Autologous Neutrophils Inhibit Production of Colony Stimulating Activity by Normal Human Lymphocytes

S ummary. Experiments were designed to study the way in which normal human polymorphs (PMNs) inhibit the production or release of colony stimulating activity (CSA) by normal lymphocytes incubated alone or in conjunction with normal monocytes. PMNs were first incubated with lymphocytes for varous periods at various concentrations. The PMNs were then removed and the 'conditioned' lymphocytes were used alone or after addition to adherent mononuclear cells (monocytes) for the production of conditioned medium. The samples of conditioned medium were then assayed for CSA in a standard system for culturing granulocyte/macrophage progenitor cells (CFU-C) in agar. We found that the capacity of PMNs to inhibit CSA production by lymphocytes or by lymphocytes plus monocytes was directly proportional to the number of PMNs originally incubated and maximal at relatively short incubation times (i.e. 2–4 h). Such inhibition could be counteracted by the introduction of known stimulators of CSA production by monocytes, e.g. phytohaemagglutinin or bacterial toxin.
We conclude that normal lymphocytes 'conditioned' or 'programmed' by contact with PMNs may themselves have a reduced capacity to produce CSA and may also act to reduce CSA production by monocytes. Such programmed lymphocytes could thus be a component of the mechanism by which PMNs exert a physiological inhibition on CSA-dependent granulopoiesis in vivo.     

Comparison of two calcium blockers on hemodynamics, left ventricular mass, and coronary vasodilatory in advanced hypertension

Dihydropyridine and nondihydropyridine calcium channel blockers (CCB) differ in pharmacologic characteristics. Few clinical studies distinguish effects of CCB as monotherapy. We conducted a comprehensive comparison of two CCB on patients with moderate to severe hypertension. Thirty patients with pretreatment diastolic blood pressures > or = 100 mm Hg were randomly assigned to either nifedipine-GITS or verapamil-SR. Dose titration achieved a diastolic blood pressure of < or = 95 mm Hg or a decrease of > or = 15 mm Hg over 4 weeks. Clinic blood pressure (BP), 24-h ambulatory BP, exercise BP, left ventricular mass, systolic and diastolic function by echocardiography, and coronary flow reserve by split-dose thallium-201 imaging with adenosine were assessed at baseline, end of titration, 3 months and 6 months of treatment. Plasma renin activity, atrial natriuretic peptide, norepinephrine, and epinephrine were assayed. Both drugs caused similar reductions in clinic and 24-h ambulatory BP and similar reductions in left ventricular mass index. Compared to nifedipine-GITS, verapamil-SR produced a significantly lower resting and peak exercise heart rate. Nifedipine-GITS elicited a lower peak exercise systolic BP. At end titration nifedipine-GITS produced lower plasma atrial natriuretic peptide levels, no longer apparent by 6 months. Plasma norepinephrine was lower with verapamil-SR, also at end titration and at 3 months, but not at 6 months. Plasma epinephrine and plasma renin activity were unchanged by either drug. There was no difference for systolic or diastolic left ventricular function or coronary flow reserve between the two treatments. Once daily nifedipine-GITS and verapamil-SR are equally effective for reduction of arterial pressure in moderate to severe hypertension. Differences in their hemodynamic profiles and neurohormonal responses are consistent with preclinical pharmacologic characteristics. The clinical implications of their similarities and differences remain to be fully evaluated in outcome studies.     

Adolescents are not adults: developmental considerations in alcohol users

Much of the work in adolescent substance abuse assessment and treatment has been a direct transport from tools and modalities used in adult substance use populations. There was a consensus among symposium participants that developmental issues are important in assessment, evaluation, and treatment of adolescents with substance use disorders. These issues directly impact outcome at all levels. Presentations from the symposium may be helpful for conceptualizing the problems of adolescent substance use as well as formulating strategies for future research. Information from the symposium may be viewed as a springboard for future research and clinical intervention in adolescent substance abuse.     

Bone marrow transplantation for patients with Philadelphia chromosome- positive acute lymphoblastic leukemia

We report the treatment outcome of allogeneic bone marrow transplantation in ten patients with Philadelphia chromosome-positive acute lymphoblastic leukemia. Six patients are alive and well for 6 to 30 months (median 19 months) after transplantation. Four patients died with transplant related complications. In view of the poor prognosis associated with this disease, marrow ablation followed by allogeneic or syngeneic marrow grafting may be the preferred treatment modality if a suitable marrow donor is available.     

Naltrexone alone and with sertraline for the treatment of alcohol dependence in Alaska natives and non-natives residing in rural settings: a randomized controlled trial

Background: Access to specialty alcoholism treatment in rural environments is limited and new treatment approaches are needed. The objective was to evaluate the efficacy of naltrexone alone and in combination with sertraline among Alaska Natives and other Alaskans living in rural settings. An exploratory aim examined whether the Asn40Asp polymorphism of the μ‐opioid receptor gene (OPRM1) predicted response to naltrexone, as had been reported in Caucasians. Methods: Randomized, controlled trial enrolling 101 Alaskans with alcohol dependence, including 68 American Indians/Alaska Natives. Participants received 16 weeks of either (1) placebo (placebo naltrexone + placebo sertraline), (2) naltrexone monotherapy (50 mg naltrexone + sertraline placebo) and (3) naltrexone + sertraline (100 mg) plus nine sessions of medical management and supportive advice. Primary outcomes included Time to First Heavy Drinking Day and Total Abstinence. Results: Naltrexone monotherapy demonstrated significantly higher total abstinence (35%) compared with placebo (12%, p = 0027) and longer, but not statistically different, Time to First Heavy Drinking Day (p = 0.093). On secondary measures, naltrexone compared with placebo demonstrated significant improvements in percent days abstinent (p = 0.024) and drinking‐related consequences (p = 0.02). Combined sertraline and naltrexone did not differ from naltrexone alone. The pattern of findings was generally similar for the American Indian/Alaska Native subsample. Naltrexone treatment response was significant within the group of 75 individuals who were homozygous for OPRM1 Asn40 allele. There was a small number of Asp40 carriers, precluding statistical testing of the effect of this allele on response. Conclusions: Naltrexone can be used effectively to treat alcoholism in remote and rural communities, with evidence of benefit for American Indians and Alaska Natives. New models of care incorporating pharmacotherapy could reduce important health disparities related to alcoholism.     

