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Late Onset Myasthenia Gravis Is Associated with HLA DRB1*15:01 in the Norwegian Population
Angelina H. Maniaol ,
* E-mail: angman@ous-hf.no
Affiliations Department of Neurology, Oslo University Hospital, Ullevål, Oslo, Norway, Department of Immunology, Oslo University Hospital, Rikshospitalet, Oslo, Norway
Ahmed Elsais,
Affiliations Department of Neurology, Oslo University Hospital, Rikshospitalet, Oslo, Norway, Institute of Clinical Medicine, University of Oslo, Oslo, Norway
Åslaug R. Lorentzen,
Jone F. Owe,
Affiliation Department of Neurology, Haukeland University Hospital, Bergen, Norway
Marte K. Viken,
Affiliations Department of Immunology, Oslo University Hospital, Rikshospitalet, Oslo, Norway, Department of Medical Genetics, University of Oslo, Oslo, Norway
Hanne Sæther,
Siri T. Flåm,
Affiliation Department of Immunology, Oslo University Hospital, Rikshospitalet, Oslo, Norway
Geir Bråthen,
Affiliation Department of Neurology, St. Olavs Hospital, Trondheim, Norway
Margitta T. Kampman,
Affiliations Centre for clinical research and education, University Hospital of North Norway, Tromsø, Norway, Department of Clinical Medicine, University of Tromsø, Tromø, Norway
Rune Midgard,
Affiliation Department of Neurology, Molde Hospital, Molde, Norway
Marte Christensen,
Affiliation Department of Neurology, Stavanger University Hospital, Stavanger, Norway
Anna Rognerud,
Affiliation Department of Neurology, Lillehammer Hospital, Lillehammer, Norway
Emilia Kerty,
Nils Erik Gilhus,
Affiliations Department of Neurology, Haukeland University Hospital, Bergen, Norway, Department of Clinical Medicine, University of Bergen, Bergen, Norway
Chantal M. E. Tallaksen,
Affiliations Department of Neurology, Oslo University Hospital, Ullevål, Oslo, Norway, Institute of Clinical Medicine, University of Oslo, Oslo, Norway
Benedicte A. Lie ,
Contributed equally to this work with: Benedicte A. Lie, Hanne F. Harbo
[ ... ],
Hanne F. Harbo
Angelina H. Maniaol,
Rune Midgard
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Angelina H. Maniaol Ahmed Elsais ... Hanne F. Harbo
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Acquired myasthenia gravis (MG) is a rare antibody-mediated autoimmune disease caused by impaired neuromuscular transmission, leading to abnormal muscle fatigability. The aetiology is complex, including genetic risk factors of the human leukocyte antigen (HLA) complex and unknown environmental factors. Although associations between the HLA complex and MG are well established, not all involved components of the HLA predisposition to this heterogeneous disease have been revealed. Well-powered and comprehensive HLA analyses of subgroups in MG are warranted, especially in late onset MG.
This case-control association study is of a large population-based Norwegian cohort of 369 MG patients and 651 healthy controls. We performed comprehensive genotyping of four classical HLA loci (HLA-A, -B, -C and -DRB1) and showed that the DRB1*15:01 allele conferred the strongest risk in late onset MG (LOMG; onset ≥60years) (OR 2.38, pc7.4×10−5). DRB1*13:01 was found to be a protective allele for both early onset MG (EOMG) and LOMG (OR 0.31, pc 4.71×10−4), a finding not previously described. No significant association was found to the DRB1*07:01 allele (pnc = 0.18) in a subset of nonthymomatous anti-titin antibody positive LOMG as reported by others. HLA-B*08 was mapped to give the strongest contribution to EOMG, supporting previous studies.
The results from this study provide important new information concerning the susceptibility of HLA alleles in Caucasian MG, with highlights on DRB1*15:01 as being a major risk allele in LOMG.
Citation: Maniaol AH, Elsais A, Lorentzen ÅR, Owe JF, Viken MK, Sæther H, et al. (2012) Late Onset Myasthenia Gravis Is Associated with HLA DRB1*15:01 in the Norwegian Population. PLoS ONE 7(5): e36603. https://doi.org/10.1371/journal.pone.0036603
Editor: Jianming Tang, University of Alabama at Birmingham, United States of America
Received: January 27, 2012; Accepted: April 3, 2012; Published: May 9, 2012
Copyright: © 2012 Maniaol et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Funding: The study was funded by the South-Eastern Norway Regional Health Authority and partly by grants from the Norwegian Association for Patients with Muscle Diseases (Foreningen for Muskelsyke) and Odd Fellow Society, Norway, all to AHM. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
Competing interests: The authors have declared that no competing interests exist.
Acquired myasthenia gravis (MG) is a rare autoimmune neuromuscular disease with an overall prevalence of 10–20 per 100 000 [1]. MG is caused by impaired neuromuscular transmission leading to abnormal muscle fatigability affecting in some cases only the eye muscles (ocular MG), but in most cases several muscles groups (generalised MG) [2], [3]. The muscle fatigability is mediated by pathogenic autoantibodies against the muscle acetylcholine receptors (AChR-abs) detectable in the majority of patients (80–85%) [4]. Among the remaining patients without AChR-abs, 10–50% have antibodies to the muscle specific kinase (MuSK) [5], [6]. Recent studies have revealed that some might have low-affinity AChR-abs, to date not detectable with routinely used assays [7]. MG is characterized by remarkable heterogeneity, including degree of thymus involvement and clinical presentation like age at onset, disease severity and response to treatment [8].
The two major subgroups of patients are currently classified according to age at onset: early onset MG (EOMG) and late onset MG (LOMG). Age-cut off between these subgroups differs between studies, ranging from 40 and 50 years at onset [9]. Another MG subgroup consists of patients with thymoma, which is a paraneoplastic condition that occurs in 10–15% of all MG patients and at any age [10]. Typically, EOMG shows thymus hyperplasia and a strong female preponderance, while LOMG has a male predominance and normal or atrophic thymus findings [8]. LOMG is considered to be a more heterogeneous group than EOMG. Some LOMG patients with age at onset between 40 and 50 years might represent EOMG with delayed onset [11], [12]. A subset of LOMG with detectable anti-titin antibodies (ATA) in about 50% of the cases has also been reported, whereas ATA is rarely found in EOMG [13], [14]. Thus, to define a more homogeneous group of LOMG, some clinical studies have used 60 years as age cut-off [15].
The aetiology of MG is complex and explained by a combination of genetic and unknown environmental factors [16]. The genetic associations found in MG are several [17], and the most important genetic risk factor is conferred to the human leukocyte antigen (HLA) complex, as it is for many other autoimmune diseases [18]. The first genetic studies of Caucasian MG showed different associations to HLA alleles in both Class I (HLA-A, -B and -C) and Class II (HLA-DRB1 and -DQB1), suggesting that the heterogeneity of the disease may be explained partly on a genetic basis [19]–[26]. An increased prevalence of the extended HLA A1-B8-DR3 haplotype (also called the ancestral haplotype AH 8.1) was found in patients with disease onset before the age of 40 years i.e. EOMG, while an association with the HLA-B7-DR2 haplotype was reported in patients with onset age older than 40 years i.e. LOMG. MG with thymoma has consistently not shown associations with HLA, except for a recent study reporting a positive association with the HLA-A locus [27].
