Diagnostic and predictive value of urine PCA3 gene expression for the clinical management of patients with altered prostatic specific antigen.

OBJECTIVE: Analyze the impact of the introduction of the study of PCA3 gene in post-prostatic massage urine in the clinical management of patients with PSA altered, evaluating its diagnostic ability and predictive value of tumor aggressiveness. METHODS: Observational, prospective, multicenter study of patients with suspected prostate cancer (PC) candidates for biopsy. We present a series of 670 consecutive samples of urine collected post-prostatic massage for three years in which we determined the "PCA3 score" (s-PCA3). Biopsy was only indicated in cases with s-positive PCA3. RESULTS: The s-PCA3 was positive in 43.7% of samples. In the 124 biopsies performed, the incidence of PC or atypical small acinar proliferation was 54%, reaching 68,6% in s-PCA3≥100. Statistically significant relationship between the s-PCA3 and tumor grade was demonstrated. In cases with s-PCA3 between 35 and 50 only 23% of PC were high grade (Gleason≥7), compared to 76.7% in cases with s-PCA3 over 50. There was a statistically significant correlation between s-PCA3 and cylinders affected. Both relationships were confirmed by applying a log-linear model. CONCLUSIONS: The incorporation of PCA3 can avoid the need for biopsies in 54% of patients. s-PCA3 positivity increases the likelihood of a positive biopsy, especially in higher s-PCA3 100 (68.6%). s-PCA3 is also an indicator of tumor aggressiveness and provides essential information in making treatment decisions.

S-100beta and MIA in advanced melanoma in relation to prognostic factors.

We compared the sensitivity and specificity of S-100 and MIA in advanced melanoma, in 96 patients with no evidence of disease (NED) and 86 patients with metastatic melanoma. Abnormal S100 (>0.2 microg/l) and MIA (>14 ng/ml) results were found in 1.1% and 3.2% of NED patients and in 59.3% and 54.6% of the patients with active melanoma (p<0.001). Using both tumor markers simultaneously, the sensitivity increased up to 69.8% with the same specificity 96.8%. S100 serum levels were not related to growth patterns. By contrast, MIA levels seemed to be related to the growth pattern, with higher levels in nodular melanoma (60.6+/-87.1 ng/ml) compared with acral-lentigous melanoma (11.9+/-5.4 ng/ml) (p=0.02). Likewise, S100 was related to the metastases site with significantly higher sensitivity and mean concentrations in patients with brain metastases (p=0.01) with the lowest in those with lung MI. MIA was related to the same metastases locations but without statistical significance. In summary, both S100 and ML4 are useful markers related to prognostic factors, being more effective when used in combination.

Long-term biochemical response after bisphosphonate therapy in Paget's disease of bone. Proposed intervals for monitoring treatment.

OBJECTIVES: To monitor the long-term evolution of Paget's disease activity after treatment with tiludronate by using serum total alkaline phosphatase (TAP) and more sensitive markers such as bone alkaline phosphatase (BAP), procollagen type I N propeptide (PINP) and urinary N-terminal cross-linking telopeptide of type I collagen (NTX); to analyse the predictors of long-term response to therapy; and to study the most appropriate intervals of time for monitoring the response to therapy. METHODS: Thirty-two patients with Paget's disease were included in the study. All received 400 mg of oral tiludronate daily for 3 months. A total of 21 patients completed the study. In these patients, serum TAP, BAP and PINP and urinary NTX were measured at baseline and at 1, 6, 12 and 24 months after discontinuation of therapy. Quantitative bone scintigraphy was performed at baseline and at 6 and 24 months after the end of treatment, obtaining a scintigraphic activity index (SAI). Patients were classified into two groups depending on the long-term response to treatment: Group 1, patients who presented a persistent and significant decrease in disease activity at this time, n = 12 (57%) and Group 2, patients who presented a relapse in the activity of the disease at 24 months after treatment, n = 9 (43%). The relapse of disease activity was defined as a significant increase of SAI (>13%) between 6 and 24 months after the end of treatment, whereas the response to therapy was defined as a significant reduction in SAI (>13%) at 6 months after the end of treatment. In addition, these results were compared with the biochemical evolution of bone markers. RESULTS: Biochemical markers and SAI decreased significantly after therapy and the nadir response was observed at 6 months. At this time 100% of patients responded to therapy. The persistent long-term response was associated with lower baseline indices of bone turnover (serum BAP<60 ng/ml or TAP<600 IU/l). The intervals of time for monitoring depended on the marker used: no patient from Group 1 presented a biochemical relapse in serum TAP at 1 and 2 yr after the end of treatment whereas 33 and 45% of these patients showed relapsed serum BAP at these time points. Moreover, all patients from Group 2 presented a biochemical relapse of serum BAP at 2 yr whereas in only 33% of these patients did serum TAP relapse at this time. CONCLUSION: Most of the Pagetic patients treated with tiludronate presented a long-term response, which persisted 2 yr after the end of treatment. The nadir response to treatment was observed 6 months after discontinuation of therapy whereas the relapse of disease activity was already observed 1 yr after the end of therapy and depended on both the baseline disease activity and the bone marker used in the evaluation.

