Effects of individual and combined dietary weight loss and exercise interventions in postmenopausal women on adiponectin and leptin levels.

BACKGROUND: Excess body weight and a sedentary lifestyle are associated with the development of several diseases, including cardiovascular disease, diabetes and cancer in women. One proposed mechanism linking obesity to chronic diseases is an alteration in adipose-derived adiponectin and leptin levels. We investigated the effects of 12-month reduced calorie, weight loss and exercise interventions on adiponectin and leptin concentrations. METHODS: Overweight/obese postmenopausal women (n = 439) were randomized as follows: (i) a reduced calorie, weight-loss diet (diet; N = 118), (ii) moderate-to-vigorous intensity aerobic exercise (exercise; N = 117), (iii) a combination of a reduced calorie, weight-loss diet and moderate-to-vigorous intensity aerobic exercise (diet + exercise; N = 117), and (iv) control (N = 87). The reduced calorie diet had a 10% weight-loss goal. The exercise intervention consisted of 45 min of moderate-to-vigorous aerobic activity 5 days per week. Adiponectin and leptin levels were measured at baseline and after 12 months of intervention using a radioimmunoassay. RESULTS: Adiponectin increased by 9.5% in the diet group and 6.6% in the diet + exercise group (both P ≤ 0.0001 vs. control). Compared with controls, leptin decreased with all interventions (diet + exercise, -40.1%, P < 0.0001; diet, -27.1%, P < 0.0001; exercise, -12.7%, P = 0.005). The results were not influenced by the baseline body mass index (BMI). The degree of weight loss was inversely associated with concentrations of adiponectin (diet, P-trend = 0.0002; diet + exercise, P-trend = 0.0005) and directly associated with leptin (diet, P-trend < 0.0001; diet + exercise, P-trend < 0.0001). CONCLUSION: Weight loss through diet or diet + exercise increased adiponectin concentrations. Leptin concentrations decreased in all of the intervention groups, but the greatest reduction occurred with diet + exercise. Weight loss and exercise exerted some beneficial effects on chronic diseases via effects on adiponectin and leptin.

Effect of tumour necrosis factor alpha antagonists on serum transaminases and viraemia in patients with rheumatoid arthritis and chronic hepatitis C infection.

BACKGROUND: Tumour necrosis factor alpha (TNF alpha) antagonists are effective for the treatment of rheumatoid arthritis (RA), but concerns remain about the safety of these agents in the presence of chronic infections, including hepatitis C virus (HCV) infection. OBJECTIVE: To examine the influence of treatment with TNF alpha antagonists on levels of HCV viraemia and serum transaminases in patients with RA and HCV. METHODS: In a retrospective survey the course of 16 HCV infected patients with RA who had received the TNF alpha antagonists etanercept or infliximab was analysed. Eight additional patients with RA and HCV were also enrolled into a three month prospective trial of etanercept. Serum concentrations of albumin, alkaline phosphatase, aspartate aminotransferase, alanine aminotransferase, and HCV were followed. RESULTS: Viraemia was measured in 22 patients receiving a TNF alpha antagonist at the start of treatment and after 1-34 months (median 9 months follow up). Twenty four patients had serial tests of liver related enzymes and albumin. None of the differences between liver related tests at baseline and at follow up achieved significance (p>0.05). Similarly, the mean HCV measurement at 1-3, 4-6, 7-12, and 13-34 months did not differ significantly from baseline (p>0.05). CONCLUSION: In this study, liver related blood tests and HCV viral load measurements did not change substantially. These findings suggest that TNF alpha antagonists merit further study for the treatment of RA in HCV infected patients. Larger and longer term studies are still needed.

Cryoglobulinemic glomerulonephritis in thymic stromal lymphopoietin transgenic mice.

