Leydig cell tumors of the testis with unusual features: adipose differentiation,calcification with ossification,and spindle-shaped tumor cells

We report 19 Leydig cell tumors (LCTs) of the testis with adipose differentiation (n = 12) and/or spindle cell growth (n = 8) in patients 28-70 years of age; three tumors with adipose differentiation showed psammomatous calcifications, two of which also had foci of ossification. In eight tumors fat-like cells apparently derived from lipid accumulation within neoplastic Leydig cells and appeared as focal to prominent clusters in a background of vacuolated, neoplastic Leydig cells. The fat-like cells were usually immunoreactive for Leydig cell markers (inhibin-alpha, calretinin, and melan-A) but were typically strongly positive for the adipose tissue marker, S-100 protein, supporting a hybrid cell phenotype. Four tumors had fat of stromal derivation. In two of these there were intermixed mature adipocytes, but in two others only lipoblastic cells were present. These four tumors lacked vacuolated, neoplastic Leydig cells, and the fat cells in the single case studied were negative for inhibin-alpha and melan-A but positive for S-100. Three of the 12 LCTs with adipose differentiation were clinically malignant, and each had several of the established malignant features. Eight tumors with spindle cells occurred in men 34-70 years of age. Two tumors had ill-defined fascicles of spindle cells, and three showed prominent edematous to myxoid areas with spindle-shaped tumor cells. Two additional tumors had a fibroma-like spindled component that blended with islands of more plump, polygonal to spindle-shaped Leydig cells. Finally, one tumor had foci resembling an unclassified sarcoma that merged with conventional LCT; the spindle cell component in this case did not react for Leydig cell markers in contrast to the spindle cells in five of the six other cases in which immunostains were performed. Spindle cell differentiation, by itself, did not appear to have prognostic significance. Of the six patients with available follow-up, two developed metastases, but their tumors had malignant features apart from spindle cells; the remaining four patients were disease free at a mean of 3.6 years. Awareness of these unusual patterns in LCTs may prevent misinterpretation of fat admixed with neoplastic Leydig cells as evidence of extratesticular growth (a criterion for malignant LCT) may help avoid misdiagnosis of a LCT as a testicular "tumor" of the adrenogenital syndrome (which may contain fat) and may prevent misdiagnosis of a LCT with spindle cells as a sarcoma or unclassified sex cord-stromal tumor.     

Paraoxonase 1 Q192R (PON1-192) polymorphism is associated with reduced lipid peroxidation in R-allele-carrier but not in QQ homozygous elderly subjects on a tomato-rich diet

Summary. Background: The oxidative modification of LDL is considered to play a central role in the pathogenesis of atherosclerosis and coronary heart disease (CHD). Paraoxonase (PON1) protects LDL from oxidation and may therefore retard the developement of atherosclerosis. The PON1–192 polymorphism is associated with diminished PON1 concentrations and an increased risk for CHD in RR-allele subjects. Aim of the study: To investigate the effect of tomato juice consumption on PON1 activity and other parameters related to oxidative stress in healthy elderly subjects. Furthermore, the PON1–192 genotype has been determined in the volunteers in order to see whether possible treatment effects are related to the PON1–192 polymorphism. Methods: Fifty elderly subjects were randomly assigned to control (mineral water) or intervention group (tomato juice). Subjects of the tomato juice group consumed daily 330 mL tomato juice for 8 weeks. Antioxidant status was measured as LDL oxidation, plasma malondialdehyde, ferric reducing ability of plasma (FRAP) and PON1 activity. The PON1–192 polymorphism was determined by restriction fragment length polymorphism polymerase chain reaction (RFLP-PCR). Plasma carotenoids were analyzed by HPLC. Results: Tomato juice consumption reduced LDL-oxidation and improved antioxidant status in R-allele carriers, but not in the QQ genotype group. PON1 activity increased irrespective of the genotype in both, control and intervention group. Conclusions: The changes in antioxidant status after tomato juice consumption seem to depend on the PON1–192 genotype. Healthy elderly, carrying the R-allele, could specificly reduce their higher cardiovascular risk by changing dietary habits. Received: 9 October 2002, Accepted: 28 October 2002 Correspondence to: Achim Bub     

Feature selection for structure-activity correlation using binary particle swarms

We present a new feature selection algorithm for structure-activity and structure-property correlation based on particle swarms. Particle swarms explore the search space through a population of individuals that adapt by returning stochastically toward previously successful regions, influenced by the success of their neighbors. This method, which was originally intended for searching multidimensional continuous spaces, is adapted to the problem of feature selection by viewing the location vectors of the particles as probabilities and employing roulette wheel selection to construct candidate subsets. The algorithm is applied in the construction of parsimonious quantitative structure-activity relationship (QSAR) models based on feed-forward neural networks and is tested on three classical data sets from the QSAR literature. It is shown that the method compares favorably with simulated annealing and is able to identify a better and more diverse set of solutions given the same amount of simulation time.     

