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The chemical structure information in patents remains difficult to access, partly because it is frequently expressed in the form of Markush structures, which can encompass enormous numbers of individual compounds. Early search systems were based on chemical ‘fragment codes’ that have still not been entirely superseded by the ‘topological’ systems developed during the 1980s. There are a number of databases of specific patented structures, which can be searched using standard substructure search software, and the more recently developed ones use automated data mining techniques to extract chemical nomenclature from patent text and translate it into searchable representations. Although some work has been done on automatic reconstruction of searchable Markush structures from patent text, this has proved to be considerably more refractory. A number of alternative approaches to chemical patent searching are being explored, some involving similarity and nearest-neighbor searching concepts, and some based on both existing curated databases and direct utilization of full-text patents. In-house systems, which facilitate integration with other cheminformatics systems, are also under development. These new systems may allow improvements in retrieval performance, especially with regard to search precision. © 2011 John Wiley & Sons, Ltd. WIREs Comput Mol Sci 2011 1 727-741 DOI: 10.1002/wcms.41

We found HLA-DR5 to be present among 53% of 40 patients with goitrous autoimmune (Hashimoto's ) thyroiditis compared to 26% of 80 controls. No deviations from those expected in the incidences of HLA-A, B, C antigens were seen. In contrast HLA-DR3 was increased among 50 patients with atrophic thyroiditis (65%) compared to controls (24%). These findings stress the immunogenetic heterogeneity between the goitrous and atrophic varieties of thyroiditis.

One-hundred-and-forty-seven patients with autoimmune thyroiditis were studied with respect to HLA antigens as they related to various clinical features. HLA--B8 was found to be significantly increased among 59 patients with atrophic thyroiditis (57% vs. 26% for controls) but was identical to controls in 88 patients with goitrous thyroiditis (26%). No relation was found in either group between B8 and thyroid autoantibody titer or, in the case of goitrous thyroiditis, the rate of progression of the disease. Thus a link seems to be established between Graves' disease and atrophic thyroiditis in that both are significantly associated with HLA-B8. This study stresses the need to take clinical features into consideration when examining for HLA/disease associations.

Barnard Chemical Information Ltd.'s software products for generation of fragment-dictionary-based chemical structure fingerprints and for hierarchical and nonhierarchical clustering of large files of structures are described.

The privatisation and reorganisation of British Telecom (BT) presented its various divisions with the problem of transferring commercial awareness at the top management level to middle management level. A management development programme was designed which combined computer‐based business strategy modelling and “best practice” modelling in human relations. These areas were previously treated separately. The greatest problem for senior managers was modifying their values. For middle managers the problem was that their values were overturned and themselves threatened. The one‐week courses allowed fears and confusions to be aired and examined. By exposing managers to “best practice” procedures they were given frameworks to help them determine how to forge a relationship between a sensible economic strategy and a complementary culture. The programme has been very successful and is to be implemented in other BT businesses.

A familial aggregate of seven cases of Hodgkin's disease (HD) has been investigated by HLA typing. Over 600 people in the immediate population (i.e. about half) have been HLA typed and haplotypes have been obtained for 95% of them. It was expected that the cases would share a particular HLA haplotype or at least that they would have one or two HLA antigens of the same series in common. However, this was not the case so no simple idea of association of HLA with HD cases was upheld. When antigen frequencies were examined in the whole population, it was found that HLA B18 increased progressively in incidence from 0.08 to 0.4 in successive groups of individuals each one more closely related to the HD cases. Similarly the community with the highest incidence of HD also had the highest incidence of B18. Thus B18, which in the world figures carries the highest relative risk, emerged as important in this study. Of four proposed interpretations of the data, we are most interested in the idea that the important HLA association is at a population level rather than at the level of the individual patient. A hypothesis, based on the concept of a "healthy carrier" for the HD agent, explains how such an association might operate. It is possible that B18-linked complement deficiency could be the basis for such a carrier state.

Mergers, takeovers and changes in products or markets confront managers with major cultural change in their organisations. This article looks specifically at British Telecom, the different demands made on managers pre‐ and post‐privatisation and describes now management development programmes helped managers to change their style.

