Bcr-Abl induces autocrine IGF-1 signaling.

Bcr-Abl oncogene is responsible for the initial phase of chronic myelogenous leukemia (CML), which is effectively treated by the Bcr-Abl inhibitor imatinib. Over time patients become resistant to treatment and progress to blast crisis, an event that is driven by additional genetic and epigenetic aberrations. Recently, we showed that Riz1 expression decreases in blast crisis and that re-expression of Riz1 inhibits IGF-1 expression. IGF-1 signaling is required in many stages of hematopoiesis and inappropriate activation of autocrine IGF-1 signaling may facilitate transformation to blast crisis. We observed that in 8 out of 11 matched CML patient biopsies the IGF-1 expression is elevated in blast crisis. We examined mechanisms used by CML blast crisis cell lines to activate IGF-1 expression. We found that Bcr-Abl activates autocrine IGF-1 signaling using Hck and Stat5b. Inhibition of these signaling components using small molecule drugs or shRNA decreases proliferation and enhances apoptosis. Together, our study suggests that aberrant IGF-1 signaling is an important event in blast crisis transformation and it provides a mechanism to explain the activity of IGF-1R and Hck inhibitors in blocking CML blast crisis phenotypes.

Large granular lymphocyte leukemia and its association with oral neutropenic ulcerations: a case report.

Large granular lymphocyte leukemia is a rare chronic indolent disorder commonly associated with severe neutropenia. The pathogenesis of the neutropenia is unclear. A case is presented of a 74-year-old man who had recurrent oral ulcerations for over a year before a diagnosis was made. These recurrent oral ulcers cleared with treatment and have not returned. The differential diagnosis of persistent oral ulcerations includes trauma; viral, fungal, and bacterial infections; systemic disease; or various malignant conditions. The oral ulcers in this man were likely infectious in nature and related to the severe chronic neutropenia. This case serves to illustrate the potentially complex nature of oral ulcers.

Biologic and clinical significance of CD7 expression in acute myeloid leukemia.

CD7 antigen, a T-cell lineage associated antigen, is expressed in a minority of patients with acute myeloid leukemia (AML). The biologic and clinical significance of this finding is not clearly established. In this retrospective study of patients with de novo acute myeloid leukemia, we have identified CD7 expression and analyzed its association with markers expressed early in hemopoietic ontogeny and clinical parameters. Among 60 consecutive AML patients, we found six (10%) expressing CD7 on leukemic cells. There were five males and one female and the mean age was 59.6 years (age range: 32-76 years) with no demographic peculiarities. The FAB subtypes were: M0 (2), M1 (1), M2 (1), and M4 (2). CD7 expression was associated with immature antigens CD34, HLA-DR, and terminal deoxynucleotidyl transferase (TdT) and antigen receptor gene rearrangements (rearrangements of T-cell receptor gamma chain in 6/6 and immunoglobulin heavy chain in 2/6). Hepatomegaly was present in three and this was associated with splenomegaly with lymphadenopathy in one patient. Mediastinal or central nervous system involvement was absent. Complete remission was achieved in two patients with standard chemotherapy; one of these is in remission and alive (5 years later), while one died following relapse 9 months later. Three patients had significantly lower response to standard therapeutic regimen (two died during induction and one died 7 months later without ever achieving complete remission). One patient has been excluded in determining the prognostic significance of CD7 due to early death. Our results suggest origin of CD7+ AML from early hemopoietic precursors and indicate biologic aggressiveness in a significant proportion of patients. We suggest evaluation of CD7 in all patients with AML at the time of diagnosis in view of poor clinical outcome.

Alloantigen-blocking antibodies in sera from highly sensitized uremic patients: antibody class and relationship with lymphocytotoxins.

BACKGROUND: Previously, we identified an antimitogenic IgG antibody separated from sera of patients with known kidney transplant chronic rejection. This antibody inhibits individual patients' own unprimed T helper cell responses to alloantigens as well as a third-party mixed lymphocyte response, but does not inhibit autologous unprimed T helper cell proliferation to adherent anti-CD3 antibody. We suggest that the mechanism of inhibitory action is allogeneic-dependent. METHODS: We used a series of similar experimental designs to test the presence of this antibody in uremic, sensitized patients and have studied its relationship to sensitization as defined by the presence of lymphocytotoxins in four uremic groups: highly sensitized with or without previous graft loss, moderately sensitized with or without graft loss, nonsensitized without previous graft loss, and nonsensitized with graft loss. RESULTS: (1) Sensitization is associated with the presence of a potent antibody that blocks primary mixed lymphocyte response. Primed cells are less susceptible to its antimitogenic action. (2) The blocking antibody activity is present only in sensitized patients who have IgG lymphocytotoxic activity against the same HLA class I antigens. (3) The blocking activity is unequal in the following order: IgG 3 > IgG 1 > IgG 2. (4) Although IgG 1 and 2 fractions contain lymphocytotoxic activity against HLA class I antigens, the IgG 3 fraction does not. CONCLUSIONS: The differential effect of IgG antibodies on naive and memory T cells may explain why humeral responses to alloantigens can be maintained in the presence of blocking antibodies.

