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Comprehensive data were reported to the International Bone Marrow Transplant Registry by 24 worldwide teams regarding 144 patients with severe aplastic anemia who were treated with HLA-identical, allogeneic bone marrow transplantation between 1975 and 1978. One hundred fourteen patients received one transplant and 30 received two. Sustained engraftment of donor marrow occurred on the first transplant attempt in 76% of the patients whose engraftment status could be evaluated. Moderate, severe, or lethal graft-vs-host disease (GVHD) occurred in 52% of the engrafted patients. The one-year survival rate for all patients was 44% (64/144). Among the one-year survivors, the primary disease was apparently cured in 90% and improved in 10%. Thus far, four patients died one to five years after transplant. Of the 60 patients currently alive, ten have chronic GVHD and the remainder are in good health. Multivariate analyses of the data disclosed a number of pretransplant factors associated with engraftment, GVHD, and one-year survival. The most important finding was that the use of male donors was preferable to female donors because of a higher rate of engraftment, less severe GVHD, and a higher one-year survival rate.

Pretransplant and posttransplant data for 69 patients with severe combined immunodeficiency disease are presented. Both B and T lymphocyte functions were absent in approximately 80% of the children and markedly depressed in the remainder. Transplantation of marrow from HLA genotypically identical donors provided the highest six-month survival rate (63%); six-month survival rates for patients who received fetal tissue transplants (43%) or marrow from mixed leukocyte culture (MLC) negative donors (38%) were significantly higher (P less than .05) than for patients treated with marrow from MLC positive donors (5%). Additional factors appeared to influence survival and the severity of graft-vs-host (GVH) disease. Patients more than 6 months of age had more intense GVH disease than younger patients. Survival rates were lower and GVH disease more intense when boys received transplants from girl donors than the reverse.

An association of coronary artery occlusion, as determined by coronary arteriography with age, prevalence of risk factors and alcohol intake was studied in 1635 male and 371 female heart patients. The degree of coronary artery occlusion was positively related to elevated cholesterol, elevated triglycerides, diabetes, age and history of smoking for both male and female patients. Hypertension was related to the degree of occlusion only for female patients. Male and female patients who had a higher alcohol intake tended to have less extensive occlusion. No positive association was found between obesity and the degree of occlusion. When the patients were divided on the basis of age (less than 50 and greater than or equal to 50 years) the findings did not differ. The lack of finding a relation between obesity and occlusion or between hypertension and occlusion for males differs from the general findings of epidemiologic studies on the relation between these risk factors and coronary heart disease. The authors believe that this discrepancy may either be explained by the way they selected patients (i.e., they selected patients who underwent a diagnostic angiographic examination), or that obesity and hypertension are not directly related to coronary occlusion but influence occlusive disease through some secondary mechanism.

Adoptive immunotherapy in the form of a transient graft of mismatched DBA/2 BM + LN cells was used in combination with several chemoradiotherapy regimens to treat AKR mice bearing advanced SLL. Leukemic mice treated in this manner had a significant prolongation of their MST and significantly higher survival rates 60 and 90 days posttreatment than corresponding control groups. Syngeneic- or allogeneic-matched cells did not provide substantial GVL effect. An inverse relationship that influenced survival was observed between the radiation dose and the dose of GVL effector cells used to treat leukemic AKR mice in the treatment model. Recurrence leukemia remains a major problem.

Patients who died one or more years after aortocoronary bypass surgery showed, at the time of the operation, higher prevalence of hypertension, and history of smoking and had higher plasma lipid levels than the patients who survived the operation for similar periods of time. No such differences in risk factors were seen between patients who survived or have died during the first 30 days after the operation. These findings suggest that pateints with abnormal risk factors have a poorer long-term prognosis.

The prevalence of farmer's lung disease and antibodies to farmer's lung antigens were studied in a probability sample of over 1,400 farmers in north central Wisconsin. The prevalence rate of farmer's lung disease was 4.2 per 1,000 farmers. The most prevalent antibody type was directed against Micropolyspora faeni, with 6% of the study population precipitin-positive. Prevalence of antibodies to M. faeni was associated with dairy farming, larger farms, and larger dairy herds. An additive effect of hay acreage and size of dairy herd was observed. An independent relationship was also observed for cigarette smoking, with antibodies to M. faeni more prevalent among nonsmokers.

