Lithium augments GM-CSA generation in canine cyclic hematopoiesis

Cyclic hematopoiesis in gray collie dogs can be cured by lithium treatment. We examined the mechanism of lithium's effect by developing an assay for the canine equivalent of GM-CSF (called GM-CSA). Phytohemagglutinin (PHA)-stimulated canine blood mononuclear cells produce GM-CSA in a dose-dependent manner; this GM-CSA stimulates more neutrophil-containing colonies than does endotoxin-treated dog serum. Production of GM-CSA by PHA-stimulated normal dog cells was not altered by lithium. However, cells from gray collies during their neutrophilic period increased their GM-CSA when lithium (2 mEq/L) was added to low doses of PHA, whereas neutropenic gray collie cells did not. These data suggest that lithium could modulate cyclic hematopoiesis by increasing intramedullary GM-CSA at the time when marrow neutrophilic progenitor cells are at their nadir.     

The effects of exercise and education,individually or combined,in women with fibromyalgia

OBJECTIVE: To examine the effectiveness of a supervised aerobic exercise program, a self-management education program, and the combination of exercise and education for women with fibromyalgia (FM). METHODS: One hundred fifty-two women were randomized into one of 4 groups: exercise-only, education-only, exercise and education, or control. The duration of the study was 12 weeks. All subjects were analyzed at 3 times: before study, immediately upon completion, and 3 months after completion of the intervention program on measures of disability, self-efficacy, fitness, tender point count, and tender point tenderness. Of the 152 women, complete data were available for 95 and 69 who complied with the protocol. In order to determine the group time interaction, a 2 way analysis of variance with repeated measures was used for each measure. RESULTS: The only significant group time interaction was reported with the compliance analysis for the Self-Efficacy Coping with Other Symptoms subscale and the Six Minute Walk. If the program was followed, the combination of a supervised exercise program and group education provided persons with FM with a better sense of control over their symptoms. Fitness improved in the 2 groups undergoing supervised aerobic exercise programs. However, the improvement in fitness was maintained at followup in the exercise-only group and not the combined group. Conclusion. Subjects receiving the combination of exercise and education and who complied with the treatment protocol improved their perceived ability to cope with other symptoms. In addition, a supervised exercise program increased walking distance at post-test, an increase that was maintained at followup in the exercise-only group. Results demonstrate the challenges with conducting exercise and education studies in persons with FM.     

Fibronectin in artery subendothelium is important for platelet adhesion

The role of subendothelial fibronectin in platelet interaction with subendothelium was studied. Human umbilical artery subendothelium was exposed to flowing blood containing 111In-labeled platelets in an annular perfusion chamber. Platelet adhesion was determined from the 111In radioactivity on the vessel wall. When perfusions were performed for five minutes at a wall shear rate of 1,800 s-1, platelet adhesion was the same whether normal plasma or fibronectin-free plasma was used. Preincubation of subendothelium with rabbit anti-human fibronectin serum, however, resulted in a marked inhibition of platelet adhesion. Preincubation with normal rabbit serum had no effect. Platelet adhesion was also diminished when the vessel wall was preincubated with anti- fibronectin IgG fraction or F(ab')2 fragment. After the latter preincubations, frozen sections of 4 micron were incubated with fluorescein isothiocyanate-conjugated goat anti-rabbit IgG, F(ab')2 fragment specific. Fluorescence was seen throughout the subendothelium both before and after perfusion. No fluorescence was seen when subendothelium was preincubated with normal rabbit IgG or F(ab')2 or with anti-fibronectin IgG that had been absorbed with purified fibronectin. After absorption of anti-fibronectin IgG with purified fibronectin, the inhibiting effect on platelet adhesion was also no longer present. Preincubation of the vessel wall with anti-fibronectin IgG reduced platelet adhesion significantly at a wall shear rate of 800 s-1. This effect was even greater at 1,800 s-1. At low shear rate (400 s-1), there was no inhibition.     

