A multicenter two by two factorial trial of cognitive behavioral therapy and aerobic exercise for Gulf War veterans' illnesses: design of a veterans affairs cooperative study (CSP #470).

The Department of Veterans Affairs (VA) Cooperative Studies Program (CSP) Study #470 is a 2 x 2 factorial trial designed to evaluate the hypothesis that both cognitive behavioral therapy (CBT) and aerobic exercise will significantly improve physical function in participants with Gulf War veterans' illnesses (GWVI), and that adding CBT to aerobic exercise will provide further incremental benefit. One thousand three hundred fifty-six veterans will be randomized to one of four treatment arms: CBT plus aerobic exercise plus usual and customary care, aerobic exercise plus usual and customary care, CBT plus usual and customary care, or usual and customary care alone. The study duration is 2.5 years with 1.5 years of intake and 1 year of follow-up. The primary outcome measure is the proportion of veterans improved more than seven units on the physical component summary (PCS) scale of the Short Form Health Survey for Veterans (SF-36V) measured 12 months after randomization. This generic quality-of-life measure was chosen because there is no disease-specific measure for GWVI and the symptoms of GWVI span a wide range of physical manifestations that are related to the domains covered by the PCS scale. Sample size was determined to detect all six pairwise comparisons between the four treatment arms with 90% power and a Bonferroni adjustment for an overall type I error of 0.05 or 0.05/6 = 0.0083. CSP #470 was initiated in May 1999 in 18 VA and two Department of Defense medical centers. To date this represents the largest randomized trial designed to evaluate treatments for individuals with unexplained physical symptoms. This paper will focus on the rationale and unique features of the study design. Control Clin Trials 2001;22:310-332

Immunotherapy of sepsis: flawed concept or faulty implementation?

Gram-negative bacillary sepsis is a leading cause of death among patients hospitalized in intensive care units. While initial clinical studies with the passive administration of anti-endotoxin core-glycolipid (CGL) antibodies for the treatment and prophylaxis of sepsis showed promising results, subsequent studies failed to show a consistent benefit. There appears to be a good correlation between anti-CGL antibody levels at the onset of sepsis and maintenance of antibody levels during sepsis with outcome. Previous clinical studies may have failed because insufficient amounts of antibody were administered early in the course of sepsis. Unlike the case with anti-CGL antibodies, polyvalent, hyperimmune type-specific antibody preparations may prevent the development of infections; however, these antibodies also must be provided in adequate amounts and in close proximity to infection in order to provide a beneficial effect. These pharmacokinetic requirements may limit the utility of passive immunotherapy for the prophylaxis of sepsis. Active immunization of acutely traumatized patients or of rats subsequently rendered neutropenic with cyclophosphamide induced high antibody levels for extended periods of time. Since trauma and other conditions are associated with a Th(2) response, these conditions may favor antibody formation following active immunization. Active immunization with both anti-CGL and/or polyvalent-specific vaccines for the prophylaxis of sepsis with passive supplementation at the onset of sepsis is an approach that merits further investigation.

Statistical evaluation of the role of Helicobacter pylori in stress gastritis: applications of splines and bootstrapping to the logistic model.

Stress gastritis is a serious problem in the intensive care unit population. The recent discovery of the causal nature of Helicobacter pylori (H. pylori) in the development of gastric ulcers led us to examine its relationship with stress gastritis. We investigated this relationship in 874 veterans admitted to intensive care units who were tested for the presence of H. pylori and followed for 6 weeks for the development of stress gastritis. We fit spline models to assess functional relationships and used the logistic model to determine the association between H. pylori and stress gastritis. The predictive ability of the model was assessed with receiver operating characteristic (ROC) curve analysis and validated with the bootstrapping technique. Increased anti-H. pylori immunoglobulin A concentrations were found to be an important predictor of stress gastritis independent of other known risk factors.

Tetracycline therapy for chronic Lyme disease.

