The distribution of KIR-HLA functional blocks is different from north to south of Italy.

The killer cell immunoglobulin-like receptor (KIR)-human leukocyte antigen (HLA) interaction represents an example of genetic epistasis, where the concomitant presence of specific genes or alleles encoding receptor-ligand units is necessary for the activity of natural killer (NK) cells. Although KIR and HLA genes segregate independently, they co-evolved under environmental pressures to maintain particular KIR-HLA functional blocks for species survival. We investigated, in 270 Italian healthy individuals, the distribution of KIR and HLA polymorphisms in three climatic areas (from cold north to warm south), to verify their possible geographical stratification. We analyzed the presence of 13 KIR genes and genotyped KIR ligands belonging to HLA class I: HLA-C, HLA-B and HLA-A. We did not observe any genetic stratification for KIR genes and HLA-C ligands in Italy. By contrast, in a north-to-south direction, we found a decreasing trend for the HLA-A3 and HLA-A11 ligands (P = 0.012) and an increasing trend for the HLA-B ligands carrying the Bw4 epitope (P = 0.0003) and the Bw4 Ile80 epitope (P = 0.0005). The HLA-A and HLA-B KIR ligands were in negative linkage disequilibrium (correlation coefficient -0.1211), possibly as a consequence of their similar function in inhibiting NK cells. The distribution of the KIR-HLA functional blocks was different along Italy, as we observed a north-to-south ascending trend for KIR3DL1, when coupled with HLA-B Bw4 ligands (P = 0.0067) and with HLA-B Bw4 Ile80 (P = 0.0027), and a descending trend for KIR3DL2 when coupled with HLA-A3 and HLA-A11 ligands (P = 0.0044). Overall, people from South Italy preferentially use the KIR3DL1-HLA-B Bw4 functional unit, while those from the North Italy equally use both the KIR3DL2-HLA-A3/A11 and the KIR3DL1-HLA-B Bw4 functional units to fight infections. Thus, only KIR3DL receptors, which exert the unique role of microbial sensors through the specific D0 domain, and their cognate HLA-A and HLA-B ligands are selectively pressured in Italy according to geographical north-to-south distribution.

Interleukin-4RA gene polymorphism is associated with oral mucous membrane pemphigoid.

OBJECTIVE: The aim of this study was to analyse whether the polymorphisms of several pro- and anti-inflammatory cytokines may influence the susceptibility to predominantly oral Mucous membrane pemphigoid (MMP) in a Northern Italian population. MATERIAL AND METHODS: DNA was obtained from 41 MMP patients (29 with exclusively oral pemphigoid [OP]) and 140 unrelated bone marrow donors. Thirteen cytokine genes with 22 single-nucleotide polymorphisms (SNP) were studied by a sequence-specific PCR assay. RESULTS: There was no significant difference between the patients taken together and healthy controls for any cytokine gene polymorphism studied. However, the allele A of the IL-4 receptor A (IL-4RA) was significantly more frequent in OP than controls (P < 0.05), causing an increased frequency of genotype A/A in OP patients (89.7 vs. 67.9, odds ratio: 4.11, 95% confidence intervals 1.18-14.28, P = 0.023, Pc = 0.046). CONCLUSION: IL-4RA-1902 A/A genotype has been associated with a reduced response to IL-4 and has been found in 90% OP patient. Giving the supposed importance of IL-4 in MMP fibrotic process, our results can partially explain the low likelihood of scarring in OP patients.

HLA-C/KIR genotypes in oral lichen planus patients infected or non-infected with hepatitis C virus.

OBJECTIVES: Oral Lichen Planus (OLP) is associated with hepatitis C virus (HCV) infection and resembles graft-versus-host disease (GVHD) both clinically and histologically. The killer cell immunoglobulin-like receptor (KIR) genes encode a family of receptors expressed on NK and T cells and are supposed to play a significant role in GVHD and HCV infection. The aim of this study was to analyze the association among OLP, HCV infection and variants in KIR gene expression. METHODS: A total of 81 patients with OLP (36 HCV+ve and 45 HCV-ve) and 217 healthy controls (HCV-ve) were typed for the presence of eight KIR genes and of HLA-Cw* alleles by polymerase chain reaction-sequence specific primer. RESULTS: There were no significant differences in the frequency of the KIR genes and HLA-C1/C2 group alleles between cases and controls. We only found a significant difference in the frequency of the gene KIR2DL2 between HCV+ve and HCV-ve OLP patients. CONCLUSIONS: The present data suggest that OLP is not associated with particular KIR genes or with HLA-Cw* alleles in patients without HCV infection. Contrarily, the role of the genes in OLP-HCV+ve patients remains unclear and might warrant further researches.

