Guar attenuates fall in postprandial blood pressure and slows gastric emptying of oral glucose in type 2 diabetes

Postprandial hypotension occurs frequently in diabetes; the fall in blood pressure is greatest after ingestion of carbohydrate, particularly glucose and, in type 2 diabetes, is related to the rate of gastric emptying. The aim of this study was to determine whether slowing of gastric emptying by guar gum reduces the fall in blood pressure after oral glucose in patients with type 2 diabetes. Eleven type 2 patients managed by diet alone, age 61.9 ± 1.3 years, had measurements of gastric emptying, blood pressure, blood glucose, and serum insulin on two occasions after ingestion of 300 ml water containing 50 g glucose, with or without 9 g guar gum. The magnitude of the fall in blood pressure was less (P < 0.05) and gastric emptying slower (P < 0.05) after guar. Blood glucose (P < 0.05) and serum insulin (P < 0.01) concentrations were lower after guar. The magnitude of the fall in systolic blood pressure was related to gastric emptying of glucose at 30 min on the control day (r = 0.67, P < 0.05). We conclude that guar gum attenuates the fall in blood pressure after oral glucose in patients with type 2 diabetes mellitus, presumably by slowing glucose absorption.     

Murine cytomegalovirus m157 mutation and variation leads to immune evasion of natural killer cells

Effective natural killer (NK) cell recognition of murine cytomegalovirus (MCMV)-infected cells depends on binding of the Ly49H NK cell activation receptor to the m157 viral glycoprotein. Here we addressed the immunological consequences of variation in m157 sequence and function. We found that most strains of MCMV possess forms of m157 that evade Ly49H-dependent NK cell activation. Importantly, repeated passage of MCMV through resistant Ly49H+ mice resulted in the rapid emergence of m157 mutants that elude Ly49H-dependent NK cell responses. These data provide the first molecular evidence that NK cells can exert sufficient immunological pressure on a DNA virus, such that it undergoes rapid and specific mutation in an NK cell ligand enabling it to evade efficient NK cell surveillance.     

Platelet surface-bound IgG in patients with immune and nonimmune thrombocytopenia

We quantitated the amount of platelet surface-bound IgG using an 125I monoclonal anti-IgG assay in 149 patients with thrombocytopenia and 260 normal donors. The normal subjects had 122 +/- 5 molecules of IgG/platelet (mean +/- SE). Fifty-five patients with nonimmune thrombocytopenia had 338 +/- 37 molecules of IgG/platelet, whereas 67 patients with immune thrombocytopenia studied at the time of their initial evaluation had 4,120 +/- 494 molecules of IgG/platelet. An analysis of the distribution of values in these two groups indicated that 90% of the patients with immune thrombocytopenia had greater than 800 molecules of IgG/platelet, whereas only 7% of patients with nonimmune thrombocytopenia exceeded this amount. The immune thrombocytopenia patients included 39 idiopathic, 14 secondary, and 14 drug-induced disorders, and they did not significantly differ in their distribution of values for platelet IgG. The nonimmune thrombocytopenic patients included 12 cases with a platelet destructive mechanism; their platelet-bound IgG was similar to that of the other nonimmune patients. Twenty-seven patients with treatment resistant immune thrombocytopenia were also studied they had 2,100 +/- 670 molecules of IgG/platelet. Their values were significantly greater than those of the nonimmune thrombocytopenic patients and not significantly different from those of immune thrombocytopenic group. Their distribution of values was much broader, however, with 33% of patients having less than 800 molecules of IgG/platelet, suggesting possible alternate mechanisms in their thrombocytopenia. Thus, patients with immune thrombocytopenia have a high frequency of elevated IgG on the platelet surface which reflects the pathophysiology of this disorder. Quantitation of platelet-bound IgG provides a useful laboratory tool in the differential between immune and nonimmune thrombocytopenia.     

