Pretreatment of urine samples with SDS improves direct identification of urinary tract pathogens with matrix-assisted laser desorption ionization-time of flight mass spectrometry.

We pretreated with SDS 71 urine samples with bacterial counts of >10(5) CFU/ml and matrix-assisted laser desorption ionization-time of flight (MALDI-TOF) identification scores of <2, in order to minimize failure rates. Identification improved in 46.5% of samples, remained unchanged in 49.3%, and worsened in 4.2%. The improvement was more evident for Gram-negative (54.3%) than for Gram-positive (32%) bacteria.

Mitochondrial genome depletion dysregulates bile acid- and paracetamol-induced expression of the transporters Mdr1, Mrp1 and Mrp4 in liver cells.

BACKGROUND AND PURPOSE: Mitochondria are involved in the toxicity of several compounds, retro-control of gene expression and apoptosis activation. The effect of mitochondrial genome (mtDNA) depletion on changes in ABC transporter protein expression in response to bile acids and paracetamol was investigated. EXPERIMENTAL APPROACH: Hepa 1-6 mouse hepatoma cells with 70% decrease in 16S/18S rRNA ratio (Rho cells) were obtained by long-term treatment with ethidium bromide. KEY RESULTS: Spontaneous apoptosis and reactive oxygen species (ROS) generation were decreased in Rho cells. Following glycochenodeoxycholic acid (GCDCA) or paracetamol, Rho cells generated less ROS and were more resistant to cell death. Apoptosis induced by GCDCA and Fas was also reduced. The basal expression of Mdr1 was significantly enhanced, but this was not further stimulated by GCDCA or paracetamol, as observed in wild-type (WT) cells. Basal expression of Mrp1 and Mrp4 was similar in WT and Rho cells, whereas they were up-regulated only in WT cells after GCDCA or paracetamol, along with the transcription factors Shp and Nrf2, but not Fxr or Pxr. Increased expression of Nrf2 was accompanied by its enhanced nuclear translocation. Glycoursodeoxycholic acid failed to cause any of the effects observed for GCDCA or paracetamol. CONCLUSIONS AND IMPLICATIONS: The Nrf2-mediated pathway is partly independent of ROS production. Nuclear translocation of Nrf2 is insufficient to up-regulate Mdr1, Mrp1 and Mrp4, which requires the participation of other regulatory element(s) whose activation in response to GCDCA and paracetamol is impaired in Rho cells and hence probably sensitive to ROS.

Rapid method for direct identification of bacteria in urine and blood culture samples by matrix-assisted laser desorption ionization time-of-flight mass spectrometry: intact cell vs. extraction method.

Matrix-assisted laser desorption ionization time-of-flight (MALDI-TOF) mass spectrometry (MS) is a fast and reliable technology for the identification of microorganisms with proteomics approaches. Here, we compare an intact cell method and a protein extraction method before application on the MALDI plate for the direct identification of microorganisms in both urine and blood culture samples from clinical microbiology laboratories. The results show that the intact cell method provides excellent results for urine and is a good initial method for blood cultures. The extraction method complements the intact cell method, improving microorganism identification from blood culture. Thus, we consider that MALDI-TOF MS performed directly on urine and blood culture samples, with the protocols that we propose, is a suitable technique for microorganism identification, as compared with the routine methods used in the clinical microbiology laboratory.

Microorganisms direct identification from blood culture by matrix-assisted laser desorption/ionization time-of-flight mass spectrometry.

Matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF MS) allows a fast and reliable bacterial identification from culture plates. Direct analysis of clinical samples may increase its usefulness in samples in which a fast identification of microorganisms can guide empirical treatment, such as blood cultures (BC). Three hundred and thirty BC, reported as positive by the automated BC incubation device, were processed by conventional methods for BC processing, and by a fast method based on direct MALDI-TOF MS. Three hundred and eighteen of them yield growth on culture plates, and 12 were false positive. The MALDI-TOF MS-based method reported that no peaks were found, or the absence of a reliable identification profile, in all these false positive BC. No mixed cultures were found. Among these 318 BC, we isolated 61 Gram-negatives (GN), 239 Gram-positives (GP) and 18 fungi. Microorganism identifications in GN were coincident with conventional identification, at the species level, in 83.3% of BC and, at the genus level, in 96.6%. In GP, identifications were coincident with conventional identification in 31.8% of BC at the species level, and in 64.8% at the genus level. Fungaemia was not reliably detected by MALDI-TOF. In 18 BC positive for Candida species (eight C. albicans, nine C. parapsilosis and one C. tropicalis), no microorganisms were identified at the species level, and only one (5.6%) was detected at the genus level. The results of the present study show that this fast, MALDI-TOF MS-based method allows bacterial identification directly from presumptively positive BC in a short time (<30 min), with a high accuracy, especially when GN bacteria are involved.