Two hundred seventy-seven patients with chronic Lyme disease were treated with tetracycline for 1 to 11 months (mean, 4 months); the outcomes for these patients were generally good. Overall, 20% of the patients were cured; 70% of the patients' conditions improved, and treatment failed for 10% of the patients. Improvement frequently did not take place for several weeks; after 2 months of treatment, 33% of the patients' conditions were significantly improved (degree of improvement, 75%-100%), and after 3 months of treatment, 61% of the patients' conditions were significantly improved. Treatment outcomes for seronegative patients (20% of all patients) were similar to those for seropositive patients. Western immunoblotting showed reactions to one or more Borrelia burgdorferi-specific proteins for 65% of the patients for whom enzyme-linked immunosorbent assays were negative. Whereas age, sex, and prior erythema migrans were not correlated with better or worse treatment outcomes, a history of longer duration of symptoms or antibiotic treatment was associated with longer treatment times to achieve improvement and cure. These results support the use of longer courses of treatment in the management of patients with chronic Lyme disease. Controlled trials need to be conducted to validate these observations.

Risk factors for upper gastrointestinal bleeding in intensive care unit patients: role of helicobacter pylori. Federal Hyperimmune Immunoglobulin Therapy Study Group.

OBJECTIVE: To determine the role of preexisting Helicobacter pylori infection in the development of acute upper gastrointestinal (GI) hemorrhage in intensive care unit (ICU) patients in relation to other potential predisposing risk factors. DESIGN: Prospective, multicenter, cohort study. SETTING: Medical and surgical ICUs in six tertiary care Department of Veterans Affairs Medical Centers. PATIENTS: Eight-hundred seventy-four patients without previous GI bleeding or peptic ulcer disease who were enrolled in a multicenter, randomized, controlled trial of prophylactic intravenous immunoglobulin to prevent ICU-associated infections. INTERVENTIONS: This substudy of the larger intravenous immunoglobulin study only involved data analysis and had no intervention. All patients were enrolled in the larger study where they received intravenous immunoglobulin or placebo as intervention. MEASUREMENTS AND MAIN RESULTS: Patients were prospectively evaluated for the development of acute upper GI hemorrhage while in an ICU. Anti-H. pylori immunoglobulin G and immnoglobulin A concentrations were determined by enzyme immunoassay on preintervention serum samples. Seventy-six (9%) patients had over upper GI bleeding and a mortality rate of 49%, as compared with a 15% mortality rate in patients who did not bleed (p < .001). By logistic regression analysis, the following factors were associated with an increased risk of bleeding: acute hepatic failure, prolonged duration of nasogastric tube placement, alcoholism, and an increased serum concentration of anti-H. pylori immunoglobulin A. CONCLUSIONS: Increased anti-H. pylori immunoglobulin A concentrations, prolonged nasogastric intubation, alcoholism, and acute hepatic failure were found to be independently correlated with the development of acute GI bleeding in an ICU setting. These observations should be prospectively confirmed in an independent population before being used for treatment guidelines.

Immunoprophylaxis against klebsiella and pseudomonas aeruginosa infections. The Federal Hyperimmune Immunoglobulin Trial Study Group.

To determine if passive immunization could decrease the incidence or severity of Klebsiella and Pseudomonas aeruginosa infections, patients admitted to intensive care units of 16 Department of Veterans Affairs and Department of Defense hospitals were randomized to receive either 100 mg/kg intravenous hyperimmune globulin (IVIG), derived from donors immunized with a 24-valent Klebsiella capsular polysaccharide plus an 8-valent P. aeruginosa O-polysaccharide-toxin A conjugate vaccine, or an albumin placebo. The overall incidence and severity of vaccine-specific Klebsiella plus Pseudomonas infections were not significantly different between the groups receiving albumin and IVIG. There was some evidence that IVIG may decrease the incidence (2.7% albumin vs. 1.2% IVIG) and severity (1.0% vs. 0.3%) of vaccine-specific Klebsiella infections, but these reductions were not statistically significant. The trial was stopped because it was statistically unlikely that IVIG would be protective against Pseudomonas infections at the dosage being used. Patients receiving IVIG had more adverse reactions (14.4% vs. 9.2%).