Identification of an erythropoietin-sensitive cell line

The murine lymphoblastic cell line DA-1 has been characterized as dependent upon both interleukin-3 (IL-3, multicolony-stimulating factor [multi-CSF]) and granulocyte-macrophage colony-stimulating factor (GM- CSF) for survival and growth. Here we demonstrate that it is responsive to a third hematopoietic factor, the erythroid-specific hormone, erythropoietin (Epo). DA-1 cells are stimulated to proliferate by partly purified natural murine and human Epo, and pure recombinant human Epo. Antibody to Epo specifically blocks Epo-stimulated growth. Maximal growth stimulated by Epo and GM-CSF is similar, and considerably less than that stimulated by multi-CSF. Proliferation stimulated by Epo and GM-CSF is transient, decreasing within 24 to 48 hours of exposure. However, Epo acts cooperatively with GM-CSF to sustain proliferation. With or without GM-CSF, no obvious erythroid differentiation of DA-1 cells occurs after exposure to Epo for up to 72 hours. This is the first report of a growth factor-dependent cell line also responsive to Epo for survival and growth. The availability of this cell line model should greatly facilitate biochemical analysis of the mechanism of Epo growth-stimulating action.     

Cytogenetically aberrant cells in the stem cell compartment (CD34+lin-) in acute myeloid leukemia

Leukemia may be viewed as a clonal expansion of blast cells; however, the role of primitive cells and/or stem cells in disease etiology and progression is unclear. We investigated stem cell involvement in leukemia using fluorescence in situ hybridization (FISH), immunofluorescence labeling of hematopoietic subpopulations, and flow cytometric analysis/sorting to discriminate and quantify cytogenetically aberrant stem cells in 12 acute myeloid leukemia (AML) and three myelodysplastic (MDS) specimens. Flow cytometric analysis and sorting were used to discriminate and collect a primitive subpopulation enriched in stem cells expressing CD34+ and lacking CD33 and CD38 (CD34+lin-). A subpopulation containing progenitors and differentiating myeloid cells expressed CD34, CD33, and CD38 (CD34+lin+). Nine specimens contained less than 10% CD34+ cells and, thus, were considered to be CD34- leukemias. Mature lymphoid, myeloid, and erythroid subpopulations were sorted on the basis of antigen-linked immunofluorescence. Cytogenetically aberrant cells in sorted subpopulations were identified using FISH with enumerator probes selected on the basis of diagnosis karyotype. Cytogenetically aberrant CD34+lin- cells were present at frequencies between 9% and 99% in all specimens. CD34+lin- cytogenetically aberrant cells comprised between 0.05% and 11.9% of the marrow/blood specimens. Cytogenetically aberrant CD34+lin+ cells constituted 0.01% tp 56% of the marrow/blood population. These data demonstrate that aberrant cells are present in primitive CD34+ stem cell compartments, even in CD34- leukemias. Stem cell involvement was confirmed further by sorting lymphoid and erythroid subpopulations from eight specimens in which the predominant leukemic population lacked lymphoid/erythroid differentiation markers. In these specimens, as well as in multiple lineages, suggests involvement of a cell(s) with multilineage capabilities. The ability of aberrant CD34+lin- stem cells to contribute to clonal and compartment expansion within immunofluorescently defined subpopulations was evaluated to explore the functional phenotype of aberrant CD34+lin- cells. Analysis of compartment size and aberrant cell frequency suggests that frequency of cytogenetically aberrant stem cells is uncoupled from compartment size. These data suggest that cytogenetically aberrant cells in the primitive compartment show varying abilities to expand primitive compartments. Cytogenetically aberrant CD34+lin- cells precede the blast subpopulation in hierarchical maturation and may in some cases by considered preleukemic, requiring maturation or additional mutations before transformation (eg, compartmental expansion) occurs.     