Partial androgen deficiency in aging type 2 diabetic men and its relationship to glycemic control.

Aging in the male is associated with both a higher incidence of type 2 diabetes and hypogonadism. However, little information is available about the complex of symptoms and hormonal changes related to partial androgen deficiency in aging (called andropause) in type 2 diabetic men. Here, for the first time, we used a combination of clinical and hormonal criteria to define andropause and to analyze the relationships between the androgen environment and glucose metabolism in 55 type 2 diabetic men (63.6 +/- 7.9 years, mean +/- SD). Low plasma levels of total testosterone (< or =3.4 ng/mL) and free testosterone (< or =11 pg/mL) were found in 20% and 54.5%, respectively, of the diabetic men. The fraction of diabetic men with subnormal levels of total testosterone increased with aging: 14.2% (50 to 59 years), 17.4% (60 to 69 years) and 36% (> 70 years). The corresponding figures for subnormal values of free testosterone were 38%, 69.6%, and 54.5%, respectively. In the whole group of type 2 diabetic men, no significant linear correlations between total or free testosterone with fasting plasma glucose, insulin, C-peptide, or fructosamine values could be established. Total testosterone was positively correlated with glycosylated haemoglobin (HbA(1c)) levels (r =.322, P =.01). Although fasting plasma glucose was marginally higher in aging type 2 diabetic patients with andropause than in those without andropause (162 +/- 6.9 v 139 +/- 8.9, mean +/- SEM, P =.05), there were no differences between both subgroups for plasma fasting insulin, C-peptide, fructosamine, or HbA(1c) levels. Replacement therapy (150 mg intramuscular [IM] of enanthate of testosterone every 14 days for 6 months) was applied in 10 type 2 diabetic men with clinical features of andropause associated with subnormal concentrations of serum testosterone. The treatment induced significant increases in total plasma testosterone (baseline: 3.9 +/- 0.3; at 6 months: 7.1 +/- 0.9 ng/mL, mean +/- SEM, P =.003) and free testosterone (baseline: 9.3 +/- 0.6; at 6 months 17.6 +/- 2.4 pg/mL, P =.003), but had a neutral effect on overall glycemic control. These data show a high prevalence of andropause in aging type 2 diabetic men and suggest that the endogenous androgen environment, as well as correction of the partial androgen deficiency, do not have a meaningful effect on glycemic control.

Biological variation of interleukin-1beta, interleukin-8 and tumor necrosis factor-alpha in serum of healthy individuals.

Components of biological variation can be used to assess the usefulness of reference values, to evaluate the significance of changes in serial results from an individual and to define objective analytical goals. The aim of the study was to assess, in 15 healthy subjects studied at regular monthly intervals over a period of 6 consecutive months, the biological variation of interleukin-1beta (IL-1beta), interleukin-8 (IL-8), and tumor necrosis factor-alpha (TNF-alpha). Biological variation data (within-subject and between-subject coefficient of variation (CV)) were determined using a simple nested analysis of variance. Derived parameters (index of individuality, reliability coefficient and critical diferences) were calculated from within-subject and between-subject CV. The mean and standard deviation (SD), within-subject CV, between-subject CV, index of individuality and reliability coefficient were as follows: for IL-1beta, 0.67 (0.32) pg/ml, 30%, 36%, 0.85, and 0.76; for IL-8, 3.68 (1.45) pg/ml, 24%, 31%, 0.85 and 0.75; and for TNF-alpha, 3.14 (1.87) pg/ml, 43%, 29%, 1.56 and 0.50, respectively. We conclude that between-subject variation and within-subject variation are quite similar for IL-1beta and IL-8 and are relatively high for the three cytokines studied. Index of individuality is less than 1.4 for IL-1beta and IL-8, and thus reference intervals based on population studies are of limited value. On the contrary, the index of individuality for TNF-alpha is greater than 1.4 and reference values can be used for diagnosis. Quality goals for imprecision are easily achieved for the three cytokines with current methodology.

Lack of cross-reactivity of anti-DNA antibodies to ribonucleoproteins in a new commercial blot system for specific ANAs.