Glucómetros de uso hospitalario: creación de un equipo pluridisciplinar para el proceso de selección y seguimiento Seis años de experiencia / Glucometers for hospital use: creation of a multi-disciplinary team for the selection and monitoring process

This work highlights what the authors consider to be critical aspects for setting up POCT (point-of-care testing) measurements, whether simple ones such as glucometers or critical ones such as those made with blood gas analyser (AU)

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Prospective evaluation of CEA and CA 15.3 in patients with locoregional breast cancer.

The tumor markers, CEA and CA 15.3, were prospectively studied in the sera of 1057 untreated patients with locoregional breast cancer diagnosed from 1983 to 2001. Abnormal CEA and CA 15.3 serum levels were found in 13% and 18.8% of the patients, respectively. One tumor marker or another was abnormal in 22.8% of the patients. Both tumor markers were correlated with tumor size and nodal involvement, with significantly higher concentrations in patients with larger tumors or in patients with nodal involvement. CEA was also related to the histological type and CA 15.3 with the histological grade. Univariate prognostic evaluation showed that tumor size, nodal involvement, histological grade, steroid receptors, adjuvant treatment, CEA, CA 15.3 and treatment before surgery were prognostic factors in both disease-free survival (DFS) and overall survival (OS). Similar results were obtained in node-positive patients, with the same factors being prognostic, excluding adjuvant treatment and CA 15.3, in both DFS and OS. Multivariate analysis showed that tumor size, nodal involvement, histological grade, ER and CEA were independent prognostic factors in both DFS and OS in the whole group as well as in node-positive patients. In contrast, tumor size was the only useful parameter in the prognosis of node-negative patients. CA 15.3 was useful for prognosis (OS) in node-negative patients. In summary, tumor markers are useful tools in the prognostic evaluation of patients with breast cancer.

Prospective evaluation of tumor markers (c-erbB-2 oncoprotein, CEA and CA 15.3) in patients with locoregional breast cancer.

Tumor markers were prospectively (CEA and CA 15.3) or retrospectively (c-erbB-2) studied in the sera of 503 untreated patients with breast cancer diagnosed from 1988 to 2001. Abnormal c-erbB-2 levels (> 15 U/ml) were found in 7%, CEA in 12% and CA 15.3 in 13% of the 503 patients. C-erbB-2 serum levels were only related to c-erbB-2 in tissue, with significantly higher concentrations in patients with positivity in tissue. All the tumor markers (c-erbB-2 only in patients with positivity in tissue) were correlated with tumor size, TNM and nodal involvement. CEA was also related to menopausal status, c-erbB-2 overexpression in tissue and ER. Univariate analysis (mean follow-up 8 years) showed that CEA and CA 15.3 were prognostic factors with significantly shorter disease-free survival (DFS) and overall survival (OS) in patients with pretreatment tumor marker positivity. Multivariate analysis in DFS and in OS showed that nodal involvement CEA and ER but not tumor size, menopausal status, histological grade, histology, CA 15.3, c-erbB-2, PgR, adjuvant treatment, p53 (345 patients) or c-erbB-2 in tissue are independent prognostic factors. In summary, tumor markers are a useful, inexpensive and reproducible tool for prognosis in breast cancer.

Serum osteoprotegerin and its ligand in Paget's disease of bone: relationship to disease activity and effect of treatment with bisphosphonates.

