Pyoderma gangrenosum avec anticorps anti-cytoplasme des neutrophiles de type anti-protéinase 3 (PR3-ANCA) induits par le propylthiouracile

Publication date: Available online 11 March 2017
Source:Annales de Dermatologie et de Vénéréologie
Author(s): A. Coster, J.-L. Dargent, N. de Visscher, P. Levecque, P.-P. Roquet-Gravy
IntroductionLes antithyroïdiens de synthèse peuvent être responsables du développement d'anticorps anti-cytoplasme des neutrophiles (ANCA) et de vasculites liées à la présence de ces ANCA, ou de dermatoses neutrophiliques. Le propylthiouracile (PTU) est l'antithyroïdien de synthèse le plus souvent incriminé et ces ANCA sont surtout de type anti-myélopéroxydase (MPO-ANCA). À notre connaissance, aucune publication n'a rapporté d'association entre pyoderma gangrenosum (PG) et ANCA anti-protéinase 3 (PR3-ANCA) induits par le PTU.ObservationUne femme de 68 ans était traitée par du PTU pour un goitre multinodulaire toxique. Elle se présentait en raison d'une ulcération nécrotique étendue de la partie inférieure de l'abdomen. L'anamnèse, la clinique, les prélèvements bactériologiques et histologiques permettaient de poser le diagnostic de pyoderma gangrenosum. Celui-ci était accompagné d'ANCA de spécificité antigénique anti-protéinase 3. L'arrêt du PTU, associé à une courte cure de corticothérapie générale et de ciclosporine, permettait une résolution rapide et complète du pyoderma gangrenosum, parallèlement à une décroissance des ANCA. Aucune rechute n'était objectivée à un an de l'arrêt de tout traitement.DiscussionNous rapportons un cas de PG accompagné de PR3-ANCA induits par le PTU, en l'absence de toute vasculite démontrable.BackgroundSynthetic antithyroid drugs are often used in the treatment of hyperthyroidism, regardless of aetiology. They may cause various side effects, including the development of anti-neutrophil cytoplasmic antibodies (ANCA), ANCA-associated vasculitis, and neutrophilic dermatoses. Propylthiouracil (PTU) is the antithyroid drug most frequently implicated in ANCA-associated diseases specifically involving anti-myeloperoxidase ANCA (MPO-ANCA). To our knowledge, there are no clinical reports describing the association of pyoderma gangrenosum (PG) and anti-proteinase3-ANCA (PR3-ANCA) induced by PTU, with ANCA levels decreasing after antithyroid drug withdrawal.Patients and methodsA 68-year-old woman was treated with propylthiouracil (PTU) for toxic multinodular goitre. She presented necrotic ulceration of the lower abdomen. The patient's history, physical examination, and bacteriological and histological samples led to a diagnosis of pyoderma gangrenosum. This pyoderma involved ANCA with antigenic specificity for proteinase 3. Withdrawal of PTU and a short course of corticosteroids and cyclosporine resulted in rapid and complete resolution of the pyoderma gangrenosum as well as a decrease in ANCA. No relapse was observed one year after cessation of treatment.DiscussionWe report a case of PG associated with PR3-ANCA induced by PTU, without any demonstrable vasculitis.



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Bioinformatic approaches to interrogating vitamin D receptor signaling

Publication date: Available online 10 March 2017
Source:Molecular and Cellular Endocrinology
Author(s): Moray J. Campbell
Bioinformatics applies unbiased approaches to develop statistically-robust insight into health and disease. At the global, or "20,000 foot" view bioinformatic analyses of vitamin D receptor (NR1I1/VDR) signaling can measure where the VDR gene or protein exerts a genome-wide significant impact on biology; VDR is significantly implicated in bone biology and immune systems, but not in cancer. With a more VDR-centric, or "2000 foot" view, bioinformatic approaches can interrogate events downstream of VDR activity. Integrative approaches can combine VDR ChIP-Seq in cell systems where significant volumes of publically available data are available. For example, VDR ChIP-Seq studies can be combined with genome-wide association studies to reveal significant associations to immune phenotypes. Similarly, VDR ChIP-Seq can be combined with data from Cancer Genome Atlas (TCGA) to infer the impact of VDR target genes in cancer progression. Therefore, bioinformatic approaches can reveal what aspects of VDR downstream networks are significantly related to disease or phenotype.