Mixed cryoglobulins are complexes of immunoglobulins that reversibly precipitate in the cold and lead to a systemic disease in humans. Renal involvement usually manifests as a membranoproliferative glomerulonephritis with marked monocyte infiltration and, at times, intracapillary thrombi. Thymic stromal lymphopoietin (TSLP) is a recently cloned cytokine that supports differentiation and long-term growth of B cells. Here we report that TSLP overexpression in mice results in the development of mixed cryoglobulins, with renal involvement closely resembling cryoglobulinemic glomerulonephritis as it occurs in humans. One hundred twenty-three mice were sacrificed at monthly intervals, with at least five TSLP transgenic mice and five controls in each group. Blood, kidneys, spleen, liver, lung, and ear were collected and studied by routine microscopy, immunofluorescence, immunohistochemistry, and electron microscopy. TSLP transgenic animals developed polyclonal mixed cryoglobulinemia (type III) and a systemic inflammatory disease involving the kidney, spleen, liver, lung, and ears. Renal involvement was of a membranoproliferative type demonstrating thickened capillary walls with cellular interposition and double contours of the basement membrane, expansion of the mesangium because of increased matrix and accumulation of immune-deposits, subendothelial immune-deposits, focal occlusion of capillary loops, and monocyte/macrophage influx. In contrast to the severe glomerular lesions, the tubulointerstitium was not involved in the disease process. The renal lesions and the disease course were more severe in females when compared to males. We describe a mouse strain in which a B-cell-promoting cytokine leads to formation of large amounts of mixed cryoglobulins and a systemic inflammatory injury that resembles important aspects of human cryoglobulinemia. This is the first reproducible mouse model of renal involvement in mixed cryoglobulinemia, which enables detailed studies of a membranoproliferative pattern of glomerular injury.

A genomewide screen in multiplex rheumatoid arthritis families suggests genetic overlap with other autoimmune diseases.

Rheumatoid arthritis (RA) is an autoimmune/inflammatory disorder with a complex genetic component. We report the first major genomewide screen of multiplex families with RA gathered in the United States. The North American Rheumatoid Arthritis Consortium, using well-defined clinical criteria, has collected 257 families containing 301 affected sibling pairs with RA. A genome screen for allele sharing was performed, using 379 microsatellite markers. A nonparametric analysis using SIBPAL confirmed linkage of the HLA locus to RA (P < .00005), with lambdaHLA = 1.79. However, the analysis also revealed a number of non-HLA loci on chromosomes 1 (D1S235), 4 (D4S1647), 12 (D12S373), 16 (D16S403), and 17 (D17S1301), with evidence for linkage at a significance level of P<.005. Analysis of X-linked markers using the MLOD method from ASPEX also suggests linkage to the telomeric marker DXS6807. Stratifying the families into white or seropositive subgroups revealed some additional markers that showed improvement in significance over the full data set. Several of the regions that showed evidence for nominal significance (P < .05) in our data set had previously been implicated in RA (D16S516 and D17S1301) or in other diseases of an autoimmune nature, including systemic lupus erythematosus (D1S235), inflammatory bowel disease (D4S1647, D5S1462, and D16S516), multiple sclerosis (D12S1052), and ankylosing spondylitis (D16S516). Therefore, genes in the HLA complex play a major role in RA susceptibility, but several other regions also contribute significantly to overall genetic risk.

Low-grade systemic inflammation in overweight children.

OBJECTIVE: Human adipose tissue expresses and releases the proinflammatory cytokine interleukin-6, potentially inducing low-grade systemic inflammation in persons with excess body fat. To limit potential confounding by inflammation-related diseases and subclinical cardiovascular disease, we tested the hypothesis that overweight is associated with low-grade systemic inflammation in children. DESIGN AND SETTING: The third National Health and Nutrition Examination Survey, 1988-1994, a representative sample of the US population. PARTICIPANTS: A total of 3512 children 8 to 16 years of age. OUTCOME MEASURES: Elevated serum C-reactive protein concentration (CRP; >/=.22 mg/dL) and white blood cell count (10(9) cells/L). RESULTS: Elevated CRP was present in 7.1% of the boys and 6.1% of the girls. Overweight children (defined as having a body mass index or a sum of 3 skinfolds (triceps, subscapula, and supra-iliac) above the gender-specific 85th percentile) were more likely to have elevated CRP than were their normal-weight counterparts. After adjustment for potential confounders, including smoking and health status, the odds ratio (OR) was 3.74 (95% confidence interval [CI]: 1.66-8.43) for overweight boys and the OR was 3.17 (95% CI: 1.60-6.28) for overweight girls, based on the body mass index. Based on the sum of 3 skinfolds, these ORs were 5.11 (95% CI: 2.36-11.06) and 2.89 (95% CI: 1.49-5.59) for boys and girls, respectively. Overweight was also associated with statistically significant higher white blood cell counts. The results were similar when restricted to healthy, nonsmoking, nonestrogen-using children. CONCLUSIONS: In children 8 to 16 years of age, overweight is associated with higher CRP concentrations and higher white blood cell counts. These findings suggest a state of low-grade systemic inflammation in overweight children. inflammation, obesity, children.

