Neutropenia in three patients with rheumatic disorders. Suppression of granulopoiesis by control-sensitive thymus-dependent lymphocytes.

A man with polymyalgia rheumatica (patient 1) and two patients (2 and 3) with Felty's syndrome had neutropenia at the time of diagnosis. Bone marrow samples in each patient were cellular but showed an "arrest" of granulocyte maturation at the myelocyte stage. Agar colony growth of marrow cells from each patient was subnormal but increased after removal of sheep erythrocytes rosette-forming cells (thymus-dependent [T] cells) from marrow cell suspensions before culture. Preincubation of marrow cells with cortisol also enhanced colony growth. Maximum enhancement with cortisol occurred at 1 mM (patient 1), 1 microM (patient 2), and 10 nM (patient 3). Cortisol failed to enhance colony growth after removal of T cells from marrow cell suspensions. Peripheral blood lymphocytes (PBL) and PBL-conditioned medium from all three patients inhibited colony growth of normal human marrow cells. Cortisol treatment of PBL or T depletion from PBL abrogated the inhibition in coculture and with conditioned medium. Prednisone therapy resulted in the disappearance of suppressor T-cell function concomitant with hematologic improvement in patients 2 and 3, but suppressor T cells persisted in patient 1, who did not respond to prednisone. We conclude that cortisol-sensitive T lymphocytes inhibited granulopoiesis in vitro probably by elaboration of a soluble factor or factors. Our results suggest (a) that neutropenia in these patients resulted, at least in part, from T-cell suppression of granulopoiesis, (b) that the effectiveness of prednisone therapy was a result of its inhibition of suppressor T cells, and (c) that responses to glucocorticoid therapy may be predicted in such patients with the agar culture technique and cortisol dose response in vitro.     

Recovery of T cell subsets after autologous bone marrow transplantation is mainly due to proliferation of mature T cells in the graft

In 22 patients with malignancies, treated with high-dose chemoradiotherapy and autologous bone marrow transplantation (BMT), peripheral blood T cell subsets and functions were studied. In ten cytomegalovirus (CMV)-negative patients, CD4+ and CD8+ T cells (representing T cells of the helper/inducer phenotype and T cells of the suppressor/cytotoxic phenotype, respectively), recovered slowly and simultaneously. In 12 CMV-positive patients, however, CD8+ T cells recovered more rapidly than CD4+ T cells and rose to increased counts. No T cells with an immature phenotype (CD1+, OKT6+) were observed. Lymphocyte stimulation by herpes simplex virus infected fibroblasts (and by CMV-infected fibroblasts in CMV-positive patients) in contrast remained high and even increased after BMT in both groups. These data indicate that T cell recovery after autologous BMT is mainly due to proliferation of mature T cells present in the BM graft and not to generation of new T cells from T cell precursors.     

Cost-effectiveness of counseling and pedometer use to increase physical activity in the Netherlands: a modeling study

Background

Counseling in combination with pedometer use has proven to be effective in increasing physical activity and improving health outcomes. We investigated the cost-effectiveness of this intervention targeted at one million insufficiently active adults who visit their general practitioner in the Netherlands.

Methods

We used the RIVM chronic disease model to estimate the long-term effects of increased physical activity on the future health care costs and quality adjusted life years (QALY) gained, from a health care perspective.

Results

The intervention resulted in almost 6000 people shifting to more favorable physical-activity levels, and in 5100 life years and 6100 QALYs gained, at an additional total cost of EUR 67.6 million. The incremental cost-effectiveness ratio (ICER) was EUR 13,200 per life year gained and EUR 11,100 per QALY gained. The intervention has a probability of 0.66 to be cost-effective if a QALY gained is valued at the Dutch informal threshold for cost-effectiveness of preventive intervention of EUR 20,000. A sensitivity analysis showed substantial uncertainty of ICER values.

Conclusion

Counseling in combination with pedometer use aiming to increase physical activity may be a cost-effective intervention. However, the intervention only yields relatively small health benefits in the Netherlands.     