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Restored Plasma Anandamide and Endometrial Expression of Fatty Acid Amide Hydrolase in Women With Polycystic Ovary Syndrome by the Combination Use of Diane-35 and Metformin

Publication date: Available online 11 March 2017
Source:Clinical Therapeutics
Author(s): Na Cui, Xiaoye Feng, Zhiming Zhao, Jie Zhang, Yueming Xu, Luning Wang, Guimin Hao
PurposePolycystic ovary syndrome (PCOS) is a metabolic and endocrinal disorder affecting a number of women of reproductive age. We aimed to reveal the correlation between the endocannabinoid system and PCOS, which may provide a new therapeutic target for PCOS treatment.MethodsSerum levels of anandamide and 2-arachidonoylglycerol andexpression of cannabinoid receptors and fatty acid amide hydrolase (FAAH) in the endometrium were compared between women with PCOS and infertile women without PCOS, as well as women with PCOS before and after treatment with Diane-35 and metformin. Cannabinoid receptors and FAAH in the endometrium were stained using the immunohistochemical method. Results were analyzed by calculating integrated optical density.FindingsPlasma anandamide was increased significantly in women with PCOS compared with infertile women without PCOS. Treatment with Diane-35 and metformin reversed this increase in women with PCOS. No significant difference in 2-arachidonoylglycerol was observed between the infertile women with or without PCOS. The women with PCOS had lower endometrial expression of FAAH compared with infertile women without PCOS, whereas no significant difference in endometrial expression of cannabinoid receptors was observed between the women with PCOS and infertile women without PCOS. We found that after treatment with Diane-35 and metformin, FAAH expression tended toward a significant increase compared with women before the treatment.ImplicationsEndocannabinoid system may be involved in the progression of PCOS, and serum anandamide could serve as a potential biomarker of clinical diagnosis of PCOS.



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A Real-world Cost-effectiveness Analysis of Sevelamer Versus Calcium Acetate in Korean Dialysis Patients

Publication date: Available online 11 March 2017
Source:Clinical Therapeutics
Author(s): Jang-Hee Cho, Hye Min Jang, Hee-Yeon Jung, Ji-Young Choi, Sun-Hee Park, Chan-Duck Kim, Chul Woo Yang, Dong-Chan Jin, Yong-Lim Kim
PurposeSevelamer, a noncalcium phosphate binder, has been shown to attenuate the progression of vascular calcification and improve survival in patients with chronic kidney disease undergoing dialysis compared with calcium-based binders. Using real-world data from a cohort study and the Health Insurance Review and Assessment Service database, we conducted a cost-effectiveness analysis comparing sevelamer with calcium acetate in dialysis patients from the perspective of the National Health Insurance Service in South Korea.MethodsData (demographic, diagnostic, laboratory, and survival) from 4674 patients undergoing dialysis enrolled in a multicenter prospective cohort study conducted in South Korea between September 2008 and December 2012 were linked to phosphate binder use, hospitalization, and cost data available from the Health Insurance Review and Assessment Service database. After propensity score matching, a dataset comprising comparable patients treated with either sevelamer (n = 501) or calcium acetate (n = 501) was used in the cost-effectiveness analysis. A Markov model was used to estimate costs, life years, quality-adjusted life years (QALYs), and cost-effectiveness over each patient's lifetime. Forty-month treatment-specific overall survival (OS) data available from the dataset were extrapolated to lifetime survival with the use of regression analysis.FindingsPatients had a mean age of 56.3 years and were treated with dialysis for a mean duration of 67.6 months. Compared with calcium acetate, sevelamer was associated with an incremental cost of South Korean Won (₩) 12,246,911 ($10,819) and a gain of 1.758 life years and 1.108 QALYs per patient. This outcome yielded incremental cost-effectiveness ratios of ₩6,966,350 ($6154) and ₩11,057,699 ($9768) per life year and QALY gained, respectively. Conclusions regarding sevelamer's cost-effectiveness were insensitive to alternative assumptions in time horizon, discount rate, hospitalization rate, costs, and health utility estimates, and they remained consistent in 100% of the model iterations, considering a willingness-to-pay threshold of ₩31,894,720 ($28,176) per QALY gained.ImplicationsThis analysis of real-world data found that sevelamer's higher cost relative to calcium acetate was adequately offset by improved survival among patients undergoing dialysis in South Korea. As such, sevelamer offers good value for money, representing a cost-effective alternative to calcium-based binders.



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Combining stable insect cell lines with baculovirus-mediated expression for multi-HA influenza VLP production