OBJECTIVE: To test the following hypotheses: 1) osteoprotegerin (OPG) and receptor activator of nuclear factor kappa B ligand (RANKL) serum levels in patients with Paget's disease are related to disease activity and are different from those in healthy individuals; 2) interleukin-6 (IL-6), a cytokine that has been shown to have higher levels in Paget's disease, modulates these factors; and 3) the antiresorptive effect of bisphosphonates in Paget's disease of bone may be mediated through these local factors. METHODS: The study group comprised 31 patients with Paget's disease who received 400 mg/day of oral tiludronate for 3 months. Serum levels of OPG, RANKL, IL-6, bone alkaline phosphatase (AP), N-terminal type I procollagen propeptide, urinary N-terminal crosslinking telopeptide of type I collagen, and urinary alpha-C-terminal crosslinking telopeptide of type I collagen were measured at baseline and 1 month after the end of therapy. In addition, the RANKL:OPG ratio was calculated, and disease activity was evaluated at baseline by quantitative bone scintigraphy. RESULTS: Mean baseline OPG values were higher in patients with Paget's disease than in healthy control subjects (P < 0.005), but RANKL and IL-6 values and RANKL:OPG ratios in the 2 groups were similar. OPG concentrations decreased significantly after treatment with tiludronate (P < 0.005), whereas no significant changes were observed in serum RANKL values. No correlation was found between either bone markers or quantitative scintigraphic indices and serum levels of OPG, RANKL, IL-6, and RANKL:OPG ratios. Serum OPG decreased significantly only in those patients with baseline OPG values >4.1 pM/liter. CONCLUSION: Serum OPG increases in Paget's disease and decreases after treatment with tiludronate, especially in patients with the highest OPG values. In contrast, RANKL serum levels and RANKL:OPG ratios are unmodified in patients with Paget's disease. Although serum OPG, RANKL, and IL-6 values were unrelated to disease activity, the increase in OPG may reflect a protective mechanism of the skeleton to compensate for increased bone resorption.

BTA TRAK urine test increases the efficacy of cytology in the diagnosis of low-grade transitional cell carcinoma of the bladder.

BACKGROUND: Among urinary tumor markers we studied the utility of the BTA TRAK assay to diagnose transitional cell carcinoma of the bladder in highly suspiscious patients, in comparison to urine cytology. MATERIALS AND METHODS: A preliminary study of 65 patients was made (21 transitional cell carcinoma (TCC), 36 without TCC and 8 excluded patients who received BCG therapy, endocavitary mytomicin or radiotherapy), using the BTA TRAK, cytology and cystoscopy. RESULTS: 12 out of the 21 selected patients were pTa (9 G1and 3 G2), 2 carcinoma in situ (CIS), 2pT1 (1 G2 and 1 G3) and 5 muscle invasive tumors (all of them G3). Setting our cut-off at 18 U/ml, a sensitivity of 52.3% and a specificity of 88.9% was reached. BTA TRAK detected 11 out of 21 of the tumors as well as urine cytology. However, BTA TRAK was more sensitive in the detection of low grade tumors (p<0.05). When considering both tests as complementary, a combined sensitivity of 80.9% and specificity of 88.5% were obtained. CONCLUSION: BTA TRAK is a valid test for the diagnosis of TCC of the bladder, which is not superior to urine cytology but complementary. More extensive prospective studies are required to validate this application and others of the BTA TRAK assay used either alone or in combination with urinary cytology in the management of bladder cancerpatients.

Estructura y función de las citocinas

A partir de la década de los ochenta, una vez conseguida su clonación y con la disposición de anticuerpos monoclonales específicos para cada citocina, se ha realizado un paso decisivo en su conocimiento. En la actualidad, la diversidad de métodos disponibles permite un enfoque plural al estudio de las citocinas y sus receptores. Dichos métodos ofrecen información tanto sobre la concentración en distintos líquidos biológicos de las citocinas y sus receptores como sobre su expresión en la superficie de un tipo celular concreto. Por otro lado, las técnicas de biología molecular permiten estudiar los mecanismos genéticos implicados en la regulación de su síntesis y han puesto en evidencia la existencia de polimorfismos genéticos en las regiones reguladoras de diversas citocinas, cuya trascendencia clínica ha sido puesta de manifiesto a través de diversos estudios. Todo ello es la base sobre la cual se concreta una vía de colaboración entre el laboratorio y la clínica, cuyo impacto se ha dejado sentir en forma de un gran número de publicaciones a lo largo de la última década y que, con toda seguridad, con el desarrollo de nuevas técnicas cada vez más minuciosas será aún mayor en los próximos años (AU)

Usefulness of biochemical markers of bone turnover in assessing response to the treatment of Paget's disease.