Etanercept exerts beneficial effects on articular cartilage biomarkers of degradation and turnover in patients with ankylosing spondylitis

OBJECTIVE: Anti-tumor necrosis factor-alpha (TNF-alpha) therapies are not only beneficial for reducing symptoms in rheumatoid arthritis (RA) but also for structural damage visible on plain radiographs and serological biomarkers of articular cartilage damage. It is not known if these therapies also prevent structural damage in ankylosing spondylitis (AS). The low sensitivity to change over time of plain radiographic instruments mandates a search for the effects of these therapies on possible biomarkers of cartilage damage. METHODS: We studied 2 populations of patients with AS: (1) patients recruited to a placebo controlled trial of etanercept in AS for 16 weeks; (2) an observational cohort receiving infliximab for disease refractory to conventional therapy. Clinical (morning stiffness, nocturnal pain, Bath AS Disease Activity Index) and laboratory [erythrocyte sedimentation rate (ESR), C-reactive protein (CRP)] assessments of disease activity were performed at baseline and at either 16 weeks (clinical trial cohort) or at 14 weeks (observational cohort). We measured serum matrix metalloproteinase-1 (MMP-1), MMP-3, human cartilage glycoprotein-39 (YKL-40), and cartilage oligomeric matrix protein by ELISA at the same timepoints. We also measured serum concentrations of 2 novel biomarker epitopes, C2C and 846, by competitive ELISA. The C2C assay detects a neoepitope at the carboxy terminus of the long three-quarter amino-terminal fragment generated following cleavage of type II collagen by collagenases. Aggrecan 846 epitope is a chondroitin sulfate epitope present on intact aggrecan molecules. Both these assays would detect products originating from both hyaline cartilages and intervertebral discs. RESULTS: There was a significant reduction in levels of C2C (p = 0.005) and a significant increase in the 846 epitope (p = 0.01) in patients who received etanercept compared to placebo controls. Changes in C2C correlated significantly with changes in ESR (r = 0.51, p = 0.04) and CRP (r = 0.48, p = 0.048). Significant changes in C2C were not evident in the infliximab observational cohort, although significant reductions were noted in levels of MMP-3 (p = 0.04) and MMP-1 (p = 0.02) at 14 weeks that were not observed in the etanercept group. Analysis of all baseline samples showed a significant correlation between levels of MMP-3 with CRP (r = 0.73, p < 0.0001), and YKL-40 (r = 0.71, p < 0.0001). No correlation was evident at baseline between levels of C2C or 846 epitope and either acute phase reactants or other biomarkers. CONCLUSION: Our data suggest that an anti-TNF-alpha agent, etanercept, may modify cartilage turnover. These include decreased degradation of type II collagen and increased turnover of aggrecan. Additional therapeutic properties of some anti-TNF-alpha agents in AS, such as infliximab, may be related to decreased expression of MMP. Additional studies in larger populations are therefore warranted.     

A randomized controlled phase III trial of recombinant human granulocyte colony-stimulating factor (filgrastim) for treatment of severe chronic neutropenia

Patients with idiopathic, cyclic, and congenital neutropenia have recurrent severe bacterial infections. One hundred twenty-three patients with recurrent infections and severe chronic neutropenia (absolute neutrophil count < 0.5 x 10(9)/L) due to these diseases were enrolled in this multicenter phase III trial. They were randomized to either immediately beginning recombinant human granulocyte colony- stimulating factor (filgrastim) (3.45 to 11.50 micrograms/kg/d, subcutaneously) or entering a 4-month observation period followed by filgrastim administration. Blood neutrophil counts, bone marrow (BM) cell histology, and incidence and duration of infection-related events were monitored. Of the 123 patients enrolled, 120 received filgrastim. On therapy, 108 patients had a median absolute neutrophil count of > or = 1.5 x 10(9)/L. Examination of BM aspirates showed increased proportions of maturing neutrophils. Infection-related events were significantly decreased (P < .05) with approximately 50% reduction in the incidence and duration of infection-related events and almost 70% reduction in duration of antibiotic use. Asymptomatic splenic enlargement occurred frequently; adverse events frequently reported were bone pain, headache, and rash, which were generally mild and easily manageable. These data indicate that treatment of patients with severe chronic neutropenia with filgrastim results in a stimulation of BM production and maturation of neutrophils, an increase in circulating neutrophils, and a reduction in infection-related events.     