Three decades ago, Compston and colleagues first addressed the different HLA genetic risk factors in EOMG and LOMG [23]. Since then, several studies have aimed to find the diseases causative locus in MG subgroups (Figure 1) [28]–[36], but the strong linkage disequilibrium (LD) in the HLA complex has long hampered this search [28], [29], [37]. There has also been lack of comprehensive HLA genotyping in population-based studies comprising a sufficient number of both EOMG and LOMG cases. The association with haplotype AH 8.1 in EOMG has been largely consistent, and several studies have suggested HLA-B8 as the predominant associated allele in this haplotype [30]–[32], [35]. In LOMG, the search for HLA risk alleles has been more challenging, partly because of limited sample sizes and the clinical heterogeneity within the subgroup. Although previous studies have pointed out HLA-B7 and/or DR2 as associated loci [23], [30], [37] and recently DR7 in a subset of nonthymomatous anti-titin antibodies (ATA) positive LOMG [35], definite HLA genetic risk factors for LOMG have not yet been established.
PowerPoint slide
Figure 1. Schematic overview of associated HLA alleles in MG.
The HLA complex on chromosome 6 with its division into three classes. Some key genes and their order on the chromosome are given. Associated HLA alleles reported earlier in Caucasian MG patients (see text for complete references) are illustrated together with the results from the present study.
https://doi.org/10.1371/journal.pone.0036603.g001
Based on this background, this study aimed to investigate a large Norwegian MG population with well defined subgroups of patients, and carry out comprehensive genotyping of HLA Class I and II loci in order to better characterise the genetic risk factors in MG subgroups In particular, we aimed to focus on finding the major HLA risk allele in the LOMG subgroup.
Patients and Controls
In this population-based study, subjects with acquired MG (≥16 years) were collected from all neurological departments and clinics with private neurologists in Norway in the period of 1.1.2005–1.11.2009. The inclusion criteria for acquired MG were at least "1 and 2" or "1 and 3" of the following criteria: 1) clinical MG, 2) neurophysiologic evidence consistent with MG (decrement >10% at 3 Hz after repetitive motor nerve stimulation, increased jitter on single-fibre electromyogram [38] or both), and 3) elevated level of acetylcholine receptor (AChR) antibodies or muscle specific kinase (MuSK) antibodies. Exclusion criteria were age <16 years, and lack of both criteria 2 and 3, mentioned above.
A total of 532 MG patients were identified, and 404 (76%) consented to participate in the genetic study by donating blood samples for DNA preparation. Retrospectively, clinical information from the study participants (n = 404) was obtained from the patient's medical records, and antibodies titres were checked with the AChR-abs Register at the Department of Neurology, Haukeland University Hospital, and Bergen, Norway. Clinical information registered include: age at disease onset, AChR-abs, concomitant immune-mediated diseases, thymectomy, thymus histopathology and highest score of disease severity according to revised classification proposed by the Task Force of The Medical Advisory Board of the Myasthenia Gravis Foundation of America (MGFA) [39].
To minimize possible population stratification, all MG subjects included in the HLA case-control study were ethnically Norwegian, as were the control subjects. Hence, 26 non-ethnic Norwegian MG patients were excluded, among whom one was MuSK positive. Only one additional MuSK positive patient was recognised and also excluded. Altogether, 378 unrelated Norwegian Caucasian MG patients were included in the HLA case-control study.
The control samples (n = 651, female: male ratio 1.9) were randomly selected among healthy Norwegian bone marrow donors recruited through the Norwegian Bone Marrow Donor Registry (http:/www.nordonor.org/). The same control sample set has been used in other studies [40]. Written informed consent was obtained from all study participants. The study was approved by The Regional Committee for Research Ethics.
Sub-classification of MG
The sub-classification of patients was done according to age at onset and presence or absence of thymoma. EOMG was defined as age at onset of 40 years or younger. Because of the uncertainty as to where to set the age-cut off for LOMG, as previously described by Aarli and colleagues [12], we classified MG with onset over 40 years into two groups: an "intermediate group" with age at onset of 41–59 years, and a late onset group (LOMG) with age at onset of 60 years or older.
HLA Genotyping
Genomic DNA was extracted from peripheral blood lymphocytes using an in-house desalting method. HLA Class I (HLA-A, - B, and -C) genotypes of the MG patients were resolved to a consistent two-digit resolution level, and Class II (HLA-DRB1) to a four-digit resolution level, using in-house sequencing-based approaches. Ambiguities at DRB1 were resolved by selecting the most probable genotype based on allele frequencies reported in Caucasians (http://bioinformatics.nmdp.org/HLA). If the ambiguous genotypes had similar probabilities the genotype was assigned as missing. The genotyping method used is described elsewhere [41] and involves a polymerase chain reaction (PCR) amplification using the Platinum® Taq PCRx DNA polymerase kit (Invitrogen, Carlsbad, CA, USA) followed by sequencing of exon 2 and 3 (for Class I) and exon 2 (for Class II) using BigDye® Terminator v3.1 chemistry (Applied Biosystems, Foster City, CA, USA) and an ABI3730 capillary sequencer (Applied Biosystems). Primers and protocols used for sequencing of the individual HLA loci are available from the authors upon request. Allele assignment was performed using Assigns SBT® v3.2.7b (Conexio Genomics, Applecross, Australia) and the IMGT/HLA database v. 2.28.0 (http://www.ebi.ac.uk/imgt/hla/). HLA data for the healthy controls were available from the Norwegian Bone Marrow Donor Registry, and were at the same resolution level as the patients'.
Statistical analysis of genetic associations was performed using UNPHASED v.2.404-w32 [42]. Rare alleles (n<2 in patients and controls) were excluded. Conditional logistic regression ("main effects" test) was used to evaluate the dependency of the risk contribution of the different loci HLA-A, -B, -C and -DRB1 in EOMG in order to determine the most strongly associated locus. The expectation maximization algorithm was used to estimate maximum likelihood haplotype frequencies of B and DRB1 from the genotypes at each locus, assuming Hardy-Weinberg equilibrium. The haplotype method [43] and the Svejgaard method [44] were used to assess which alleles and loci showed the primary association and which appeared to be secondary due to LD. Values for D' and r2 were calculated for allele combination. Odds ratios (OR) and 95% confidence intervals (CI) were calculated with Woolf's formula with Haldane's correction for nominal p-values (pnc). P-values <0.01 after correction for number of comparisons in the initial global locus tests (n = 4) were considered significant. For allelic associations, novel associations were corrected for number of comparisons before claiming significant associations. Only the number of tested alleles at each locus were corrected using Bonferroni correction (pc), as the alleles at HLA loci do not fully represent independent tests due to the strong LD (n = 8 for HLA-A, n = 21 for HLA-B, n = 13 for HLA-C and n = 38 for HLA-DRB1). For alleles previously published to be associated, uncorrected p-values (pnc) are also shown. When assessing the strongest associations by conditional analyses, no corrections were performed in order to avoid camouflaging weak effects due to LD.