Antibodies to human myeloperoxidase in glomerular immune deposits of systemic lupus erythematosus.

Antibodies to human myeloperoxidase and cathepsin G have been detected in the serum of some patients with systemic lupus erythematosus. Therefore, the presence of antibodies to human myeloperoxidase and cathepsin G was examined in glomerular immune deposits. Glomerular basement membrane fragments were prepared from renal tissues obtained at autopsy from 19 patients with systemic lupus erythematosus. IgG was extracted from the glomerular basement membrane fragments and tested with sensitive immunoassays for antibodies to myeloperoxidase and cathepsin G. Antibodies to cathepsin G were not detected in the extracts but antibodies to human myeloperoxidase were found in extracts of one specimen. In the extract with 6M guanidine hydrochloride these antibodies were enriched 103-fold, compared to the initial supernatant of glomeruli, which served as a serum surrogate. The recovered antibodies to myeloperoxidase accounted for 12% of the recovered IgG. These findings add autoantibodies to human myeloperoxidase to the list of antibodies that have been shown to be present in glomerular immune deposits of patients with lupus glomerulonephritis.

The influence of age, sex, and race on the upper reference limit of serum C-reactive protein concentration.

OBJECTIVE: The recommended reference range for serum C-reactive protein (CRP) concentrations is usually not adjusted for age and sex. We sought to determine if age, sex, and race or ethnicity influence the distribution of CRP values, and if upper reference limits of CRP should be adjusted by demographic factors. METHODS: Interviews, physical examinations, and blood draws were performed on > 22,000 individuals age > or = 4 yrs representative of the noninstitutionalized population of the United States, as part of the Third National Health and Nutrition Evaluation Survey (NHANES III). Serum CRP concentrations were measured by nephelometric immunoassay. RESULTS: The 95th percentile value of CRP in the overall population was 0.95 mg/dl for males and 1.39 mg/dl for females, and varied with age and race. For ages 25-70 yrs, the age adjusted approximate upper reference limit (mg/dl) was CRP = age/50 for males, and CRP = age/50 + 0.6 for females. The upper limits for Mexican-Americans and non-Hispanic whites were similar, whereas for non-Hispanic black adults the approximate upper limit was CRP = age/30 for males and CRP = age/50 + 1.0 for females. Even after accounting for identified inflammatory conditions, demographic factors influenced the reference limits of CRP. The 95th percentile values were uniformly lower in children than in older adults. CONCLUSION: Demographic factors, including age, sex, and race, should be used to adjust the upper reference limit for CRP. Clinicians should be aware of these factors when using CRP values to assess inflammatory diseases.

SR proteins are autoantigens in patients with systemic lupus erythematosus. Importance of phosphoepitopes.