Anti-DNA antibodies often exhibit cross-reactivity. It has been observed that anti-DNA antibodies cross-react with A and D snRNP proteins in an in-house developed Western blot assay but do not cross-react with native U1RNP in ELISA or immunoprecipitation experiments. We have analyzed the cross-reactivity of anti-DNA antibodies to snRNP A and D in a recently developed commercial blot assay (InnoLIA, Innogenetics). In our experience anti-DNA antibodies do not cross-react with proteins A and D in this blot system. Hence this new blot system avoids the cross-reactivity problems in the assessment of antinuclear antibody specificity for both Sm and U1snRNP.

Biological variation of interleukin 6 (IL-6) and soluble interleukin 2 receptor (sIL2R) in serum of healthy individuals.

The biological variation of interleukin 6 (IL-6) and soluble interleukin 2 receptor (sIL2R), measured by automated enzyme immunoassay, in fifteen subjects studied at regular monthly intervals over a period of 6 consecutive months was measured. The mean and standard deviation (SD), within-subject CV, between-subject CV, individuality index (II) and reliability coefficient (R) were as follow: for sIL2R 571 (231) U/ml, 5.84%, 38.81%, 0.21 and 0.93; and for IL-6 1.43 (0.9) pg/ml, 48.48%, 39.38%, 1.44, and 0.37. The data indicate a relatively high between-subject CV, quite similar in both cases, and a within-subject CV much higher for IL-6 than for sIL2R. Thus, reference values can be used for diagnosis for IL6 (high II), while not for sIL2R (low II). However, the low R for IL-6 implies that more than one measurement are needed. sIL2R has a very high R and a relatively small critical differences, a circumstance appropriate for follow-up.

Serum zinc, copper, insulin and lipids in Alzheimer's disease epsilon 4 apolipoprotein E allele carriers.

BACKGROUND: Copper (Cu) and zinc (Zn) have been implicated in the development of Alzheimer's disease (AD) and, in this regard, Cu and Zn serum concentrations have been analysed but with inconclusive results. Serum insulin, glucose and cholesterol concentrations have been related to the apolipoprotein E genotype in non-AD populations. DESIGN: In this study, we have analysed the relationship between serum Cu, Zn, insulin, glucose and lipid parameters (cholesterol, triglycerides, apoA and apoB apolipoproteins) in AD and AD epsilon 4 apolipoprotein E carriers by multivariate analysis using logistic regression, including the variables that showed a significance of P < 0.05 in the bivariate analysis. RESULTS: The results obtained show that epsilon 4 apoE allele is an independent AD risk factor (OR = 6. 67, 95% CI = 2.59-17.16). In AD epsilon 4 apoE allele carriers, we found significantly higher Zn, Cu and insulin serum concentrations. Non-demented control subjects with at least one epsilon 4 apoE allele had the lowest serum insulin concentrations. There was no significant association between epsilon 4 apolipoprotein E allele and lipid parameters in the sample studied. CONCLUSIONS: In AD we have found a significant association between higher serum Zn, Cu and insulin concentrations and the presence of an epsilon 4 apoE allele, but only greater serum Zn concentration appears to be an independent risk factor associated with the development of AD.

[Recent-onset headache is a risk factor of intracranial lesion. A prospective study of 299 patients]. / La cefalea de comienzo reciente es un factor de riesgo de lesión intracraneal. Estudio prospectivo de 299 pacientes.

BACKGROUND: There is some controversy in the medical literature concerning the need to perform neuroimaging studies in neurologically normal patients complaining of headaches. The objective of the study is to determine the detection rate of intracranial abnormalities by computed tomography in patients with different headache durations. METHOD: Consecutive patients with the chief complaint of headache referred for neurological evaluation from January 1996 to April 1997 were studied both clinically and by computed tomography scanning. Brain magnetic resonance imaging was performed in 15 patients. Cerebrospinal fluid and/or blood analyses were performed when clinically indicated to rule out subarachnoid hemorrhage, meningitis or temporal arteritis. RESULTS: 15 (5%) out of the 299 patients available for study had significant intracranial lesion. 3 (1%) out of the 266 patients with headaches lasting for more than 1 month had computed tomography findings considered clinically significant and neurological examination was normal in 2 (0.7%) patients with abnormal scans. Patients with a headache duration of 1 month or less had the following case-finding rate: an overall significant intracranial abnormality of 36% (12/33) and significant intracranial abnormality in neurologically normal patients of 15% (5/33). CONCLUSION: Patients with headache of recent onset (duration of 1 month or less), even with normal neurological examination, are at greater risk of significant intracranial abnormality than patients with long-lasting headaches. These patients at risk should be studied by cranial computed tomography and lumbar puncture if the computed tomography scan is normal and the cause of the headaches cannot be clinically determined.