Physician preferences in the diagnosis and treatment of Lyme disease in the United States.

To assess physician preferences in the diagnosis and treatment of Lyme disease, questionnaires were sent to physicians in various Lyme disease endemic areas in the U.S. Seventy-eight responses were analyzed. Both ELISA and Western blot were ordered by 86% of responders. Fifty percent of responders believed that 25% or more of patients who have Lyme disease were seronegative. The treatment was influenced by physician specialty. Antibiotic treatment for tick bite was prescribed by 20% of responders. Erythema migrans rash was treated by all responders without serologic confirmation. The median treatment duration of erythema migrans was 4 weeks. For post-erythema migrans Lyme disease, 43% of responders treat 3 months or more; for chronic Lyme disease, 57% of responders treat 3 months or more. Our survey documents significant differences between published recommendations and actual practices. Physician education and clinical trials are needed to clarify the reasons for these differences.

Inhibition of Shiga-like toxins by brefeldin A.

The effects of Shiga-like toxins on the morphology and protein synthetic capability of HeLa cells in tissue culture could be prevented by brefeldin A, an inhibitor of certain intracellular Golgi functions. Brefeldin A was without effect on the binding of Shiga-like toxin to cells. These results provide evidence that the Shiga-like toxins are first processed by the Golgi before moving to their 60S ribosome target site.

Inhibition of heat-labile cholera and Escherichia coli enterotoxins by brefeldin A.

Cholera enterotoxin and the related heat-labile enterotoxins of Escherichia coli enter their target cells through noncoated vesicles, but how the toxins are processed intracellularly and how they get to their targeted enzyme, adenylate cyclase, remain to be defined. Brefeldin A, an inhibitor of the trans-Golgi network, is shown herein to transiently block the morphologic and enzymatic effects of the toxin at a step distal to the initial binding process but prior to activation of adenylate cyclase by the toxin. It is likely, therefore, that these toxins are processed by the Golgi apparatus before trafficking to the membrane adenylate cyclase.

Inhibition of beta-adrenergic binding by fungal metabolites.

Strains of Aspergillus flavus, Fusarium sp., Rhizopus sp. and Candida albicans all produced inhibitors of beta-adrenergic receptor binding; strains of Saccharomyces sp. and Schizosaccharomyces sp. did not. In tests with glutamic acid as the sole nutrient source, a Fusarium sp. produced four-fold larger amounts of inhibitor than the other fungi. The inhibitor from the Fusarium sp. was further purified by lyophilisation and sequential solvent extraction in chloroform, ethyl acetate and butanol; 60% of the original activity was recovered. The inhibitor had an estimated molecular size of 650 Da, and did not absorb light in the visible or ultraviolet range. When compared with a similar inhibitor from Escherichia coli, the Fusarium sp. inhibitor appeared to be a more potent inhibitor of beta-adrenergic and dopaminergic binding to mammalian cells.

Binding of class II Escherichia coli enterotoxins to mouse Y1 and intestinal cells.

The binding of class II Escherichia coli heat-labile enterotoxins (LT) to Y1 tissue-cultured cells and mouse intestinal cells was studied and compared with that of class I toxins, including cholera enterotoxin. All radioiodinated (125I) toxins retained their biological activities in both model systems, but only LTIIb could be shown to bind specifically to target cells. LTIIa could inhibit the binding of both class I and LTIIb toxins, a finding which correlates with its ability to bind to multiple gangliosides. LTIIb could not inhibit the binding of the other enterotoxins. The binding and activity of class II toxins could not be modulated by prior exposure of target cells to the B subunit of LTI.

Intravenous immunoglobulin therapy for toxic shock syndrome.

Staphylococcus aureus and group A Streptococcus pyogenes produce toxic shock syndrome characterized by hypotension and multisystem organ failure. While conventional therapy has consisted of antibiotics and intensive supportive care, some experimental evidence suggests that immunoglobulins directed against the toxins may be effective additional therapy. We report a case of "toxic strep syndrome" in which intravenous immunoglobulin was administered when signs and symptoms were worsening while the patient was receiving conventional therapy. Within hours of administration of the intravenous immunoglobulin, the patient experienced dramatic clinical improvement. This response suggests a possible therapeutic benefit of intravenous immunoglobulin in toxic shock syndrome.

