into BALB/C mice at a dose of 8 mg/kg/week. GNPs of 3, 5, 50, and 100 nm did not show harmful effects; however, GNPs ranging from 8 to 37 nm induced severe sickness in mice. Mice injected with GNPs in this range showed fatigue, loss of appetite, change of fur color, and weight loss. Starting from day 14, mice in this group exhibited a camel-like back and crooked spine. The majority of mice in these groups died within 21 days. Injection of 5 and 3 nm GNPs, however, did not induce sickness or lethality in mice. Pathological examination of the major organs of the mice in the diseased groups indicated an increase of Kupffer cells in the liver, loss of structural integrity in the lungs, and diffusion of white pulp in the spleen. The pathological abnormality was associated with the presence of gold particles at the diseased sites, which were verified by ex vivo Coherent anti-Stoke Raman scattering microscopy. Modifying the surface of the GNPs by incorporating immunogenic peptides ameliorated their toxicity. This reduction in the toxicity is associated with an increase in the ability to induce antibody response. The toxicity of GNPs may be a fundamental determinant of the environmental toxicity of nanoparticles
Ethnic variation in validity of the estimated obesity prevalence using self-reported weight and height measurements
<p>Abstract</p> <p>Background</p> <p>We examined ethnic differences between levels of body mass index (BMI) based on self-reported and measured body height and weight and the validity of self-reports used to estimate the prevalence of obesity (BMI≥30 kg/m<sup>2</sup>) in Turkish, Moroccan, and Dutch people in the Netherlands. Furthermore, we investigated whether BMI levels and the prevalence of obesity in Turkish and Moroccan people with incomplete self-reports (missing height or weight) differ from those with complete self-reports.</p> <p>Methods</p> <p>Data on self-reported and measured height and weight were collected in a population-based survey among 441 Dutch, 414 Turks and 344 Moroccans aged 18 to 69 years in Amsterdam, the Netherlands in 2004. BMI and obesity were calculated from self-reported and measured height and weight.</p> <p>Results</p> <p>The difference between measured and estimated BMI was larger in Turkish and Moroccan women than in Dutch women, which was explained by the higher BMI of the Turkish and Moroccan women. In men we found no ethnic differences between measured and estimated BMI. Sensitivity to detect obesity was low and specificity was high. In participants with available self-reported and measured height and weight, self-reports produced a similar underestimation of the obesity prevalence in all ethnic groups. However, many obese Turkish and Moroccan women had incomplete self-reports, missing height or weight, resulting in an additional underestimation of the prevalence of obesity. Among men (all ethnicities) and Dutch women, the availability of height or weight by self-report did not differ between obese and non obese participants.</p> <p>Conclusions</p> <p>BMI based on self-reports is underestimated more by Turkish and Moroccan women than Dutch women, which is explained by the higher BMI of Turkish and Moroccan women. Further, in women, ethnic differences in the estimation of obesity prevalence based on self-reports do exist and are due to incomplete self-reports in obese Turkish and Moroccan women. In men, ethnicity is not associated with discrepancies between levels of BMI and obesity prevalence based on measurements and self-reports. Hence, our results indicate that using measurements to accurately determine levels of BMI and obesity prevalence in public health research seems even more important in Turkish and Moroccan migrant women than in other populations.</p
Comparison of two recombinant erythropoietin formulations in patients with anemia due to end-stage renal disease on hemodialysis: A parallel, randomized, double blind study
BACKGROUND: Recombinant human erythropoietin (EPO) is used for the treatment of last stage renal anemia. A new EPO preparation was obtained in Cuba in order to make this treatment fully nationally available. The aim of this study was to compare the pharmacokinetic, pharmacodynamic and safety properties of two recombinant EPO formulations in patients with anemia due to end-stage renal disease on hemodialysis. METHODS: A parallel, randomized, double blind study was performed. A single 100 IU/Kg EPO dose was administered subcutaneously. Heberitro (Heber Biotec, Havana, formulation A), a newly developed product and Eprex (CILAG AG, Switzerland, formulation B), as reference treatment were compared. Thirty-four patients with anemia due to end-stage renal disease on hemodialysis were included. Patients had not received EPO previously. Serum EPO level was measured by enzyme immunoassay (EIA) during 120 hours after