Antiphosphatidylserine antibodies in patients with autoimmune diseases and HIV-infected patients: effects of Tween 20 and relationship with antibodies to beta2-glycoprotein I.

Antiphospholipid antibodies (aPL) react with negatively charged phospholipids, which may often be complexed with a protein cofactor such as beta2 glycoprotein (beta2GPI) and prothrombin. Cofactor requirements may be assessed by measuring antibodies to beta2GPI or by adding Tween 20 to some reagents in the assays for aPL (anticardiolipin and antiphosphatidyIserine). We have measured anticardiolipin antibodies (aCL), antiphosphatidylserine antibodies (aPS), and anti beta2 glycoprotein antibodies (abeta2GPI) in the serum of 10 normal subjects, 20 patients with systemic autoimmune diseases (SAD) diagnosed as having systemic lupus erythematosus (SLE) or antiphospholipid syndrome (APS), and 12 patients with HIV infection. Adding Tween 20 to aPS, the assay couldn't differentiate protein cofactor dependent from independent antibodies, but this can be done by measuring abeta2GPI (P= 0.0008). There was a significant correlation between aCL and a(beta)2GPI in the control group and in the patients with SAD, but not in the HIV-positive (HIV+) patients. After excluding the HIV+ patients, the best Spearman correlation was obtained between a(beta)2GPI and aCL (0.64, P< 0.0005). In 3 out of 7 patients with positive a(beta)2GPI and in 5 out of 6 patients with moderate or high positive aCL of the group of SAD, there was a history of venous thrombosis. The presence of moderate or high values of aCL either alone or together with a(beta)2GPI was significantly associated with a history of venous thrombosis (P < 0.05). Moderate or high aCL concentrations and their association with a(beta)2GPI seems to be useful for the assessment of the risk of venous thrombosis in unselected patients with SLE or APS.

La cefalea de comienzo reciente es un factor de riesgo de lesión intracraneal. Estudio prospectivo de 299 pacientes / Headache of recent onset is a risk factor for intracranial lesion: a prospective study of 299 patients

Fundamento: La necesidad de realizar o no estudios de neuroimagen a los pacientes neurológicamente normales que consultan por cefaleas es un tema controvertido en las publicaciones médicas. El objetivo de este estudio es determinar la proporción de anormalidades intracraneales detectadas mediante tomografia computarizada en pacientes con cefalea de distinta duración. Método: Se estudiaron clínicamente y con tomografia computarizada los pacientes consecutivos enviados para valoración neurológica por cefalea como síntoma fundamental entre Enero 1996 y Abril 1997. Se practicó estudio con resonancia magnética en 15 pacientes. Se realizó análisis de sangre o de líquido cefalorraquídeo cuando se estimó necesario para descartar hemorragia subaracnoidea, meningitis o arteritis de la arteria temporal. Resultados: 15 (5%) de los 299 pacientes disponibles para el estudio tuvieron alguna lesión intracraneal significativa. 3 (1%) de los 266 pacientes con cefalea de más de 1 mes de duración tuvieron lesiones en la tomografia computarizada consideradas clínicamente significativas y en 2 (0,7%) de estos pacientes la exploración neurológica fue normal. Los pacientes con una duración de la cefalea igual o inferior a 1 mes tuvieron la siguiente proporción de hallazgos: Anormalidad intracraneal significativa global en 36% (12/33) y en los pacientes neurológicamente normales la anormalidad intracraneal significativa fue del 15% (5/33). Conclusión: Los pacientes con cefalea de comienzo reciente (duración igual o inferior a 1 mes), incluso con exploración neurológica normal, tienen un riesgo de albergar una lesión intracraneal significativa mayor que los pacientes con cefaleas de larga evolución. A estos pacientes con aumento de riesgo se les debería practicar una tomografia computarizada craneal y una punción lumbar si la tomografia es normal y el origen de la cefalea no se ha aclarado clínicamente (AU)

Utility of a synthetic poly dT band included in a commercial blot assay to detect anti-DNA antibodies.