A total of 369 Norwegian MG patients were successfully genotyped for all four loci genotyped; 9 patients were excluded due to missing genotypes and technical difficulties in genotyping. The clinical characteristics of the MG cohort investigated are shown in Table 1, and the associations between HLA loci and MG subgroups are shown in Table 2. There were significant associations of both the HLA Class I (HLA-A, -B and -C) loci and the Class II (HLA-DRB1) locus in the EOMG group. LOMG showed a strong association with only the DRB1 locus. No significant associations were observed in any HLA loci in the intermediate group (onset at 41–59 years) or to MG with thymoma. The most frequent haplotype was AH 8.1 in both EOMG (21%) and controls (9%), while HLA-A*02- or A*03-B*07-C*07-DRB1*15:01 haplotype was most frequent in LOMG (13%). An overview of allele frequencies in MG subgroups and controls is available as supporting information in Table S1. The clinical characteristics of MG patients carrying the most strongly associated HLA genotypes reported in this study are shown in Table S2 as supporting information.
Table 1. Clinical characteristics of the Norwegian myasthenia gravis study cohort (n = 369).
https://doi.org/10.1371/journal.pone.0036603.t001
Table 2. The association between HLA loci and myasthenia gravis subgroups (p-values).
LOMG
The DRB1 locus showed a strong association to LOMG (pnc = 1.2.5×10−6), while the B-locus was not associated (pnc = 0.04). The strongest associated alleles in LOMG are shown in Table 3, pointing to the DRB1*15:01 allele conferring the strongest risk (OR 2.38, pnc = 2.0×10−6, pc = 7.4×10−5). Interestingly, other DR2 alleles, e.g. DRB1*15:02 were not associated (pnc = 0.11). The DRB1*03:01 (pnc = 0.001, pc = 0.05) and DRB1*13:01(pnc = 0.004, pc = 0.15) alleles showed modest novel negative associations, however, when correcting for number of comparisons (n = 38) in this analysis, these associations were no longer significant, as also observed for the negative association with B*08 (pnc = 0.003, pc = 0.07). The previously reported association to HLA-B7 in LOMG was only weakly present in our study (pnc = 0.01). Haplotype analysis of the DRB1*15:01 versus other HLA-B alleles showed the strongest LD with B*07 (D' = 0.5, r2 = 0.2). This might explain the borderline association found to B*07, and support that DRB1*15:01 is the superior risk allele in LOMG. Sub-analysis of the nonthymomatous ATA positive late onset MG patients over 40 years (n = 47) did not show significant association with the DRB1*07:01 allele (pnc = 0.18).
Table 3. Associated alleles in late onset myasthenia gravis (LOMG).
In EOMG, positive associations were observed for the well-established HLA-A*01, -B*08, -C*07 and -DRB1*0301 alleles (Table 4). Conditional tests showed that virtually all associations at the other loci disappeared when conditioning on either HLA-B or -DRB1 (Table 5), indicating that these two loci are stronger determinants than HLA-A and -C. In order to assess which of the positively associated alleles at these two loci displayed the strongest association, we performed a conditional haplotype analysis of HLA-B*08 and -DRB1*03:01. Strong LD between the two alleles was confirmed (D' = 0.8, r2 = 0.7). HLA-B*08 was found to confer risk to EOMG both when carried on the same haplotype as DRB1*03:01 (p = 0.037) and in the absence of DRB1*03:01 (p = 0.005), while DRB1*03:01 was not associated after stratifying the haplotypes according to B*08 (Table 6). Novel negative associations were seen with HLA-A*02 (pnc = 4.6×10−4, pc = 3.7×10−3), C*05 (pnc = 4.6×10−3, pc = 0.06) and DRB1*13:01(pnc = 3.1×10−3, pc = 0.1), however, only A*02 was significant associated after correction. This negative association of the most common HLA-A allele could be explained by a reduction in A*02 among patients expressing the protective A*01/B*08 haplotype. Hence, conditional haplotype analysis of HLA-A*02 and -B*08 was performed, and the results showed that HLA-A*02 did not confer significant protection when carried on the same haplotype as B*08 (p = 0.51) nor did it do so when carried on haplotypes without B*08 (p = 0.097) (data not shown).
Table 4. The most strongly associated HLA alleles in early onset myasthenia gravis (EOMG).
Table 5. Conditional analyses of the HLA-A, -B, -C and DRB1 loci (p-values) in early onset myasthenia gravis (EOMG).
Table 6. Assessment of the strongest association on the HLA-B*08-DRB1*03:01 haplotype in early onset myasthenia gravis (EOMG).
To test whether the suggested negative association of HLA-DRB1*13:01 found in both EOMG and LOMG could be a general protective factor for MG, we pooled all MG subgroups (except MG with thymoma) and compared the groups with controls. This showed that the DRB1*13:01 allele was significantly associated with MG (OR 0.31, 95% CI 0.18–0.52, pc = 4.71×10−4). To elaborate on the results showing that B*08/DRB1*03:01 are hazardous to EOMG and weakly protective to LOMG, we compared the allele frequency of both alleles between EOMG and LOMG subgroups. A significantly differential distribution between EOMG and LOMG was seen for both B*08 (pc = 2.95×10−9), and also DRB1*03:01 (pc = 2.56×10−5).
We have investigated the HLA associations of Class I and Class II alleles by performing comprehensive genotyping in a large and representative Norwegian MG population, and explored potential risk alleles in the different MG subgroups. Genetic differences between EOMG and LOMG have been reported before, but our study was able to define the primary risk alleles in EOMG and LOMG to be HLA-B*08 and HLA-DRB1*15:01, respectively, in our population. We also identified HLA-DRB1*13:01 as a general MG protective allele that confers protection to both EOMG and LOMG, a finding not reported before.
In LOMG, no genetic risk factors have been consistently described previously, but associations with HLA- B7 and/or -DR2 and DR 7 have been reported [23], [35]. A possible explanation for the divergent results may be that the cut-off age at onset used for LOMG has varied and that LOMG subgroups have been heterogeneous [11], [35]. By using age cut-off at 60 years for LOMG in this study, as suggested also by others [15], we were able to investigate a homogenous LOMG group. In doing so, we identified a significant association to the HLA-DR2 allele DRB1*15:01, which has not previously been reported by others. This allele is known to be quite common in particular European and Asian populations and is also the main genetic risk factor in another autoimmune neurological disease, i.e. multiple sclerosis [45]. It is, however, not known whether the occurrence of LOMG is lower in other MG populations of African or Amerindian origin where DRB1*15:01 is less frequent.
The DRB1 locus in LOMG has been examined in a previous family-based study of a large French MG cohort, but neither of the two DR2 alleles, DR15 or DR16, were found to be associated in a subset of LOMG comprising predominantly of males with normal thymus histopathology [35]. Instead, a subset of ATA positive LOMG was significantly associated with HLA-DR7 and negatively associated with DR3. This could not be reproduced in the subset of ATA positive LOMG in our Norwegian MG cohort. A borderline negative association of DRB1*03:01 was seen in the overall group of LOMG in our cohort, but no association was observed for DRB1*07:01. The lack of concordance between the results from LOMG in our cohort and the French MG cohort may be due partly to different inclusion criteria and genotyping methods. Further, a population specific association to DRB1*15:01 in the Norwegian MG population cannot be ruled out.