administration. Clinical and laboratory variables were determined as pharmacodynamic and safety criteria until 216 hours. RESULTS: Both groups of patients were similar regarding all demographic and baseline characteristics. EPO kinetics profiles were similar for both formulations; the pharmacokinetic parameters were very close (i.e., AUC: 4667 vs. 4918 mIU.h/mL; Cmax: 119.1 vs. 119.7 mIU/mL; Tmax: 13.9 vs. 18.1 h; half-life, 20.0 vs. 22.5 h for formulations A and B, respectively). The 90% confidence intervals for the ratio between both products regarding these metrics were close to the 0.8 – 1.25 range, considered necessary for bioequivalence. Differences did not reach 20% in any case and were not determined by a formulation effect, but probably by a patients' variability effect. Concerning pharmacodynamic features, a high similitude in reticulocyte counts increments until 216 hours and the percentage decrease in serum iron until 120 hours was observed. There were no differences between formulations regarding the adverse events and their intensity. The more frequent events were pain at injection site (35.3%) and hypertension (29%). Additionally, further treatment of the patients with the study product yielded satisfactory increases in hemoglobin and hematocrit values. CONCLUSION: The formulations are comparable. The newly developed product should be acceptable for long-term application
Clinical effectiveness of usual care with or without antidepressant medication for primary care patients with minor or mild-major depression: a randomized equivalence trial
<p>Abstract</p> <p>Background</p> <p>Minor and mild-major depression are highly prevalent in primary care. There is insufficient evidence for the effectiveness of antidepressants in the treatment of minor and mild-major depression. We compared the effectiveness of usual primary care treatment, with or without antidepressants, in minor and mild-major depression.</p> <p>Methods</p> <p>A pragmatic patient-randomized equivalence trial with 52 weeks follow-up was conducted in The Netherlands. In total, 59 primary care physicians (PCPs) recruited and treated 181 adult patients with minor or mild-major depression. Patients were randomized to four consultations within 3 months of usual care plus antidepressants (UCandAD) or usual care alone (UCnoAD). The Montgomery Åsberg Depression Rating Scale (MADRS) was used to assess changes in severity of depressive symptoms. The predefined equivalence margin was set at five points. Multilevel analysis was used to analyze the data. Secondary outcome measures were the Short-Form 36 (SF-36), and the Client Satisfaction Questionnaire (CSQ-8).</p> <p>Results</p> <p>Patients received on average 3.0 (SD 1.4) 15-min consultations within 3 months with (n = 85) or without paroxetine (n = 96). Equivalence of UCandAD and UCnoAD was demonstrated in the intention-to-treat analyses as well as the per-protocol analysis after 6 weeks, but not at 13, 26 and 52 weeks follow-up. No statistical differences in effectiveness between treatment groups were found in the intention-to-treat analysis. No differences in the physical and mental functioning (SF-36) were found between the treatment groups. Patients allocated to UCandAD were slightly more satisfied with their treatment at 13 weeks follow-up (but not at 52 weeks follow-up) than patients allocated to UCnoAD. Preliminary analyses suggested that subgroups such as patients with mild-major (instead of a minor) depression might benefit from antidepressant treatment. Patients who were assigned to their preferred treatment (in particular to UCnoAD) were more often compliant and had better clinical outcomes.</p> <p>Conclusion</p> <p>UCandAD was as effective as UCnoAD over the first 6 weeks, but not at 13, 26, and 52 weeks. However, superiority of either treatment could not be demonstrated either. The question whether antidepressants add any clinical effect to usual care remains unresolved. We recommend future studies to look for subgroups of patients who may benefit from antidepressants.</p> <p>Trial registration</p> <p>Dutch Trial Registry ISRCN03007807.</p
Genome-Wide Analysis of Müller Glial Differentiation Reveals a Requirement for Notch Signaling in Postmitotic Cells to Maintain the Glial Fate