The relationship of clinical diabetes to body fat distribution and obesity level was examined in 15,532 women. After adjusting for relative weight, all upper body segment girth measurements (neck, bust, and waist) had strong positive associations with diabetes. In contrast, the lower body segment girth measurement (hips) had an equally strong but inverse association with diabetes. Based upon waist-to-hip girth ratio, women were divided into four subgroups. The prevalence of diabetes increased with increasing values of this ratio. Women in the upper quartile had about three times the prevalence of diabetes as women of comparable obesity level in the lowest quartile. Women with both upper body fat predominance and severe obesity had a relative risk of diabetes 10.3 times as great as nonobese subjects with lower body fat predominance. The results suggest that localization of fat in the upper body segment and severe obesity are two distinct additive risks for diabetes.

Treatment modalities of end-stage renal disease (ESRD) patients include in-center dialysis, home dialysis, and kidney transplant. We present a model to account for all aspects of modality use to aid in planning regional facilities. Five years of data for 979 patients on dialysis in Wisconsin between 1970 and 1975 are used. The model shows movement (transit probabilities) from one modality to another, eg, transition from in-center dialysis to transplantation, and data were used to derive all transitional probabilities characterizing patient movement from one modality to another. Model and probabilities were used to predict number of patients in each modality in 1976, and the model was used to predict number of patients in each treatment modality through 1990. These figures may be used for planning regional facilities. Extrapolation of this model and derived probabilities for nationwide projections may be possible.

Lethally irradiated CBA (H-2k) mice were treated with small numbers of liver cells from strain-A (H-2a) fetal donors. Recovery from the radiation injury was dependent upon the dose of liver cells administered. Giving very small numbers of fetal thymus cells, in addition to liver cells, had a highly significant and salutary effect on survival. The results suggest that clinical transplantation of liver cells from a single fetus might succeed if thymus cells are added.

A study of 540 patients who had the aortocoronary vein bypass operation (from several transplant teams) showed that grafts within a patient closed independently of one another during the first-two year postoperative period. For patients with a single vein graft, there was a 23% chance of closure during the first two year postoperative period. The chance that all grafts would close during this period for patients with two grafts was 5%, and it was 1% for patients with three grafts. The knowledge of these closure probabilities may be used by the surgeon when planning the optimal surgical maneuver.

Long-term prospective studies in monkeys have shown that vasectomy is associated with an increase in atherosclerotic disease. The purpose of the present investigation is to evaluate whether vasectomy in men is associated with atherosclerotic disease in the coronary arteries. In this study information was obtained on the vasectomy status in a series of 7,420 men who had previously been referred for coronary angiography because of cardiovascular symptomatology and have been followed for as long as 9 years to evaluate coronary artery bypass surgery and the natural history of the disease. It was found that 5.0% had a vasectomy prior to angiography. Two different data analysis procedures were used to determine whether the vasectomized men had a greater degree of angiographically determined coronary occlusive disease than the nonvasectomized men. Subgroups with minimal and extensive coronary artery disease were also analyzed. Results of all analyses show that the vasectomized men did not have more coronary occlusive disease. Possible patient selection biases in this study are discussed.

A reassessment of HLA-A and B antigen associations in patients with severe aplastic anaemia confirmed the significantly elevated frequency of HLA-A2 in Caucasoid patients reported by Albert et al. (1976). In addition, a highly significant increase in the frequency of HLA-B14 in Italian patients was observed in an initial sample of 25 patients and confirmed in a second sample of 16 patients. This latter finding was cancelled out when the Italian Caucasoid patients were pooled with the non-Italian Caucasoid patients. These results suggest that the classification of populations as "Caucasoids", without examining their ethnic origins, may introduce a serious confounding error into HLA and disease studies.

Previous studies have suggested an association between adipose tissue cellularity and body fat distribution, and between adipose tissue cellularity and ability to lose weight. To determine whether there was an association between body fat distribution and ability to lose weight, we prospectively studied 187 severely obese women. The women were all 50 percent or more above ideal body weight, with personal physician documentation of no known major illnesses. Weights were recorded at the beginning and end of a 3-week hospitalization and every 3 months following hospitalization, for up to 2 years. The ratio of waist girth to hip girth (WHR) was used as an index of body fat distribution. A statistical analysis which adjusted for age and weight on admission did not find any association between WHR and weight loss during hospitalization, or at any time up to 2 years after hospital discharge. We conclude that the WHR index of body fat distribution is not a useful prognostic indicator of weight change for severely obese women with refractory obesity.

