Binding potency of paroxetine analogues for the 5-hydroxytryptamine uptake complex.

The in-vitro inhibition constants (Ki) of 14 structural analogues of the potent 5-hydroxytryptamine (5-HT)-uptake inhibitor paroxetine were determined to assess the structure-affinity relationship of these derivatives. A goal of these studies was to determine those positions on paroxetine which could be derivatized without significantly decreasing the affinity of the drug for the binding site, so that radiolabels such as [18F]fluoroalkyl groups might be appended for future in-vivo imaging studies of the 5-HT uptake system. Using the methyl moiety as a steric probe for these studies, it was found that the rank order of potency of various methyl-substituted paroxetine analogues for inhibiting the binding of [3H]paroxetine to the 5-HT re-uptake site was: 4'-approximately equal to 3'-approximately equal to 2'- > 2'-approximately equal to 1- > 5'- > 6'-methyl. The in-vitro equipotent molar ratios (EPMR, Ki(analogue)/Ki(paroxetine)) of the analogues were determined, and the EPMRs of the 4'-, 3'-, and 2'-methyl derivatives were 1.9, 2.2 and 2.2, respectively. The 4'- and 2'-fluoromethyl and -fluoroethyl analogues were synthesized, and the EPMRs of the 4'- and 2'-fluoromethyl derivatives were determined to be 2.0 and 3.5, and those of the 4'- and 2'-fluoroethyl analogues were 5.2 and 6.2, respectively. The 2'-fluoromethyl analogue was unstable in aqueous solutions, and it is not a promising ligand for in-vivo studies.(ABSTRACT TRUNCATED AT 250 WORDS)     

Circulating prostate specific antigen-positive cells correlate with metastatic prostate cancer.

Analytical flow cytometry was used to study circulating prostate specific antigen (PSA)-positive cells in 40 consecutive patients with newly diagnosed, untreated prostate cancer; 25 patients (63%) had metastatic disease confirmed by a positive bone scan. Cell suspensions were prepared for each patient from both the primary tumour and peripheral blood samples. The cells were stained with a monoclonal antibody against PSA, and analysed by flow cytometry; PSA-positive cells were sorted according to their immunofluorescence and light scatter properties. The cellular deoxyribonucleic acid (DNA) content of each specimen was also analysed to establish ploidy status. PSA-positive cells were detected in the peripheral blood of 33 patients (83%). The presence of these cells in the circulation showed a higher degree of sensitivity and specificity in predicting positive bone scans than did serum PSA levels. Circulating PSA-positive cells may represent either a subpopulation of tumour cells with distinct metastatic properties or, alternatively, host immunocytes which take up PSA in an active or passive manner.     

Relationship between oxidative stress and embryotoxicity of hydrosalpingeal fluid

BACKGROUND: Oxidative stress mechanisms are involved in the pathophysiology of many reproductive disorders. The objective of this study was to characterize oxidative stress parameters in hydrosalpingeal fluid (HSF) and examine their possible role in early embryo development. METHODS AND RESULTS: HSF was aspirated at laparoscopic salpingectomy in 11 infertile women. Reactive oxygen species (ROS), total (non-enzymatic) antioxidant capacity (TAC) and lipid peroxidation (LPO) were assayed. Two-cell mouse embryos were incubated with 25, 50 or 75% HSF and the blastocyst development rate was observed. ROS was detected in five of 11 (45%) HSF samples with a mean of 4.2 x 10(4) c.p.m. LPO was detected in all samples at a mean (+/- SD) value of 5575.4 +/- 6091.9 micromol/l malonaldehyde. The mean blastocyst development rate at 25, 5+/- 0 and 75% HSF and in the control group was 88.9 +/- 9.4, 65.7 +/- 19.1, 45.7 +/- 5.7 and 96.7% respectively (P < 0.0001). The blastocyst development rate was positively correlated to ROS concentrations (P < 0.02) but was not significantly related to LPO. CONCLUSIONS: The blastocyst development rate decreased with increasing concentrations of HSF. For the first time, the presence of ROS, LPO and TAC activity in human HSF was characterized. A possible role of oxidative stress in the embryotoxicity of HSF is suggested.     