Due to the limited number of MG with thymoma (n = 30), the statistical power to detect the HLA-A association recently reported by others [27] may have been too low in our study. Only 8% had thymoma, which is lower than expected in a representative MG population [10]. However, strong HLA associations have not been reported in previous studies, and the susceptibility of MG patients with thymoma may be more likely explained by a paraneoplastic aetiology of the disorder [46].
For EOMG, the strongest predisposition observed in our study was for the HLA-B*08 allele. Previous studies have suggested the causative loci to be close to the Class III and Class I region of the HLA complex, pointing out HLA-B as a more superior risk locus than HLA-DRB1 [30], [32]. However, many of these studies were conducted at a time when genomic HLA typing was not available, and the knowledge of the genetic diversity of the HLA complex was more limited than today. It was therefore important to readdress this in our large MG study cohort using the higher resolution methods for HLA genotyping. In spite of the strong LD on the extended HLA -A1-B8-DR3 haplotype, we were able to map the primary HLA association to the B*08 allele.
Our results underline a clear difference in the association of B*08/DRB1*03:01 genotype between EOMG and LOMG, especially between EOMG with age at onset below 40 years and late onset MG with disease onset after 60 years. The intermediate group of late onset MG with age at onset between 41–59 years appears to be an overlapping group of MG, with a mixture of EOMG and LOMG genetic risk factors. Based on these results, it is still difficult to determine if the subset of LOMG with age of onset 41–59 years belongs to an EOMG or a LOMG subphenotype. This suggests that disease management and treatment of these MG patients should still be evaluated individually, as also implied by others [11], [47].
The main strengths of our study are the large sample of EOMG and LOMG patients from one population, extensive clinical measures of the study cohort, and the use of comprehensive HLA genotypin. However, there are also some limitations. As we did not genotype the HLA-DQB1 and DQA1 loci, which are in strong LD with the DRB1 locus, we cannot rule out that one of these (or in fact other surrounding loci in LD) is the primary risk locus. Both the haplotypes DRB*15:01- DQB1*06:02 and DRB*13:01-DQB1*06:03 are inherited together in our Norwegian population, which would hamper our ability to pinpoint the causal locus also in the presence of full class II genotyping data. We also note that the clinical characteristics of patients (e.g. thymus histopathology and MGFA scores) were reported by different clinicians from the collaborating neurological departments, and could have biased the classification of subgroups. Further, the method used for correcting p-values, using Bonferroni correction only within each locus, may be too anti-conservative. However, due to the strong LD between the loci, a more conservative method could overestimate p-values and camouflage novel associations. Therefore, weak associations reported in this study need to be interpreted with caution. Nevertheless, HLA-DRB1*13:01 was weakly negative associated with both EOMG and LOMG separately, but was highly significant when the total MG population (excluding MG with thymoma) was investigated. Because MG is a rare and also a heterogeneous disease, low sample sizes of the different MG subgroups have long hampered genetic studies of MG. Thus, for future investigation of genetic risk factors in MG, collaborative networks will be essential.
To the best of our knowledge, this study with comprehensive genotyping of four HLA loci in MG is the first to provide detailed HLA data in a large sample of MG patients comprising both EOMG and LOMG subtypes. The HLA alleles also continue to play a leading role in the genetic risk in other complex autoimmune diseases such as type-1 diabetes, multiple sclerosis and rheumatoid arthritis [18]. Even in the present time of genome-wide association studies (GWAS), well-designed studies dissecting the nature of the HLA associations in subgroups of MG patients are much needed.
In conclusion, this study provides both novel and supporting information of major HLA-associations in Caucasian MG. The novelties of our findings are the identification of DRB1*15:01 as the strongest HLA risk allele in LOMG, and the finding of DRB1*13:01 being a general protective allele for MG in our population. Furthermore, HLA-B*08 was mapped to be the primary risk allele in EOMG, underlining the distinct different genetic HLA profile in EOMG and LOMG subgroups. This needs to be taken into consideration in further studies investigating risk factors in MG.
Table S1.
Allele frequencies in MG subgroups and controls. Allele groups that include rare alleles are: HLA-A*09 (23, 24), A*10 (25, 26, 34, 66), A*19 (29, 30, 31, 32, 33), A*28 (68, 69), B*05 (51, 52), B*12 (44, 45), B*15 (62), B*16 (38, 39), B*17 (57, 58), B*21 (49, 50), B*22 (54, 55, 56), B*40 (60, 61).
https://doi.org/10.1371/journal.pone.0036603.s001
(DOC)
Clinical characteristics of the MG study cohort (n = 339) in relation to the most strongly associated HLA genotypes of this study. 1According to MGFA classification [39]: ocular MG (MGFA grade I), generalised MG (MGFA grade II-V), not available in 12 cases. 2Thymus histopathology: hyperplasia or normal/atrophy, not available in 26 cases. 3Concomitant immune-mediated diseases in patients include thyroid disease (hypo-, hyperthyroidsm, thyroiditis), type 1-diabetes, rheumatic diseases, systemic lupus erythematosus (SLE), celiac disease, inflammatory bowel diseases (Crohńs disease or ulcerative colitits). *MG patients with thymoma (n = 30) were excluded. − = positives, − = negatives.
We would like to thank the Departments of Neurology at; Akershus University Hospital, Nordlandssykehuset in Bodø, Buskerud Hospital, Førde Hospital, Haugesund Hospital, Namsos Hospital, Sørlandet Hospital HF (Kristiansand and Arendal), Vestfold Hospital, Østfold Hospital, Telemark Hospital and Ålesund Hospital, Norway, for help in including MG patients to this study. We also thank all MG patients for participating. The Norwegian Bone Marrow Donor Registry is thanked for supplying the control samples.
Conceived and designed the experiments: AHM CMET BAL HFH. Performed the experiments: AHM Ã…RL HS STF. Analyzed the data: AHM BAL HFH. Contributed reagents/materials/analysis tools: AE JFO MKV HS STF GB MTK RM MC AR EK NG. Wrote the paper: AHM CMET BAL HFH.
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36. Spurkland A, Gilhus NE, Ronningen KS, Aarli JA, Vartdal F (1991) Myasthenia gravis patients with thymus hyperplasia and myasthenia gravis patients with thymoma display different HLA associations. Tissue Antigens 37: 90–93.
37. Machens A, Loliger C, Pichlmeier U, Emskotter T, Busch C, et al. (1999) Correlation of thymic pathology with HLA in myasthenia gravis. Clin Immunol 91: 296–301.
38. Keesey JC (2004) Clinical evaluation and management of myasthenia gravis. [Review] [166 refs]. Muscle & Nerve 29: 484–505.
39. Jaretzki A , Barohn RJ, Ernstoff RM, Kaminski HJ, Keesey JC, et al. (2000) Myasthenia gravis: recommendations for clinical research standards. Task Force of the Medical Scientific Advisory Board of the Myasthenia Gravis Foundation of America. [Review] [51 refs]. Neurology 55: 16–23.
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There is a wide range of qualifications available to suit all leaders and managers in the adult care sector.
The higher apprenticeship is for those in a manager or business development role in adult social care, or for those who need a high level of knowledge or specific specialism. It has two pathways - a general and a specialist pathway.