OBJECTIVE: To determine whether members of the highly phosphorylated SR protein family are autoantigens and, if so, to determine the frequency and molecular basis of antigen recognition. METHODS: Native human SR proteins were purified to homogeneity from HeLa cells, and an enzyme-linked immunosorbent assay (ELISA) was developed. Further studies employed immunoblotting of both phosphorylated and dephosphorylated SR proteins. RESULTS: Anti-SR protein reactivity was frequently detected in the sera of patients with systemic lupus erythematosus (SLE). Sera from 52% of the SLE patients in a group of patients with a variety of autoimmune and other disorders (n = 137) and from 50% of the SLE patients in a separate group (n = 102) were positive in an ELISA. In contrast, sera from patients with other disorders, such as rheumatoid arthritis and primary antiphospholipid syndrome, reacted infrequently. Reactivity with double-stranded DNA (dsDNA), used in the diagnosis of SLE, did not correlate with SR protein reactivity. Anti-SR autoantisera did not bind highly charged unphosphorylated peptides related to the SR domain, which is rich in arginine and phosphoserine residues. Surprisingly, many of the epitopes were influenced by the presence or absence of SR protein phosphorylation. In immunoblots, some patient sera lost reactivity upon SR protein dephosphorylation, while others significantly gained reactivity. CONCLUSION: We have identified a novel set of autoantigens in SLE, the SR protein family of non-small nuclear RNP pre-messenger RNA splicing factors. Anti-SR autoantibodies are distinct from those which bind dsDNA. The identification of this new set of autoantigens and the observation that the auto-epitope(s) involves posttranslational modification offer new possibilities for understanding autoimmunity and its development.

Elevated C-reactive protein levels in overweight and obese adults.

CONTEXT: Human adipose tissue expresses and releases the proinflammatory cytokine interleukin 6, potentially inducing low-grade systemic inflammation in persons with excess body fat. OBJECTIVE: To test whether overweight and obesity are associated with low-grade systemic inflammation as measured by serum C-reactive protein (CRP) level. DESIGN AND SETTING: The Third National Health and Nutrition Examination Survey, representative of the US population from 1988 to 1994. PARTICIPANTS: A total of 16616 men and nonpregnant women aged 17 years or older. MAIN OUTCOME MEASURES: Elevated CRP level of 0.22 mg/dL or more and a more stringent clinically raised CRP level of more than 1.00 mg/dL. RESULTS: Elevated CRP levels and clinically raised CRP levels were present in 27.6% and 6.7% of the population, respectively. Both overweight (body mass index [BMI], 25-29.9 kg/m2) and obese (BMI, > or =30 kg/m2) persons were more likely to have elevated CRP levels than their normal-weight counterparts (BMI, <25 kg/m2). After adjustment for potential confounders, including smoking and health status, the odds ratio (OR) for elevated CRP was 2.13 (95% confidence interval [CI], 1.56-2.91) for obese men and 6.21 (95% CI, 4.94-7.81) for obese women. In addition, BMI was associated with clinically raised CRP levels in women, with an OR of 4.76 (95% CI, 3.42-6.61) for obese women. Waist-to-hip ratio was positively associated with both elevated and clinically raised CRP levels, independent of BMI. Restricting the analyses to young adults (aged 17-39 years) and excluding smokers, persons with inflammatory disease, cardiovascular disease, or diabetes mellitus and estrogen users did not change the main findings. CONCLUSION: Higher BMI is associated with higher CRP concentrations, even among young adults aged 17 to 39 years. These findings suggest a state of low-grade systemic inflammation in overweight and obese persons.

Utility of laboratory testing in autoimmune inner ear disease.

OBJECTIVES: To assess the utility of various laboratory tests used to diagnose autoimmune inner ear disease. STUDY DESIGN: Retrospective study of 82 patients evaluated at the University of Washington Otology Clinic from 1996 through 1998 with review of clinical history, laboratory tests, audiograms, response to therapy, and final diagnoses. METHODS: Charts were reviewed for presenting history and initial workup including test results for erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), Clq binding assay, anticardiolipin antibody (aCL), antineutrophil cytoplasmic antibody (ANCA), microhemagglutinin assay for Treponema pallidum (microhemagglutination assay), Lyme disease titers, and the Western blot for heat shock protein 70 (hsp 70). RESULTS: The Western blot for hsp 70 is the best test for predicting corticosteroid responsiveness. The sensitivity was low at 42%, although the specificity was 90%, and the positive predictive value of this test was excellent at 91%. The ESR was as good as the CRP in detecting acute-phase reactants. The other, more specific tests in the laboratory panel (aCL, ANCA, MHA, and Lyme disease titers) did not detect any new cases of autoimmune disease in addition to those which were already identified by an abnormal ESR. CONCLUSIONS: A diagnostic test panel for autoimmune inner ear disease should include an ESR and the Western blot for hsp70. More specific laboratory testing for systemic disease is warranted when the ESR is elevated. In patients with a positive Western blot, a trial of corticosteroid therapy can be given with good conviction because the test is quite specific. However, many people who are Western blot negative may also respond to corticosteroid therapy because the test lacks sensitivity.

