A study of human leukocyte D locus related antigens in Graves' disease.

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.

HLA-D--related (DRw) antigens in juvenile diabetes mellitus.

We studied the distribution of HLA-D--related (DRw) antigens in 40 patients with juvenile diabetes mellitus (JDM) and 79 matched controls. We found that DRw2 was significantly decreased in the JDM group, suggesting a protective effect of the antigen and that the decrease observed in B7 was secondary. HLA-DRw3 and HLA-DRw4 were increased in the diabetic group, and, as with B8/B15, these two antigen predisposed to the disease additively. The susceptibility for JDM was found to be more strongly related to HLA-DRw3 that to B8. On the other hand, B15 rather than DRw4 showed the stronger association with JDM. Moreover, we found that this second diabetogenic gene is associated primarily with B15 and only secondarily with Cw3, which is in linkage disequilibrium with B15. This study further emphasizes the immunogenetic heterogeneity of JDM.

Thyroid autoimmune disease in a large Newfoundland family: the influence of HLA.

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.

Fetal response to carbon dioxide pneumoperitoneum in the pregnant ewe.

OBJECTIVE: To determine the effects of maternal abdominal carbon dioxide (CO2) insufflation on placental blood flow and fetal blood gas measurements in the pregnant ewe. METHOD: Five time-bred ewes at 110 days' gestation were surgically prepared with maternal and fetal catheters placed for subsequent measurement of vascular pressures, blood gas tensions, and placental blood flows. On surgical recovery day 3, the ewe was anesthetized, placed on her right side, intubated, and manually ventilated to maintain a constant maternal carbon dioxide pressure (PCO2) range (37.1 +/- 3.3 mmHg) for the duration of the experiment. The maternal abdomen was inflated with CO2 to maintain an intraabdominal pressure of 20.7 +/- 0.6 mmHg. Maternal and fetal blood flows and blood gases were determined at 30 minutes of ventilation, 60 minutes of insufflation, and 40 minutes of desufflation. Simultaneous maternal and fetal organ blood flows were determined using the radioactive microsphere technique. RESULTS: Maternal perfusion pressure fell 22% (P = .01) in response to insufflation, whereas pressure in the inferior vena cava rose 53% (P = .003). Maternal placental blood flow fell to 61% (P = .002) of control. Seventy-seven percent of this blood-flow change was in response to the decreased perfusion pressure, with 23% resulting from an increased placental vascular resistance of 32% (P = .02). Maternal blood gas values did not change with insufflation or desufflation. Despite the marked decrease in maternal placental blood flow, the fetal placental perfusion pressure and blood flow, pH, and blood gas tensions were unaffected by insufflation or desufflation. CONCLUSION: The sheep fetus has sufficient placental flow reserves or compensatory responses to maintain adequate gas exchange during a 1-hour, 20 mmHg maternal pneumoperitoneum. Laparoscopic surgical procedures may prove to be a safe alternative to laparotomy during pregnancy.

Use of Markush structure analysis techniques for descriptor generation and clustering of large combinatorial libraries.

This article outlines a system in which a Markush structure representation is used for analysis of a combinatorial library, giving savings in terms of storage and processing requirements when compared with an enumerated library. The Markush representation used is described, along with the way in which it can be built from a reaction- and precursor-based description of a library. The process used to generate SMILES, and structure fingerprint and calculated property descriptors for each specific molecule in the library is discussed. Comparative performance figures are given for the Markush approach and various standard fingerprint generation programs based on the enumerated members of the library; the former shows time savings of a couple of orders of magnitude. The use of these rapidly generated fingerprints for clustering of large combinatorial libraries is described.

The occupational health nurse's contribution to epidemiology.

Epidemiologic studies usually require a team approach. The value of involving occupational health nurses in epidemiologic studies is the basis of this paper. Examples of epidemiologic studies to which nurses have contributed substantially are presented. The trained occupational health nurse who is responsible for a defined population of workpeople has a unique position in the workplace. Her (or his) training and experience as an observer, and knowledge of toxicology and environmental health effects, should enable her (or him) to identify groups of workers requiring specific health monitoring and surveys and to assist in epidemiologic studies. The potential contribution of the occupational health nurse to the work of the team conducting epidemiologic surveys, or as an independent health practitioner undertaking studies on her own, is discussed. Better opportunities for training should be made available in order for the occupational health nurse to contribute to epidemiologic studies in the workplace.

A comparison of different approaches to Markush structure handling.