The aim of this study was to investigate the usefulness of biochemical markers of bone turnover for monitoring treatment efficacy of Paget's disease of bone, and also to evaluate the utility of biological variation data in choosing the best markers for assessment of biochemical response to therapy. Thirty-eight patients with Paget's disease were included in a prospective study. All received 400 mg/day of oral tiludronate for 3 months. In 31 patients that completed treatment, biochemical markers were measured at baseline and at 1 and 6 months after treatment ended. In serum we determined the levels of total alkaline phosphatase (tAP), bone alkaline phosphatase (bAP), procollagen type I N-terminal propeptide (PINP), and C-terminal telopeptide of type I collagen (sCTx). Urine samples were analyzed for hydroxyproline (Hyp) and for C- and N-terminal telopeptides of type I collagen (CTx and NTx, respectively). Quantitative bone scintigraphy was performed at baseline and at 6 months after discontinuation of therapy. A ratio for monitoring response to treatment was obtained for each marker. This ratio reflected the size of treatment response of the marker in relation to the value of its critical difference. Thus, ratio values of >1 indicated a significant decrease of the marker after therapy. In addition, response to therapy was evaluated according to disease activity. Mean values of all markers of bone turnover decreased significantly after therapy. Serum bAP and PINP and urinary NTx showed the highest percentage reduction (between 58% and 68%). Furthermore, serum bAP and PINP showed the highest ratios for monitoring changes induced by treatment, followed by serum tAP and urinary NTx. sCTx and urinary CTx as well as Hyp showed mean ratios for monitoring changes of <1, indicating a low sensitivity for monitoring treatment. Patients with polyostotic disease showed a continuous decrease in mean values for all markers at 6 months from the end of therapy, whereas, in monostotic patients, there was a trend toward increased levels at this timepoint. In conclusion, serum bAP and PINP were the most sensitive markers for monitoring treatment efficacy in Paget's disease, although serum tAP and urinary NTx were also sensitive markers for monitoring changes. Data on biological variation are useful for assessing actual changes induced by treatment.

Circulating levels of Th1/Th2 cytokines in patients with primary Sjögren's syndrome: correlation with clinical and immunological features.

OBJECTIVE: To analyse the circulating levels of Th1 and Th2 cytokines in patients with primary Sjögren's syndrome (SS), as well as to investigate their association with clinical and immunological manifestations. METHODS: We included 62 consecutive patients (58 women and 4 men) seen in our Unit. All patients fulfilled 4 or more of the European diagnostic criteria for SS. Serum levels of IL-6 (pg/mL), IL-2 (pg/mL), srIL-2 (pM), TNFalpha (pg/mL) and IL-10 (pg/mL) were determined using a solid phase enzyme immunoassav performed on microtiter plate. RESULTS: When compared with the control group, high levels of Th1 (11-2, srIL-2) and Th2 (IL-6, IL-10) cytokines were detected in SS patients, although only IL-6 levels reached statistical significance. On the other hand, analysis of the mean serum concentrations of cytokines showed distinct patterns of elevated cytokines according to the organ involved, and elevated levels of IL-6 (126.5 v 20.6 pg/mL, p < 0.05) and IL-10 (10.6 v 2.2 pg/mL, p < 0.005) were observed in those patients with liver involvement. Analysis of the cytokine levels according to the presence of immunological features showed: higher levels of srIL-2 (95.6 v 54.0 pM, p < 0.05) in patients with anti-Ro/SS-A antibodies; increased levels of srIL-2 (111.4 v 59.4 pM, p < 0.05) in patients with antiLa/SS-B antibodies; higher levels of srIL-2 (90.4 vs 50.8 pM, p < 0.05) and TNFalpha (37.9 v 22.6 pg/mL, p = 0.001) in patients with RF and higher levels of IL-6 (88.0 v 23.1 pg/mL, p < 0.05) in patients with cryoglobulins and in those with hypocomplementemia (130.3 vs 21.0 pg/mL, p < 0.05). CONCLUSION: We found a significant elevation of several circulating cytokines in some clinical and immunological subsets of patients with primary SS. These cytokine patterns may be markers for specific extraglandular involvement in SS and could be of interest in assessing the response to treatment protocols or in monitoring the disease evolution.