Role of non-HLA genetic polymorphisms in graft-versus-host disease after haematopoietic stem cell transplantation.

Graft-versus-host disease (GvHD) is the main complication after haematopoietic stem cells transplantation (HSCT) and acute forms (aGvHD) occur in 20-40% of cases even after donor (D) and recipient (R) HLA matching, apparently because of D/R minor histocompatibility antigen (mHA) mismatches and cytokine polymorphisms. The genotype of cytokines and mHA of 77 haematological R following HSCT from HLA identical siblings were determined to detect genetic polymorphisms correlated with GvHD. We analysed TNFA (-863 C/A, -857 C/T and G/A at positions -574, -376, -308, -244, -238), IL-10 (-1082 G/A, -819 C/A, -592 C/T), IL-1B (T/C +3953), IL-1RA (VNTR), HA-1 (H/R allele) and CD-31 (C/G at codon 125, A/G at codon 563). Allele frequencies were in Hardy-Weinberg equilibrium and similar to those of 77 healthy controls. We observed positive correlations between a lower risk of clinically significant aGvHD and both the presence of -1082G -819C -592C IL-10 haplotype when both R and D are considered together and the absence of R IL-1RA allele 2. Furthermore, we observed an association between the absence of TNF-A -238 A allele and the risk of extensive chronic GvHD. mHA and cytokines genotyping would thus seem a valid source of information for the prior identification of recipients with a higher risk of aGvHD.

Hepatitis C virus-associated oral lichen planus: is the geographical heterogeneity related to HLA-DR6?

BACKGROUND: The association between hepatitis C virus (HCV) and oral lichen planus (OLP) is more common in the Mediterranean area and Japan, possibly because of immunogenetic factors. METHODS: Intermediate-resolution HLA-DRB typing by hybridization with oligonucleotide probes was performed in 31 Italian OLP patients with HCV infection, in 45 Italian OLP and in 48 British OLP patients without HCV infection. As healthy controls we included data from 145 unrelated Italian and 101 unrelated British bone marrow donors. RESULTS: Italian HCV+ve OLP patients possessed the HLA-DR6 allele more frequently than Italian and British OLP patients without HCV infection (51.6% vs. 17.7% vs. 16.7%; P corrected = 0.028 and 0.017, respectively). There was no difference in the frequency of the HLA-DR6 allele between Italian and British control subjects. CONCLUSIONS: The present data suggest that HLA-DR6 may be responsible for the peculiar geographic heterogeneity of the association between HCV and OLP.

Genotyping for cytokine polymorphisms: allele frequencies in the Italian population.

It has been demonstrated that many cytokine genes [e.g. tumour necrosis factor alpha (TNF-alpha) and interleukin 10 (IL-10)] show polymorphisms which may affect gene transcription, causing individual variations in cytokine production. The majority of polymorphisms described are single nucleotide polymorphisms (SNPs). In 140 healthy Italian subjects, the allelic and genotype frequencies were determined for the cytokine genes IL-1 alpha (T/C -889), IL-1 alpha (C/T -511, T/C +3962), IL-12 (C/A -1188), interferon (IFN)-gamma (A/T UTR 5644), transforming growth factor (TGF)-alpha (C/T codon 10, G/C codon 25), TNF-alpha (G/A -308, G/A -238), IL-2 (T/G -330, G/T +166), IL-4 (T/G -1098, T/C -590, T/C -33), IL-6 (G/C -174, G/A nt565), IL-10 (G/A -1082, C/T -819, C/A -592), IL-1R (C/T pst11970), IL-1RA (T/C mspa111100) and IL-4RA (G/A +1902). All typings were performed with PCR-SSP assays. Allele and genotype frequencies and linkage disequilibria were calculated and compared with those of other populations.

HLA-DQB1 alleles in Italian patients with mucous membrane pemphigoid predominantly affecting the oral cavity.