This will be replaced by the new Apprenticeship: Leader in adult care (level 5) on 1st September 2018 which is currently in development.
Local colleges and a number of training providers offer this apprenticeship – contact N&SCS for details.
This apprenticeship is eligible for Workforce Development Funding.
Lead Practitioner in Adult Care will guide and inspire team members to make positive differences to someone's life when they are faced with physical, practical, social, emotional or intellectual challenges. They will have achieved a level of self-development to be recognised as a lead practitioner within the care team, contributing to, promoting and sustaining a values-based culture at an operational level. They will have specialist skills and knowledge in their area of responsibilities which will allow them to lead in areas such as care needs assessment, occupational therapy, physiotherapy, rehabilitation and enablement, telecare and assistive technology. They will be a coach and mentor of others and will have a role in assessing performance and quality of care delivery. Lead Practitioners in Adult Care may work in residential or nursing homes, domiciliary care, day centres, a person's own home or some clinical healthcare settings.
It's expected that this new apprenticeship will be available towards the end of 2018.
This is the current qualification recommended for those wishing to become a registered manager is the It provides learners with the knowledge and skills needed to effectively manage practice and lead others in adult care services.
This qualification may also be undertaken as part of the Higher Apprenticeship in Care Leadership and Management.
N.B. This Diploma is being replaced by the new Level 5 Diploma in Leadership and Management in Adult Care.
Local colleges and a number of training providers offer this qualification – contact N&SCS for details.
This qualification is eligible for Workforce Development Funding.
This qualification will support learners to develop specialist knowledge and skills in their area of responsibility and enable learners to promote a values-based culture within their setting. This qualification can act as a progression route from the Level 3 Diploma in Adult Care qualification to the Level 5 Diploma in Leadership and Management for Adult Care qualification.
Contact N&SCS for details of training providers that offer this qualification.
This qualification helps learners to develop their knowledge and understanding of leadership and management within adult care to bridge the gap between working at a care and support level and management roles. It maps closely to Skills for Care's revised Manager Induction Standards and both align with the new Level 5 Diploma in Leadership and Management for Adult Care. As such the Level 4 Certificate is suitable for learners who are currently working at level 3 and aspire to progress into management. It can also be used by managers new in post as an accredited route to the Manager Induction Standards.
A small number of training providers can offer this programme under licence from Skills for Care. The nearest provider is Training2Care, but a full list is available on the Skills for Care website.
Local colleges and the Open University offer a number of higher level courses suitable for current and aspiring leaders and managers.
Skills for Care has a number of leadership development programmes for social care leaders in varying roles, from managers to directors, who want to develop their leadership skills and learn alongside their peers.
The Institute for Leadership and Management (ILM).
An interactive roadshow bringing together the STP workforce to explore how disruptive technology and innovations might transform the way we deliver health and care.
Events aimed at bringing together existing and aspiring leaders from across Norfolk and Waveney STP.
Mercure Hotel Norwich 121 – 131 Boundary Road, Norwich, NR3 2BA.
Delivered by The King's Fund, a 4-day course designed to support patient and citizen representatives to hone their leadership skills.
Delivered by Byron Lee (Added Value Learning Ltd) to help build the necessary awareness, understanding and skills for supporting compassionate inclusive leadership practice across health and care systems.
Some of the N&SCS endorsed learning providers offer courses suitable for leaders and managers.
To find these visit the 'Find a learning provider' page and search 'leadership and management' via the category dropdown menu.


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Africa – Kenya to Tanzania
February 15, 2019 Katamarino Comments 0 Comment
I took a taxi to the Aero Club arriving at around 0900, and bumped straight into our engineer Rick. We first walked over to Phoenix to find out exactly where they wanted us to bring the aircraft; being a Sunday not many people were around, but Rick had spoken to one of the facility's managers beforehand and arranged for us to work there on the weekend. We were directed to take the aircraft to the closer hangar, and once we arrived back with the airplane the standby engineers descended upon us keen to help out and learn about the unusual diesel engine. On a normal day, they told us, they'd simply have to hang around doing nothing so the chance to help out on the diesel was apparently a welcome change!
Airplane supplies
The Phoenix hangar
With Rick, myself, and some help from the resident engineers the aircraft inspection was completed in record time. If the stores had been open to pick up the required replacement brake pad and lightbulbs, we'd have been entirely finished in less than a day. The work was very thorough; 30+ inspection panels all across the aircraft were opened up; glow-plugs, fuel injectors, and filters throughout the engine were replaced, the cylinder compressions were checked, and the oil changed along with a multitude of other tasks. With the work almost complete, the aircraft was put to bed for the night and Rick and I retired to the Intercontinental for another excellent curry.
I made it out to the airport a little later than the day before, and Rick was already hard at work at Phoenix. The lightning pace of the previous day had ground to a halt. Phoenix's chief engineer had turned up, and taken great umbrage at the fact we would dare to work at the facility on a Sunday. The fact that it had been organised with one of the managers of the company seemed to be of no consequence to him, and he'd given Rick a very hard time. The engineers assisting us this time were working at a glacial pace; the intervention of the boss had definitely not helped. When I arrived he came and had a go at me as well, and stalked off without replying when I pointed out that we could hardly be help responsible for any deficiencies in their internal communications. We didn't see him again.
Bush 'plane in Nairobi
Preparing for the run-up
Mid-morning, a large group of middle-aged men wandered along the apron, dressed in high-vis vests. With them was a representative from the airport authority. They were all clutching notebooks, and it became clear that this was a group of hardcore plane-spotters. They were going from aircraft to aircraft, scribbling down the registration numbers, and had even organised to come into the Phoenix hangars to ensure they noted down every aircraft that was undergoing maintenance as well. They were perfectly harmless, but it was odd to see that they were entirely uninterested in the aircraft themselves; they simply wanted to collect registration numbers for their notebooks.
The plane spotters
Late that morning we tested the alternator and, as I had guessed, found it to be defective. Instead of the required 28 volts, it was producing only 23 or so. All the evidence pointed to an alternator that had been provided defective from the manufacturer, and had been slowly deteriorating. In a flurry of activity it was arranged that a new part would be sent out. A few options were investigated, including carrying the part on a Phoenix jet that was visiting Frankfurt that week, but it was eventually decided that the part would be carried out by a friend of the owner who happened to be flying to Nairobi. It would arrive early on Thursday morning, by which time our engineer would have departed, but thankfully another qualified engineer was located. He was arriving into Nairobi on Wednesday, quite by chance, and staying for some months; perfect! We moved the aircraft out of the Phoenix facility and down the airport to the hangar of the Mission Aviation Fellowship (MAF) whose engineer would be replacing the part for us.
Rick and I carried out a few last tasks on the aircraft, including removing the old alternator to be returned to the owner. This done, he departed for the airport and his flight home to Holland. That afternoon I caught up on some work, and also arranged with a local flying school to take one of the Cessna 172s for a short trip the following day; the plan was to go with their chief instructor and practice some dirt strip flying south of the city. It would make a welcome change from hanging around on the ground! The families had departed this day; my parents to Cape Town, and Sophia's family to elsewhere in Kenya for a week's safari. It felt quite strange to be just the two of us again.