Clinicopathologic correlations in lupus nephritis in Lima, Peru.

BACKGROUND: We assessed whether immunohistologic markers for glomerular or tubulointerstitial injury might provide better correlations with ongoing renal function and disease activity as compared with the WHO classification or the NIH activity and chronicity indices in lupus nephritis. METHODS: Thirty-three patients with clinically defined systemic lupus underwent renal biopsy over a 1-year period at Hospital Loayza in Lima, Peru. Biopsy specimens were evaluated for macrophages, proliferating cells, alpha-actin expression, and type IV collagen deposition in both glomeruli and the tubulointerstitium and the results compared with the current WHO and NIH classifications in relation to the clinical presentation. RESULTS: Patients with WHO class IV lupus nephritis were more likely to have lower serum complements, greater proteinuria and hematuria, and worse renal function. An elevated NIH activity index correlated with microhematuria, proteinuria, and impaired renal function, whereas an elevated chronicity index correlated with renal function, hypertension, and microhematuria, but not with proteinuria. The presence of glomerular macrophages correlated with both glomerular alpha-actin expression and type IV collagen deposition, but did not correlate with renal function or proteinuria. In contrast, interstitial macrophages correlated not only with interstitial collagen deposition and myofibroblast accumulation, but also correlated with both renal function and the presence of nephrotic syndrome. CONCLUSIONS: Both the WHO classification and the NIH activity/chronicity indices correlate with clinical manifestations of lupus nephritis. While glomerular macrophage accumulation correlates with mesangial cell activation (alpha-actin expression) and collagen deposition, and interstitial macrophage accumulation correlates with interstitial fibroblast activation and collagen deposition, only interstitial macrophages correlate with renal function. Of particular interest will be future studies to determine whether these markers correlate with the prognosis.

Destructive tophaceous calcium hydroxyapatite tumor of the infratemporal fossa. Case report and review of the literature.

Tophaceous pseudogout is one of the rarest forms of crystal deposition disease, typically presenting as a destructive and invasive mass involving the temporomandibular joint or the infratemporal fossa region in the absence of any other articular manifestations. Previous cases have been assumed to be caused by calcium pyrophosphate dihydrate (CPPD) crystal deposition, based on finding weakly birefringent crystals in the involved tissues. The authors present the unique case of a 65-year-old woman with a destructive and invasive facial mass extending to the middle cranial fossa with microscopic and clinical features consistent with tophaceous pseudogout. High-resolution x-ray crystallographic powder diffraction and Fourier transformed infrared spectroscopy subsequently revealed that the crystals were composed of calcium hydroxyapatite without CPPD. The patient was later found to have primary hyperparathyroidism and mild hypercalcemia. This case demonstrates that tissue deposits of calcium hydroxyapatite can cause a destructive and invasive mass containing weakly birefringent crystals and raises the question of whether previous cases attributed to tophaceous pseudogout resulting from CPPD actually were composed of birefringent calcium hydroxyapatite.

Teaching the microscopic examination of urine sediment to second year medical students using the Urinalysis-Tutor computer program.

