The proportion of prostate-specific antigen (PSA) complexed to alpha(1)-antichymotrypsin improves the discrimination between prostate cancer and benign prostatic hyperplasia in men with a total PSA of 10 to 30 microg/L.
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BACKGROUND: The aim of this study was to assess the diagnostic accuracy of the proportion of prostate-specific antigen (PSA) complexed to alpha(1)-antichymotrypsin (PSA-alpha(1)ACT:PSA ratio) in the differential diagnosis of prostate cancer (CaP) and benign prostatic hyperplasia (BPH) in men with total PSA of 10-30 microg/L. METHODS: We used our immunoassays (ELISAs) for total PSA and PSA-alpha(1)ACT complex to study 146 men. In 123, total PSA was between 10 and 20 microg/L; 66 of these had CaP and 57 BPH. In 23 men, total PSA was between 20 and 30 microg/L; 14 of these had CaP and 9 BPH. We calculated the area under the ROC curves (AUC) for total PSA, PSA-alpha(1)ACT complex, and PSA-alpha(1)ACT:PSA ratio, and determined the cutoff points that gave sensitivities approaching 100%. RESULTS: In the total PSA range between 10 and 20 microg/L, the AUC was significantly higher for the PSA-alpha(1)ACT:PSA ratio (0.850) than for total PSA (0.507) and PSA-alpha(1)ACT complex (0.710; P <0.0001). A cutoff ratio of 0.62 would have permitted diagnosis of all 66 patients with CaP (100% sensitivity) and avoided 19% of unnecessary biopsies (11 of 57 patients). In the total PSA range between 20 and 30 microg/L, the AUC for the PSA-alpha(1)ACT:PSA ratio (0.980; 95% confidence interval, 0.82-0.99) was greater than the AUC for total PSA (0.750; 95% confidence interval, 0.51-0.89; P = 0.042). In this range, a cutoff point of 0.64 would have permitted the correct diagnosis of all 14 patients with CaP and 6 of the 9 with BPH. CONCLUSIONS: The diagnostic accuracy of the PSA-alpha(1)ACT:PSA ratio persists at high total PSA concentrations, increasing the specificity of total PSA. Prospective studies with large numbers of patients are needed to assess whether the ratio of PSA-alpha(1)ACT to total PSA is a useful tool to avoid unnecessary prostatic biopsy in patients with a total PSA >10 microg/L. (+info)
Identification and expression of human cytomegalovirus transcription units coding for two distinct Fcgamma receptor homologs.
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Cellular receptors for the Fc domain of immunoglobulin G (IgG) (FcgammaRs) comprise a family of surface receptors on immune cells connecting humoral and cellular immune responses. Several herpesviruses induce FcgammaR activities in infected cells. Here we identify two distinct human cytomegalovirus (HCMV)-encoded vFcgammaR glycoproteins of 34 and 68 kDa. A panel of HCMV strains exhibited a slight molecular microheterogeneity between Fcgamma-binding proteins, suggesting their viral origin. To locate the responsible genes within the HCMV genome, a large set of targeted HCMV deletion mutants was constructed. The mutant analysis allowed the identification of a spliced UL119-UL118 mRNA to encode vFcgammaR gp68 and TRL11/IRL11 to encode vFcgammaR gp34. Both vFcgammaRs are surface resident type I transmembrane glycoproteins. Significant relatedness of sequences in the extracellular chain of gpUL119-118 and gpTRL11 with particular immunoglobulin supergene family domains present in FcgammaR I and FcgammaRs II/III, respectively, indicates a different ancestry and function of gpUL119-118 and gpTRL11. The HCMV-encoded vFcgammaRs highlight an impressive diversification and redundancy of FcgammaR structures. (+info)
Estimation of the effect of the acute phase response on indicators of micronutrient status in Indonesian infants.