Publication date: Available online 11 March 2017
Source:Vaccine
Author(s): Daniela P. Sequeira, Ricardo Correia, Manuel J.T. Carrondo, António Roldão, Ana P. Teixeira, Paula M. Alves
Safer and broadly protective vaccines are needed to cope with the continuous evolution of circulating influenza virus strains and promising approaches based on the expression of multiple hemagglutinins (HA) in a virus-like particle (VLP) have been proposed. However, expression of multiple genes in the same vector can lead to its instability due to tandem repetition of similar sequences. By combining stable with transient expression systems we can rationally distribute the number of genes to be expressed per platform and thus mitigate this risk. In this work, we developed a modular system comprising stable and baculovirus-mediated expression in insect cells for production of multi-HA influenza enveloped VLPs. First, a stable insect High Five cell population expressing two different HA proteins from subtype H3 was established. Infection of this cell population with a baculovirus vector encoding three other HA proteins from H3 subtype proved to be as competitive as traditional co-infection approaches in producing a pentavalent H3 VLP. Aiming at increasing HA expression, the stable insect cell population was infected at increasingly higher cell concentrations (CCI). However, cultures infected at CCI of 3×10⁶cells/mL showed lower HA titers per cell in comparison to standard CCI of 2×10⁶cells/mL, a phenomenon named "cell density effect". To lessen the negative impact of this phenomenon, a tailor-made refeed strategy was designed based on the exhaustion of key nutrients during cell growth. Noteworthy, cultures supplemented and infected at a CCI of 4×10⁶cells/mL showed comparable HA titers per cell to those of CCI of 2×10⁶cells/mL, thus leading to an increase of up to 4-fold in HA titers per mL. Scalability of the modular strategy herein proposed was successfully demonstrated in 2L stirred tank bioreactors with comparable HA protein levels observed between bioreactor and shake flasks cultures. Overall, this work demonstrates the suitability of combining stable with baculovirus-mediated expression in insect cells as an efficient platform for production of multi-HA influenza VLPs, surpassing the drawbacks of traditional co-infection strategies and/or the use of larger, unstable vectors.



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Health professional feedback on HPV vaccination roll-out in a developing country

Publication date: Available online 11 March 2017
Source:Vaccine
Author(s): Collette Venturas, Kanayo Umeh
BackgroundWorldwide, Zambia has the highest cervical cancer incidence rates (58.4/100,000 per year) and mortality rates (36.2/100,000 per year). The human papilloma virus (HPV) vaccine is considered a vital preventative measure against cervical cancer, particularly in sub-Saharan countries, such as Zambia. Past research suggests health professionals' experiences with HPV vaccination rollout can have practical implications for effective delivery.ObjectiveTo explore health professionals' perspectives on the HPV vaccination programme in Zambia.MethodsResearcher travelled to Zambia and conducted semi-structured interviews with fifteen health professionals working in private, government, and missionary clinics/hospitals. Observation was conducted for triangulation purposes. Thematic analysis was used to analyse the data.FindingsFive main themes emerged; medical misconceptions about the HPV vaccination, particularly with regards to infertility; fear of the unknown, including possible side effects and inadequate empirical research; need for prior desensitisation to resolve cultural barriers prior to vaccination rollout; a rural-urban divide in health awareness, particularly in relation to cancer vaccines; and economic concerns associated with access to the HPV vaccination for most of the Zambian population.ConclusionOverall, the findings indicate that an essential avenue for facilitating HPV vaccination rollout in Zambia is by implementing a pre-rollout community effort that removes or softens cultural barriers, particularly in rural areas. It is also essential to correct erroneous HPV presumptions health professionals may have around infertility. Affordability remains a seemingly intractable hindrance that hampers HPV vaccination rollout in Zambia.



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Does seasonal vaccination affect the clinical presentation of influenza among the elderly? A cross-sectional analysis in the outpatient setting in France, 2003–2014

Publication date: Available online 11 March 2017
Source:Vaccine
Author(s): Anne Mosnier, Isabelle Daviaud, Saverio Caini, Hervé Berche, Jean-Michel Mansuy, Sylvie van der Werf, Jean Marie Cohen, Bruno Lina
Vaccine-induced protection against influenza is not optimal, however it has been suggested that the vaccine may reduce the severity of symptoms among those who develop illness despite being vaccinated. We tested this hypothesis within a countrywide, sentinel general practitioners-based surveillance system in France. We included 2277 individuals aged 65years or older (of whom 1293 had been vaccinated against influenza, 56.8%) who consulted a general practitioner because of an acute respiratory infection (ARI) during 2003–2014. All patients were taken a nasopharyngeal swab, and information was collected on demographic characteristics and symptoms at disease onset. All specimens were tested for respiratory viruses and, if positive for influenza, the virus type and subtype were determined. We compared the average maximum temperature and the frequency of each symptom, between non-vaccinated and vaccinated influenza patients. We then used logistic regression models to calculate the odds of presenting with each symptom between vaccinated vs. non-vaccinated patients, adjusting by age group, virus (sub)type and season. Overall, 675 ARI patients (29.6%) tested positive for influenza. The A(H3) virus caused the majority of cases (55.1%), followed by influenza B (22.9%), A not-subtyped (11.7%), and A(H1) (10.3%) viruses. Compared to non-vaccinated influenza patients, those who had been vaccinated had a slightly reduced maximum temperature and presented less frequently with myalgia, shivering and headache. In stratified analyses, the observed effect was limited to patients infected with A(H3) or type B viruses. After adjusting by age group, virus (sub)type and season, the difference remained statistically significant only for headache, which was less frequent among vaccinated individuals (odds ratio 0.69, 95% confidence intervals 0.48–0.98). In conclusion, the vaccine was found to be modestly associated with less severe clinical presentation of influenza among the elderly. Our findings reinforce the need for influenza vaccines providing better protection.



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