One-year prospective real-world assessment of effectiveness and safety of erenumab in migraine prevention: results of the French FHU INOVPAIN registry study.

BACKGROUND: Randomized clinical trials have demonstrated efficacy and safety of erenumab. The aim of this study is to evaluate the effectiveness and safety of erenumab in a real-world setting in French patients with migraine associated with extreme unmet needs. METHODS: This is a one year-prospective real-word study with enrolment of all consecutive adult patients included in the FHU InovPain registry who participated in a compassionate erenumab use program. RESULTS: Of 144 patients included, 140 patients (82.1% female / mean age of 50.9 ± 11.4) received at least one dose of erenumab and were concerned by effectiveness and safety assessment. All patients had failed 11 oral preventive treatments. Most of them suffered from chronic migraine (88.6%) and presented a medication overuse (90.7%) at baseline. Thirty-eight (27.1%) discontinued treatment during the 12-month follow-up, with 22 (15.7%), 11 (7.9%) and 5 (3.6%) patients before 3, 6 or 9 months of treatment. The proportion of ≥ 50% responders at M3, M6, M9 and M12 was 74/140 (52.9%), 69/118 (58.5%), 61/107 (57.0%) and 60/102 (58.8%) respectively. At M3, the rate of reversion from chronic migraine to episodic migraine was 57.3% and the rate of transition from medication overuse to non-overuse was 46.5%. For monthly migraine days, the median (IQR) was 18.0 (13.0-26.0), 9.0 (5.0-17.0), 7.5 (5.0-14.0), 8.0 (5.0-12.5) and 8.0 (5.0-12.0) at M0, M3, M6, M9 and M12 respectively. For HIT-6 score, the median (IQR) was 68.0 (63.8-73.3), 60.0 (54.0-65.0), 60.0 (50.3-53.0), 59.0 (50.0-63.0) and 58.0 (50.0-62.9) at M0, M3, M6, M9 and M12 respectively. Fifty-three (37.9%) patients reported at least one of the following adverse events: cutaneous erythema and/or pain at the injection site for 42 (30%) patients, constipation for 22 (15.7%) patients, muscle spasm for 2 (1.4%) patients, alopecia for one (0.7%) patient and blood pressure increase in one (0.7%) patient. There was no serious adverse event. One female patient became pregnant after 5 months of exposure to erenumab with a safe evolution after treatment discontinuation. CONCLUSION: This first French real-world study related to migraine prevention with CGRP-mAbs confirms effectiveness and safety of erenumab in patients with extreme unmet needs.

[Characteristics and management of Uveitis-Glaucoma-Hyphema syndrome]. / Caractéristiques et prise en charge du syndrome Uvéite-Glaucome-Hyphéma.

INTRODUCTION: Uveitis-Glaucoma-Hyphema syndrome (UGH) is caused by mechanical chafing of anterior segment structures by an intraocular lens, especially an anterior chamber lens. The objective of this study was to characterise the clinical course and risk factors of UGH syndrome at a time when posterior chamber implantation is the gold standard. PATIENTS AND METHODS: This was a retrospective study of 30 cases of UGH syndrome managed between January 2014 and September 2018. Data from the initial clinical examination, the type of implant involved and the clinical management were analysed. RESULTS: Thirty eyes of 28 patients were included. Intra ocular lenses were iris-sutured (15/30, 50 %), in the bag (6/30, 20 %), scleral-fixated (4/30, 13.3 %), in the ciliary sulcus (3/30,10 %) or "in and out" (2/30, 6.7 %). Initial management was medical (18 eyes) or surgical (12 eyes). Surgical procedures were explantation (n=4), IOL repositioning (n=7) or trabeculectomy (n=1). Recurrences occurred with medical treatment (9/18), but not in the surgical group (p=0.02). Ocular hypertension became chronic in 19 cases out of 30 (63.3 %). CONCLUSION: UGH syndrome can be caused by any type of pseudophakic lens. An intraocular lens in the bag should not rule out the diagnosis. Despite the decreasing popularity of anterior chamber intraocular lens implantation, UGH syndrome remains a current condition and must be recognised in order to adapt therapeutic management.

I-FABP is a Novel Marker for the Detection of Intestinal Injury in Severely Injured Trauma Patients.