Expression of adhesion molecules on CD34+ cells: CD34+ L-selectin+ cells predict a rapid platelet recovery after peripheral blood stem cell transplantation

Adhesion molecules play a role in the migration of hematopoietic progenitor cells and regulation of hematopoiesis. To study whether the mobilization process is associated with changes in expression of adhesion molecules, the expression of CD31, CD44, L-selectin, sialyl Lewisx, beta 1 integrins very late antigen 4 (VLA-4) and VLA-5, and beta 2 integrins lymphocyte function-associated 1 and Mac-1 was measured on either bone marrow (BM) CD34+ cells or on peripheral blood CD34+ cells mobilized with a combination of granulocyte colony- stimulating factor (G-CSF) and chemotherapy. beta 1 integrin VLA-4 was expressed at a significantly lower concentration on peripheral blood progenitor cells than on BM CD34+ cells, procured either during steady- state hematopoiesis or at the time of leukocytapheresis. No differences in the level of expression were found for the other adhesion molecules. To obtain insight in which adhesion molecules may participate in the homing of peripheral blood stem cells (PBSCs), the number of CD34+ cells expressing these adhesion molecules present in leukocytapheresis material was quantified and correlated with hematopoietic recovery after intensive chemotherapy in 27 patients. The number of CD34+ cells in the subset defined by L-selectin expression correlated significantly better with time to platelet recovery after PBSC transplantation (r = - .86) than did the total number of CD34+ cells (r = -.55). Statistical analysis of the relationship between the number of CD34+L-selectin+ cells and platelet recovery resulted in a threshold value for rapid platelet recovery of 2.1 x 10(6) CD34+ L-selectin+ cells/kg. A rapid platelet recovery (< or = 14 days) was observed in 13 of 15 patients who received > or = 2.1 x 10(6) CD34+ L-selectin+ cells/kg (median, 11 days; range, 7 to 16 days), whereas 10 of 12 patients who received less double positive cells had a relative slow platelet recovery (median, 20 days; range, 13 to 37 days). The L-selectin+ subpopulation of CD34+ cells also correlated better with time to neutrophil recovery (r = - .70) than did the total number of reinfused CD34+ cells (r = -.51). However, this latter difference failed to reach statistical significance. This study suggests that L-selectin is involved in the homing of CD34+ cells after PBSC transplantation.     

Characterization of endogenous cytokine concentrations after high-dose chemotherapy with autologous bone marrow support

Endogenous cytokines are thought to mediate numerous biologic processes and may account for some adverse effects experienced following the administration of recombinant proteins. This study describes the pattern of endogenous cytokine exposure following high-dose chemotherapy. Blood concentrations of interleukin-6 (IL-6), tumor necrosis factor-alpha (TNF-alpha), macrophage colony-stimulating factor (M-CSF), and erythropoietin (EPO) were measured by enzyme-linked immunosorbent assay (ELISA) methods in 68 patients receiving the same ablative chemotherapy regimen (cyclophosphamide, cisplatin, carmustine). Patients were grouped according to cellular support (autologous bone marrow [BM] CSF-primed peripheral blood progenitor cells [PBPCs]) and prescribed growth factor (recombinant human granulocyte or granulocyte-macrophage colony-stimulating factor [rHuG- CSF or rHuGM-CSF]). Leukocyte reconstitution was most accelerated in the groups treated with PBPCs and rHuG-CSF. IL-6, M-CSF, and TNF-alpha concentrations were higher in the groups treated with rHuGM-CSF and without PBPCs. Maximal endogenous cytokine concentrations occurred approximately 12 days after BM reinfusion. High concentrations of EPO occurred in patients experiencing significant hypotension despite routine transfusions for hematocrit < 42%. High M-CSF and IL-6 levels were associated with increased platelet transfusion requirements. Concentrations of all four cytokines were significantly higher in patients experiencing renal or hepatic toxicity, with elevations occurring in a predictable sequence and M-CSF elevations occurring first. This report shows that endogenous cytokine concentrations may be influenced by either cellular or CSF support and are associated with differences in platelet reconstitution and organ toxicity.     