The incidence of cardiovascular disease risk factors and other indicators of cardiac impairment were studied in 478 patients prior to their aortocoronary vein bypass operation and 194 patients who had angiographic examination but did not undergo the operation because the clinical and coronary angiographic findings were not considered serious enough to warrant the bypass procedure. The patients referred for surgery had higher plasma cholesterol and triglyceride levels (259 and 219 vs 233 and 180 mg/100 ml), tended to be older (53 vs 49 years) and had more extensive occlusive disease (occlusion score 200 vs 70) than the group without the operation. There was little difference in the proportion of smokers (81 vs 83%) or prevalence of hypertension (33 vs 30%). In comparison with 9,964 participants of a local health screening program, both patient groups had markedly higher prevalence of smoking, hypertension, chest pain and previous myocardial infarcts.

Spleen and lymph node cells from DBA/2 (H-2d) donor mice treated with multiple injections of bacterial lipopolysaccharide (LPS) were tested in vivo for reactivity against normal tissues of host AKR (H-2k) mice against an AKR long-passage, acute lymphoblastic leukemia (BW5147). LPS treatment of donor mice resulted in a reduction in graft-versus-host (GVH) reactivity without loss of graft-versus-leukemia (GVL) reactivity. Immunocompetent cells from LPS treated DBA/2 donors were effective when used for adoptive immunotherapy (in combination with chemoradiotherapy) of BW5147 leukemia. GVH associated mortality decreased as the dose of spleen cells from LPS treated histoincompatible donors was increased as much as four times the number necessary to eliminate leukemia. The mechanism by which LPS reduced GVH reactivity without eliminating GVL reactivity is unclear; however, it does not appear to be the result of a dilution in the number of GVH reactive cells by nonlymphoid elements in the donor spleen nor of the adjuvant effects of LPS on resistance to bacterial infections.

In 117 patients with chronic myelogenous leukaemia (CML) treatment with a combination of high-dose chemoradiotherapy plus transplantation of allogeneic bone-marrow from HLA-identical, mixed-lymphocyte-culture-identical siblings resulted in an actuarial probability of 3-year survival of 63 +/- 16% (95% confidence interval) for 39 patients transplanted in chronic phases; 36 +/- 14% for 56 transplanted in accelerated phase; and 12 +/- 15% for 22 transplanted during blast crisis. Irrespective of disease status at the time of transplantation, and in contrast to chemotherapy, a plateau-effect was observed in the survival curves starting 14 to 19 months after transplantation. The actuarial probability of recurrent or persistent leukaemia at 3 years was 7 +/- 9% for patients transplanted in chronic phase, 41 +/- 19% for accelerated phase, and 41 +/- 39% for blastic phase. All relapses occurred within 18 months of transplantation. This study demonstrates that long-term disease-free survival in CML can be achieved with bone-marrow transplantation. Best results were obtained in patients transplanted during chronic phase of the disease.

The effect of aortocoronary vein-bypass operation on changes in occupational status was investigated in a cohort of 893 men. The median period of time between the operation and follow-up evaluation of postoperative occupational status was 14 months. The patients were divided into two age groups, with 55 years as the dividing point. The results showed that 11% of the younger men and 26% of the older group who were employed before the operation retired following the operation. In addition, 30% of the patients changed their occupational status following the operation. When occupational changes also resulted in changes in physical demands, 49% of the patients took new jobs that were less demanding physically, while 40% took jobs that were more demanding. Close to 9% of the patients were retired prior to the operation; about one fifth of them came out of retirement following the operation.

Independently of the amount of adipose tissue, certain patterns of fat distribution increase the risk of non-insulin-dependent diabetes. Although the ratio of waist to hip (WHR) circumferences has been consistently related to diabetes mellitus, it is possible that only two measures do not completely characterize fat topography. The current study, therefore, examines the cross-sectional relation of six girths (waist, hip, neck, bust, wrist, and ankle) to diabetes mellitus in 43,595 women. As compared with non-diabetics, Quetelet index (kg/m2) and all circumferences were elevated among diabetics. Stratified analyses showed that WHR, and waist, neck, and bust girths were consistently related to diabetes independently of the degree of overweight. As estimated from a logistic regression model that simultaneously controlled for age and all anthropometric variables, the prevalence of diabetes mellitus was positively related to Quetelet index, and to the waist, bust, and neck girths, with odds ratios (ORs) ranging from 1.4 to 2.6. However, diabetes was inversely related to hip (OR = 0.61) and ankle (OR = 0.73) girths; p less than 0.005 for each association. Although cross-sectional in nature, these results suggest that an adverse body fat distribution is not limited to the abdominal region, but that a relative preponderance of adipose tissue in various regions of the upper body is associated with diabetes mellitus in women.

