Askanas et al., Los Angeles, USA Pathophysiology of inflammatory and PD0325901 autoimmune myopathies M.C. Dalakas, Philadelphia,

USA Myositis or dystrophy? Traps and pitfalls O. Benveniste, et al., Paris, France Therapy of polymyositis and dermatomyositis I. Marie, Rouen, France “
“Inflammatory or necrotizing myopathies, myositides and other acquired myopathies, new insight in 2011 Benveniste O et al., Paris, France Observations on the classification of the inflammatory myopathies Hilton-Jones D, Oxford, United Kingdom Pathogenic aspects of dermatomyositis, polymyositis and overlap myositis Gherardi RK, Créteil, France Sporadic inclusion-body myositis: conformational multifactorial aging-related degenerative muscle disease associated with proteasomal and lysosomal inhibition, endoplasmic reticulum stress, and accumulation of amyloid-β42 oligomers and phosphorylated tau Askanas V et al., Los Angeles, USA Pathophysiology

of inflammatory and autoimmune myopathies Dalakas MC, Athens, Greece Myositis or dystrophy? Traps and pitfalls Benveniste O et al., Paris, France Therapy of polymyositis BLZ945 clinical trial and dermatomyositis Marie I, Rouen, France “
“Inflammatory or necrotizing myopathies, myositides and other acquired myopathies, new insight in 2011 Benveniste O et al., Paris, France Observations on the classification of the inflammatory myopathies Hilton-Jones D, Oxford, United Kingdom Pathogenic aspects of dermatomyositis, polymyositis and overlap myositis Gherardi RK, Créteil, France Sporadic inclusion body myositis:

conformational multifactorial aging-related degenerative muscle disease associated with proteasomal and lysosomal inhibition, endoplasmic reticulum stress, and accumulation of amyloid-β42 oligomers and phosphorylated tau Askanas V et al., Los Angeles, USA Pathophysiology of inflammatory and autoimmune myopathies Dalakas MC, Philadelphia, USA Myositis or dystrophy? Traps and pitfalls Benveniste O et al., Paris, France Therapy of polymyositis and dermatomyositis Marie I, Rouen, France “
“Immune thrombocytopenic Casein kinase 1 purpura: major progress in knowledge of the pathophysiology and the therapeutic strategy, but still a lot of issues Bertrand Godeau Pathogenesis of immune thrombocytopenia Douglas B Cines, Adam Cuker, John W Semple ITP and international guidelines, what do we know, what do we need? Francesco Rodeghiero, Marco Ruggeri Thrombopoietic agents: There is still much to learn James B. Bussel, Madhavi Lakkaraja Is B-cell depletion still a good strategy for treating immune thrombocytopenia? Bertrand Godeau, Roberto Stasi Novel treatments for immune thrombocytopenia Andrew Shih, Ishac Nazi, John G. Kelton, Donald M.

Significantly higher levels of IL-2, IL-5, GM-CSF, and IFN-γ were released by flagellin-stimulated

cells AZD2281 purchase from LCFS-immunized mice (Table 3). By immunization with the cSipC + FliC mixture, the flagellin-stimulated cells produced significant levels of IL-4, IL-5, and IL-12, and cSipC-stimulated cells released relatively large amounts of IL-4, IL-10, IL-12, and TNF-α. The cSipC-stimulated cells from the cSipC-primed group released higher levels of IL-5 than the control group. The rest of the values were not significantly different. Genetically modified L. casei strains that produced a SE antigen with or without FliC-fusion were constructed. Flow cytometric analysis showed that these recombinant strains exhibited antigens on their cell surfaces. In order to investigate whether these recombinant lactobacilli have TLR5-stimulating activity, IL-8 release from stimulated Caco-2 cells was determined. The results showed that remarkable amounts of IL-8 were detected from each culture Selleck Crizotinib stimulated with recombinant L. casei producing either FliC or FliC-fusion antigens. Thus, the induction of an immune response through TLR-5 was suggested. Unexpectedly, the IL-8 accumulation evoked by the strains expressing FliC-fusion proteins

was greater than that with the strain expressing FliC alone. Because the TLR5-stimulating activity was dose dependent, this result indicated that the contact between FliC-fusion proteins of recombinant bacteria and TLR5 of Caco-2 cells was more frequent than that between cell-anchored FliC and TLR5.