Systemic lupus erythematosus (SLE) patients exhibit anti-DNA antibodies with a heterogeneous pattern of individual specificity of binding. Likewise, the methods used for the measurement of anti-DNA antibodies exhibit a wide spectrum of binding avidities detection. We have evaluated the clinical utility of a band of synthetic poly dT included as an antigen in a recently commercialized blot system for antinuclear antibodies to detect anti-DNA antibodies. Sera from 45 individuals (36 patients with SLE, 9 without autoimmune disease negative for anti-nDNA by ELISA) were evaluated by the commercial immunoblot assay, ELISA for anti-nDNA, and conventional immunofluorescence using Crithidia lucillae substrate. Kappa statistics were used to determine the agreement between assays. The results obtained show a better agreement between positive bands for poly dT and anti-nDNA antibodies measured by IIF than by ELISA (Kappa index 0.64 vs. 0.44), although there are discrepant results. Likewise, positive bands for poly dT were obtained in patients with active SLE as assessed by decreased serum C3 concentration. We conclude that anti-poly dT reactivity reveals anti-nDNA antibodies of medium-high avidity, which show best disease activity.

Comparison and variation of different methodologies for the detection of autoantibodies to nuclear antigens (ANA).

Interest in the assessment of autoantibody specificity stems from the need for an autoantibody marker capable of predicting clinical events in autoimmune disorders. However, the multiplicity of epitopes present on autoantigenic particles, the quantitative and qualitative heterogeneity of autoantibodies, as well as the nature of the tests, mean that each of the assays used in their determination have different characteristics. The aim of this study was to compare the specificities of different ANAs using four commercial assays. The routine method used for the detection of ANA is indirect immunofluorescence on Hep-2 cells. The assays used were: counterimmunoelectrophoresis (CIE), enzyme-linked immunosorbent assay (ELISA), and two immunoblotting assays. Kappa statistic was applied to evaluate the consistency between tests. Kappa index is a measure of agreement between categorical data. Kappa has a maximum of 1.00 when the agreement is perfect, a value of zero indicates no agreement better than chance, and negative values show worse than chance agreement. For SS-B antibodies, there was a good concordance between all four methods used (Kappa 0.66-0.74). For anti RNP antibodies, the results for CIE/ELISA (Kappa 0.60) were consistent as were the two immunoblot methods (Kappa 0.69). For anti Scl-70 (topoisomerase I) antibody, results from the ELISA and CIE methods were totally consistent (Kappa 1.00). In spite of the high prevalence of anti SS-A/Ro antibodies, the agreement between the methods was poor, without statistical significance. Finally, for Sm antibodies, more consistent results were obtained between CIE/ELISA (Kappa 0.51) and between one of the immunoblotting methods and ELISA (Kappa 0.54). In conclusion, CIE concurs mostly with ELISA for anti-RNP, Scl-70, Sm and SS-B antibodies, but with some disagreement for SS-A antibodies.

[Genotype and phenotype of apolipoprotein E in patients with Alzheimer's disease in Castille and Leon]. / Genotipo y fenotipo de la apolipoproteína E en enfermos de Alzheimer en Castilla y León.

We determined the variants of the apolipoprotein E (apo-E) in a sample taken from a castellano-leonesa population with Alzheimer's disease (AD). The prevalence of the allele E-4 is 0.33 in AD and 0.12 in the control group. This results allow us to estimate that the risk of suffering from the disease is higher when the patients have an allele E-4. A significant correlation was found between the presence of the allele E4 and the AD (p < 0.005).

Fuel utilization by early newborn brain is preserved under congenital hypothyroidism in the rat.

Mental retardation associated with hypothyroidism may be caused by impairment of brain ketone body-metabolizing enzymes during the suckling period. However, much evidence suggests that, immediately after delivery, lactate, instead of ketone bodies or glucose, may be the best substrate for the brain. In this work, we have studied the effect of experimentally induced congenital hypothyroidism on the rate of lactate, glucose, and 3-hydroxybutyrate utilization in early neonatal brain slices. Methimazole (MMI) administration to the mothers caused a 5.4- and 1.7-fold decrease in neonatal plasma concentrations of L-thyroxine (T4) and 3,5,3'-triiodo-L-thyronine (T3), respectively. Propylthiouracil (PTU) administration to the mothers caused a 7.3- and > 2-fold decrease in plasma T4 and T3 concentrations, respectively. MMI-induced hypothyroidism did not significantly modify the rate of lactate, glucose, or 3-hydroxybutyrate oxidation to CO2 and their incorporation into lipids by the neonatal brain. However, PTU-induced hypothyroidism decreased the rate of lactate and glucose oxidation to CO2 and their incorporation into lipids by 17% (p < 0.05). 3-Hydroxybutyrate utilization was not modified by this treatment. Separation by HPLC of the lipids revealed that PTU-mediated inhibition of lipid synthesis from lactate and glucose may be accounted for by specific inhibition of the rate of sterol synthesis (15%, p < 0.05), whereas the rate of phospholipid synthesis was unaffected. These results suggest that the early newborn may develop mechanisms aimed at avoiding the possible brain damage caused by the inhibition of lipid synthesis brought about by mild neonatal hypothyroidism.

