The C-terminus of c-ABL is required for proliferation and viability signaling in a c-ABL/erythropoietin receptor fusion protein

Activated ABL oncogenes cause B-cell leukemias in mice and chronic myelogenous leukemia in humans. However, the mechanism of transformation is complex and not well understood. A method to rapidly and reversibly activate c-ABL was created by fusing the extra-cytoplasmic and transmembrane domain of the erythropoietin (EPO) receptor with c-ABL (EPO R/ABL). When this chimeric receptor was expressed in Ba/F3 cells, the addition of EPO resulted in a dose-dependent activation of c-ABL tyrosine kinase and was strongly antiapoptotic and weakly mitogenic. To evaluate the contributions of various ABL domains to biochemical signaling and biological effects, chimeric receptors were constructed in which the ABL SH3 domain was deleted (triangle upSH3), the SH2 domain was deleted (triangle upSH2), the C-terminal actin-binding domain was deleted (triangle upABD), or kinase activity was eliminated by a point mutation, K290M (KD). The mutant receptors were stably expressed in Ba/F3 cells and analyzed for signaling defects, proliferation, viability, and EPO-induced leukemia in nude mice. When compared with the ability of the full-length EPO R/ABL receptor to induce proliferation and support viability in vitro, the triangle upSH3 mutant was equivalent, the triangle upSH2 mutant was moderately impaired, and the triangle upABD and KD mutants were profoundly impaired. None of these cell lines caused leukemia in mice in the absence of pharmacological doses of EPO. However, in mice treated with EPO (10 U/d), death from leukemia occurred rapidly with wild-type and triangle upSH3. However, time to death was prolonged by at least twofold for triangle upSH2 and greater than threefold for triangle upABD. This inducible model of ABL transformation provides a method to link specific signaling defects with specific biological defects and has shown an important role for the C-terminal actin-binding domain in proliferation and transformation in the context of this receptor/oncogene.     

A peptide sequence from platelet factor 4 (CT-112) is effective in the treatment of type II collagen induced arthritis in mice

OBJECTIVE: Platelet factor 4 (PF-4) is a critical alpha chemokine in inflammation and injury responses, with multiple effects upon cellular activities. Discrete peptide sequences of the PF-4 molecule have been shown to retain biological activity. Our aim was to examine the influence of the PF-4 derived octapeptide (CT-112; TTSQVRPR) on type II collagen induced arthritis in mice, to determine if this peptide exhibited antiinflammatory properties. METHODS: DBA/1 mice were treated with CT-112 from either the time of immunization with type II collagen or from the initial onset of arthritis. RESULTS: CT-112 both prevented the development of arthritis in mice treated prophylactically and reduced progression of disease in animals treated therapeutically, and was active when delivered by either subcutaneous injection or oral gavage. No marked immunosuppressive effects were observed during CT-112 treatment, with only moderate decrease in antibody levels and mitogen responses. A significant reduction of the circulating levels of IL-1 was a consistent finding in mice treated therapeutically with CT-112. CONCLUSION: These data suggest PF-4 derived octapeptide exerts antiinflammatory effects of experimental arthritis in mice.     

Overcoming the luddite factor: some behavioural aspects of the field supervisor's role in construction planning

The way data is presented can seriously affect the ease with which it can be understood. The objectives and results of a survey of different types of presentation are given. Some psychological aspects of the problem are analysed.     