According to the result of flow cytometric analysis, the two recombinant strains expressing FliC-fusion proteins displayed FliC more efficiently than the FliC-expressing strain. This too data seemed to correlate with the result of the IL-8 release assay. Thus, the difference in TLR5-stimulating activity could be explained by the unequal presence of FliC on the bacterial surface. There are other possibilities such as FliC-fusion proteins having higher TLR5-stimulating activity than FliC, or FliC-fusion proteins are more stable than FliC; however, there is no evidence to support these characteristics. In order to investigate antigen-specific acquired immune responses, C3H/HeJ mice were immunized with recombinant L. casei and purified SE antigens by i.p. injection. The production of antigen-specific antibodies was induced without additional adjuvants. Soluble cSipC showed immunogenicity to produce antigen-specific IgG. In combination with purified flagellin, soluble cSipC induced higher IgG production. McSorley et al. reported that bacterial flagellin provides an adjuvant effect on CD4+ T cells [26]. Thus, it is probably the same reason why cSipC-specific antibody production was enhanced in combination with flagellin.

Culture supernatants were then assayed for murine cytokines by ELISA using specific kits (BD Biosciences) or by multiplex ELISA biomarker assays (Aushon BioSystems, Billerica, MA, USA). Cytokine levels determined in the cultures from LNs of PBS-immunized animals were used as the initial time-point (0 h). Similarly, systemic cytokine levels in pooled or individual serum

samples drawn from Quizartinib manufacturer vaccinated animals via terminal bleeds at different time intervals after inoculation were measured by ELISA. Cytokine levels from the sera of PBS-immunized animals were considered as the initial time-point (0 h). All experiments on cytokine measurement in vivo were run two or three times yielding similar results for each experimental group. At different time-points after injection with SVP, free TLR agonist or PBS, mice were sacrificed,

draining popliteal lymph nodes harvested and digested for 30 min at 37 °C in 400 U/mL collagenase type 4 (Worthington, Lakewood, NJ, USA). Single cell suspensions were prepared by forcing digested lymph nodes through a 70-µm nylon filter membrane, then washed in PBS containing 2% FBS and counted using a Countess® cell counter (Life Technologies, Carlsbad, CA, USA). Cells were stained pairwise with antibodies against the following mouse surface cell molecules: B220 and CD11c, medroxyprogesterone CD3 and CD49b, F4/80 and Gr1 (BD Biosciences, CA, USA). The gating logic was as follows: plasmacytoid Selleck Panobinostat dendritic cells (CD11c+, B220+), myeloid dendritic cells (CD11c+, B220-), B cells (CD11c-, B220+), granulocytes (GR-1+, F4/80-), macrophages (GR-1-, F4/80+), NK T cells (CD49b+, CD3+), NK cells (CD49b+, CD3-), and T cells (CD49b-, CD3+). Similarly, SIINFEKL-loaded pentamers (Proimmune, Oxford, UK), were used along with anti-mouse CD8 and CD19 (to gate out non-specific pentamer binding).

Cell samples were then washed and immediately analyzed by flow cytometry. Data were analyzed with FlowJo software (Tree Star Inc., Ashland, OR, USA). TLR7/8 (R848) and TLR9 (CpG ODN 1826; mouse-specific B-type CpG ODN) agonists were encapsulated in synthetic polymer nanoparticles and tested for their ability to induce cytokines in vitro. R848 was chemically conjugated to PLGA and used for SVP formulation as PLGA-R848, and CpG ODN was passively entrapped into SVP as described in Section 2. Natural oligonucleotide sequences contain a phosphodiester (PO) backbone, which is susceptible to rapid hydrolytic cleavage by nucleases in vivo. Nuclease-resistant CpG sequences with a phosphorothioate (PS) backbone have been shown to have superior activity to PO-CpG in vivo. Both PS and PO forms of the immunostimulatory CpG ODN 1826 sequence (PS-CpG 1826 and PO-CpG 1826) were evaluated.