Hard at work with planning!
Sophia, having had enough of hanging around Nairobi, departed on a commercial flight to Mombasa. She was planning to visit some friends who lived north of there on the coast, and also do some medical work in Mombasa itself. Left to my own devices, a flight was exactly what I needed, and just after lunch the chief pilot at Pegasus flight school came to find me; he was ready early, so did I fancy going now? We pre-flighted one of the school's Cessna 172s and taxied to runway 14, the usual departure runway. It was quite a relief to have someone else doing the radio for me; the frequency was as busy as ever and just to make things more difficult the radios and intercom in this aircraft were remarkably distorted and hard to make out.
My C172 for the day
We flew south at 6,200ft, climbing to 6,500ft to just clear a small ridge before the ground dropped away dramatically into the Great Rift Valley. The floor of the valley was fairly desolate, being even hotter and dryer than the plains where Nairobi sits. One large farm could be seen; my companion told me that it was fairly new, and was not expected to last long. Our destination, Malingi, was a dirt strip sitting next to a large salt lake and serving the salt processing factory and small community that surrounded it.
A low pass cleared the herd of goats off of the runway, and we flew a circuit back around to land. Having a lot of experience with short strips and grass strips, as well as some very strange tarmaced strips in the US, the landings here were not challenging; the strip was fairly long and straight with nice clear approaches. It was good fun to land on dirt though, as a break from the usual. We flew three circuits, my first being a little rusty after some time not flying a 172, before beginning the long slow climb back to Wilson; we had to climb 2,000ft before we even made it back to Wilson's airport elevation.
Coming back into Wilson the traffic was even busier than on previous occasions. I was glad to have a local expert with me to handle the radio and point out the usual visual reporting points. We slotted into the stream of Cessna Caravans and were asked to expedite our approach; the reason for this became very clear as we were pulling off of the runway and looked back to see a Caravan pass just behind us having landed while we were still on the runway!
That evening I hung out in the lounge at the Aero Club, before being invited to join a group of regulars at the bar. There were several pilots from various operators at Wilson, a lady who worked in the flight ops at Phoenix, and the son of one pilot who'd just returned from working on a farm in Ethiopia. The evening passed quickly, with plenty of stories of exploits in Africa, prominent among them being the attack of a Lemur in a hotel in the Comoros Islands. It was well past midnight before we all retired.
Our alternator arrived as scheduled, landing at 6:30am, and was delivered to the Aero Club in a taxi. I wasted no time in heading to MAF and locating our engineer, Keith, who'd be returning the aircraft to airworthy status. A close inspection revealed that as well as installing the new alternator we'd do well to re-do the cable repairs that had been carried out in Khartoum. While serviceable, they could not exactly be described as examples of best practice. The brackets that the alternator was mounted on also showed evidence of some wear, leading to a little movement that was possible; this could well have contributed to the problems with cables breaking. A call to the engine manufacturers, SMA, confirmed that this issue had indeed been seen on other aircraft.
Parked up in the MAF hangar
Before we could complete the installation of the new alternator, Keith was called away for the day. I returned to the Aero Club to book another night's accomodation. Hopefully I would, at long last, be on my way the following day!
I met Keith at MAF a little after 0700 to finish the installation of the alternator. A couple of hours later everything on the engine was back together, the cowlings were replaced, and one of the MAF staff had even given the aircraft a thorough wash! Keith and I climbed aboard and started the engine; there was still enough battery for this, at least. Holding my breath, I flicked on the alternator; and with huge relief watched as the ammeter needle instantly pegged itself to full charge, and all electrical warning lights were extinguished! Keith got out, and I taxied over to the far side of the airport to run the engine for some time and build up charge in the battery again. It took a good half hour, but eventually the ammeter returned to normal levels and I parked up at the Aero Club to load all the gear and finalise the flight plan.
East-bound to the coast
At around 3pm, I taxied to customs. I'm not sure why this was required for an internal flight, but they insisted I go there anyway. In the end all I had to do was walk out of the arrivals gate, back in the departures gate, hand a copy of the manifest to a customs agent, and get straight back into the airplane. There seemed to be something of a lull in traffic and after a short wait while yet another Cessna Caravan departed I was on my way to Malindi, to meet up with Sophia. I followed the VFR departure route, which was helpfully marked on our charts this time, and climbed to 9,500ft to clear the hills east of Nairobi. That done, I descended to 1,000ft to head out across the plains, hopeful of spotting animals! I saw, exclusively, a great many cows.
Departing the plateau
Kenyan plains
The flight to Malindi was around two hours. I arrived at the airport shortly after a Cessna 172 arriving from the south, and flew final approach with the African coastline just a few miles away off my left wingtip. So far we had visited the northern, western, and eastern coasts of the continent; just the south left to go! The small apron was almost deserted, and within a few minutes of arriving I'd had some help to push the aircraft back onto the grass and was being greeted by Sue, one of Sophia's friends who lived nearby. We arrived back at their house at about the same time as her husband Damian, and a few minutes later Sophia turned up after her day of medical work in Mombasa.
Evening in Malindi
Although originally from Britain, the couple had now lived in Kenya for well over a decade, working in the hotel industry. There was, in fact, quite a community of expatriates in this small tourist town, primarily British and Italian. That evening we visited the local bar, located at one of the hotels along the front, where we were introduced to many of the other expats; an excellent meal was also available! With the tide well out I set out for a walk on the beach, but came across such a huge number of small, fast crabs that I retreated due to a certain concern, no doubt misplaced, about finding them running up my shoes and clawing my legs.
Given that it was the weekend we elected to remain in Malindi for another day. There would be no point in turning up in Arusha just to spend Sunday waiting around. We had a late morning, and at around 1030 we joined Sue and a few others for a walk down to the beach and out along a large sandbar that was revealed at low tide. The beach was busy but not crowded, largely with Italians from a nearby hotel. A couple of sightseeing boats arrived and disgorged their passengers before anchoring, and their crews taking a break. The views from sandbar were beautiful, the water warm and clear; just as well, as the tide was coming in and our return to the beach involved as much swimming as it did wading.
Coping with the heat
Some kind of Heron, at Malindi
After a lunch of pasta and salad Sue gave me a lift up to Damian's hotel, accompanied by David and Simon, two Brits in their twenties. David was working on a farm in the north, and his brother, an army captain, had come out to visit for a while. We had been informed that the hotel had sailing catamarans for rent, and were looking forward to an afternoon of sailing and snorkeling. On arrival we found that the catamarans had been a little over-hyped, and were in fact bright yellow roto-moulded "funboats". With three people squeezed on their buoyancy was a little questionable, but we set off out to see anyway with David cheerily humming "Yellow Submarine" as we went.
The beach in Malindi
Crystal clear Malindi waters
Enjoying the beach in Malindi
Once two occupants were turfed overboard to snorkel, the boat regained most of its performance, and it was at times possible to even get it surfing down the large swells that were rolling in towards the beach. We took it in turns to swim and sail; I saw absolutely nothing underwater apart from seaweed, but Simon spotted a little shark. It was small enough to cause him to call us over to look, rather than to try and get out of the water, but unfortunately by the time we got there it had vanished. Simon and David set out to the little rocky island (more of a rock, in fact) to inspect it and before too long I was being called over to remove them from the area. The island was covered with large crabs which were apparently "pretty nasty".