Ninety-eight members of a large Newfoundland family, seven of whose members over three generations suffered from Graves' disease, were studied with respect to the mode of transmission of the disease and its association with HLA. Compared to Newfoundland communities of similar size and geographical location, very little consanguinity was documented in this family. The susceptibility to Graves' disease appeared to be inherited as a dominant with a variable degree of expressivity; the degree of expressivity being determined by the female sex. In part of the pedigree, the susceptibility to Graves' disease entered the family with a wife. Three of her offspring who subsequently developed Graves' disease shared with her the haplotype A9, Bw16. Of the three remaining affected family members, two shared the haplotype A1, B8, whereas the third carried the haplotypes Aw32,b8; a9,bw16. Graves' disease could be associated with either of these two haplotypes in the last individual. This study shows that the susceptibility to Graves' disease is inherited associated with HLA and that whereas the disease susceptibility gene for Graves' disease is in linkage disequilibrium with HLA-B8 in Caucasians, it can be randomly associated with other HLA-B antigens.

An association between Graves' disease and the human leukocyte antigen (HLA) system has previously been reported. The disease was more strongly associated with the HLA D locus antigen Dw3 than with HLA B8. Products of the HLA D locus are determined by the interaction of test cells with standard typing lymphocytes, a technically difficult procedure. Recently, it has been possible to type serologically for D locus related (DRw) specificities on peripheral bone marrow-derived (B) lymphocytes. Blood B lymphocytes from 50 unrelated controls and 41 patients with Graves' disease were typed for seven HLA DRw specificities. 28 patients with Graves' disease (68%) were positive for DRw3, in contrast to 14 controls (28%); whereas only 21 patients (50%) were HLA B8 positive, compared with 13 (26%) controls. Thus, positivity for DRw3 afforded a relative risk for Graves' disease of 5.5, whereas that for HLA B8 amounted to 3.0. Additionally, a family with multiple cases of Graves' disease in which the disease was previously shown to be inherited with the haplotype, was linked to DRw2, which suggests that the susceptibility to the disease was inherited in association with that antigen. Two HLA B/glyoxalase recombination events were observed in this family; in both instances HLA DRw followed HLA B. This study thus demonstrates that the disease susceptibility gene for Graves' disease is in strong linkage disequilibrium with DRw3; however, it may be associated with other DRw specificities and inherited within family units in association with them.

Description d'un programme informatique permettant l'analyse syntaxique et semantique des structures generiques codifiees selon le langage GENSAL

In view of the reported variation in the association between HLA antigens and Juvenile Diabetes Mellitus (J.D.M.) among different Caucasian populations, we have undertaken a study of these antigens among 44 Caucasian Newfoundlanders and 135 matched controls. We have also studied the allotypic markers for Immunoglobulin G (Gm) and variants of C3 among 36 of these patients. We found that both HLA--B8 and B15 were increased among the patient group, resulting in a relative risk of 3.9 and 4.4 respectively. While these values are the highest to be described for J.D.M. among Caucasians, and fell outside the 95% confidence intervals for the combined relative risk calculated from published series, it is still possible that they can be accounted for by sampling. The combination of the two antigens increased the relative risk for J.D.M. in an additive fashion. Additionally, we also found that the combination of HLA B8 and B18, but not B15 and B18, also appear to act in an additive manner. The incidence of Gm allotypes and variants of C3 were not different in the J.D.M. group from those observed among controls.

Although HLA-B27 carries a high relative risk for development of ankylosing spondylitis (AS), most B27 positive individuals do not have spondylitis. One interpretation of this observation is that there may be 2 types of B27, 1 which carries the risk factor and 1 which does not. If this were the case, then with the help of markers closely linked to HLA-B, it might be possible to detect differences between the B27 haplotypes in AS patients and those in healthy probands. We studied 197 members of 18 families with known AS and 110 members of 19 families in which HLA-B27 was present without any known inflammatory spinal disease. HLA antigens A, B, and C and alleles of complement components C2, C4, and Factor B and glyoxalase-1 were determined in all cases. Detailed haplotypes were assigned and their associations with development of the disease were examined. We were unable to identify any distinct HLA-B27 haplotype associated with AS; 2 common haplotypes and several miscellaneous ones were found in both groups. Thinking that the development of AS might be influenced by the other, non-B27 haplotype, we analyzed this and found that there was no detectable influence. The data do not contradict the notion that B27 in whites is a single entity and is itself the susceptibility factor predisposing to the development of ankylosing spondylitis.