In the USA, this adolescent peak of invasive meningococcal disease is associated with a higher fatality rate than that in infants

or children [4]. In the USA, the aggregate of cases caused by serogroups C (30.9%), W-135 and non-groupables SB203580 concentration (8.9%), and Y (25.2%) together tend to account for the majority of meningococcal disease in adolescents and young adults [5] and [6]. In Europe in 2006, the majority of cases of meningococcal disease were caused by serogroups B and C, with a small proportion of cases caused by serogroups W-135 and Y [7]. The dynamic nature of meningococcal disease epidemiology was illustrated by a dramatic increase in the proportion of cases caused by serogroup Y in the USA, from 2% during 1989–1991 to 28% during 1997–2003 [8]. Similar trends have been reported in Latin America. In Colombia, serogroup Y has increased from 0% in 1994 to 50% in 2006 [9], whereas in Argentina, the latest surveillance in 2008 reports that serogroup

W-135 AZD0530 manufacturer makes up 28% of overall disease versus 6% in 2006 [10]. These examples demonstrate the unpredictable and changing meningococcal disease epidemiology and, therefore, the need for broad protection against meningococcal disease. When a quadrivalent meningococcal conjugate vaccine (MCV4) was licensed in the USA, it was immediately recommended for use in adolescents by the US Advisory Committee on Immunization Practices (ACIP). As the number of vaccines recommended for adolescents is increasing; current ACIP recommendations state that the combined tetanus (T), reduced-antigen diphtheria (d), and reduced-antigen acellular pertussis (ap) vaccine (Tdap), human papillomavirus (HPV) vaccine, and MCV4 be administered to adolescents 11–18 years of age, and if possible, should be given at the same visit [11]. Among adolescents, compliance with recommended vaccination visits is low, as multiple visits for vaccination may not be seen as a priority for otherwise

healthy individuals. In the USA in 2007, estimated vaccination coverage rates among adolescents 13–17 years of age fell well short of the Healthy People Mephenoxalone 2010 90% coverage target rate [12] for MCV4 (32.4%), Td or Tdap (72.3%), and HPV vaccine (25.1%) [13]. Concomitant use of these vaccines would minimize required physician visits for adolescents, and could lead to increased compliance and overall coverage. It is therefore important that studies are performed to analyse the immunogenicity and tolerability of concomitant use of these vaccines. This Phase III study evaluated an investigational quadrivalent meningococcal CRM197 conjugate vaccine, MenACWY-CRM, developed by Novartis Vaccines, when administered concomitantly or sequentially with Tdap and HPV. Between July 2007 and April 2008, a Phase III, single-centre, open-label, controlled, randomized study (V59P18; clinicaltrials.

Children with CP have difficulties with co-ordination and motor planning. Providing resistance in non-functional tasks (repetitive leg presses) will not enhance motor learning or translate to improvements of functional performance. We need Gemcitabine to consider the context in which we train and measure ambulatory performance using measures of habitual physical activity (Clanchy et al 2011). We should consider the density of training and

whether the number of repetitions is sufficient to drive muscle plasticity. Current research suggests the dose and density of most neurorehabilitation frequently may not be sufficient to drive neuroplasticity (Nielsen and Cohen 2008). This needs to be considered in future trials aimed at improving ambulatory performance. “
“Summary of: Stafne SN et al (2012) Regular exercise during pregnancy to prevent gestational diabetes. Obstet Gynecol 119: 29–36. [Prepared by Nora Shields, CAP Enzalutamide cost Editor.] Question: Does a 12-week exercise program prevent gestational diabetes and improve insulin resistance in healthy pregnant women with normal body mass index (BMI)? Design: Randomised, controlled trial with concealed allocation and blinded outcome assessment. Setting: Two University hospitals

in Norway. Participants: White adult women with a single fetus. High-risk pregnancies or diseases that would interfere with participation were exclusion criteria. Adenosine Randomisation of 855

participants allocated 429 to the exercise group and 426 to a control group. Interventions: Both groups received written advice on pelvic floor muscle exercises, diet, and lumbo-pelvic pain. In addition, the intervention group participated in a standardised group exercise program led by a physiotherapist, once a week for 12 weeks, between 20 and 36 weeks gestation. The program included 30–35 minutes low impact aerobics, 20–25 minutes of strength exercises using body weight as resistance and 5–10 minutes of stretching, breathing, and relaxation exercises. They were also encouraged to follow a 45-minute home exercise program at least twice a week. The control group received standard antenatal care and the customary information given by their midwife or general practitioner. Outcome measures: The primary outcomes were the prevalence of gestational diabetes, insulin resistance estimated by the homeostasis model assessment method (HOMA-IR), and fasting insulin and oral glucose tolerance tests at baseline and at the end of the training period. Fasting and 2-hour glucose levels were measured in serum by the routine methods. Gestational diabetes was diagnosed as fasting glucose level 2-hour value ≥7.8 mmol/L. Secondary outcome measures were weight, BMI, and pregnancy complications and outcomes. Results: 702 participants completed the study.