Body fat distribution and race differences in apolipoprotein A1.

OBJECTIVE: This is the first study to assess the role of waist-to-hip ratio in explaining race differences in levels of serum apolipoprotein A1, a protective risk factor for atherosclerosis. METHODS: Linear regression analyses were used in a community-based survey of 3,043 adults (23.5% African-American) to assess associations of race, age, anthropometric measures, education, diabetes, blood pressure medication use, cigarette smoking, and leisure-time physical activity with apolipoprotein A1 levels. RESULTS: Higher apolipoprotein A1 levels were observed among African-American than among white adults (African-American men: +15.6 mg/dl than white men, African-American women: +3.1 mg/dl more than white women; p < 0.05). Waist-to-hip ratio and other variables did not account for race differences among men. African-American women had +8.6 mg/dl higher levels than white women after adjustment for differing distributions of waist-to-hip ratio, age, body mass index and education. Cigarette smoking, physical activity, and medical history accounted for no further differences among women. CONCLUSIONS: Higher levels of obesity indicators and lower educational attainment among African-American women reduced a potentially greater beneficial race difference in apolipoprotein A1. These findings also suggest that other environmental and biochemical factors may play roles in explaining the higher protective levels of apolipoprotein A1 observed among African-American children and adults.

Education, health behaviors, and the black-white difference in waist-to-hip ratio.

Few epidemiologic studies have investigated the impact of body mass index, low educational attainment, cigarette smoking, and physical activity on the considerable black-white difference in waist-to-hip ratio. These relationships were assessed with multivariable linear regression among 3,094 adults (24% black) who were examined in 1987 in South Carolina. The unadjusted mean waist-to-hip ratio was lower for black men than for white men (-0.03 units) and higher for black women than for white women (+0.03 units). After adjustment for age, body mass index, education, smoking, and physical activity, the black-white difference in mean waist-to-hip ratio was -0.02 units (p < 0.001) among men and +0.01 units (p < 0.01) among women. Although differing distributions of age, body mass index, and educational attainment accounted for a 59% reduction in the black-white difference among women, these factors did not explain the difference among men. Thus, these results suggest that other environmental or biologic factors may also play an important role in the marked variation in body fat distribution between the two ethnic groups. The results also support the importance of the prevention of cigarette smoking and overweight in potentially preventing abdominal obesity in both black adults and white adults.

Waist-to-hip ratio in a biracial population: measurement, implications, and cautions for using guidelines to define high risk for cardiovascular disease.

Cutoff points for high waist-to-hip ratio (WHR) that may define high risk for cardiovascular disease have been suggested for men (0.95) and women (0.80). The WHRs of groups defined by age, race, and sex among 3,118 South Carolina adults were compared with these cutoff points. Measurement methodology, mean WHRs, and prevalence of elevated WHR in this biracial study population were compared with data from other populations. A review of anthropometric measurement methods used in recent epidemiologic studies indicates that a standard method for measuring waist and hip girth is required before comparisons of mean levels can be valid. The paucity of evidence that a high WHR is associated with cardiovascular disease mortality in black populations, and the high number of women who have an elevated WHR in this and other epidemiologic studies, support the following conclusion: Current WHR cutoff points, which are based on evidence from primarily white populations, may not be appropriate for women, older age groups, and some racial or ethnic groups in the United States.

Use of desmopressin acetate to reduce blood transfusion requirements during cardiac surgery in patients with acetylsalicylic-acid-induced platelet dysfunction.

OBJECTIVE: To determine whether desmopressin acetate (DDAVP) has the ability to reduce blood loss in patients with a known bleeding tendency. DESIGN: A randomized, double-blind, placebo controlled study. SETTING: A university teaching hospital. PATIENTS: Men under the age of 70 years who had taken acetylsalicylic acid within 7 days of scheduled coronary artery bypass surgery. Patients with an abnormal hematologic profile or a history of bleeding or who were receiving heparin or undergoing repeat coronary bypass surgery were excluded. Forty-four patients were randomized with restriction in blocks of 10; 20 received DDAVP and 24 received a placebo. MAIN OUTCOME MEASURES: Blood loss and blood transfusion requirements. RESULTS: Patients treated with DDAVP lost significantly (p < 0.01) less blood than those receiving a placebo (1543 mL versus 2376 mL respectively). Nineteen patients had a blood loss of more than 2000 mL; 15 of these were in the placebo group. Significantly (p < 0.02) fewer patients receiving DDAVP required blood transfusion (9 versus 18). CONCLUSIONS: DDAVP reduces blood loss during cardiac bypass surgery in patients who have taken acetylsalicylic acid within 7 days before operation.