Acute lymphoblastic leukemias with deletion of 11q23 or a novel inversion (11)(p13q23) lack MLL gene rearrangements and have favorable clinical features

Balanced translocations affecting the 11q23 region are among the most frequent chromosomal abnormalities in childhood acute lymphoblastic leukemia (ALL), comprising 5% to 6%. These cases consistently have a rearranged MLL gene and are associated with high-risk presenting features, hyperleukocytosis and younger age, and a poor treatment outcome. To assess the clinical and biologic significance of 11q23- associated structural chromosomal abnormalities other than translocations, we studied 17 cases of childhood ALL [14 with del(11)(q23) and 3 with inv(11)(p12q23)] that were identified among 785 cases with successful chromosome analysis. In contrast to reported cases with 11q23 and MLL gene rearrangement, our series was characterized by relatively low leukocyte counts (median, 15.1 x 10(9)/L), expression of CD10 antigen but not myeloid-associated CD15 and CDw65 antigens, a relatively high frequency of T-cell immunophenotypes, and a generally favorable prognosis. All 13 cases with interpretable molecular analysis lacked MLL gene rearrangements. We suggest that most cases with deletions or inversions affecting the 11q23 region represent clinically and biologically different entities as compared with those defined by 11q23 translocation.     

Benefits of pravastatin on cardiovascular events and mortality in older patients with coronary heart disease are equal to or exceed those seen in younger patients: Results from the LIPID trial

BACKGROUND: The effect of cholesterol-lowering therapy on death from coronary heart disease in older patients with previous coronary heart disease and average cholesterol levels is uncertain. OBJECTIVE: To compare the relative and absolute effects of pravastatin on cardiovascular disease outcomes in patients with coronary heart disease who are 65 years of age or older with those in patients 31 to 64 years of age. DESIGN: Subgroup analysis of a randomized, placebo-controlled trial. SETTING: 87 centers in Australia and New Zealand. PATIENTS: 3514 patients 65 to 75 years of age, chosen from among 9014 patients with previous myocardial infarction or unstable angina and a baseline plasma cholesterol level of 4.0 to 7.0 mmol/L (155 to 271 mg/dL). INTERVENTION: Pravastatin, 40 mg/d, or placebo. MEASUREMENTS: Major cardiovascular disease events over 6 years. RESULTS: Older patients were at greater risk than younger patients (31 to 64 years of age) for death (20.6% vs. 9.8%), myocardial infarction (11.4% vs. 9.5%), unstable angina (26.7% vs. 23.2%), and stroke (6.7% vs. 3.1%) (all P < 0.001). Pravastatin reduced the risk for all cardiovascular disease events, and similar relative effects were observed in older and younger patients. In patients 65 to 75 years of age, pravastatin therapy reduced mortality by 21% (CI, 7% to 32%), death from coronary heart disease by 24% (CI, 7% to 38%), coronary heart disease death or nonfatal myocardial infarction by 22% (CI, 9% to 34%), myocardial infarction by 26% (CI, 9% to 40%), and stroke by 12% (CI, -15% to 32%). For every 1000 older patients treated over 6 years, pravastatin prevented 45 deaths, 33 myocardial infarctions, 32 unstable angina events, 34 coronary revascularization procedures, 13 strokes, or 133 major cardiovascular events, compared with 22 deaths and 107 major cardiovascular events per 1000 younger patients. Among older patients, the numbers needed to treat were 22 (CI, 17 to 36) to prevent one death from any cause, 35 (CI, 24 to 67) to prevent one death from coronary heart disease, and 21 (CI, 17 to 31) to prevent one coronary heart disease death or nonfatal myocardial infarction. CONCLUSIONS: In older patients with coronary heart disease and average or moderately elevated cholesterol levels, pravastatin therapy reduced the risk for all major cardiovascular events and all-cause mortality. Since older patients are at greater risk than younger patients for these events, the absolute benefit of treatment is significantly greater in older patients.     