Collagen type Ialpha1 and vitamin D receptor gene polymorphisms and bone mass in primary biliary cirrhosis.

The potential influence of two gene polymorphisms, vitamin D receptor gene (VDR) and the gene encoding collagen type Ialpha1 (COLIA1) Sp1 polymorphisms, in the reduced bone mass observed in patients with primary biliary cirrhosis (PBC) was assessed in 61 women with PBC (age, 54.1 +/- 1.1 years) by restriction enzyme digestion of polymerase chain reaction (PCR)-amplified DNA extracted from whole blood. Bone mineral density (BMD) of the lumbar spine (L2-L4) and proximal femur were measured by X-ray absorptiometry. The severity of liver disease and cholestasis was also evaluated, and changes in BMD were calculated after a mean period of 2.9 +/- 0.3 years in 41 patients. Sixteen patients (26 %) had the BB, 20 the bb (33 %), and 25 Bb (41%) VDR genotypes. There were no significant baseline BMD differences among the 3 VDR genotypes. Forty-one patients (68%) had the SS, 16 the Ss (27%), and 3 the ss (5%) COLIA1 genotypes. The baseline lumbar BMD was significantly lower in patients having the s allele than in the homozygote SS patients (Z-score, -0.76 +/- 0.24 vs. -0.10 +/- 0.17, P =.02). The severity of cholestasis was not related to the VDR or COLIA1 1 polymorphisms. Lumbar bone loss was independent of VDR and COLIA1 genotypes, but it was associated with cholestasis. In conclusion, the COLIA1 but not VDR polymorphism is a genetic marker of peak bone mass in patients with PBC, although the severity of cholestasis is the main factor for osteoporosis since it is associated with the rate of bone loss.

Influence of AFP, CEA and PSA on the in vitro production of cytokines.

Several studies have demonstrated a decreased cytokine production in patients with cancer. Likewise, there is some evidence showing that tumor markers may play a role in immunoregulation. In this work, we have studied the in vitro production of IL-1beta, IL-6 and TNF-alpha in whole-blood cell cultures of 10 healthy subjects after polyclonal activation with lipopolysaccharide of Salmonella enteridis and phytohemagglutinin in the presence or absence of three markers, AFP, CEA and PSA. Each sample was incubated for 48 h at 37 degrees C in a humidified atmosphere of 5% CO(2). Subsequently, cytokine levels in the supernatant were determined. AFP did not significantly affect the production of the three cytokines compared to the basal value obtained on adding PBS. In contrast, CEA significantly increased the production of IL-6 (p <0.001) and TNF-alpha (p = 0.002), while PSA significantly decreased IL-1beta (p <0.001), IL-6 (p = 0.031) and TNF-alpha (p <0.0001) production. These results suggest a possible role of CEA and PSA in the production of these cytokines.

Free to complexed PSA ratio in differentiating benign prostate hyperplasia from prostate cancer.

BACKGROUND: The description of the different forms of circulating PSA has opened a new strategy in the diagnosis of prostate cancer. The aim of our study was to assess the diagnostic potential of PSA and the PSA fractions in the diagnosis of benign prostate hyperplasia (BPH) and prostate cancer. PATIENTS AND METHODS: We measured the serum levels of PSA (Elecsys 2010, Roche Diagnostics, Mannheim, Germany), complexed PSA (Immuno 1 system, Bayer, Tarrytown, NY USA) and free PSA (Elecsys 2010, Roche Diagnostics, Mannheim, Germany) in 178 patients with BPH and 44 patients with prostate cancer. RESULTS: ROC curves were used for comparison of the diagnostic utility of the tests assessed. The biggest areas under the curve were obtained for the ratios between free/complexed PSA and free/total PSA (0.887 and 0.872, respectively). When choosing the cut-off values to obtain a 90% sensibility, we found that the specificity for the free/total PSA ratio was 59% and for the free/complexed PSA ratio 72%. CONCLUSION: Our results suggest that replacement of the measurement of total PSA by complexed PSA in prostate cancer diagnosis may be interesting. Nevertheless, as this is a retrospective study limited to a small number of patients, it is obvious that we need more data to make a final decision with regard to this subject.

Malignant hypertrophic cardiomyopathy caused by the Arg723Gly mutation in beta-myosin heavy chain gene.