Previous studies have shown that Müller glia are closely related to retinal progenitors; these two cell types express many of the same genes and after damage to the retina, Müller glia can serve as a source for new neurons, particularly in non-mammalian vertebrates. We investigated the period of postnatal retinal development when progenitors are differentiating into Müller glia to better understand this transition. FACS purified retinal progenitors and Müller glia from various ages of Hes5-GFP mice were analyzed by Affymetrix cDNA microarrays. We found that genes known to be enriched/expressed by Müller glia steadily increase over the first three postnatal weeks, while genes associated with the mitotic cell cycle are rapidly downregulated from P0 to P7. Interestingly, progenitor genes not directly associated with the mitotic cell cycle, like the proneural genes Ascl1 and Neurog2, decline more slowly over the first 10–14 days of postnatal development, and there is a peak in Notch signaling several days after the presumptive Müller glia have been generated. To confirm that Notch signaling continues in the postmitotic Müller glia, we performed in situ hybridization, immunolocalization for the active form of Notch, and immunofluorescence for BrdU. Using genetic and pharmacological approaches, we found that sustained Notch signaling in the postmitotic Müller glia is necessary for their maturation and the stabilization of the glial identity for almost a week after the cells have exited the mitotic cell cycle
Optimal deployment of components of cloud-hosted application for guaranteeing multitenancy isolation
One of the challenges of deploying multitenant cloud-hosted
services that are designed to use (or be integrated with) several
components is how to implement the required degree
of isolation between the components when there is a change
in the workload. Achieving the highest degree of isolation
implies deploying a component exclusively for one tenant;
which leads to high resource consumption and running cost
per component. A low degree of isolation allows sharing of
resources which could possibly reduce cost, but with known
limitations of performance and security interference. This
paper presents a model-based algorithm together with four
variants of a metaheuristic that can be used with it, to provide
near-optimal solutions for deploying components of a
cloud-hosted application in a way that guarantees multitenancy
isolation. When the workload changes, the model based
algorithm solves an open multiclass QN model to
determine the average number of requests that can access
the components and then uses a metaheuristic to provide
near-optimal solutions for deploying the components. Performance
evaluation showed that the obtained solutions had
low variability and percent deviation when compared to the
reference/optimal solution. We also provide recommendations
and best practice guidelines for deploying components
in a way that guarantees the required degree of isolation
Early transcriptional response in the jejunum of germ-free piglets after oral infection with virulent rotavirus
Germ-free piglets were orally infected with virulent rotavirus to collect jejunal mucosal scrapings at 12 and 18 hours post infection (two piglets per time point). IFN-gamma mRNA expression was stimulated in the mucosa of all four infected piglets, indicating that they all responded to the rotavirus infection. RNA pools prepared from two infected piglets were used to compare whole mucosal gene expression at 12 and 18 hpi to expression in uninfected germ-free piglets (n = 3) using a porcine intestinal cDNA microarray. Microarray analysis identified 13 down-regulated and 17 up-regulated genes. Northern blot analysis of a selected group of genes confirmed the data of the microarray. Genes were functionally clustered in interferon-regulated genes, proliferation/differentiation genes, apoptosis genes, cytoskeleton genes, signal transduction genes, and enterocyte digestive, absorptive, and transport genes. Down-regulation of the transport gene cluster reflected in part the loss of rotavirus-infected enterocytes from the villous tips. Data mining suggested that several genes were regulated in lower- or mid-villus immature enterocytes and goblet cells, probably to support repair of the damaged epithelial cell layer at the villous tips. Furthermore, up-regulation was observed for IFN-γ induced guanylate binding protein 2, a protein that effectively inhibited VSV and EMCV replication in vitro (Arch Virol 150:1213–1220, 2005). This protein may play a role in the small intestine’s innate defense against enteric viruses like rotavirus
Participant experiences of mindfulness-based childbirth education: a qualitative study