Therefore, for the purpose of our study, we treated them as middle income countries. We used individual level data from the first round of GATS in each of the 15 LMICs. GATS respondents in each country who reported working indoors (or both indoors and outdoors) but outside their home were included as participants for this study. Observations with missing values in the dependent or independent variables were dropped to SB431542 in vitro obtain a final sample for each country. The proportion of missing cases ranged from 0.1% in Uruguay to 8.5% in China (Table 1). Table 1 describes the total number of participants included in our study from each of the 15 LMICs which ranged from 1174

in Romania to 12,912 in Brazil. The GATS questionnaire includes core questions on tobacco use, SHS exposure at work and in the home, and socio-demographic information. For the present study, the dependent variable was ‘living in a smoke-free home’. A participant was classified as living Doxorubicin in a smoke-free home if he/she replied ‘never’ to the question: How often does anyone smoke inside your home? If the participant responded ‘daily’,

‘weekly’, ‘monthly’, or ‘less than monthly’, he/she was considered as not living in a smoke-free home. The independent variable was ‘being employed in a smoke-free workplace’. The participant was classified as employed in a smoke-free workplace if he/she answered ‘no’ to the question: During the past 30 days, did anyone smoke in the indoor areas where you work? The potential confounders included were: age group, gender, residence, education, occupation,

current smoking, current smokeless tobacco (SLT) use and number of household members. A country-specific very region variable was also included for India, Thailand, China, Brazil, Poland and Ukraine (this information was not available for other countries). Current SLT use was not included as a covariate for Uruguay, Romania and Turkey as there were only a very small number of users or no data on SLT use was available. In China, the occupation variable consisted of five categories rather than two as the categorization for employment differed substantially from other countries (Centers for Disease Control and Prevention, 2013b). Due to a negligible number of participants educated up to primary level in Romania, Russian Federation and Ukraine, we merged these with the ‘up to secondary level’ education category. See Supplementary Table for a detailed description of the definitions of variables used in this study. We conducted country-specific, individual level data analysis for each LMIC. We tested for bivariate associations between the independent variable with the dependent variable using Chi-square tests.

The ICD 10 (G00-05) search according to the methods described above yielded a total of 73 cases (ICD-10 database). Electronic search of discharge summaries for the terms “meningitis”, “encephalitis”, “enzephalitis”, “myelitis”, “encephalomyelitis”, and “enzephalomyelitis” yielded a total of 902 cases (clinical database). The clinical database and the ICD-10 database were merged and duplicate entries and multiple hospitalizations were again deleted. Fig. 1 provides an overview of the merging process. The diagnostic labels according

to the diagnoses listed in the discharge summary yielded Quizartinib supplier the following distribution of unique and overlapping diagnoses (Fig. 2) Applying the Brighton Collaboration algorithms yielded a distribution, which was considerably less complex ( Fig. 3). A total number of 108 cases were ruled out entirely. Diagnostic labels and BC levels of diagnostic

certainty were compared. Overall rates of agreement (ORA), positive percent agreement (PPA) and negative percent agreement (NPA) were calculated for each level of diagnostic certainty. Table 1 demonstrates AZD2281 molecular weight that ORA ranged from of 77 to 98% for ENC, MYE, and ADEM. Again, as expected for a confirmatory test, levels of positive percent agreement (PPA) were lower than values for negative percent agreement (NPA). The comparison of ASM showed 67% ORA in Level 1, but a significantly lower value at Level 2 (38%), reflecting the overlap with cases of bacterial meningitis (see Section 3.5.2). Point estimates

and 95% confidence intervals were constructed, using because the total sample size for which comparative assessments were available (n = 255) for all calculations. Table 2 shows the results for ASM, BM, ENC, MYE, and ADEM for any level of diagnostic certainty. In most instances, NPA was higher than PPA, which is consistent with a confirmatory test rather than a screening tool, as reported previously in the evaluation of BC definitions [35] and [36]. As mentioned previously, cases of BM were included as negative controls and tested against the BC definition for ASM. As expected, we found significantly lower levels of agreement between a clinical case of BM and the BC category of ASM. Of the 140 cases with an exclusive clinical diagnosis of aseptic meningitis, 96 (68.6%) fulfilled the BC definition for ASM, 44 cases did not fulfill the definition for ASM. In 39 of these discordant cases, no documented gram stain report was available upon chart review. A negative gram stain is a major criterion and required for any level of diagnostic certainty in the Brighton Collaboration definition of ASM.