Proportional hazards analysis of risk factors for coronary heart disease in individuals aged 65 or older. The Framingham Heart Study

Risk factors for coronary heart disease were examined in 2,501 individuals in the Framingham Heart Study who survived to the age of 65 without evidence of coronary artery disease. We used a proportional hazards (Cox) analysis that examined risk factors over time and included events through the 16th biennial examination. The independently significant multivariate correlates of the development of coronary heart disease after the age of 65 were sex (incidence rate ratio [RR] for males of 1.7 [95% confidence interval of 1.4,2.0]), left ventricular hypertrophy (RR = 2.4 [1.7,3.5]), systolic blood pressure (RR = 2.2 [1.4,3.3] for systolic blood pressure of 160 mmHg or higher as compared with less than 120 mmHg), casual blood glucose (RR = 2.2 [1.5,3.4] for 175 mg/dL or more as compared with less than 90 mg/dL), Metropolitan relative weight from examination 1 (RR = 1.3 [1.0,1.6] for those 130% or more of ideal weight compared with those less than 110% of ideal), and total serum cholesterol (RR = 1.8 [1.3,2.5] for cholesterol in the 90th percentile or higher compared with less than 200 mg/dL). Controlling for all these risk factors, those smoking 20 cigarettes a day or more were at slightly increased risk of coronary heart disease (RR = 1.2 [.9,1.6]) compared with nonsmokers. These analyses suggest that older persons share the same risk factors for coronary artery disease that are significant in younger populations.     

Echocardiographic "smoke" is produced by an interaction of erythrocytes and plasma proteins modulated by shear forces.

OBJECTIVES. This study was designed to determine the blood elements responsible for spontaneous echocardiographic contrast. BACKGROUND. Spontaneous contrast or "smoke" is an echocardiographic image usually found in low flow conditions. Two blood elements, erythrocytes and platelets, have been related to the generation of smoke. METHODS. The echogenicity of porcine blood products was assessed in static and flow conditions and was graded on a digitized videodensity computer program that assigned a score of 0 for black and 100 for white images. Blood elements were circulated from a small tube (4-mm diameter) into a larger cylindric chamber (30-mm diameter) under controlled flow rate conditions. The following blood products were studied: whole blood, platelet-depleted blood, platelet-rich plasma, platelet-poor plasma, erythrocytes suspended in saline solution, adenosine diphosphate (ADP) added to platelet-rich plasma, and saline solution as a control medium. RESULTS. As blood flow was increased in 30 ml/min increments from 0 to 180 ml/min, whole blood echo videodensity (scale 0 to 100) progressively decreased in the larger tube from 38 and 42 to 20, 12, 14, 16 and 14, respectively. When flow increased from 0 to 30 ml/min in the smaller tube, corresponding to a wall shear rate of 0 to 80 s-1, the blood entering the chamber was completely echolucent. The echogenicity of blood products in the larger tube was for static flow (0 ml/min) and high flow (180 ml/min), respectively: platelet-depleted blood = 36 and 14; platelet-rich plasma = 2 and 2; platelet-poor plasma = 0 and 0; erythrocytes in saline solution = 8 and 12; ADP added to platelet-rich plasma = 0 and 15; saline solution = 0 and 0. Because platelets alone were nonechogenic but platelet-depleted blood produced a flow-dependent echogenicity similar to that produced by whole blood, platelets may not be involved in the production of smoke. However, when platelets were aggregated by ADP, they were echogenic but in dense clumps and in a flow-independent pattern not typical of the smokelike images. Erythrocytes suspended in saline solution had an intermediate density image. CONCLUSIONS. Echogenic smoke appears to be due primarily to the interaction of red blood cells and plasma proteins at low flow and low shear rate conditions.     

CD98: a type II transmembrane glycoprotein expressed from the beginning of primitive and definitive hematopoiesis may play a critical role in the development of hematopoietic cells

In our search for cell surface markers expressed on hematopoietic stem cells and/or very early progenitor cells we found that the Joro 177 monoclonal antibody (MoAb) bound to most hematopoietic cells in day 8/8.5 yolk sac, day 12 fetal liver, and day 13 fetal thymocytes; it stained hematopoietic stem cells and less immature lymphoid, myeloid, and erythroid-lineage cells, but not most thymocytes and splenic lymphocytes in adult mice. Joro 177 MoAb stimulated tyrosine phosphorylation of an integral of 124-kD protein and induced homotypic aggregation of lymphoid progenitor cells. Importantly, Joro 177 MoAb inhibited cell survival/growth and consequently the generation of lymphoid, myeloid, and erythroid lineage cells in vitro from early Lin- hematopoietic precursors. Joro 177 MoAb induced apoptosis of hematopoietic progenitor cells. Molecular cloning and expression indicated that Joro 177 MoAb recognizes a type II transmembrane protein, which is the mouse homologue of the human CD98 heavy chain gene. We suggest that CD98 is a cell membrane receptor involved in the control of cell survival/death of hematopoietic cells.