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Many indicators of micronutrient status change during infection because of the acute phase response. In this study, relationships between the acute phase response, assessed by measuring concentrations of C-reactive protein (CRP), alpha(1)-antichymotrypsin (ACT) and alpha(1)-acid glycoprotein (AGP), and indicators of micronutrient status were analyzed in 418 infants who completed a 6-mo randomized, double-blind, placebo-controlled, supplementation trial with iron, zinc and/or beta-carotene. The acute phase response, defined by raised CRP (plasma concentration >10 mg/L), raised AGP (>1.2 g/L), or both raised CRP and AGP, significantly affected indicators of iron, vitamin A and zinc status, independently of the effects of supplementation. Plasma ferritin concentrations were higher by 15.7 (raised AGP) to 21.2 (raised CRP and AGP) micro g/L in infants with elevated acute phase proteins compared with infants without acute phase response (P < 0.001). In contrast, plasma concentrations of retinol were lower by 0.07 (P < 0.05, raised AGP) to 0.12 (P < 0.01, raised CRP) micro mol/L, and of zinc lower by 1.49 (P < 0.01, raised AGP) to 1.89 (P < 0.05, raised CRP and AGP) micro mol/L. Hemoglobin concentrations and the modified relative dose response were not affected. Consequently, the prevalence of iron deficiency anemia was underestimated in infants with raised acute phase proteins by >15%, whereas the prevalence of vitamin A deficiency was overestimated by >16% compared with infants without acute phase response. Hence, using indicators of micronutrient status without considering the effects of the acute phase response results in a distorted estimate of micronutrient deficiencies, whose extent depends on the prevalence of infection in the population. (+info)
HIV-1 viral load and elevated serum alpha(1)-antichymotrypsin are independent predictors of body composition in pregnant Zimbabwean women.
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Human immunodeficiency virus (HIV) infection affects body composition, but their relationship has not been studied in pregnant women. We conducted a cross-sectional study among 1669 women receiving antenatal care between 22 and 35 wk of gestation in Harare, Zimbabwe. The role of HIV-1 status and viral load, malaria and elevated serum alpha(1)-antichymotrypsin (ACT, an acute phase protein) in weight, body mass index (BMI), arm circumference (AC), triceps skinfold thickness (TSF), and arm muscle (AMA) and fat (AFA) area were assessed using multiple linear regression analysis. The mean (range) age was 24.4 (14-45) y and gestational age 29 (22-35) wk. HIV infection was present in 31.5% of the women, malaria parasitemia in 0.4% and 11.4% had serum ACT >0.4 g/L. There was no difference in any anthropometric variable between HIV-infected and uninfected women. However, women with viral loads (genome equivalents/mL) between 4 and 5 and >5 log(10) had 1.1 [95% confidence interval (CI): -0.3, 2.3] and 2.5 (95% CI: 0.1, 5.1) kg lower weights compared with uninfected women; this was explained by losses of both AFA and AMA. Malaria parasitemia was associated with 6 cm(2) (95% CI: 0.4; 11.8) or 25% lower AMA. Elevated serum ACT was a negative predictor of all anthropometric variables, i.e., levels between 0.3 and 0.4, 0.4 and 0.5 and >0.5 g/L were associated with 1, 2 and 6 kg lower mean body weights, respectively. Despite the limitations of a cross-sectional design, we conclude that arm fat and muscle areas, reflecting body fat and lean body mass, seem to be unaffected in the majority of HIV-infected pregnant women, but decline with increasing viral loads. The effects of viral load are not explained by elevated serum ACT, which is a strong independent predictor of all anthropometric variables. (+info)
Improving the utility of prostate specific antigen (PSA) in the diagnosis of prostate cancer: the use of PSA derivatives and novel markers.
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Prostate specific antigen (PSA) testing is now a routine part of the investigation of men with suspected prostate cancer. While a very useful test it still has its problems, in particular its lack of specificity means abnormal results are often caused by benign disease. This review describes the current problems with PSA testing in prostate cancer diagnosis and highlights potential ways in which these may be reduced. (+info)
Dual-label immunoassay for simultaneous measurement of prostate-specific antigen (PSA)-alpha1-antichymotrypsin complex together with free or total PSA.
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BACKGROUND: A major portion of prostate-specific antigen exists in circulation as a complex with alpha(1)-antichymotrypsin (PSA-ACT), whereas a minor part is free (fPSA). The proportion of PSA-ACT is increased in prostate cancer (PCa), but immunologic determination of PSA-ACT is hampered by a background produced by nonspecific adsorption of ACT to the solid phase. To reduce the nonspecific interference, we produced an antibody specific for complexed ACT and developed immunofluorometric assays (IFMAs) for simultaneous measurement of fPSA + PSA-ACT (fPSA/PSA-ACT) and PSA-ACT + total PSA (tPSA, PSA-ACT/tPSA). METHODS: Monoclonal antibodies (MAbs) were produced by immunization with PSA-ACT. The dual-label time-resolved IFMAs for fPSA/PSA-ACT and PSA-ACT/tPSA used a capture MAb to tPSA, an Eu(3+)-labeled MAb to fPSA or complexed ACT, and an Sm(3+)-labeled MAb to complexed ACT or to tPSA as tracer antibodies. The clinical utility was evaluated using serum samples from individuals with or without PCa with PSA concentrations of 2.0-20.0 micro g/L. RESULTS: One MAb (1D10) showed low cross-reactivity with free ACT and cathepsin G-ACT. A sandwich assay for PSA-ACT with 1D10 as tracer had a detection limit of 0.05 micro g/L, and with this assay, PSA-ACT was undetectable in female sera. The detection limit for fPSA was 0.004 micro g/L. Determinations of the ratio of fPSA to PSA-ACT and the proportions of fPSA/tPSA and PSA-ACT/tPSA provided the same clinical specificity for PCa and provided significantly better clinical specificity than did tPSA. CONCLUSIONS: Background problems observed in earlier PSA-ACT assays are eliminated by the use of a MAb specific for complexed ACT as a tracer. The same clinical validity can be obtained by determination of fPSA or PSA-ACT together or in combination with tPSA. (+info)
Purification of human kallikrein 6 from biological fluids and identification of its complex with alpha(1)-antichymotrypsin.