BACKGROUND: Mucous membrane pemphigoid (MMP) used to be considered as a single entity but it is now evident that a range of variants exists. Among them, pure ocular cicatricial pemphigoid (OCP) and pure oral pemphigoid (OP) appear to be very different subsets. Previous immunogenetics studies have found increased occurrence of the DQB1*0301 allele mainly in patients with OCP whereas in patients with OP the data are more open to doubt. OBJECTIVES: To analyse HLA predisposition in a group of Italian patients with MMP predominantly affecting the oral cavity. METHODS: We carried out high-resolution typing of HLA-DQB1 alleles in 28 patients with MMP predominantly affecting the oral cavity and in 97 geographically matched, healthy controls. All were Italian caucasians. RESULTS: The frequency of HLA-DQB1*0301 was significantly increased in the MMP patients compared with the controls (96% vs. 48%; corrected P, Pc = 0.001; relative risk, RR = 28.73). A strong association with DQB1*0301 was also evident in patients with OP compared with the controls (95% vs. 48%; Pc = 0.01; RR = 20.21). There was no significant difference in DQB1*0301 frequency between patients with OP and with MMP not restricted to the oral cavity. Patients with MMP were more frequently homozygous for DQB1*0301 than the controls (43% vs. 8%; Pc < 0.001; RR = 8.34). CONCLUSIONS: Our data suggest that Italian patients with MMP lesions predominantly affecting the oral cavity present the same genetic predisposition linked to HLA-DQB1*0301 previously reported mainly in patients with OCP.

Increased frequency of HLA-DR6 allele in Italian patients with hepatitis C virus-associated oral lichen planus.

BACKGROUND: Recent controlled studies have confirmed that hepatitis C virus (HCV) is the main correlate of liver disease in patients with lichen planus (LP), mainly in southern Europe and Japan. However, a low prevalence of HCV infection has been found in LP patients in England and northern France, and significant differences in serum HCV RNA levels or HCV genotypes have not been found between LP patients and controls. Thus host rather than viral factors may be prevalent in the pathogenesis of HCV-related LP. The HLA-DR allele may influence both the outcome of HCV infection and the appearance of symptoms outside the liver. OBJECTIVES: To assess whether major histocompatibility complex class II alleles play a part in the development of HCV-related LP. METHODS: Intermediate-resolution DRB typing by hybridization with oligonucleotide probes was performed in 44 consecutive Italian oral LP (OLP) patients with HCV infection (anti-HCV and HCV RNA positive), in an age, sex and clinically comparable disease control group of 60 Italian OLP patients without HCV infection (anti-HCV and HCV RNA negative), and in 145 healthy unrelated Italian bone marrow donors without evidence of liver disease or history of LP and with negative tests for HCV. RESULTS: Patients with exclusive OLP and HCV infection possessed the HLA-DR6 allele more frequently than patients with exclusive OLP but without HCV infection (52% vs. 18%, respectively; Pc (Pcorrected) = 0.028, relative risk = 4.93). We did not find any relationship between mucocutaneous LP, HCV infection and HLA-DR alleles. CONCLUSIONS: HCV-related OLP therefore appears to be a distinctive subset particularly associated with the HLA class II allele HLA-DR6. This could partially explain the peculiar geographical heterogeneity of the association between HCV and LP.

Analysis of the turin umbilical cord blood bank registry.

BACKGROUND: The polymorphic nature of the HLA system reduces a patient's probability of finding an HLA-compatible unrelated bone marrow (BM) donor, even though more than 6 million individuals are enrolled in international registries. Recently, umbilical cord blood (UCB) has been successfully employed as a source of HPCs. The use of such cells reduces the risk of GVHD and allows transplants with one or two HLA mismatches. UCB represents an expensive resource: therefore, it is necessary to carefully manage the UCB unit inventory. STUDY DESIGN AND METHODS: The current study analyzed the genetic heterogeneity of HLA-A, -B, and -DR gene frequencies between pools of UCB and unrelated-donor BM in the Piedmont (an administrative region of Italy). An Italian hematology patient's probability of finding complete or partial matches as a function of donor pool size was determined by considering subsamples randomly selected from the local unrelated BM donors. RESULTS: The HLA gene frequencies in UCB and unrelated-donor BM pools were not significantly different. The search simulation, based on actual HLA phenotypes, showed that the percentage of Italian patients matched with an HPC unit increases remarkably if 1 or 2 mismatches are accepted, reaching a proportion of 90 percent with an inventory of only about 500 units, while the increment is not so remarkable if the number of UCB units is greater. CONCLUSION: To optimize economic resources and to be internationally competitive, UCB banks should aim to increase the genetic heterogeneity of their units rather than increasing the UCB inventory, acquire efficient quality control systems, and acquire and preserve UCB units with a greater number of nucleated cells.