Cost effectiveness of radiofrequency catheter ablation in the treatment of symptomatic supraventricular tachyarrhythmias

Abstract Background: The recent advent of radiofrequency (RF) catheter ablation as a curative therapy for supraventricular tachyarrhythmias has challenged the role of long term drug treatment, which is essentially a palliative therapy. To date, however, no data have been published on the cost-effectiveness of RF ablation as compared with drug treatment in the Australian setting. Aims: The study aimed to compare actual and projected costs of these two treatment options in a consecutive group of patients having RF ablation as treatment for symptomatic tachyarrhythmias. Methods: The cost effectiveness of RF catheter ablation was assessed in 26 patients having RF ablation, using a hypothetical model of continued drug therapy in the same group of patients. A ‘cost saving’ criterion was used for cost effectiveness. Actual costs for the RF ablation and for continued drag therapy were based on data from medical records and from the answers to a detailed patient questionnaire. Analysis included costs of prior diagnostic electrophysiology (EP) study (17/26 patients), general anaesthesia (GA: 20/26 patients), post-ablation echocardiography (10/26 patients), and late follow-up EP study (7/26 patients). The in-hospital stay for the RF ablation was two days in all cases, and no patient required implantation of a permanent pacemaker. The RF ablation procedure was successful in 23/26 patients (88.5%) with late recurrence of tachycardia in one patient. After a median follow-up of nine months, 22/26 patients no longer require antiarrhythmic drug therapy. Results: The mean per patient cost of RF ablation was $4067 in the study group. This reduces to $2546 if prior EP study and GA are excluded. The mean per patient cost of continued medical therapy was $700 per year. Extrapolating over 20 years and allowing for an annual 5% inflation factor, RF ablation becomes cost saving in 5.5 years (3.8 years if prior EP and GA are excluded). Over 20 years, continued drag therapy would be four to five times more expensive than RF ablation in the patient study group. We consider RF ablation to be a cost-effective alternative to long term drug therapy in patients with supraventricular tachyarrhythmias.     

Human herpesvirus-6-associated suppression of growth factor-induced macrophage maturation in human bone marrow cultures

Cultures of marrow mononuclear cells were exposed to medium derived from cell cultures infected with several different strains of human herpesvirus-6 (HHV-6) immediately before the addition of either of two growth factors, granulocyte-macrophage colony-stimulating factor and interleukin-3. Exposure to any of the viral preparations suppressed the outgrowth of nonspecific esterase-positive adherent macrophages induced by the factors by more than 90%. The nonadherent cell populations in the infected cultures were numerically similar to those in uninfected control cultures, demonstrating the absence of a nonspecific cytotoxic effect of the viral materials. Infectious virus was not necessary for the macrophage outgrowth suppression. These findings suggest that HHV-6 either encodes or induces a soluble mediator or mediators that can interfere with the responses of bone marrow to growth factors and possibly block the normal differentiation of macrophages from marrow precursors.     

Isolated follicular lymphoma cells are resistant to apoptosis and can be grown in vitro in the CD40/stromal cell system

Low-grade follicular non-Hodgkin's lymphomas are characterized by the presence of a t(14;18) chromosomal translocation that results in deregulation of the B-cell lymphoma (Bcl-2) gene. Studies in cell lines and transgenic animal models have suggested that this results in the suppression of apoptotic cell death in germinal centers. B lymphocytes from normal germinal centers and lymph nodes infiltrated by follicular lymphoma were isolated by immunomagnetic depletion of cells bearing CD4, CD8, or slgD for study in vitro. Follicular lymphoma cells expressing Bcl-2 protein were shown to resist apoptosis after isolation, and could be induced to proliferate in a culture system previously described for the growth of normal B lymphocytes. By the use of a mouse fibroblast monolayer transfected with the CDw32 Fc receptor to present CD40 monoclonal antibody in the presence of interleukin-4, prolonged culture was possible. Karyotypic analysis of cultured lymphoma cells showed the t(14;18) translocation, with clonal identity confirmed by polymerase chain reaction amplification of the breakpoints and direct sequence analysis. These findings support the hypothesis that resistance to apoptosis is an influence on the initiation of follicular lymphoma, and provide a novel means of studying in vitro the intercellular reactions that may be important in progression of the disease.