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BACKGROUND: Human kallikrein 6 (hK6) is significantly increased in serum in many patients with ovarian cancer and may have a role in amyloid precursor processing and Alzheimer disease. The forms of hK6 in biological fluids are poorly characterized. METHODS: hK6 protein was immunoaffinity-purified and positively identified by Western blotting, N-terminal sequencing, and mass spectrometry. hK6 in cerebrospinal fluid (CSF), milk, ascites, and serum was size-fractionated by chromatography and then measured by a highly sensitive and specific immunoassay. Hybrid assays were performed to detect the possible interactions between hK6 and proteinase inhibitors in CSF, milk, ascites fluid, and serum. RESULTS: N-Terminal sequencing identified hK6 in the proform in both CSF and milk. hK6 exists in two forms in milk and ascites fluid: a free form with a molecular mass of approximately 25 kDa and a higher molecular mass form. Hybrid sandwich assays (capture antibody for hK6 and detection antibody for inhibitors), utilizing a panel of known serine protease inhibitors, indicated that alpha(1)-antichymotrypsin forms a complex with hK6 in milk and ascites fluid. Only the free form of hK6 was detected in CSF and serum. CONCLUSIONS: hK6 exists mainly as a proenzyme in milk and CSF. A fraction of this enzyme is partially complexed with alpha(1)-antichymotrypsin in milk and ascites fluid of ovarian cancer patients. (+info)
Determination of non-alpha1-antichymotrypsin-complexed prostate-specific antigen as an indirect measurement of free prostate-specific antigen: analytical performance and diagnostic accuracy.
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BACKGROUND: A new assay measures prostate-specific antigen (PSA) not complexed to alpha(1)-antichymotrypsin (nACT-PSA) after removing PSA complexed to ACT by use of anti-ACT antibodies. We evaluated nACT-PSA and its ratio to total PSA (tPSA) as alternatives to free PSA (fPSA) and its ratio to tPSA in differentiating prostate cancer (PCa) and benign prostatic hyperplasia (BPH) in patients with tPSA of 2-20 micro g/L. METHODS: PSA in serum of 183 untreated patients with PCa and 132 patients with BPH was measured retrospectively on the chemiluminescence immunoassay analyzer LIAISON(R) (Byk-Sangtec Diagnostica) with the LIAISON tPSA and LIAISON fPSA assays. The nACT-PSA fraction was determined with a prototype assay measuring the residual PSA after precipitation of ACT-PSA with an ACT-precipitating reagent. RESULTS: nACT-PSA was higher than fPSA in samples with fPSA concentrations <1 microg/L but lower in samples with >1 microg/L fPSA. The median ratios of fPSA/tPSA and of nACT-PSA/tPSA were significantly different between patients with BPH and PCa (19.4% vs 12.2% and 17.4% vs 13.0%, respectively). Within the tPSA ranges tested (2-20, 2-10, and 4-10 microg/L), areas under the ROC curves for the fPSA/tPSA ratios were significantly larger than those for nACT-PSA/tPSA. In the tPSA ranges <10 microg/L, the areas under the ROC curves for fPSA/tPSA were significantly larger than those for tPSA, whereas the areas for nACT-PSA/tPSA were not. At decision limits for 95% sensitivity and specificity, both ratios significantly increased specificity and sensitivity, respectively, compared with tPSA, but the fPSA/tPSA ratio showed higher values. CONCLUSIONS: nACT-PSA and its ratio to tPSA provide lower diagnostic sensitivity and specificity than fPSA/tPSA. The fPSA/tPSA ratio represents the state-of-the-art method for differentiating between PCa and BPH. (+info)