The microscopic examination of urine sediment is a common diagnostic tool taught to medical students, medical technologists, and others. The urine microscopic exam is difficult to teach because supervised instruction and textbook-based teaching suffer from numerous drawbacks. Here, we describe Urinalysis-Tutor, a computer program that uses digitized microscope images and computer-based teaching techniques to systematically teach the urine microscopic exam. In addition, we report the results of a 2-year study that evaluated the effectiveness of the program in 314 second year medical students who were required to use the program. The program contained two, 20-question exams. In the first year of the study (1996), one of the exams was chosen as the pretest and the other as the posttest; the pretest had to be completed before the students viewed the contents of the program, and the posttest was taken after finishing the tutorial. In 1997, the order of the two exams was reversed. In 1996, 159 students completed the study. The mean pretest score was 34% (SD, 14%), the mean posttest score was 71% (SD, 13%), and the improvement was significant (P <0.001, paired t-test). In 1997, 155 students participated. The mean pretest score was 41% (SD, 11%), the mean posttest score was 71% (SD, 13%), and the improvement was significant (P <0.001, paired t-test). The study shows that Urinalysis-Tutor helps medical students learn to interpret the microscopic appearance of urine sediment and that it is feasible to implement this tutorial in a medical school class.

Histoplasmosis-like choroiditis in a nonendemic area: the northwest United States.

PURPOSE: Histoplasmosis is not endemic in the U.S. northwest, but a type of multifocal choroiditis resembling ocular histoplasmosis occurs there. This study was designed to find a group of affected patients and study their clinical characteristics and immunologic responses to Histoplasma antigens. METHOD: Ten patients were found in the authors' files whose geographic histories made it unlikely that they had ever been exposed to Histoplasma capsulatum and yet they had features of ocular histoplasmosis. They were recalled for examination and testing by lymphocyte-stimulation assay for previous exposure to histoplasmosis. RESULTS: The clinical features of these patients resembled those of patients with ocular histoplasmosis, but their histories and the results of the assay did not support H. capsulatum as the cause of the ocular disease. CONCLUSION: This study confirmed that there is a type of choroiditis that resembles ocular histoplasmosis but is due to another agent or agents.

Teaching the clinical interpretation of peripheral blood smears to a second-year medical school class using the PeripheralBlood-Tutor computer program.

The interpretation of peripheral blood smears has an important role in the diagnosis of hematologic diseases and is, therefore, part of the education of physicians and technologists. We describe a computer program, PeripheralBlood-Tutor (Lippincott-Raven, Philadelphia, Pa), that teaches the morphologic features of normal and abnormal peripheral blood smears; we also describe the evaluation of the effectiveness of the program in 133 second-year medical students who were required to use the program in their hematology course. The version of the PeripheralBlood-Tutor used in the study had 2 distinct but equivalent 20-question examinations; one examination, the pretest, was taken before the students viewed the contents of the program, and the other examination, the posttest, was taken after completing the program. The mean score on the pretest was 61% (SD, 14%), the mean on the posttest was 91% (SD, 10%), and the improvement was significant. In addition, 4 questions about peripheral blood smears, which were based on printed images, were administered at the end of the hematology course. The students scored an average of 2.75 (SD, 0.86), and a positive correlation was found between these scores and the scores on the Tutor posttest. The results of the study suggest that PeripheralBlood-Tutor is feasible to implement, and it helps students learn to interpret peripheral blood smears. The use of PeripheralBlood-Tutor is now a requirement in the medical school curriculum, the medical technology program, and the pathology residency at the University of Washington, Seattle.

Deposition of antibodies to the collagen-like region of C1q in renal glomeruli of patients with proliferative lupus glomerulonephritis.

OBJECTIVE: To determine if antibodies to the collagen-like region of C1q (C1q-CLR) are present in the glomerular immune deposits of patients with systemic lupus erythematosus (SLE). METHODS: Kidney tissues were obtained at autopsy, glomeruli were isolated, and glomerular basement membrane fragments were prepared. Antibodies were extracted with low pH or with DNase. RESULTS: The concentrations of antibodies to C1q-CLR recovered from the glomeruli were > or =50-fold higher per unit of IgG than that found in the serum or in the serum and interstitial fluid entrained in glomeruli. Antibodies to C1q-CLR were recovered from glomeruli of 4 of 5 patients with proliferative glomerulonephritis at autopsy. CONCLUSION: This is the first demonstration that antibodies to C1q-CLR are deposited and concentrated in the renal glomeruli of patients with SLE. These antibodies, thus, have the potential of contributing to the pathogenesis of lupus glomerulonephritis.