Binding of 125I-labelled tumor necrosis factor to Pneumocystis carinii and an insoluble cell wall fraction.

We have previously shown that tumor necrosis factor-alpha (TNF-alpha) causes loss of viability of Pneumocystis carinii. In this study, we demonstrate that TNF-alpha irreversibly binds to P. carinii in vitro. The avidity of binding is orders of magnitude greater than that by which it binds to a known sensitive target, L929 cells. A detergent-insoluble fraction of P. carinii, which consists primarily of cyst walls, bound ten times more TNF-alpha per microgram protein as did whole P. carinii.

Reovirus type 3 binds to antagonist domains of the beta-adrenergic receptor.

Reovirus type 3 interfered with the binding of beta-adrenergic antagonist ligands to receptors on Y1 adrenal, C6 glioma, and mouse L cells. This inhibition of beta-adrenergic binding was dose related. Reovirus did not interfere with dopaminergic binding or isoproterenol-induced activation of adenylate cyclase. In addition, reovirus infected Y1 cells, which bind beta-adrenergic antagonist ligands but lack agonist-induced activity. These results suggest that reovirus infection is initiated by binding to antagonist (nonfunctional) domains of the adrenergic receptor complex.

Modulation of enterotoxin binding and function in vitro and in vivo.

The use of the nontoxic B subunits of cholera and Escherichia coli enterotoxins in vitro and in vivo led to a decrease in toxin binding to target cells and a decrease in toxin-induced effects (i.e., morphological effects, adenylate cyclase activation, and fluid secretion). The reduction in toxin binding involves a process of down-regulation of cellular receptors for the toxin and not toxin occupancy of receptors. The extent of inhibition was dependent on the amount of B subunit used and on the duration of time after its use. Thus, in vivo exposure to a single bolus of B subunit was sufficient to block toxin binding and activity for up to 18 h. Because the B subunit binds extensively to the esophagus and the stomach, peroral administration will require a preparation that allows the subunit to reach the small bowel in a protected form. Our data provide a rationale for using B subunit therapy for short-term protection against the effects of enterotoxins, before the development of an immune response.

Candida detection system (CAND-TEC) to differentiate between Candida albicans colonization and disease.

Eighty-three serum specimens from 24 patients infected with Candida albicans were examined for circulating Candida protein antigens with the Candida Detection System (CAND-TEC; Ramco Laboratories, Inc., Houston, Tex.). The medical records of each patient were reviewed for clinical evidence of Candida colonization or disease, predisposing factors for infection, underlying illness, the presence of a contaminated indwelling venous catheter, intravenous amphotericin B therapy, and outcome. Forty-nine serum specimens with antigen titers of 1:2 or less were obtained either from colonized patients or at a time when disseminated disease was not yet clinically suspected. Except for five specimens from two colonized patients, one with a contaminated arterial line, the other specimens with titers of 1:8 or greater (n = 14) were obtained from patients who had been clinically diagnosed and treated for disseminated candidiasis. Serum specimens with titers of 1:4 were often from patients with deep-seated candidal infection but were not uniformly diagnostic; in this situation additional specimens should be tested for Candida antigen titers. Only 1 of 24 serum specimens from patients with no evidence of C. albicans infection had a Candida protein antigen titer of 1:8. With a 1:8 or greater titer as a criterion for dissemination, the sensitivity of the CAND-TEC system was 71%, with a specificity of 98%. If the 1:8 titer for the colonized patient with a contaminated arterial line is not considered a false-positive result, the CAND-TEC sensitivity was 83%. The latex agglutination assay appears to be a useful, rapid, and noninvasive means of laboratory diagnosis of systemic candidiasis. The recovery of C. albicans from at least three body sites may also be a useful predictor of disseminated disease.