[The Italian Registry of Bone Marrow Donors: genetic structure and recruitment strategy]. / Il Registro Italiano dei Donatori di Midollo Osseo: struttura genetica e strategie di reclutamento.

The genetic structure of the Italian bone marrow donor population was analysed by estimating the HLA-A, -B and -DR gene and haplotype frequencies for the total population and for the Italian administrative regions. The haplotype frequencies were used to predict the probability of finding HLA-compatible donors for Italian patients depending on the registry size, and the probability of recruiting in the different Italian regions a donor with a new phenotype. The analysis of these probabilities allows us to propose strategies for donors recruitment in order to increase the phenotypic variability of the registry, then its efficiency.

[Genetic analysis of Italian hematologic patients candidates for bone marrow transplantation from unrelated donors]. / Analisi genetica di pazienti ematologici italiani candidati al trapianto di midollo osseo da donatore non consanguineo.

Frequencies of HLA-A, -B and -DR antigens and haplotypes were determined in 1945 Italian patients suffering from hematologic diseases and requiring bone marrow transplantation from unrelated donors. These frequencies were compared with those obtained from the Italian bone marrow donor population. No significant differences were found when considering the number of comparisons made, suggesting that the genetic structure of the Italian patients is not different from that of the Italian donor population.

HLA polymorphisms in Italian bone marrow donors: a regional analysis.

The aim of this study was to analyse the genetic structure of the Italian bone marrow donor population on the basis of HLA polymorphisms. Maximum likelihood estimates of gene and haplotype frequencies, goodness of fit to Hardy-Weinberg predictions and heterozygosity were calculated for 18 Italian administrative regions. Moreover, the phenotypic peculiarity of the regional populations was assessed by analysing the number of "typical phenotypes" found in each region. Multivariate analyses carried out on HLA-A and HLA-B gene frequencies gave a genetic pattern of the donor pools that reflects the structure of the Italian population determined in previous population genetic studies. Sardinia shows a very large genetic difference with respect to the other regions; of these, the central-southern regions are well-differentiated from the central-northern. Southern regions present higher genetic heterogeneity and a higher probability of providing donors with phenotypes not already present in the Italian bone marrow registry. The large sample size of the bone marrow donor registry allowed us to estimate gene and haplotype frequencies with greater accuracy than in previous studies. Our results may be of use in determining strategies for donor recruitment and selecting unrelated donors for patients requiring bone marrow grafting, as well as for anthropological, epidemiological and population genetics studies.

Genetic history of cystic fibrosis mutations in Italy. I. Regional distribution.

Earlier analysis of the Italian population showed patterns of genetic differentiation that were interpreted as being the result of population settlements going back to pre-Roman times. DNA disease mutations may be a powerful tool in further testing this hypothesis since the analysis of diseased individuals can detect variants too rare to be resolved in normal individuals. We present data on the relative frequencies of 60 cystic fibrosis (CF) mutations in Italy and the geographical distribution of the 12 most frequent CF mutations screened in 3492 CF chromosomes originating in 13 Italian regions. The 12 most frequent mutations characterize about 73% of the Italian CF chromosomes. The most common mutation, delta F508, has an average frequency of 51%, followed by N1303K and G542X, both with average frequencies around 5%. Multivariate analyses show that the relative frequencies of CF mutations are heterogeneous among Italian regions, and that this heterogeneity is weakly correlated with the geographical pattern of non-DNA 'classical' genetic markers. The northern regions are well differentiated from the central-southern regions and within the former group the western and eastern regions are remarkably distinct. Moreover, Sardinia shows the presence of mutation T338I, which seems absent in any other European CF chromosome. The north-western regions of Italy, characterized by the mutation 1717-1G-->A, were under Celtic influence, while the north-east regions, characterized by the mutations R1162X, 2183AA-->G and 711 + 5G-->A, were under the influence of the Venetic culture.

Population history of Corsica: a linguistic and genetic analysis.