Biological variation of prostate specific antigen levels in serum: an evaluation of day-to-day physiological fluctuations in a well-defined cohort of 24 patients.

PURPOSE: We evaluated the daily biological variation of serum prostate specific antigen (PSA) concentrations to determine the critical difference required between 2 consecutive PSA measurements that would indicate a significant elevation. MATERIALS AND METHODS: A total of 24 men, grouped according to clinical diagnosis and PSA, underwent phlebotomy for 10 consecutive weekdays. Duplicate serum samples were measured using 3 separate lots of Tandem-E and IMx PSA assays. The biological variation was calculated and the 2 PSA assay systems were compared. The critical difference was examined to determine the percent elevation necessary to indicate (with 95% confidence) that PSA had increased beyond what would be expected from biological and analytical variation. RESULTS: The biological variation, defined in terms of percent coefficient of variation, had a log-normal distribution with a geometric mean of 7.3% coefficient of variation and a 95th percentile value of 19.2% coefficient of variation using the Tandem-E PSA assay. Assuming an analytical variation of 5% coefficient of variation, the median critical difference was 20.5% and the 95th percentile critical difference was 45.8%. There was no significant difference between the 2 PSA assay systems in biological variation. However, PSA concentrations measured by the IMx assay were consistently lower compared to values measured by the Tandem-E assay. CONCLUSIONS: Characterizing the biological variation of serum PSA assists in evaluating the significance of changes in serial PSA measurements. The degree of biological variation differs among patients, such that an increase between 2 consecutive PSA levels that is less than 20 to 46% may be due to biological and analytical variation. These data influence interpretation of repeated measurements of serum PSA with time.

Markers of inflammation and immune activation in chronic fatigue and chronic fatigue syndrome.

OBJECTIVE: Chronic fatigue syndrome (CFS) has been hypothesized to result from immune activation. We examined the role of serum markers of inflammation and immune activation among patients with CFS and in those with chronic fatigue (CF) not meeting the case definition. METHODS: Assays for soluble interleukin 2 (IL-2) receptor, IL-6, C-reactive protein, beta 2-microglobulin, and neopterin were performed in 153 fatigued patients in a referral clinic. Patients were classified according to whether they met criteria for CFS, reported onset of illness with a viral syndrome or had a temperature > 37.5 degrees C on examination. RESULTS: Compared to control subjects, mean concentrations of C-reactive protein, beta 2-microglobulin, and neopterin were higher in patients with CFS (p < or = 0.01) and CF (p < or = 0.01). Results did not distinguish CFS from CF. IL-6 was elevated among febrile patients compared to those without this finding (p < or = 0.001), but other consistent differences between patient subgroups were not observed. The presence of several markers was highly correlated (p < 0.01). CONCLUSION: Our findings that levels of several markers were significantly correlated points to a subset of patients with immune system activation. Whether this phenomenon reflects an intercurrent, transient, common condition, such as an upper respiratory infection, or is the result of an ongoing illness associated process is unknown. Overall, serum markers of inflammation and immune activation are of limited diagnostic usefulness in the evaluation of patients with CSF and CF.

Day to day changes in free and total PSA: significance of biological variation.

In this study we evaluated the physiological variation of free and total prostate-specific antigen (PSA) levels to determine how the percent free/total PSA was affected. Twenty four patients had blood drawn for ten consecutive weekdays. The percent coefficient of variation (%CV) of biological variation was calculated. The results were log-normally distributed with geometric means of 12.0% CV, 7.3% CV, and 8.8% CV for free, total, and percent free/total PSA, respectively. When applied, the percent free/total, PSA would need to fluctuate by 31% to indicate that a significant change (critical difference, P<0.05) between two measurements had occurred. Biological variation of PSA measurements is substantial.