Absorption with 30 μg/ml serotype 22F overnight has been reported previously [31] and [32] and unpublished data from our laboratory have shown this to further improve the specificity of the pneumococcal ELISA. The reference serum standard 89-SF (Food and Drug Administration, Bethesda MD) and samples for measurement of specific IgG to serotype 22F were pre-absorbed with C-PS at 10 μg/mL and incubated overnight at 4 °C. Horseradish peroxidase conjugated anti-human IgG and a TMB (3.3′, 5.5′-tetramethylbenzidine) substrate solution was used for detection. A high, medium, and low control

serum were used on each plate to assess assay performance and inter-assay variation. Results from an inter-laboratory comparison between the Pneumococcal Laboratory, Murdoch Childrens Selleck Imatinib Research Institute (Melbourne, Protein Tyrosine Kinase inhibitor Australia), Wyeth Vaccine Research Laboratory (USA) and the KTL laboratory (Finland) demonstrated a good correlation of serotype-specific antibody concentrations [33]. Laboratory staff members were blinded to the group allocation of each

serum sample This manuscript reports analytic results concerning the secondary purpose of the trial. Cleaned data were exported to Stata version 9.0 (Stata Corporation, College Station, Texas) for analysis. Serotype-specific antibody concentrations by ELISA were log (base e) transformed to calculate science GMC. Comparisons of serotype-specific GMC between 0 and 3 dose PCV-7 groups were performed using a two-sample

t-test. Comparisons of serotype-specific GMC before and after the PPV-23 were performed using the paired t test. Comparisons of the proportion of infants between groups with serotype-specific antibody concentrations ≥0.35 and ≥1 μg/mL were performed using Fisher’s exact test. Comparisons of serotype-specific antibody concentrations ≥0.35 and ≥1 μg/mL before and after the PPV-23 were performed using exact McNemar’s test. A p-value of <0.01 was considered statistically significant due to the multiple comparisons. There were 552 infants enrolled in the study (Fig. 1) and the characteristics of the randomized infants have been described elsewhere (15). The 552 participants represent a consent rate of 30.5%, of which 10% had withdrawn by 12 months and 15% by 17 months of age. The commonest reason for withdrawal was relocation outside the study area. No participant was withdrawn due to a reaction to any of the vaccines. The 12-month PPV-23 was administered to 245 children with all groups having blood drawn a median of 14 days (IQR 14–15 days) post booster. Two weeks following the PPV-23, GMC were significantly higher (each p < 0.001) for all PCV-7 serotypes for children that had received either 1, 2, or 3 PCV-7 doses in the primary series compared to levels prior to receiving PPV-23 ( Table 1).

Mice (n = 4–8 per group) were prime-boost immunised i.n./i.m. with 1 × 107 plaque forming units (PFU) rFPV followed by 1 × 107 PFU rVV expressing HIV-1 antigens and IL-13Rα2 or IL-4C118 antagonist as described in Table 1 under mild methoxyfluorane anaesthesia two weeks apart. Similarly groups of

mice were used as unimmunised controls. Immediately prior to delivery the viruses were diluted in phosphate buffered saline (PBS) and sonicated 20–30 s to obtain an homogeneous viral suspension, intranasal rFPV was given in a final volume of 20–25 μl and i.m. rVV were delivered, 50 μl per quadriceps. To evaluate CD8 T cell mediated protective immunity, 6 weeks post booster vaccination, immunised and unimmunised mice were challenged intranasally with 75–100 PFU of influenza virus PR8 expressing the KdGag197–205 epitope of HIV as described previously [23]. Body weight was monitored Selleck GDC973 for 9–10 days after challenge. The attenuated recombinant influenza virus PR8-KdGag197–205