BACKGROUND: Intestinal injury is a rare injury in multiply traumatized patients, and its diagnosis remains difficult. Delayed diagnosis of an intestinal injury increases the risk of sepsis, multiple organ failure and mortality. The intestinal fatty acid-binding protein (I-FABP) is solely expressed in the intestine and is released extracellulary after tissue damage. This study evaluates the validity of I-FABP as an early biomarker to detect an abdominal injury and particularly an injury to the intestine. PATIENTS AND METHODS: Patients with an Abbreviated Injury Scale (AIS) score for abdominal body region (AIS abdomen) ≥3 were included in this study from 07/2006 to 12/2014. Of those, ten patients retrospectively had an intestinal injury (int. injury). According to the Injury Severity Score and the AIS abdomen, corresponding patients with an abdominal injury but without an intestinal injury (no int. injury) were included for matched-pair analysis. Twenty healthy volunteers served as controls. Plasma I-FABP levels were measured at admission to the emergency room and up to 10 days daily (d1-d10). RESULTS: Median I-FABP levels were significantly higher in the "int. injury" group compared to the "no int. injury" group [2101.0 pg/ml (IQR = 1248.1-4117.8) vs. 351.4 pg/ml (IQR = 287.6-963.3), p < 0.05]. Furthermore, I-FABP levels of both groups were significantly higher compared to the control group [Ctrl: 127.2 pg/ml (IQR = 57.4-310.6), p < 0.05]. The time course of I-FABP levels showed a peak on the day of admission and a decline to the control levels in the further post-traumatic course. The development of complications such as single- or multi-organ failure, sepsis, acute respiratory distress syndrome, pneumonia and mortality was higher in the "int. injury" group; however, this difference was not statistically significant. CONCLUSION: This study confirmed our previous observation that I-FABP might be used as a suitable early biomarker for the detection of abdominal injuries in general. In addition and more specific, I-FABP may be a useful and promising parameter in the diagnosis of intestinal injuries.

SkinExplorer: a new high-tech platform to interact inside the skin by immersive virtual 3D cutaneous environment.

BACKGROUND: The confocal laser scanning microscope allows performing acquisition of several histological sections with precise visual morphological landmarks and their reconstruction. A powerful and modern confocal microscope enables to quickly reconstruct virtual 3D models. OBJECTIVE: The main goal was to develop a new platform to reconstruct complex mosaic serial data, interact with it in an immersive 3D environment, and give to the observers a feeling of 'presence' inside the skin. METHOD: We have developed novel methods that transform the data into alternative representation, well-suited to explore cutaneous structures in detail and to observe fields of data from different points of view. This new way of data reconstruction in volume requires optimization of intensities, automatic matching algorithms and depth alignment. RESULTS AND CONCLUSION: The new platform - SkinExplorer evolves as a 3D exploration prototype. This technology provides an immersive virtual environment to explore cutaneous microstructures. Several serial histological sections can be matched by stacks, aligned in depth by sections and merged together to be visualized as a whole. All these time-consuming steps have been dramatically speed-up using rapid image processing. The advantages of using virtual reality technologies such as the ones used in the SkinExplorer platform are automatic matching, precise alignment, better data perception, lower memory requirement, and higher quantity of simultaneously displayed data. This platform can render volumetric data and isosurfaces, separately or both at the same time. Lighting and depth perception are enhanced using 'Sphere Mapping', 'Ambient Occlusion', and 'Halo' methods when displaying iso-surfacic volume models with high complexity depth. The assets of the platform are to interpret complex three-dimensional data, to observe and explore 3D virtual models, and to show effects of cosmetic treatments.

Disrupted intracellular redox balance of the diplomonad fish parasite Spironucleus vortens by 5-nitroimidazoles and garlic-derived compounds.

The 5-nitroimidazole, metronidazole, has traditionally been employed in veterinary medicine to treat a range of infections including the diplomonad fish parasite Spironucleus. This study aims to determine the mode of action of metronidazole on Spironucleus vortens, including the specific mechanism of activation of the pro-drug and subsequent cellular targets of the drug metabolites. Due to the ban on use of metronidazole in the treatment of production animals in Europe and USA, garlic-derived compounds were also investigated as natural alternatives to metronidazole chemotherapy. Scanning electron microscopy (SEM) provided an overview of gross cellular damage caused by metronidazole and garlic derivatives. Proteomic analyses by 2D gel electrophoresis identified the proteins involved in specific covalent adduct formation with nitroimidazoles. Furthermore, thioredoxin reductase (TrxR) activity and non-protein thiol concentration were assayed in extracts of S. vortens before and after treatment with nitroimidazoles and garlic-derivatives. Metronidazole and garlic-derived compounds caused severe damage of trophozoites indicated by membrane blebbing and lysed cell debris. Analysis of the S. vortens proteome identified several proteins capable of specific nitroimidazole binding, including; uridine phosphorylase, enolase, protein disulphide isomerase, aminoacyl-histidine dipeptidase and malic enzyme. Of the compounds tested, metronidazole and the garlic-derived compound ajoene were the most effective at inhibiting TrxR activity and depleting non-protein thiols. These data suggest TrxR-mediated activation of nitroimidazoles, leading to depletion of non-protein thiols. Redox imbalance due to antioxidant failure is implicated as the mode of action of nitroimidazoles and garlic-derived compounds, ultimately leading to cell death. Possible synergy between garlic derivatives and metronidazole should be further investigated in vitro in order to determine their theoretical implications.