Mutations causing hypertrophic cardiomyopathy have been described in nine genes encoding sarcomeric proteins. We report a new mutation in three families, with a C-->G transversion in nucleotide 12 307 of the beta-myosin heavy chain gene, located at the essential light chain interacting region, resulting in the replacement of arginine by glycine at amino acid residue 723. PCR amplification of the selected regions followed by single strand conformation polymorphism analysis, DNA sequencing of the polymorphic patterns and restriction analysis were used to detect the mutation. A total of 23 individuals were diagnosed as carriers, and seven were obligate carriers or had been clinically diagnosed. The Arg723Gly mutation was associated with a malignant phenotype. Ten out of 30 affected members died suddenly or needed an implantable cardioverter-defibrillator at a mean age of 42, and seven members developed progressive heart failure, leading to death or heart transplant in five, at a mean age of 50 years. Echocardiography showed non-obstructive left ventricular hypertrophy in affected members older than 20 (sensitivity 68%). Mean survival of affected members was 51 years. In conclusion, a new mutation Arg723Gly in beta-myosin heavy chain gene is reported which shortens life expectancy because of sudden death and end-stage heart failure.

Collagen type Ialpha1 gene polymorphism in idiopathic osteoporosis in men.

OBJECTIVE: To analyse the distribution of polymorphism of the collagen type Ialpha1 gene (COL1A1) and its relationship with bone metabolism and bone turnover in men with idiopathic osteoporosis. METHODS: A total of 35 male patients with idiopathic osteoporosis, aged 50.4 +/- 10.3 yr, and 60 healthy males (controls), aged 47 +/- 17 yr, were included in the study. Serum osteocalcin, 25-hydroxyvitamin D and parathyroid hormone were determined in all patients. The COL1A1 Sp1 genotypes (SS, SS:, ss) were assessed by restriction enzyme digestion (BAL:1) of DNA amplified by the polymerase chain reaction. RESULTS: Patients with idiopathic osteoporosis had a higher frequency of the s allele than men in the control group (29 vs 11%, P: = 0.003) and a higher frequency of the SS: genotype (patients, 48% SS, 46% SS:, 6% ss; controls, 80% SS, 18% SS:, 2% ss; P: = 0.003). No significant differences between genotypes were observed in serum concentrations of osteocalcin, vitamin D or parathyroid hormone among either the patients or the controls. CONCLUSION: This study suggests that, in men with idiopathic osteoporosis, there is a high prevalence of the s allele and the SS: genotype that is unrelated to other parameters of bone metabolism.

S-adenosylmethionine prevents hepatic tocopherol depletion in carbon tetrachloride-injured rats.

In various experimental models, S-adenosylmethionine (SAMe) has been shown to reduce liver injury by preventing depletion of glutathione, one of the antioxidant systems that plays a critical role in defence against oxidative stress. On the other hand, alpha-tocopherol may be decreased in liver diseases, and treatment with this vitamin reduces liver injury in CCl(4)-treated rats. Since there is a close relationship among the different antioxidant systems (mainly glutathione, alpha-tocopherol and ascorbic acid), we have assessed whether, as well as restoring hepatic glutathione content, SAMe has any effect on liver alpha-tocopherol and ascorbic acid levels in CCl(4)-injured rats. Four groups of seven male Wistar rats treated for 9 weeks were studied: rats induced to cirrhosis with CCl(4), rats induced to cirrhosis plus SAMe administration (10 mg x kg(-1) x day(-1)) and their respective controls. Liver samples were obtained for measuring levels of glutathione, alpha-tocopherol, ascorbic acid and thiobarbituric acid-reactive substances (TBARS), and hydroxyproline concentration as an index of collagen content. The hydroxyproline content was higher in CCl(4)-injured rats than in the control group (4.4+/-1.8 and 1.1+/-0.3 micromol/g respectively; P<0.05). In CCl(4)-injured rats, SAMe administration decreased collagen content (2.7+/-1.0 microl/g; P<0.05) and TBARS, and corrected glutathione depletion. alpha-Tocopherol was significantly lower in CCl(4)-injured rats than in controls (17.3+/-4.9 and 23.0+/-4.0 micromol/g respectively; P<0.05). By contrast, alpha-tocopherol levels were similar (23.8+/-5.1 micromol/g) in CCl(4)-injured rats receiving SAMe and in controls. In CCl(4)-injured rats, liver ascorbic acid was decreased in comparison with controls (4.9+/-1.8 and 8.2+/-1.0 micromol/g respectively; P<0.05), levels which were not replenished by SAMe (4.6+/-0.4 micromol/g). In conclusion, SAMe not only decreases fibrosis and protects against hepatic glutathione depletion, but has a further antioxidant effect of preventing alpha-tocopherol depletion in CCl(4)-injured rats.