The history of the development of computer systems for storage and retrieval of Markush structures is reviewed briefly. The systems currently being developed by Chemical Abstracts Service, Derwent Publications/Questel/INPI, and International Documentation Company for Chemistry (IDC) are introduced, and the similarities and differences between the approaches they use for input representation and search are examined, especially in relation to the handling of generic nomenclature, the prospects for future development of such systems is discussed in light of recent and continuing research work, as is the potential for exchange of Markush structure databases between the different search systems.

The association of HLA with autoimmune thyroid disease in Newfoundland. The influence of HLA homozygosity in Graves' disease.

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.

HLA in familial Hodgkin's disease. Results and a new hypothesis;.

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.

The association of HLA--B8 with atrophic 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.

HLA haplotypes in a genetic isolate in Newfoundland. A population showing 8% homozygosity and a familial aggregate of lymphoma and immunodeficiency cases.

HLA typing was performed on 384 individuals of an isolated population of 1,500 people with a familial aggregate of lymphoma and immunodeficiency cases. Eighty-five % of the total population were descendants of the founding couple. First cousin marriages were common. There was a three-fold or higher increase of the following haplotypes as compared to the frequencies in Sheffield: HLA-A28,Bw35, HLA-A28, B18, HLA-A10, B18, HLA-A2, B18,HLA-A11, Bw40 and HLA-A11, B7. The frequency of HLA-A1, B8 was low (5.4%). The most common genotype was HLA-A2, B12/A2, B12 followed by HLA-A2, B12/A28, Bw35. We found 20 HLA homozygous individuals, of these 15 were HLA-A2, b12/a2, b12. There were two possible HLA cross-overs which may be confirmed and three postulated cross-overs which can never be confirmed as one or both parents of the individuals in question are deceased. Some of the haplotypes could be traced back to the first, second and third generations, i.e. to the first half of the nineteenth century. No single haplotype or antigen was shared by the patients.

The association of goitrous autoimmune thyroiditis with HLA-DR5.

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.

The HLA B w4/w6 diallelic system in Graves' disease.

We studied the diallelic system HLA--Bw4/w6 in patients with Graves' disease and control subjects. Twenty-one out of the 22 patients with Graves' disease were found to be HLA--Bw6 positive and 16 of these were homozygous, contrasted with 28 and 9 out of 34 controls, respectively. HLA--Bw6 positivity results in a relative risk for Graves' disease of 3.27; homozygosity for that allele further increases the risk to 7.4. It is possible that the increased risk attached to HLA--Bw6 is secondary to the increase in HLA--B8 previously described in Graves' disease.

HLA/Bf haplotypes in a Newfoundland family.

HLA/Bf haplotypes were examined in a large three-generation Newfoundland family with a high incidence of Graves' disease. In that family Graves' disease was inherited in association with the haplotype HLA Aw24, Bw39 in some instances and with HLA B8-containing haplotypes in other instances. As all seven members of the family who suffered from Graves' disease were homozygous for the Bf S allele, the study for Bf was uninformative. However, the examination of other HLA/Bf haplotypes disclosed some interesting associations. One-hundred-and-five out of 168 HLA-A, -B, -Bf haplotypes were Bf S. Although numerically deviant, no unusual HLA B/Bf associations were observed. Bf F entered the family only once. A new finding is the association between HLA B27 and Bf S1; the haplotype entered the family once and was passed on to eight family members over three generations. Bf S1 was previously reported in association with HLA B12 or W21. None of these family members had ankylosing spondylitis. The Bf allele F1 entered the family three times, always in association with HLA B18.

Differential effects of intravenous hydralazine on myoendometrial and placental blood flow in hypertensive pregnant ewes.

OBJECTIVE: The differential vasoactive effects of hydralazine on the uteroplacental vascular bed were studied. STUDY DESIGN: After control measurements were taken, near-term chronically prepared pregnant sheep were continuously infused with angiotensin II. Maternal arterial pressure was increased by 32 mm Hg. Hydralazine was then administered; the effects on regional resistance and blood flow were evaluated with a radionuclide-labeled microsphere technique. Analysis of variance for repeated measures was used to compare observations. RESULTS: When compared with the hypertensive state, hydralazine caused the following changes by 40 minutes (mean +/- SEM): Although maternal blood pressure fell 31% +/- 5% (p = 0.0005), placental blood flow was unchanged, total uteroplacental blood flow increased 24% +/- 8% (p = 0.03), total uteroplacental resistance decreased 43% +/- 4% (p = 0.0002), placental resistance decreased 19% +/- 9% (p = 0.01), myoendometrial blood flow increased 390% +/- 82% (p = 0.0005), and myoendometrial resistance decreased 82% +/- 4% (p = 0.0005). CONCLUSIONS: In angiotensin II-induced hypertensive ewes, hydralazine is an effective dilator of the uteroplacental vascular bed and can maintain placental blood flow while blood pressure.