Genetic and linguistic differentiations within Corsica were analysed and compared; the genetic relationships of Corsica to other Mediterranean populations were also studied. Lexical distances between 49 Corsican localities were computed from a standard word list; trees built from these distances were compared with average linkage and neighbour-joining trees of genetic distances. Our lexical distance results confirmed the north/south dialectal subdivision of Corsican speeches described by linguists. No clear results were achieved with genetic distances because of the low number of loci for which data were available. Nevertheless, a tight northern cluster clearly emerged. When compared to other Mediterranean populations, Corsica showed a certain degree of differentiation, although not so marked as that of Sardinia. Corsica presented genetic affinities with Campania, Sicily, Liguria, Provence and Latium, while distances with Tuscany and Sardinia were larger. These results can be interpreted as a reflection of the prehistoric isolation of Corsica and the relative contribution to the island gene pool of prehistoric and historic invaders and immigrants from several populations.

Genetic analysis of Sardinia: I. data on 12 polymorphisms in 21 linguistic domains.

(1) The microgeographic structure of Sardinia, well documented from a historical and linguistic point of view, further supported by archaeological evidence, can also be dissected at the genetic level: gene frequencies show heterogeneities which are statistically significant. (2) Dendrogram analyses performed with different methods lead to the same result: even if gene frequencies cluster linguistically defined geographic domains in agreement with historical and archaeological evidence, no phylogenetic tree can be inferred, very likely because the assumptions which allow a phylogenetic tree to be a valid model of evolution (mainly constant evolutionary rates and independence between branches) do not apply to the genetic history of Sardinia. (3) Evidence of a qualitative association between distribution of genes and distribution of languages or dialects seems to emerge also at the microgeographic level of our analysis. More linguistic and genetic data are planned to be considered.

Genetics and the origin of European languages.

A new set of European genetic data has been analyzed to dissect independent patterns of geographic variation. The most important cause of European genetic variation has been confirmed to correspond to the migration of Neolithic farmers from the area of origin of agriculture in the Middle East. The next most important component of genetic variation is apparently associated with a north-south gradient possibly due to adaptation to cold climates but also to the differentiation of the Uralic and the Indo-European language-speaking people; however, the relevant correlations are not significantly different from zero after elimination of the spatial autocorrelation. The third component is highly correlated with the infiltration of the Yamna ("Kurgan") people, nomadic pastoralists who domesticated the horse and who have been claimed to have spread Indo-European languages to Europe; this association, which is statistically significant even when taking spatial autocorrelations into account, does not completely exclude the hypothesis of Indo-European as the language of Neolithic farmers. It is possible that both expansions were responsible for the spread of different subfamilies of Indo-European languages, but our genetic data cannot resolve their relative importance.

Analysis of HLA-A, C, B, DR and DQ loci in an Italian sample of possible Celtic origin.

Trino Vercellese, a village of Piedmont (Italy), was selected with the aim at reconstructing the genetic history of a putative Celtic sample known to be settled in Italy with the name of Rigomagus since pre-roman times. The HLA-A, Cw, B, DR and DQ antigens of 101 unrelated individuals have been typed. The antigens characterizing this sample for their higher frequency are shown to be A3, A11, A32, B35, B39, Bw52, Cw4, DRw11, DRw13, DQw7. Gene frequencies are estimated by maximum likelihood and Hardy-Weinberg equilibrium was tested with no deviant genetic locus. Two-locus haplotype frequencies were also estimated and those with significant associations tabulated. "Extended" haplotypes were reconstructed: the three most frequent haplotypes (covering a total frequency of 11.5%) share the same Cw, B, DR and DQ alleles. Comparisons with other Italian and European samples are indicated to challenge archeological evidence of a pre-roman genetic stratification of the people living in our old Rigomagus.

Carrier detection for prenatal diagnosis of hemophilia A in Italian families.

BACKGROUND: The results obtained from a comparative analysis between phenotypic bioassays as the ratio of factor VIII: C clotting activity to factor VIII: C-related antigen, and DNA haplotypes from RFLP's TaqI/St14 and BclI/F8A in 12 hemophilia A (HeA) families are described. METHODS: DNA from HeA patients and related at-risk women has been analyzed by Southern blotting with two probes: the intragenic F8A and the extragenic St14. Factor VIII: C coagulant activity was measured by a one-stage method, and the Factor VIII-related antigen (FVIII: RAg) was assayed with bidimensional electrophoresis. Linkage analysis was performed with the LINKAGE computer programs; in particular, the risks of carrying HeA were calculated using the MLINK program. RESULTS: The observed heterozygosity for the flanking marker DXS 52 (TaqI/St14 RFLP) in combination with intragenic BclI/F8A polymorphism was 0.94. A statistically significant difference in frequency was detected at the DXS 52 locus (allele 4) in comparison with other Caucasian populations. Linkage analysis made it possible to combine the plasma bioassay values with the DNA marker haplotypes to determine the probability of carriership; 22 females at risk were investigated: 4 of them were identified as carriers and 18 were excluded. The risk of carrying hemophilia A for some women at risk in six families is reported. CONCLUSIONS: This study compares a classic method and DNA analysis in genetic counselling for hemophilia A. In some cases the two methods may give different results when identifying carriers in at-risk families. From these data it is possible to conclude that DNA analysis combined with the phenotypic bioassays for carrier detection gives more information that the two analyses taken separately.