Background: Childbirth is an important transitional life event, but one in which many women are dissatisfied stemming in part from a sense that labour is something that happens to them rather than with them. Promoting maternal satisfaction with childbirth means equipping women with communication and decision making skills that will enhance their ability to feel involved in their labour. Additionally, traditional antenatal education does not necessarily prepare expectant mothers and their birth support partner adequately for birth. Mindfulness-based interventions appear to hold promise in addressing these issues. Mindfulness-based Child Birth Education (MBCE) was a pilot intervention combining skills-based antenatal education and Mindfulness Based Stress Reduction. Participant experiences of MBCE, both of expectant mothers and their birth support partners are the focus of this article. Methods: A generic qualitative approach was utilised for this study. Pregnant women between 18 and 28 weeks gestation, over 18 years of age, nulliparous with singleton pregnancies and not taking medication for a diagnosed mental illness or taking illicit drugs were eligible to undertake the MBCE program which was run in a metropolitan city in Australia. Focus groups with 12 mothers and seven birth support partners were undertaken approximately four months after the completion of MBCE. Audio recordings of the groups were transcribed verbatim and analysed thematically using the method of constant comparison by all four authors independently and consensus on analysis and interpretation arrived at through team meetings.Results: A sense of both ‘empowerment’ and ‘community’ were the essences of the experiences of MBCE both for mothers and their birth support partner and permeated the themes of ‘awakening my existing potential’ and ‘being in a community of like-minded parents’. Participants suggested that mindfulness techniques learned during MBCE facilitated their sense of control during birth, and the content and pedagogical approach of MBCE enabled them to be involved in decision making during the birth. The pedagogical approach also fostered a sense of community among participants which extended into the postnatal period. Conclusions: MBCE has the potential to empower women to become active participants in the birthing process, thus addressing common concerns regarding lack of control and satisfaction with labour and facilitate peer support into the postnatal period. Further education of health professionals may be needed to ensure that they respond positively to those women and birth support partners who remain active in decision making during birth
AAV Exploits Subcellular Stress Associated with Inflammation, Endoplasmic Reticulum Expansion, and Misfolded Proteins in Models of Cystic Fibrosis
Barriers to infection act at multiple levels to prevent viruses, bacteria, and parasites from commandeering host cells for their own purposes. An intriguing hypothesis is that if a cell experiences stress, such as that elicited by inflammation, endoplasmic reticulum (ER) expansion, or misfolded proteins, then subcellular barriers will be less effective at preventing viral infection. Here we have used models of cystic fibrosis (CF) to test whether subcellular stress increases susceptibility to adeno-associated virus (AAV) infection. In human airway epithelium cultured at an air/liquid interface, physiological conditions of subcellular stress and ER expansion were mimicked using supernatant from mucopurulent material derived from CF lungs. Using this inflammatory stimulus to recapitulate stress found in diseased airways, we demonstrated that AAV infection was significantly enhanced. Since over 90% of CF cases are associated with a misfolded variant of Cystic Fibrosis Transmembrane Conductance Regulator (ΔF508-CFTR), we then explored whether the presence of misfolded proteins could independently increase susceptibility to AAV infection. In these models, AAV was an order of magnitude more efficient at transducing cells expressing ΔF508-CFTR than in cells expressing wild-type CFTR. Rescue of misfolded ΔF508-CFTR under low temperature conditions restored viral transduction efficiency to that demonstrated in controls, suggesting effects related to protein misfolding were responsible for increasing susceptibility to infection. By testing other CFTR mutants, G551D, D572N, and 1410X, we have shown this phenomenon is common to other misfolded proteins and not related to loss of CFTR activity. The presence of misfolded proteins did not affect cell surface attachment of virus or influence expression levels from promoter transgene cassettes in plasmid transfection studies, indicating exploitation occurs at the level of virion trafficking or processing. Thus, we surmised that factors enlisted to process misfolded proteins such as ΔF508-CFTR in the secretory pathway also act to restrict viral infection. In line with this hypothesis, we found that AAV trafficked to the microtubule organizing center and localized near Golgi/ER transport proteins. Moreover, AAV infection efficiency could be modulated with siRNA-mediated knockdown of proteins involved in processing ΔF508-CFTR or sorting retrograde cargo from the Golgi and ER (calnexin, KDEL-R, β-COP, and PSMB3). In summary, our data support a model where AAV exploits a compromised secretory system and, importantly, underscore the gravity with which a stressed subcellular environment, under internal or external insults, can impact infection efficiency
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