Evaluation and validation of the patient acceptable symptom state (PASS) in patients with ankylosing spondylitis

OBJECTIVE: The Patient Acceptable Symptom State (PASS) constitutes an absolute level of patient well-being and represents an ambitious target for disease management. We explored contributors to PASS, validated the PASS concept, and assessed thresholds of self-reported outcomes below which patients considered themselves in PASS. METHODS: Patients with ankylosing spondylitis completed a questionnaire that included self-reported assessments of pain, fatigue, disease activity, function, patient global, quality of life (QOL), and whether they considered their current disease state satisfactory or not. Stepwise logistic regression was used to assess contributors to PASS. PASS was validated by analyzing proportions of patients reporting need for a rheumatologist and who were in current flare. PASS thresholds for self-reported outcomes were estimated using an anchoring method based on the patient's opinion and targeting the 75th percentile of the cumulative distribution. RESULTS: PASS data were available for 291 patients, of whom 169 (58%) were in PASS. Significant contributors were age (Exp[B] 1.05; P = 0.003), patient global disease activity (Exp[B] 0.79; P = 0.008), and function (Bath Ankylosing Spondylitis Functional Index [BASFI]; Exp[B] 0.72; P < 0.001). PASS reflected need to consult the rheumatologist and current flare (71% and 73% correctly classified, respectively) and significantly contributed to QOL (B = -5.99; 95% confidence interval -7.16, -4.08). PASS thresholds were 5.0 for patient global disease activity, 5.0 for total back pain, 22.8 for fatigue, 4.8 for disease activity (Bath Ankylosing Spondylitis Disease Activity Index), and 4.0 for function (BASFI). CONCLUSION: A majority of patients (58%) reported being in PASS. PASS thresholds for pain and function were unexpectedly high, possibly suggesting adaptation to the consequences of the disease.     

Steroid injection for osteoarthritis of the hip: a randomized, double-blind, placebo-controlled trial

OBJECTIVE: To determine the efficacy of fluoroscopically guided corticosteroid injection for hip osteoarthritis (OA) in a randomized, double-blind, placebo-controlled trial. METHODS: Fifty-two patients with symptomatic hip OA were randomly allocated to receive placebo (10 mg bipuvicaine, 2 ml saline) (n = 21) or corticosteroid treatment (10 mg bipuvicaine, 40 mg triamcinolone hexacetonide) (n = 31). Patients were followed up for 1, 2, 3, and 6 months. The primary outcome measure was the pain improvement response, defined as a 20% decrease in the Western Ontario and McMaster Universities OA Index (WOMAC) pain score (on 5 100-mm visual analog scales [VAS]) (WOMAC20) from baseline to 2 months postinjection. Secondary outcomes were a 50% decrease in the WOMAC pain score (WOMAC50), changes in other WOMAC subscale scores, patient's global assessment of health (on a 100-mm VAS), and Short Form 36 (SF-36) quality of life indices. Analyses were based on the intent-to-treat principle. RESULTS: The mean WOMAC pain score fell 49.2% (decreasing from 310.1 mm to 157.4 mm) at 2 months postinjection in patients receiving corticosteroid, compared with a decrease of 2.5% (from 314.3 mm to 306.5 mm) in the placebo group (P < 0.0001). The proportion of WOMAC20 responders at 2 months' followup was significantly higher in the corticosteroid group (67.7%) compared with the placebo group (23.8%) (P = 0.004); similar proportions of WOMAC50 responders were observed between groups (61.3% in the corticosteroid group versus 14.3% in the placebo group; P = 0.001). Response differences were maintained at 3 months' followup (58.1% responders in the corticosteroid group versus 9.5% responders in the placebo group; P = 0.004). Significant differences in the WOMAC stiffness and physical function scores (P < 0.0001), patient's global health scores (P = 0.005), and SF-36 physical component scores (P = 0.04) were observed, with patients in the corticosteroid group showing greater improvements. There were no differences in the frequency of adverse events between groups. CONCLUSION: This placebo-controlled trial confirms that corticosteroid injection can be an effective treatment of pain in hip OA, with benefits lasting up to 3 months in many cases. Future studies should address questions related to the benefits of repeated steroid injection and the effects of this treatment on disease modification.