Consideration on a few aspects of the stability studies post licensure.

Stability studies represent a significant workload for both manufacturers and regulatory reviewers and therefore a careful selection of the study design and of the stability indicator test is required to make sure that the study will provide the relevant information. Moreover, alternatives to the existing regulatory approaches should be favoured in order to better or quicker analyze the impact of a specific change. In this article, examples of alternative approaches are given. For the stability monitoring study, emphasis is put on the bulk stability program. Concerning comparability stability study, two case studies illustrating how accelerated stability studies could be used to support manufacturing changes are presented.

Stability post-licensure: compatibility container content - a practical case study.

Numerous variations to a manufacturing process may take place during the life cycle of a vaccine. To support these variations, the regulator requires providing stability data according to the existing ICH guidelines; these have been designed for documenting the licence of a new vaccine. Comparative studies and adapted stability designs specific to the variation will give far more confidence to the manufacturer and the regulator than the classical model. The following case study applied to a change of a stopper illustrates this approach.

Structure and content of the Entamoeba histolytica genome.

The intestinal parasite Entamoeba histolytica is one of the first protists for which a draft genome sequence has been published. Although the genome is still incomplete, it is unlikely that many genes are missing from the list of those already identified. In this chapter we summarise the features of the genome as they are currently understood and provide previously unpublished analyses of many of the genes.

In vitro activity of hexadecylphosphocholine (miltefosine) against metronidazole-resistant and -susceptible strains of Trichomonas vaginalis.

OBJECTIVES: Trichomonas vaginalis is the causative agent of trichomoniasis, a sexually transmitted disease with worldwide significance. Trichomoniasis can be treated with metronidazole; however, resistant strains of T. vaginalis have been isolated and there is a lack of useful alternative drugs. The aim of the present study was to examine the activity of hexadecylphosphocholine (HePC; miltefosine), a membrane-active alkylphospholipid, that is licensed as an antileishmanial agent against T. vaginalis. METHODS: The efficacy of HePC after 30 min, 1 h, 16 h and 24 h against four different T. vaginalis strains (with varying resistance to metronidazole) was evaluated. RESULTS: It was shown that all isolates, including the metronidazole-resistant strains, were susceptible to HePC, with EC50s of between 8 and 40 microM and EC90s of between 8 and 80 microM depending on time and on the medium used for the experiments. Treatment of trichomonads with HePC resulted in rounding up and, at concentrations of >or=40 microM, in subsequent total lysis of the organisms. CONCLUSIONS: HePC may be a promising new candidate for the treatment of trichomoniasis.

Validation of a new ELISA method for in vitro potency assay of hepatitis B-containing vaccines.

The discontinuation of the Auszyme kit used by vaccine manufacturers and national control laboratories to determine the Hepatitis B surface antigen (HBsAg) content of hepatitis B vaccines has led GlaxoSmithKline (GSK) to develop an alternative inhibition ELISA method. Validation of this ELISA was performed according to The International Conference of Harmonization and reproducibility was assessed in a feasibility study with four Official Medicines Control Laboratories (OMCLs). The dose response curve demonstrated linearity (R2>0.99) in the range of 60-360 ng/ml HBsAg. The repeatability (CV<7%), intermediate precision (CV<10%) and accuracy (91-113% recovery) were similar to the Auszyme method. The commercial antibodies used in the assay were shown to contain antibodies that bind to a protective epitope of HBsAg and the specificity of the method for HBsAg was demonstrated. There was a good concordance with the Auszyme method, although the ELISA yielded higher results (25.3 vs. 24.4 micro.g/ml for Engerix-B (n=64), 28.9 vs. 27.0 micro.g/ml for Twinrix (n= 69) and 25.5 vs. 21.6 micro.g/ml for Infanrix penta (n=62)). The method was successfully transferred to the four OMCLs. It has been demonstrated that the ELISA is suitable for its intended purpose with hepatitis B-containing vaccines from GSK and thus could be used for these vaccines by national control laboratories and authorities. Further validation studies should focus on the use of this ELISA with vaccines from other manufacturers.