Plasma Free Fatty Acids and Metabolic Effect in Type 2 Diabetes,an Ancillary Study from a Randomized Clinical Trial

Most nutrition studies looking at the association of food with cardiometabolic markers rely on food frequency questionnaires, which are prone to recall bias. Pentadecanoic acid, heptadecanoic acid and trans-palmitoleic acid are fatty acids that are not synthesized endogenously but are obtained from the diet, particularly dairy, making them reasonable biomarkers of dairy consumption. We investigated the association of dairy fatty acid biomarkers with glycated hemoglobin (HbA1c) and cardiovascular risk factors in type 2 diabetes (T2D). In a clinical trial, 111 participants with T2D (age 58.5 ± 8.9 years, HbA1c 8.09 ± 0.96%) were randomized into three groups: a control group that maintained baseline dairy intake, a low-fat (LF) group that incorporated ≥3 servings/day of LF dairy and a high-fat (HF) group that incorporated ≥3 servings/day of HF dairy. We compared the fatty acids (FA) composition between the three groups at 24 weeks. Pentadecanoic acid and trans-palmitoleic acid increased in the HF group by 14.1% ± 5.4% and 17.5% ± 5.1%, respectively, but not in the control and LF groups (p = 0.0474 and p = 0.0025 for group-by-time interaction, respectively). Those increases were positively associated with changes in total cholesterol, very-low-density lipoprotein cholesterol VLDL-C and triglycerides but were not associated with changes in HbA1c from baseline to 24 weeks. These results suggest that the intervention was successful and that participants were likely compliant, which supports the validity of the main trial.     

Molecular characterization of scl rearrangements in T-cell all from India and egypt

SCL gene rearrangement is the most common molecular lesion (25%) identified so far in T-cell acute lymphoblastic leukemia (T-ALL). Since the frequency of T-ALL appears to be relatively higher in developing countries, we wished to determine as to what fraction of T-ALL from this population harbor SCL rearrangements. We show in this study that although the overall frequency of SCL/SIL rearrangements in T-ALL is similar to the Western countries this is at the expense of increased type A rearrangements. Whether the paucity of type B rearrangements reflects a difference in disease etiology in this part of the world is to be determined.     

Leukemic reticuloendotheliosis: polyclonal surface immunoglobulin on "hairy" cells.

The cytochemistry, surface markers and functional properties of purified mononuclear cells obtained from the peripheral blood and spleen of a patient with leukemic reticuloendotheliosis were studied. Nonspecific esterase activity, a monocyte marker, was demonstrable in 83% of the peripheral blood mononuclear cells and 84% of the splenic mononuclear cells. Rosetting techniques failed to detect T or B lymphocyte surface markers on the majority of the cells. Direct immunofluorescence revealed capped, noncytophilic surface immunoglobulin on the cells with all immunoglobulin classes being detectable. Since noncapping conditions ahd been used during immunofluorescence staining, the observed caps were attributed to in vivo binding of autoantibodies to the "hairy" cells. This conclusion was supported by the demonstration of susceptibility of the "hairy" cells to lysis mediated by normal allogeneic lymphocytes. It is postulated that the "hairy" cells in this patient are leukemic monocytes which bear autoantibodies directed against leukemia associated antigens.     

Neural network analysis of combined conventional and experimental prognostic markers in prostate cancer: a pilot study.

Prostate cancer is the second most common malignancy in men in the UK. The disease is unpredictable in its behaviour and, at present, no single investigative method allows clinicians to differentiate between tumours that will progress and those that will remain quiescent. There is an increasing need for novel means to predict prognosis and outcome of the disease. The aim of this study was to assess the value of artificial neural networks in predicting outcome in prostate cancer in comparison with statistical methods, using a combination of conventional and experimental biological markers. Forty-one patients with different stages and grades of prostate cancer undergoing a variety of treatments were analysed. Artificial neural networks were used as follows: eight input neurons consisting of six conventional factors (age, stage, bone scan findings, grade, serum PSA, treatment) and two experimental markers (immunostaining for bcl-2 and p53, which are both apoptosis-regulating genes). Twenty-one patients were used for training and 20 for testing. A total of 80% of the patients were correctly classified regarding outcome using the combination of factors. When both bcl-2 and p53 immunoreactivity were excluded from the analysis, correct prediction of the outcome was achieved in only 60% of the patients (P = 0.0032). This study was able to demonstrate the value of artificial neural networks in the analysis of prognostic markers in prostate cancer. In addition, the potential for using this technology to evaluate novel markers is highlighted. Further large-scale analyses are required to incorporate this methodology into routine clinical practice.