A group of over 900 patients who underwent coronary arteriography were asked about their alcohol intake. The patients who were abstainers or consumed less than an equivalent of 180 ml absolute alcohol per week had higher coronary artery occlusion scores than the group consuming more than that amount, though the latter group smoked more and had higher plasma triglyceride levels.

Data from 547 patients with aplastic anaemia who received bone marrow transplants from HLA-identical siblings were analysed to determine factors associated with the risk of interstitial pneumonia (IPn). IPn developed in 92 patients (17%). 37% of cases were associated with cytomegalovirus infection and 22% with other organisms; in 41% of cases no organism was identified. The case fatality rate was 64%; the mortality rate due to IPn was 11%. In multivariate analysis, four factors were associated with an increased probability of interstitial pneumonia: use of methotrexate rather than cyclosporine after transplantation (relative risk, 2.8; P less than 0.0008); occurrence of moderate to severe acute graft-versus-host disease (relative risk, 2.2; P less than 0.002); inclusion of total body radiation in the pretransplant preparative regimen (relative risk 2.2, P less than 0.004); and patient age greater than 20 (relative risk 1.7, P less than 0.002). The probability of IPn ranged from 4% for patients with none of these adverse risk factors to 51% (relative risk of 13.4) for patients with all four. The incidence of IPn decreased significantly between 1978 and 1985, paralleling a decrease in the use of total body radiation pretransplant for immune suppression and methotrexate post-transplant for prophylaxis against graft-versus-host disease.

106 patients with acute lymphoblastic leukaemia (ALL) who received bone-marrow transplants from HLA-identical siblings during first or second remission had an actuarial survival rate at 4 years of 43 +/- 12% and an actuarial relapse rate of 32 +/- 12%. 98 patients with more advanced disease had a significantly lower probability of survival (15 +/- 9%) and a significantly higher probability of relapse (67 +/- 14%). Among high-risk patients, those transplanted in first remission had a higher survival probability (55 +/- 22%) than those transplanted in second remission (41 +/- 15%). Relapse rates in the two groups were comparable (28 +/- 24% and 31 +/- 19% respectively). Standard-risk and high-risk patients transplanted in second remission had comparable relapse rates, but there was a trend towards higher survival probability in standard-risk patients. Thus long-term disease-free survival in ALL can be achieved with bone-marrow transplantation. It is not yet certain whether transplants in first remission will result in higher survival rates than transplants in second remission; relapse rates were similar in the two groups.

Recurrence of carcinoma of the breast after radical mastectomy was associated with preoperative body weight among patients observed for up to 24 years. Patients who had no axillary lymph node metastases and who weighed 130 pounds or less had an accumulative recurrence free survival superior to that of heavier patients. The advantage was unassociated with significant differences in menopausal status, clinical stage, or tumor size. High fat diet and large body mass have been linked epidemiologically with high risk for breast cancer; whatever biologic mechanisms are involved may also promote growth of residual tumor after potentially curative surgery. Diet and weight reduction may represent empirical means for improving the prognosis of heavy individuals with early stages of breast cancer.

Although levels of triglycerides have consistently shown a strong association with cardiovascular disease in both case-control and cohort studies, it remains controversial whether this relation exists independently of levels of cholesterol and other risk factors. The association of arteriographically documented coronary artery disease with plasma levels of triglycerides, total cholesterol, and high density lipoprotein (HDL) cholesterol was therefore examined in 5,216 white adults (81% were male) referred to two Milwaukee hospitals between 1972 and 1986. Elevated levels of triglycerides were related to the extent of coronary artery disease (estimated using the total number and severity of stenoses) in both sexes; this association existed independently of total cholesterol, age, obesity, hypertension, smoking, and alcohol consumption. In addition, the association between triglycerides and coronary artery occlusion was strongest at total cholesterol levels less than or equal to 250 mg/dl. However, both stratified and regression analyses indicated there was no residual association between triglyceride levels and occlusion after controlling for HDL cholesterol. (Levels of HDL cholesterol and triglycerides showed a moderate inverse association: r = -0.39 to -0.51.) These results indicate that the association between coronary artery occlusion and levels of triglycerides is indirect, and that the disparate findings of earlier studies may have resulted from not controlling for HDL cholesterol.

In a study using data from 254 families with 546 non-biologically related children and 10 337 families with 25 554 biologically related children an analysis of variance technique was used to evaluate the effect of family environment and heredity for children ages 4-11. Family environment accounted for 32% of the variation in obesity if all children were used and more than 39% of the variation in obesity using subgroups of children similar with respect to sex and age. The estimate of heritability was quite low, only 11%. These results suggest that family environment, which consists of such things as parental example and child rearing techniques, has an important effect on childhood obesity.