Psychosocial factors among members of religious and secular kibbutzim

Mortality in 11 secular kibbutzim between 1970 and 1985 was nearly twice that of 11 matched religious kibbutzim. A cross-sectional study was undertaken in 1991 in 10 of these settlements, 5 religious and 5 secular, to determine whether differences in risk factors could explain the unequal survival. These comprised physical, physiologic and biochemical measurements, health-relevant behaviors and psychosocial variables. This report addresses the psychosocial aspect of the study, which included assessment of sense of coherence, hostility, satisfaction with self, work-related stress, social supports and social contacts using self-administered questionnaires. The response rate among the sample of men and women, aged 35-64 years, was 76% (437 respondents, 208 men and 229 women). Analysis of variance and logistic regression (the latter comparing the upper or lower fourths of the distribution vs. the rest) were used. Religious kibbutz members reported a higher sense of coherence (odds ratio = 1.58, 95% CI 1.02 to 2.46) and a lower level of hostility (odds ratio = 0.49, 95% CI 0.33 to 0.75) than their secular counterparts. Findings for satisfaction with self and work-related stress were inconsistent; there were significant interactions between religious affiliation, sex and age. Younger women reported less satisfaction with self and higher work-related stress than the other age-sex groups in both types of kibbutz. There was no difference in social support or frequency of social contact between religious and secular kibbutzim. Voluntary work was more frequent among the religious kibbutzim. The findings are consistent with an interpretation that Jewish religious observance may enhance the formation of certain protective personality characteristics. Membership in a cohesive religious kibbutz community may increase host resistance to stressors and thereby promote overall well-being and a positive health status. This could reflect an interplay of individual and collective attributes of religion.     

Serum lipids and incidence of coronary heart disease. Findings from the Systolic Hypertension in the Elderly Program (SHEP)

BACKGROUND: The association of serum lipids with coronary heart disease has been studied extensively in middle-aged men and, to a lesser extent, in similar women. Less well defined are lipid variables predictive of CHD in individuals of age > or = 60 years. METHODS AND RESULTS: The Systolic Hypertension in the Elderly Program recruited 4736 persons (mean age, 72 years; 14% were black; and 43% were men). Mean systolic and diastolic blood pressures were 170 and 77 mm Hg, respectively. Baseline mean total cholesterol was 6.11 mmol/L (236 mg/dL); HDL cholesterol, 1.39 mmol/L (54 mg/dL); and non-HDL cholesterol, 4.72 mmol/L (182 mg/dL). Triglyceride levels were 1.62 mmol/L (144 mg/dL) for fasting participants and 1.78 mmol/L for the total group. LDL cholesterol, estimated in fasting samples with triglycerides of < 4.52 mmol/L, averaged 3.98 mmol/L (154 mg/dL). Mean follow-up was 4.5 years. In multivariate Cox regression analyses, baseline total, non-HDL, and LDL cholesterol levels and the ratios of total, non-HDL, and LDL to HDL cholesterol were significantly related to CHD incidence. HDL cholesterol and triglycerides were not significant in these analyses. In fasting participants with triglyceride levels of < 4.52 mmol/L, a 1.03 mmol/L (40 mg/dL) higher baseline total, non-HDL, or LDL cholesterol was associated with a 30% to 35% higher CHD event rate. CONCLUSIONS: The results of this study support the concept that serum lipids are CHD risk factors in older Americans.     

Penetrating cardiac wounds: prospective study of factors influencing initial resuscitation

A prospective study of 66 consecutive patients with cardiac wounds seen over a 27-month period is reported. No patient was excluded. Patients were stratified by injury mechanism and by physiologic scoring at admission using the cardiovascular-respiratory elements of the Trauma Score (CVRS). Admission cardiac rhythm was obtained in patients with a CVRS of 0 and a Glasgow Coma Scale (GCS) score of 3. Information concerning the anatomic extent of the cardiac wound, the presence or absence of tamponade, and the degree of injury to other structures was also collected prospectively. Seventy percent of the cardiac wounds were caused by gunshots. The probability of successful resuscitation was significantly related to mechanism of injury and physiologic condition on arrival. Among patients arriving with a CVRS of 0 and a GCS score of 3, survival correlated with cardiac rhythm. Pericardial tamponade did not prove to be an independent predictor of early survival. The presence of tamponade was statistically linked to the mechanism of injury. Transport by non-official conveyance was associated with a higher CVRS on arrival. Intoxication with alcohol or cocaine had no evident effect on resuscitation probability.