Demographic and educational differences in smoking in a tobacco-growing state.

National studies have documented an excessive rate of cigarette smoking in black men; however, a 1987 survey conducted in two urban areas in South Carolina documents a high rate of smoking in young white men with fewer than 12 years of education (67%; 95% confidence interval [CI] = 58.3, 75.7). Differences in smoking rates by educational level were significant only for those younger than 40. Young blacks were less likely to smoke and smoked fewer cigarettes than whites. As a result, the population burden of cigarettes in young black men with fewer than 12 years of education was only 27% of the burden carried by their white peers. Television, physicians, and radio were all seen as likely sources of health information to prevent heart disease, but newspapers were less likely to be cited by those younger than 40 or by those with fewer than 12 years of education. Reported physician counseling for smoking cessation did not differ significantly by race, sex, or educational level of the patient, but reported counseling was higher for individuals with a personal history of cardiovascular disease (odds ratio [OR] = 2.32, CI = 1.27, 4.25) and somewhat lower for the elderly. We highlight the population burden of cigarettes, a predictor of the eventual disease burden attributable to smoking, as a useful priority measure for smoking intervention efforts.

Familial systemic lupus erythematosus characterized by digital ischemia.

We describe a family in which 3 members each developed systemic lupus erythematosus complicated by ischemic vasculopathy. The calendar years and patient ages of disease onset and the clinical courses were remarkably similar for all 3 patients, although their genotypes were not. The potential contributions of heredity and environment to the concordance of disease expression in this family are discussed.

HLA typing in polymorphous light eruption.

Human leukocyte antigen typing of 41 white patients with polymorphous light eruption (limited concept) showed no significant differences when compared with the typing of 51 white control subjects. We previously found that actinic prurigo, an idiopathic photodermatosis particularly associated with Amerindians, has a positive association with antigens A24 and Cw4 and a negative association with A3. We suggest, on the basis of both laboratory and clinical findings, that polymorphous light eruption (limited concept) and actinic prurigo are two different and distinct diseases.

HLA typing in actinic prurigo.

Thirty-two actinic prurigo patients of Cree ancestry underwent human lymphocyte antigen (HLA) typing and were compared with 32 control subjects of Cree ancestry. We found a significantly increased frequency of HLA-A24 and Cw4 antigens and a significant decrease in the frequency of the A3 antigen in actinic prurigo patients. These HLA associations may be helpful in determining whether actinic prurigo is a distinct disease or a variant of polymorphous light eruption.

Lessons from a doctoral thesis.

The production of a doctoral thesis is a time-consuming affair that until recently was done in conjunction with professional publishing services. Advances in computer technology have made many sophisticated desktop publishing techniques available to the microcomputer user. We describe the computer method used, the problems encountered, and the solutions improvised in the production of a doctoral thesis by computer. The Apple Macintosh was selected for its ease of use and intrinsic graphics capabilities. A scanner was used to incorporate text from published papers into a word processing program. The body of the text was updated and supplemented with new sections. Scanned graphics from the published papers were less suitable for publication, and the original data were replotted and modified with a graphics-drawing program. Graphics were imported and incorporated in the text. Final hard copy was produced by a laser printer and bound with both conventional and rapid new binding techniques. Microcomputer-based desktop processing methods provide a rapid and cost-effective means of communicating the written word. We anticipate that this evolving technology will have increased use by physicians in both the private and academic sectors.

Protective HLA-DR phenotypes in rheumatoid arthritis.

In a study of HLA-DR phenotypes in patients with rheumatoid arthritis (RA) and controls from the Saskatoon area and in Newfoundland, we found that certain phenotypes occurred more frequently in the patients than in healthy controls in both populations ("increased risk phenotypes"). The reverse was also true: certain phenotypes were reduced or excluded from patients with RA compared with controls. Three increased risk phenotypes with twice the expected frequencies or more were HLA-DR1,DR4; DR4 and DR4,DR5. Four "protective" phenotypes with half or less the expected frequencies were HLA-DR1, DR5; DR2; DR2,DR3 and DR3,DR7. We speculate that at least for the DR3,DR7 phenotype, the protective effect may be due to a hybrid DQw2 molecule.