[MRI sequences in the detection of cavernous angiomas]. / Séquences de résonance magnétique dans la détection de cavernomes.

We prospectively evaluated 30 patients with CNS cavernous angioma with a high field (1.5T) magnetic resonance imager. In all patients the MRI protocol included: gradient echo T1*-weighted imaging, spin echo T2*-weighted imaging and gradient echo T2*-weighted imaging. We evaluated each case for the number of lesions detected on each sequence. Gradient echo T2*-weighted imaging with a long TE (TE: 35ms) was the most sensitive sequence for the detection of cavernous angiomas allowing detection of small lesions that were not identified on the other sequences.

Molecular and immunological characterization of arginine kinase from the Indianmeal moth, Plodia interpunctella, a novel cross-reactive invertebrate pan-allergen.

IgE recognition of indoor allergens represents a major cause of allergic asthma in atopic individuals. We found that 52 of 102 patients suffering from allergic symptoms indoors contained IgE Abs against allergens from the Indianmeal moth (Plodia interpunctella), a ubiquitous food pest. Using serum IgE from a moth-sensitized patient we screened an expression cDNA library constructed from P. interpunctella larvae. cDNAs coding for arginine kinase (EC 2.7.3.3), a 40-kDa enzyme commonly occurring in invertebrates that is involved in the storage of such high-energy phosphate bonds as phosphoarginine, were isolated. Recombinant moth arginine kinase, designated Plo i 1, was expressed in Escherichia coli as a histidine-tagged protein with enzymatic activity, and purified to homogeneity by nickel chelate affinity chromatography. Purified recombinant arginine kinase induced specific basophil histamine release and immediate as well as late-phase skin reactions. It reacted with serum IgE from 13 of the 52 (25%) moth-allergic patients and inhibited the binding of allergic patients' IgE to an immunologically related 40-kDa allergen present in house dust mite, cockroach, king prawn, lobster, and mussel. Our results indicate that arginine kinases represent a new class of cross-reactive invertebrate pan-allergens. Recombinant arginine kinase may be used to identify a group of polysensitized indoor allergic patients and for immunotherapy of these individuals.

Recombinant dissection of myosin heavy chain of Toxocara canis shows strong clustering of antigenic regions.

Myosins from nematode parasites elicit strong humoral and cellular immune responses and have been investigated as vaccine candidates. In this study we cloned and sequenced a cDNA coding for myosin heavy chain from Toxocara canis, a nematode parasite of canids which may also infect humans and cause various unspecific symptoms. To determine the major antigenic regions the myosin heavy chain was systematically dissected into ten overlapping recombinant fusion polypeptides which were purified by metal chelate chromatography. Single fragments were then tested for their IgG reactivity in sera from toxocarosis patients and healthy probands. Two regions, one region at the mid to carboxy-terminal end of the head domain and one region in the rod domain, were identified as major antigens, which in combination were positive with 86% of the sera. The other domains were less reactive. This shows that the patients' IgG reactivity was not directed evenly against all parts of the molecule, but was rather clustered in few regions.

Effects of miltefosine and other alkylphosphocholines on human intestinal parasite Entamoeba histolytica.

The protozoan parasite Entamoeba histolytica is the cause of amoebic dysentery and liver abscess. It is therefore responsible for significant morbidity and mortality in a number of countries. Infections with E. histolytica are treated with nitroimidazoles, primarily with metronidazole. At this time, there is a lack of useful alternative classes of substances for the treatment of invasive amoebiasis. Alkylphosphocholines (alkyl-PCs) such as hexadecyl-PC (miltefosine) were originally developed as antitumor agents, but recently they have been successfully used for the treatment of visceral leishmaniasis in humans. We examined hexadecyl-PC and several other alkyl-PCs with longer alkyl chains, with and without double bond(s), for their activity against two strains of E. histolytica. The compounds with the highest activity were oleyl-PC, octadecyl-PC, and nonadecenyl-PC, with 50% effective concentrations for 48 h of treatment between 15 and 21 microM for strain SFL-3 and between 73 and 98 microM for strain HM-1:IMSS. We also tested liposomal formulations of these alkyl-PCs and miltefosine. The alkyl-PC liposomes showed slightly lower activity, but are expected to be well tolerated. Liposomal formulations of oleyl-PC or closely related alkyl-PCs could be promising candidates for testing as broad-spectrum antiprotozoal and antitumor agents in humans.