A critical factor limiting the availability of histocompatible platelet transfusions for alloimmunized, thrombocytopenic patients is the large pool of HLA-typed donors needed to procure platelets perfectly matched for HLA antigens. We have, therefore, investigated the effectiveness of platelets obtained from donors having lesser degrees of histocompatibility. In 421 transfusions administered to 59 alloimmunized patients who were refractory to "random donor" platelets, it was found that platelets mismatched for 1 or 2 "cross-reactive" HLA antigens were in most instances as effective in increasing circulating platelet levels as perfectly matched platelets. A significant number of patients also responded to platelets from donors selectively mismatched for non-cross-reactive HLA antigens. The latter group had a significantly reduced frequency of the antigen HLA-A2 (13%) in comparison to the total patient population (49%). Use of donors whose HLA antigens are serologically cross-reactive with those of alloimmunized patients provides approximately 10 times as many prospective donors as does selection based on matching for HLA and simplifies the procurement of hemostatically effective platelets for such patients.

Groups of AKR mice bearing spontaneous leukemia-lymphoma were treated with five different combinations of chemotherapy or chemoradiotherapy. Each treatment combination was given in two sequences--high dose first and low dose last, or low dose first and high dose last--administered over 6-7 days. When the initial treatment was a high dose of chemotherapy, radiotherapy, or chemoradiotherapy, mortality in the first 24 hours exceeded 40%, and at least 70% of the mice in each group were dead within 2 weeks. When low-dose chemotherapy was given first, mortality in the first 24 hours was minimal but, most significantly, no deaths occurred in the 24 hours after subsequent high-dose treatment. In the most successful group (100 mg cyclophosphamide/kg on day 0, and 250 mg cyclophosphamide/kg and 400 R total-body X-irradiation on day 7), the median survival time increased significantly as compared with the median survival time among mice given the same regimen in reverse sequence (p less than 0.001) or among untreated control mice (p less than 0.01). With this regimen, survival 60 days after the last treatment was 47%. No mouse survived 30 days when the sequence of treatments was reversed. From these results, we conclude that chemotherapeutic and chemoradiotherapeutic regimens for AKR spontaneous leukemia-lymphoma should be designed so that low, minimally lethal doses precede higher doses.

Treatment of DBA/2 (H-2d) mice with bacterial endotoxin prior to transplantation of their spleen and lymph node cells into immunosuppressed AKR (H-2k) mice prevented acute mortality from graft-versus-host (GVH) disease. AKR mice that received immunocompetent cells from untreated DBA/2 mice had a median survival time (MST) of 13 days. In contrast, AKR mice that received immunocompetent cells from endotoxin-treated DBA/2 donors had an MST of 54 days. Endotoxin treatment of AKR recipients was not essential for preventing mortality from acute GVH disease. Chimerism was proved by demonstrating that the lymphoid cells of long-term surviving AKR mice had the characteristics of DBA/2 lymphoid cells as measured by their response in mixed leukocyte culture (MLC) tests. Spleen cells from endotoxin-treated DBA/2 mice were able to stimulate, and to be stimulated by, AKR spleen cells in MLC assays. Furthermore, spleen cells from endotoxin-treated DBA/2 mice did not suppress the responses of DBA/2 or AKR spleen cells in 'three-party' MLC tests.

A three-step treatment plan incorporating adoptive immunotherapy and chemoradiotherapy was used to treat AKR (H-2k) mice bearing spontaneous leukemia-lymphoma (SLL). 1) Leukemic mice were treated with chemoradiotherapy for immunosuppression and leukemia cytoreduction. 2) To introduce a graft-versus-leukemia reaction against residual malignant cells, the immunosuppressed AKR mice were given immunocompetent cells from H-2 mismatched DBA/2 (H-2d) donors. 3) To "rescue" the AKR hosts from incipient graft-versus-host disease, the mismatched DBA/2 cells were killed with combination chemotherapy, and cells from allogeneic H-2 matched RF (H-2k) donors were administered to restore hematopoiesis. Leukemic AKR mice thus treated had significant prolongation of their median survival time and a higher 60-day survival rate post treatment than did untreated controls, chemoradiotherapy controls, or control mice that received chemoradiotherapy plus cells from syngeneic donors. Therefore, adoptive immunotherapy may be useful as an adjunct to conventional therapy for treatment of SLL in AKR mice.