Analysis of type T1 and T2 cytokines in patients with prostate cancer.

BACKGROUND: It has been proposed that a dysregulation in the balance between type T1 (IL-2, IFN-gamma) and type T2 (IL-4, IL-10) cytokines may be implicated in the development of cancer. METHODS: We determined the expression of IL-2, IL-4, IL-10, and IFN-gamma in CD4 and CD8 lymphocytes by flow cytometry in 12 patients with prostate cancer and in 7 healthy subjects. In addition to the basal expression of these cytokines, their expression was also determined, following stimulation of lymphocytes with PMA (phorbol 12-mystirate 13 acetate) and ionomycin. RESULTS: The basal expression of cytokines was scarce, while following stimulation this increased markedly. On the other hand, there was a dysregulation in the balance between T1 and T2 lymphocytes in patients with prostate cancer. To this effect, in relation to healthy subjects, we observed an increase in IL-10 expression and a decrease in IL-2 expression. CONCLUSIONS: The disequilibrium observed in the balance between type T1 and type T2 cytokines may be implicated in the evolution of neoplastic disease.

Components of biological variation of biochemical markers of bone turnover in Paget's bone disease.

The aims of this study were to evaluate the components of biological variation of the new markers of bone turnover in patients with Paget's bone disease and to compare the results with data obtained in healthy subjects. Fifteen patients with Paget's disease in a stable period of the disease and 12 healthy premenopausal women were included for a 1 year follow-up study. Within- and between-subject biological variation, indices of individuality, and critical differences were evaluated for the following biochemical markers: in serum, total (tAP), and bone (bAP) alkaline phosphatases, procollagen type I N-terminal propeptide (PINP) and beta-carboxyterminal telopeptide of type I collagen (sCTx); in urine, hydroxyproline (Hyp), and amino (NTx) and beta-carboxyterminal (CTx) telopeptides of collagen type I. Serum markers of bone turnover showed lower biological variability than urinary markers. Within-subject biological variation was higher in pagetic patients than in healthy subjects for all serum markers. In both groups, bAP presented the lowest within-subject biological variation. In pagetic patients, all markers presented indices of individuality of <0.6, indicating their usefulness for patient monitoring. Critical differences were lower for serum markers than for urinary markers. Among pagetic patients, serum bAP and PINP showed the lowest critical differences with values close to 30%, whereas urinary CTx presented the highest critical differences (near 70%). Conversely, in healthy subjects, tAP was the marker with the lowest critical differences, being two-fold higher in pagetic patients. This study confirms the lower sensitivity of urinary markers to detect significant changes and indicates that data obtained on biological variations from healthy populations cannot always be extrapolated to pathological conditions. In addition, serum bAP and PINP seem to be the markers that best reflect a significant change in activity of Paget's disease.

Usefulness of urinary nuclear matrix protein 22 (NMP22) as a marker for transitional cell carcinoma of the bladder.

OBJECTIVES: The purpose of this study was to evaluate an immunoassay for urinary nuclear matrix protein, NMP22, as a novel marker for urothelial cancer. PATIENTS AND METHODS: NMP22 values were determined for 71 patients and 21 healthy volunteers. Each subject provided a single (3 voids) urine sample for analysis at the time of entry into the study. Each sample was assayed for levels of NMP22. RESULTS: When the cut-off value was set at 10 U/ml, the positive rate for urinary NMP22 in bladder cancer was 37.8% (17 out of 45), whereas that in post-treatment cases and benign diseases was 30.8% (8 out of 26) compared to 14.3% (3 out of 21) for healthy volunteers. This cut-off value provided a sensitivity of 37.8% and a specificity of 80.9%. In the bladder cancer group, NMP22 levels were related to tumor size, shape, grade and stage. CONCLUSIONS: Despite the many reports that suggest NMP22 as a promising urinary marker for monitoring transitional cell carcinoma, this study does not support its usefulness as a substitute tool for urinary cytology in the control of bladder tumors.