Dinner on the dow
That evening we were taken out for dinner, along with 10 or so others, on a dow belonging to another one of the expat social circle. This was usually run as a business taking tourists for night cruises. The dow was surprisingly speedy and we headed up the creek away from the ocean under a brilliant full moon. Dinner of steak and accompaniments was cooked on board, and even Pina Coladas were available! After a few enjoyable hours we motored back upwind to the jetty, and headed home.
We were at the airport by 0900 preparing to finally get underway again on the trip. The original plan had been to fly via Mombasa in order to clear customs and immigration but it turned out that, with a short wait, someone could be summoned to Malindi to handle these formalities and save us a stop. We refueled and took care of the paperwork while we waited, and once the immigration official arrived it was just a few minutes before we could be on our way. The first leg would be a two hour flight to Kilimanjaro airport, the international airport just 30 miles from our final destination of Arusha.
Heading east into Tanzania
We set off along the coast south, as we wanted to fly past the village we'd spent the last couple of days in before we turned inland towards Kilimanjaro. Approaching it, we descended to a few hundred feet and flew low and slow over the beach to take photographs of the house and surroundings, and also try and spot the family! We failed to do this, but later heard that they had been out walking and had clearly seen us pass by; we just hadn't spotted them waving!
Fishing boat comes in
Malindi coastline
Turning inland, we climbed up to 8,500ft to stay above the scattered cloud layer. The winds were favourable and we cruised at 130 knots ground speed. After an hour or so, Kilimanjaro came into view in the distance. Approaching the Tanzanian border the clouds cleared away and Sophia spotted a herd of animals down below; a quick descent revealed them to be a huge quantity of wildebeest. Trotting along to the side of them were a group of 5 or 6 elephants! Well pleased with this sighting, we had flown only another 20 miles or so before we came across more elephants, but this time a herd of 100 or more animals. Despite the heat and the turbulence down low, we lingered for a while watching them before continuing to Kilimanjaro airport.
Plains of southern Kenya
Kilimanjaro was not a busy airport. We quickly procured aircrew visa for the country, and having exited through the arrivals hall immediately re-entered at the other end of the airport to file our flight plan and pay the considerable navigation and permit charges. "Navigation" charges are one of the biggest rip-offs in African aviation; almost no air traffic control is offered, and in those places where it is available it is often of a very poor standard. It can certainly not be considered decent value for money! Fees paid, we relaxed by the aircraft for some time to consume the sandwiches that Sue had kindly sent us off with, and chatted with some local pilots who were very interested in our unusual diesel engine.
Hanging out at Kilimanjaro
Lunch at Kilimanjaro
Sophia's comfortable perch
Pilot gets relegated to the ground!
The flight to Arusha took only twenty minutes. This local airport, much smaller than Kilimanjaro, was nonetheless much busier and the apron was packed with Cessna Caravans and other light aircraft. We were parked down one end near the fuel pumps but warned to leave the parking brakes off as they would most likely have to move the aircraft to deal with future traffic. As we made our way out of the terminal, intending to locate a taxi, we were approached by a western gentleman addressing us in French; he had spotted our aircraft registration. This turned out to be Ben, a Belgian pilot volunteering for a local charity, the Flying Medical Service. They operated two Cessna 206s as air ambulances, as well as visiting villages for vaccination campaigns. Ben introduced us to Pat, the director, and we were soon offered accommodation in their compound which we gratefully accepted.
Cessna 206 from FMS
Welcome to Arusha
Arsuha airport
Pat was busy replacing an antenna on one of the 206s. We set to work helping him; as a result of a recent accident that had wiped out the other 206, he was temporarily unable to lift any heavy items. The work took a half hour to finish, and we then all piled into the little Suzuki Jimny and headed back to the compound; Ben had gone ahead on his bicycle, a brave man in the heat and surrounded by African drivers! At the compound we met Elsa, an American volunteer, and Kylie the Australian administrator for the group, who warmly welcomed us and set up a room for us in the main building.
Arusha town
View from FMS camp
The FMS camp
That evening we joined the FMS crew, and a number of other expats, for dinner in the city at a Chinese restaurant. While not particularly traditional cuisine, it was apparently one of the very few places where you could have a meal in less than four hours; Tanzania is, it seems, notorious for incredibly slow restaurant service.
Click here to read the next part of the story.
Flight for Every Mother
Africa – Tanzania and Malawi
Africa – Ethiopia to Kenya

redpajama_set_name: RedPajamaCommonCrawl


Since things haven't been getting done here at the house I've got a little extra built up in the building fund. So I'm going shopping today with out leaving the comfort of my own home.
I've wanted these bathroom fixtures from Restoration Hardware for a long time. They will go into the master bathroom.
I also got a JC Penny's sale catalog and they have curtains that would look great in the big bedroom for sale, so I think I'll get those too.
Then we just have to get the door on the guest bathroom and I think people will be a little more willing to stay with us.


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Nightfall #9: "The Body Snatchers"
August 29th, 2011 | Author: NeilM
This is one of my favorite adaptations. It's creepy, it's shocking and it's one of the show's best period pieces.
This episode features Graham Haley (photo left), who appears in many episodes, but who also penned two of the series' more interesting adaptations: "The Room" and "Mkara", both originally written by South African radio drama personality, Michael McCabe. (Haley might be better known to the geek crowd as the voice of Pyro in the 1990s animated X-Men series.)
McEnaney's adaptation is very true to the original Stevenson story, with a couple of exceptions. The episode tells Fettes' tale of the original events, but leaves off the prologue where Fettes has an unpleasant encounter with MacFarlane decades later at an inn, which triggers Fettes' telling of the tale to one of his friends. Also different is a scene added by McEnaney which introduces the character of Jane Galbraith, the barmaid whose suspiciously-fresh body is later brought to the school by Burke and Hare.
Air Date: 8/29/1980
Writer(s): Frank W. McEnaney (based on the short story The Body-Snatcher by Robert Louis Stevenson)
Featuring: Neil Munro, Graham Haley, Robert Christie, Richard Donat, Sean Mulcahy, Wendy Thatcher, Michael Wincott, Eric House
Commercial Synopsis: An adaptation of Robert Louis Stevenson's classic by Frank W . McEnaney, set in Edinburgh, 1828, where the infamous Burke and Hare are providing suspiciously fresh corpses to the local medical school. (NPR)
Posted in Episodes | Tags: 1980, adaptations, classic episodes, episodes, eric house, frank mcenaney, graham haley, michael wincott, neil munro, richard donat, robert christie, sean mulcahy, wendy thatcher


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BACK COMMUNITY Insight
Head backstage with us at Pierre Cardin tribute show
A 177-foot-high replica of an Ariane 5 rocket stood at the centre of a runway set up on the tarmac of the Musée national de l'air et de l'espace next to Le Bourget airport on the outskirts of Paris. All around, was a tribute to Pierre Cardin, the late Franco-Italian designer who brought space into fashion and fashion into the future.