Hydrolytic enzyme of the alveolar macrophage in diffuse pulmonary interstitial disease.

Hydrolytic enzymes [acid phosphatase, beta-glucuronidase, beta-D-N-acetyl glucosaminidase (beta-D-NAGA), lysozyme and angiotensin-converting enzyme (ACE)] are the major constituents of alveolar macrophages (AM). These enzymes play a crucial role in the pathogenesis of interstitial lung diseases. Cell-associated activity of several enzymes in alveolar macrophages obtained from control subjects (n = 5) and patients suffering five representative types of interstitial pulmonary diseases [sarcoidosis (n = 10), extrinsic allergic alveolitis (n = 5), idiopathic pulmonary fibrosis (n = 5), neoplastic infiltration of the lung (n = 5) and Pneumocystis carinii pneumonia (n = 5)] were evaluated. Cells were obtained by bronchoalveolar lavage and isolated by Ficoll-Hypaque gradient. Enzymatic activity was assessed by standardized tests. Bronchoalveolar lavage (BAL) lymphocyte counts were significantly elevated in the patients with active sarcoidosis (median: 57%), allergic extrinsic alveolitis (median: 51%) and neoplastic infiltration (median: 31%) as compared with the other groups, whereas BAL neutrophil and eosinophil counts were significantly elevated in the patients with idiopathic pulmonary fibrosis (neutrophil median: 29%; eosinophil median: 3%). The highest alveolar macrophage enzymatic activities were obtained in the active sarcoidosis group (median ACE: 23.38 microKat 10(-6) AM; median lysozyme: 8.64 nKat 10(-6) AM; median beta-glucuronidase: 324.22 U 10(-6) AM; median acid phosphatase: 0.78 nKat 10(-6) AM; median beta-D-NAGA: 1.85 nKat 10(-6) AM) which was significantly greater than in the control group (median ACE: 6.69 microKat 10(-6) AM; median lysozyme: 1.95 nKat 10(-6) AM; median beta-glucuronidase: 39.88 U 10(-6) AM; median acid phosphatase: 0.38 nKat 10(-6) AM; median beta-D-NAGA: 0.44 nKat 10(-6) AM). However, intracellular lysosomal enzymatic activities of alveolar macrophages from patients with allergic extrinsic alveolitis, a disease in which the degree of alveolar macrophage activation is maximal, were similar to those of the control group. These findings demonstrated a different pattern of expression of alveolar macrophage's hydrolytic enzymes in lymphocytic diffuse pulmonary interstitial disease. In sarcoidotic patients, hydrolytic enzymes were increased whereas in allergic extrinsic alveolitis, hydrolytic enzyme activities were similar to control groups. Indirect data suggest that the release of lysosomal enzymes by alveolar macrophages during allergic extrinsic alveolitis may be a factor involved in the pulmonary lesions appearing in this disease.

Reversal of cyclosporine A-induced alterations in biliary secretion by S-adenosyl-L-methionine in rats.

This study examines the ability of S-adenosyl-L-methionine to prevent or antagonize the cyclosporine A-induced adverse effects on biliary secretion in the rat. S-adenosyl-L-methionine was administered as a single bolus 3, 5 and 8 hr before administering a single dose of cyclosporine A, and also concurrently administered with cyclosporine A for 1 or 2 wk. Acute S-adenosyl-L-methionine preadministration attenuated the cyclosporine-induced cholestasis and inhibition of bile acids, cholesterol and phospholipid biliary secretion. S-adenosyl-L-methionine pretreatment for 1 wk and simultaneous cotreatment with cyclosporine for 1 or 2 wk not only maintained the beneficial effects reported above but further improved them because the adverse effects of the immunosuppressor drug were prevented or antagonized by S-adenosyl-L-methionine. These results provide the first direct evidence of the ability of exogenously administered S-adenosyl-L-methionine to antagonize cyclosporine-induced abnormalities in biliary bile acids, lipids and protein secretion. The beneficial effects of S-adenosyl-L-methionine could be related, at least in part, to the improvement in the hepatobiliary transport of bile acids.