Peripheral leucocytes from healthy controls, patients with Hashimoto's thyroiditis or patients with Graves' disease were assayed for susceptibility to the cytotoxic activity of cold agglutinins. Lymphocytes from patients with thyroiditis were killed as readily as control cells, however, lymphocytes of patients with Graves' disease were clearly less susceptible to lysis by cold agglutinins. Lymphocytes from patients with Graves' disease cultured for 3 days in the presence or absence of PHA, were as susceptible to cold agglutinins as were control lymphocytes and lymphocytes from patients with thyroiditis. We suggest that the amounts of Ii antigens on the surface of Graves' lymphocytes may be modulated by autoantibodies which are present in many of these patients.

An increased frequency of HL-A 1 and HL-A 8 was found in patients with Graves’ disease and Hashimoto’s thyroiditis, when compared to a control group from the same geographic area, and drawn from a pool of subjects attending one diagnostic centre. Furthermore, an increased incidence of W15 and W17 was found in Hashimoto’s thyroiditis; however, these were not detected in any patient with Graves’ disease.

Association between Graves' disease and HLA—B8 has been previously documented, as have been associations between 1 gG heavy chain allotype markers (Gm). We found a significant increase in the phenotype fnb/fb (ie. positivity for fb) in patients with Graves' diesase compared to controls, raising the possibility of allotypic restriction of thyroid stimulating antibodies thought to be causally related to the disease. The influence of fb on the susceptibility to Graves' disease was found to be independent of HLA—B8 status suggesting that the immunological network operated by the Histocompatibility-linked genes is independent of that centered around IgG allotypes. It is postulated that, whereas the former genes determine the level of helper T lymphocyte function in the production of thyroid stimulating antibodies in Graves' disease, a person who also happens to carry the Gm marker fb would be assured of the production of IgG antibodies with thyroid stimulatory activity.

Forty-seven patients with Graves’ disease, 73 with thyroiditis and 128 controls drawn from the same geographical area of Newfoundland were HLA typed. The frequency of HLA-B8 was significantly increased in the Graves’ disease patients when compared to the control group giving a relative risk of 3.9. There were no significant HLA differences between the thyroiditis and control groups. Homozygosity for the HLA haplotype, which is common in this island population, was more common in Graves’ disease patients (12.8%) than in controls (5.5%) but did not reach statistical significance in this sample. Homozygosity was due in five of the six cases to either an A1;B8 haplotype or an A2;B8 haplotype. This contrasted with an apparently random assortment of haplotypes in the control and thyroiditis groups. Calculations suggest that homozygosity for a B8 haplotype confers an additional risk over heterozygosity for B8 of about 3.5 fold; however, homozygosity had no observable influence on the severity of the disease. These results strengthen the idea that B8, or an allele in linkage disequilibrium with it, determines in part the susceptibility of an individual to developing Graves’ disease.

OBSERVATIONS in laboratory animals suggested an association of experimental and spontaneous thyroiditis with histocompatibility genes.1 2 3 However, in contrast to the definite association between Graves' disease and specific human leukocyte (or histocompatibility) antigens (HLA),4 5 6 7 no such relation was shown for Hashimoto's thyroiditis.7 8 9 10 11 In this study 127 patients with thyroiditis were typed for HLA-A and HLA-B antigens; 40 were also tested for HLA-D-related (DRw) specificities. Materials and Methods All 262 subjects (135 controls and 127 patients) studied were referred for investigation of thyroid function. The patients satisfied at least three of five of the criteria for the diagnosis of Hashimoto's thyroiditis.7 The . . .