[A survey of cardiological emergencies in Piedmont]. / Indagine conoscitiva sulle emergenze cardiologiche in Piemonte.

OBJECTIVES AND DESIGN: In order to assess the current behavioural status of patients receiving emergency cardiological treatment and the emergency services in the Piedmont Region, our Division carried out a survey of the Region's DEA and first aid centres based on the compilation of a questionnaire for each patient who passed through these structures over a 5-month period. The study included only patients hospitalised within 12 hours of symptoms' onset. The questionnaire aimed to assess the time the patient took to reach a decision, the eventual call for a home visit, the type of doctor called, the time spent by the doctor, the use of either a private vehicle or of an ambulance for transport to hospital, the time taken to get to the hospital, and the overall time taken to admit the patient to the emergency cardiological ward. The statistical analysis of data was carried out using both single and multiple variables. The selection of prognostic variables was carried out using a stepwise method. RESULTS: Data presented in this study refer to 1705 records, collected in 39 Piedmontese hospitals (75% of those with DEA or First Aid Center). Patients with acute myocardial infarction were 970 (57%). A doctor was requested at home in nearly half of the cases (49.3%). There was no correlation between the type of emergency and the request for a home visit, whereas the latter varied in relation to the different geographical areas and to the patients' age. A small majority of patients used personal transport to get to the hospital (55.5%) in comparison to those using an ambulance (44.5%) (p less than 0.001). Time taken to reach a decision was related to the type of pathology (acute pulmonary edema less than acute myocardial infarction less than arrhythmia) and to geographical area; mean decision time in the overall sample was 125 +/- 158 minutes. The mean duration of doctors' intervention at home was 74 +/- 82 minutes. The mean time taken to reach the hospital using private transport was 22 minutes, and the time taken using ambulance was the same, but this should be added to the time taken for the ambulance to reach the patient (a mean total time of 15 minutes). Overall mean hospitalisation time was 192 minutes. CONCLUSIONS: The critical factors causing delay in hospitalisation time are the poor levels of health education of the population in general, and the poor activation capacity of certain peripheral parts of the National Health Service. In particular, it is worth drawing attention to the delay due to the intervention of the family doctor in the current organisational model. Doctors called from first aid stations are able to provide a more rapid intervention, but are currently unable to meet the requirements of patients needing emergency cardiological treatments. These data confirm the rationale for intervention projects in cardiological emergencies, considering on one hand that a fleet of special vehicles be created, and on the other that doctors from first aid stations be specifically trained and increasingly involved.

Actuarial analysis of the occurrence of remissions following thymectomy for myasthenia gravis in 400 patients.

The role of thymectomy in the treatment of myasthenia gravis (MG) was analysed in 400 patients affected with generalised MG operated on between 1974-83, and prospectively followed up for five years after surgery. The occurrence of stable remission (SR) (that is, complete clinical drug-free remission that remains stable for all the subsequent follow up) was the endpoint of survival analyses and the distribution of SR time (SRT, that is, the interval from thymectomy to the occurrence of SR) was assessed by actuarial and Cox multivariate analyses. SRT distribution after surgery showed a slow progressive increase of cumulative SR rate that could both be ascribed to a delayed effect of thymectomy as well as reflect the natural history of MG, itself characterised by an increasing probability of spontaneous remission with time. SRT distribution was similar after stratification for all variables studied except when patients without thymoma were stratified for the need for immunosuppressive treatment in addition to thymectomy. Patients without thymoma who did not require additional immunosuppressive therapy (n = 130) had the highest SR rate occurring in the two years after thymectomy, and differed from patients treated with immunosuppressive drugs who showed the highest SR rate five years after surgery. Actuarial analysis has therefore identified a subgroup of patients where SR, occurring in the first years after surgery, is more likely to be ascribed to thymectomy than merely reflect the natural course of the disease.