Chronic MK421 fails to modify evolution of hypertension in neonatally coarcted pups

In inbred dogs with neonatally induced coarctation hypertension, prior serial studies during the first year after aortic banding showed extracellular volume excess with normal plasma renin activity (PRA). The present studies test the hypothesis that slowly evolving aortic constriction in this model will yield intrarenal angiotensin II excess, peripherally undetectable, with continuous slightly positive sodium balance, and thus that chronic blockade of angiotensin II formation will prevent generation of hypertension. Accordingly, we used MK421 (enalapril, 3 mg/kg twice daily), a long-acting angiotensin converting enzyme inhibitor, or placebo, administered orally, from the time of banding through 4 months after banding in sex-matched littermates randomly assigned to one of four groups: coarcted/MK421; control/MK421; coarcted/placebo; control/placebo. Results indicate that MK421 caused identical lowering of absolute forelimb systolic blood pressure in coarcted and control pups but failed to modify evolution of a significant (p less than 0.005) systolic blood pressure difference in coarcted versus control dogs. Thus, neither temporal course nor final magnitude of relative hypertension was altered by MK421. Efficacy of MK421 was documented by 83% inhibition of the pressor response to angiotensin I at nadir of drug effect and by sustained increases in angiotensin I and renin concentration throughout the period of study. Coarcted and control pups responded similarly to MK421 for all measured variables. Glomerular filtration rate and extracellular volume (measured by [14C]inulin disappearance) did not differ among groups. Thus, chronic administration of MK421 failed to prevent hypertension and did not impair maintenance of normal renal function in the evolving phase of neonatally induced coarctation hypertension. We conclude that, although angiotensin II may participate in the untreated model, it does not appear essential to generation of hypertension. We propose that the renal pressure-natriuresis mechanism regulates distal pressure, that stenosis-related resistance independently determines the proximal-distal difference, and that chronic converting enzyme inhibition lowers the set point of the former without influencing stenosis evolution, thus secondarily lowering proximal pressure by an equal degree.     

Botryomycosis as an obstructive hepatic disease

Botryomycosis is a disorder caused by certain nonfilamentous bacteria that produce lesions that resemble actinomycosis. We describe a previously well, young man who initially had apparent hepatitis due to Pseudomonas aeruginosa which spread hematogenously to involve both lungs. He was treated successfully with antibiotics.     

Preparation of factor IX deficient human plasma by immunoaffinity chromatography using a monoclonal antibody

A murine hybridoma clone is described that grows continuously in culture and produces a monoclonal antibody we have called Royal Free Monoclonal Antibody to factor IX No. 1 (RFF-IX/1). This has high affinity for a coagulation site on factor IX. RFF-IX/1 immobilised on sepharose can be used to deplete factor IX from normal human plasma. This immunoaffinity depleted plasma is indistinguishable from severe Christmas disease plasma and can be used as the substrate in a one stage coagulation assay for factor IX. The affinity column has high capacity and can be regenerated so that large scale production from normal plasma of factor IX deficient plasma as a diagnostic reagent is now feasible.     

Interferon-gamma-induced apoptotic responses of Fanconi anemia group C hematopoietic progenitor cells involve caspase 8-dependent activation of caspase 3 family members

Hematopoietic progenitor cells (HPC) from mice nullizygous at the Fanconi anemia (FA) group C locus and children with Fanconi anemia group C (FA-C) are hypersensitive to interferon-gamma (IFN-gamma) and tumor necrosis factor-alpha. This hypersensitivity results, in part, from the capacity of these cytokines to prime the fas pathway. Because fas-mediated programmed cell death in many cells involves sequential activation of specific caspases, we tested the hypothesis that programmed cell death in FA HPC involves the ordered activation of specific caspase molecules. Lysates from lymphoblasts treated with both agonistic anti-fas antibody and IFN-gamma contained activated caspase 3 family members (caspases 3, 6, and 7), as well as caspase 8, whereas activation of caspases 1, 2, 4, 9, and 10 was not detected. The apoptotic effects of fas agonists in IFN-gamma-treated human and murine FA-C cells were blocked when pretreated with inhibitors (ac-DEVD-cho, CP-DEVD-cho, Z-DEVD-FMK) of the caspase 3 protease. Inhibitors (ac-YVAD-cho, CP-YVAD-cho, Z-YVAD-FMK) of caspase 1 did not block apoptosis or caspase 3 activation. Treatment of FA cells with the fluoromethyl ketone tetrapeptide caspase 8 inhibitor (ac-IETD-FMK) did suppress caspase 3 activation. A 4-fold greater fraction of IFN-induced FA-C cells expressed caspase 3 than FA-C cells complemented by retroviral-mediated transfer of FANCC. Therefore fas-induced apoptosis in Fanconi anemia cells of the C type involves the activation of caspase 8, which controls activation of caspase 3 family members and one direct or indirect function of the FANCC protein is to suppress apoptotic responses to IFN-gamma upstream of caspase 3 activation. (Blood. 2000;96:4204-4211)