incorporates the H2-Kd restricted immuno-dominant epitope AMQMLKETI [32] into the influenza virus neuraminidase stalk, constructed as described by Cukalac et al. [39]. Intra-nasal challenge of naïve BALB/c Bioactive Compound Library price (H2-Kd) mice with PR8-KdGag197–205 induces significant weight loss, followed by weight gain as the mice recover from a mild flu, over a 10 day period. The cells infected with PR8-KdGag197–205 present the MHC-I restricted HIV-Gag epitope, and in HIV Gag immunised mice CD8+ CTL specific for HIVGag197–205 will kill the infected cells limiting replication and dissemination of the recombinant influenza virus significantly reducing weight loss. The ability to maintain body weight however specifically at peak infection (4–7 days) is considered a measure of CD8+ T cell mediated protective immunity not antibody immunity. To measure systemic and mucosal T cell responses mice were euthanized at different time intervals (2 and 8 weeks) post-boost immunisation, and 10 days post influenza-KdGag197–205 challenge; spleen, genito-rectal nodes (GN) or iliac lymph nodes and Peyer’s patch (PP) were

removed and cell suspensions prepared in complete (5% FBS) RPMI as described previously [20], [40] and [41]. Allophycocyanin-conjugated KdGag197–205 tetramers were synthesised at the Bio-Molecular Resource Facility at The John Curtin School of Medical Research (BRF/JCSMR), ANU. 2–5 × 106 splenocytes or mucosal lymphocytes were stained with anti-CD8-FITCα antibody (Biolegend, USA) and Allophycocyanin-conjugated KdGag197–205 tetramer at room temperature and analysed as described previously [20], [40] and [42]. All the appropriate controls were performed and the background tetramer counts in naïve mice were found to be between 0.05 and 0.5% in spleen, 0.02–0.05% in mucosal tissue and GN. Also following KdGag197–205 tetramer staining the dissociation assays were performed as described before [21] and [43].

Aluminium-containing vaccinations against infectious diseases are adjuvanted with comparably low amounts of aluminium and are usually applied only a few times. Nevertheless, these amounts contribute to the cumulative overall human body burden of aluminium. In light of the

growing number of toxicological considerations and as a tribute to the public discussion, research in aluminium-free vaccines should be encouraged and promoted. The prevalence of allergic disease is on the rise, it is estimated that almost half the population will develop some form of allergic disease during the course of their life. Allergen-specific immunotherapy commonly consists of administering subcutaneous injections using preparations of relevant allergens (Fig. 2), with the aim to gradually desensitise the allergic patient to the causative allergen. This may be achieved through the gradual Raf inhibition release Abiraterone of natural/modified allergen extracts using a depot mediator (e.g. aluminium salts). By doing so, the natural course of the disease may be altered, being shown to redirect the immune response toward a Th1 immunoglobulin-type G profile and away from a predominant Th2 immunoglobulin-type E profile which is linked to the causative symptoms of allergy. There are various regimens for SCIT treatment (Table 1) [55]. Usually, a phase of titration of the dose upwards is followed by a maintenance

phase at a fixed dose. Some preparations allow for application intervals of up to 8 weeks, monthly injections are the recommended and customary practice. For inhalant allergies, the specified therapy duration is 3 years with up to 5 years for house dust mite allergies [55]. SCIT is usually recommended for a duration of 5 years for hymenoptera venom allergies, whereas life-long monthly therapy may be given to sub-groups of patients who have an increased risk of more severe anaphylactic reactions. These sub-groups may have co-morbidities, or be prone to

increased exposure (e.g. Bee-keepers) [56]. For a typical 3-year therapy, which would usually consist of, approximately 16 up-titration injections followed by monthly injections for a duration of 3 years, a patient will receive over 50 injections within this time-frame [57], [58] and [59]. Five years all of therapy as part of a house dust mite SCIT or hymenoptera venom allergy, >70 injections are administered in total [58]. Taking into account the subgroup of risk patients in hymenoptera venom allergy, the number of injections of this lifelong immunotherapy rises infinitely. Unlike the aforementioned vaccines, the manufacturers of SCIT products are not required to specify the amount of aluminium in their SmPCs (summary of product characteristics) or PIs (package leaflets). This is, however, in accordance to the German legislation = § 11 Arzneimittelgesetz (AMG). In Europe, 1.