The house of Pierre Cardin marked the first anniversary of its founder's passing with a fashion show in front of an Ariane 5 rocket
Initially scheduled for December 29, 2021, exactly one year after the Parisian couturier's passing, the fashion house paid tribute to Pierre Cardin on the last day of the Haute Couture shows, unveiling the 'Cosmocorps 3022' collection.
The decorations were out of this world, including giant screens on the runway and real planes as a part of the museum's collection. The show included nearly 200 designs from the archives and the brand new pieces by the house's current team, inspired by the designer's legacy.
Catching the references to the Space Age that the couturier adored in the 1960s, Istituto Marangoni students were honoured to collaborate with historical brand Pierre Cardin as both models and dressers.
A moment from Pierre Cardin tribute show for the fashion house's late founder
We asked some participants about their experiences, and they told us about the magic that happened behind the scenes. Rodrigo Basilicati-Cardin, the founder's great-nephew who leads the brand's design team, can rest assured that the designer's legacy will continue to inspire the new generations.
Thea Abboud, a first-year student in the Fashion Design programme
Were you familiar with the brand before? What does Pierre Cardin's legacy represent to you?
I knew Pierre Cardin's work long before this internship: his vision, avant-garde style and geometric shapes often inspired me when conceiving a new design or sketching.
How would you describe your experience working on this tribute show?
It was a very fulfilling one. It helped me sharpen my knowledge of the show process and everything that happens backstage. I not only learned about the different roles and tasks and the sequence of things a show needs, but I also put together a pretty convincing picture of the interaction with the whole team, from the models to the hair and makeup artists and, of course, Pierre Cardin's key stakeholders.
What was your most and least favourite part of the work?
My favourite part was being able to experience the emotions and action behind the scenes, time management and coordination. My least favourite was the stress and pressure we had to endure to get everything done with precision and perfection.
Did you enjoy your time as a dresser?
I enjoyed it mostly because the model I dressed was very nice to me, and we got along very well. Perhaps the only hard work was getting her dressed and ready quickly.
What did you love most about the show?
I loved watching the finale walk. It felt like a relief, and it was spectacular.
Finale at Pierre Cardin 'Cosmocorps 3022' fashion show
Eléah-May Bourmanne, a student in the Master's programme in Fashion Promotion, Communication and Digital Media
I knew the brand by name, but I had the chance to learn more about it from the fashion show. I realised that Pierre Cardin himself is a key part of the brand's legacy with his vision and creativity.
It is hard to compare since I had never worked on a fashion show before. But I greatly appreciated the experience. Everyone was very attentive; you could feel that the organisers really wanted this show to be a tribute to Pierre Cardin through the clothes. Every little detail counted. It was both a warm and a moving show.
I had the chance to work with a model from my own country (Belgian). We got along very well, and I have great memories of it! What I may have liked the least was the 'non-organisation' during the fittings, but everything went well at the end of the day.
Being backstage at a fashion show is a gratifying experience! Contrary to popular belief, you don't need to stress if you organise everything well. The experience is simply inspiring.
I loved the last part, when all the models walked on stage to show all the looks simultaneously. I think about the moment when the models come back one by one, with stars in their eyes, and everyone is clapping and relieved that the show went well! It's an incredible experience!
Hugo Trouzet, a second-year student of the BA in Fashion Design
I already had a close connection with the brand, as I worked with them as part of my studies during my first semester. Of course, I learned the fascinating story of Mr Cardin at that time. I think of Pierre Cardin as a man who figured out how to break the rules in fashion with the shift from haute couture to ready-to-wear – such a revolutionary act in the 1960s. He was also well known as a visionary, with his Cosmo period and his approach to other cultures, and a global pioneer for the fashion world.
It was familiar, emotional and exciting.
The least – the bus journeys.
The most – the moment right after the show was over!
Did you enjoy your time as a model?
As I knew Mr Cardin's brand and history, I felt proud to wear one of his looks.
The audience and team applause at the end – everyone was so excited and joyful.
Do you think this experience will be helpful for your future career?
It's always important to gain experience, especially for us students, no matter the industry in which you work. Experiences shape your identity and who you are, in both professional and private life!
Models on the catwalk at Pierre Cardin tribute show
Elizaveta Ostanina
Editorial team, Paris
Fashion Design & Womenswear


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Dr Mahathir, former Malaysian Prime Minister, was the man who had visualised the East Asian grouping. He had wanted a bloc of East Asians comprising ASEAN members, China (natch!), Japan and Korea to have a common stand on issues relating to the World Trade Organisation and globalisation, and principally to counter American economic influence in the region.
Now, he's fairly upset that his vision has been corrupted with the expansion of the bloc to include the very nations who would instead support policies in favour of American interests. That's contrary to his vision of providing a rein to the American crude steamroller, which Mahathir fears would flatten the interests of smaller nations in the region. Mahathir hasn't quite forgiven the West for toppling his economic-financial cart during the Asian meltdown.
He has also viewed the American dominated IMF and World Bank having a propensity to demand economic-financial reforms of the weak 3rd world without considering those countries' unique and historical circumstances, and the severe hardship that would accompany the 'cold-turkey' treatment the IMF or World Bank would prescribe.
Every recommendations of those two giant financial institutions have appeared to, and most times did work in the American favour and very seldom to those smaller nation's true advantage. He's not entirely wrong in his perception of the American interest at work in this regard, unlike his former deputy and arch-enemy, Anwar Ibrahim who was more ready to toe the IMF line.
As a warm up to his outrage at the altered East Asian Bloc, Mahathir has lashed out at his old political bete noir, Australia, for being invited as a participant. He reckons the Aussies will be working as Washington's proxy, to project American views and interests. Of course to him, that's blasphemous conduct.
He said: "I have always opposed the idea of Australia and New Zealand being in the group simply because Australia and New Zealand are not really East nor are they Asian. Australia is basically European and it has made clear to the rest of the world that it is the deputy sheriff for America (trust him to jab John Howard right in the ribs on this). Therefore Australia's views would represent not the East, but the views representing the stand of America."
He predicted that the East Asia Summit in Kuala Lumpur next week will fail to find a common voice on trade issues because the 'deputy sheriff' will be pushing pro-US policies.
I suppose, just to be fair and not considered an Asian racist, he didn't spare Japan as well, quite understandably, because Japan under Prime Minister Koizumi has moved very strongly into the US camp. Japan has done that probably because its fears an increasingly powerful China. Mahathir warned of a very pro-US Japan in the grouping, even to the extent of being a US spokesman.
He lamented that East Asian countries, being polite Asians (unlike him), will simply submit to strong Western pressures, which then makes the whole grouping quite useless. I reckon the petulant doctor might be sulking a wee bit here, as China is hardly likely to kowtow to anyone that easily. Perhaps it's a plaintive cry to be recalled to take charge once again, at least in the hosting of the East Asian Summit?
Dr Mahathir is still going strong and in a funny sort of way, very engaging. From an entertaining point of view, I would love to see him addressing the East Asian Summit next week. He might throw in a couple of Jews and American neo-cons as appetizers.
Posted by KTemoc at 9:33 am
Methinks the good Dr is a man of energetic (some say recalcitrant) vision.
If (even) Japan doesn't think it can influence China's line I don't think little Australia could make a real dent on preceedings.


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