A peroxyoxalate chemiluminescence-based assay for the evaluation of hydrogen peroxide scavenging activity employing 9,10-diphenylanthracene as the fluorophore

INTRODUCTION: A simple, rapid, sensitive, and enzyme-free analytical method for estimating scavenging of hydrogen peroxide (H2O2) was developed. METHODS: Peroxyoxalate chemiluminescence (POCL) was measured, using 9,10-diphenylanthracene as fluorophore. RESULTS: The chemiluminescence signal was found to be linear in response to increasing amounts of H2O2 in ethyl acetate/acetonitrile (9:1) (r2 = .9990), within a range of concentrations varying from 9.0 to 72.0 microM. In contrast, acetonitrile was highly unsuitable because of poor linearity (r2 = .3736) and poor signal stability. The linearity of POCL inhibition, as a measure of H2O2 scavenging, was tested employing well-known, lipid-soluble antioxidants, including beta-carotene, butylated hydroxytoluene (BHT) and alpha-tocopherol, and also the more polar flavonol quercetin, and the water-soluble L-ascorbic acid (AA). Under the experimental conditions, the corresponding values of H2O2 scavenging activity (SA(HP)) for quercetin, beta-carotene, alpha-tocopherol, and L-AA were 19.1 +/- 0.4, 70.9 +/- 20.1, 8.4 +/- 0.4, and 44.8 +/- 5.6 x 10(-3) microM(-1) DISCUSSION: The data establish the assay as a method for assessing the H2O2 quenching activity of lipid-soluble antioxidants.     

Roles of the two active sites of somatic angiotensin-converting enzyme in the cleavage of angiotensin I and bradykinin: insights from selective inhibitors

Somatic angiotensin-converting enzyme (ACE) contains two homologous domains, each bearing a functional active site. The in vivo contribution of each active site to the release of angiotensin II (Ang II) and the inactivation of bradykinin (BK) is still unknown. To gain insights into the functional roles of these two active sites, the in vitro and in vivo effects of compounds able to selectively inhibit only one active site of ACE were determined, using radiolabeled Ang I or BK, as physiological substrates of ACE. In vitro studies indicated that a full inhibition of the Ang I and BK cleavage requires a blockade of the two ACE active sites. In contrast, in vivo experiments in mice demonstrated that the selective inhibition of either the N-domain or the C-domain of ACE by these inhibitors prevents the conversion of Ang I to Ang II, while BK protection requires the inhibition of the two ACE active sites. Thus, in vivo, the cleavage of Ang I and BK by ACE appears to obey to different mechanisms. Remarkably, in vivo the conversion of Ang I seems to involve the two active sites of ACE, free of inhibitor. Based on these findings, it might be suggested that the gene duplication of ACE in vertebrates may represent a means for regulating the cleavage of Ang I differently from that of BK.     

The diagnostic validity of the Athens Insomnia Scale

OBJECTIVE: To provide documentation for the diagnostic validity of the Athens Insomnia Scale (AIS), a self-assessment psychometric tool which has previously shown high consistency, reliability and external validity for the evaluation of the intensity of sleep difficulty. METHODS: The AIS was administered to a total of 299 subjects (105 primary insomniacs, 100 psychiatric outpatients, 44 psychiatric inpatients and 50 nonpatient controls) who were also assessed for the ICD-10 diagnosis of "nonorganic insomnia" blindly in terms of the AIS scores. RESULTS: 176 subjects were identified as insomniacs and 123 as noninsomniacs. Logistic regression of AIS total score against the ICD-10 diagnosis of insomnia demonstrated that a score of 6 is the optimum cutoff based on the balance between sensitivity and specificity. When diagnosing individuals with a score of 6 or higher as insomniacs, the scale presents with 93% sensitivity and 85% specificity (90% overall correct case identification). For this cutoff score, in the general population, the scale has a positive predictive value (PPV) of 41% and a negative predictive value (NPV) of 99%. For the same cutoff score, among unselected psychiatric patients, the PPV was found to be 86% and the NPV 92%. Other cutoff scores can be also considered, however, depending on the importance of avoiding false positive or false negative results; for example, for a cutoff score of 10, the PPV in the general population reaches about 90% without the NPV becoming lower than 94%. CONCLUSION: The AIS can be utilized in clinical practice and research, not only as an instrument to measure the intensity of sleep-related problems, but also as a screening tool in reliably establishing the diagnosis of insomnia.     

Total and corrected antioxidant capacity in hemodialyzed patients

Background  

Oxidative stress may play a critical role in the vascular disease of end stage renal failure and hemodialysis patients. Studies, analyzing either discrete analytes and antioxidant substances, or the integrated total antioxidant activity of human plasma during hemodialysis, give contradictory results.     

Clinical presentation of the "depression-executive dysfunction syndrome" of late life.

It has been proposed that a "depression-executive dysfunction (DED) syndrome" occurs in late life. This assertion was based on clinical, neuropathological, and neuroimaging findings suggesting that frontostriatal dysfunctions contribute to the development of both depression and executive dysfunction and influence the course of depression. The authors describe the clinical presentation of DED and its relationship to disability, studying 126 elderly subjects with major depression and evaluating depressive symptoms, cognitive functioning, disability, and personality dimensions. Patients with the DED syndrome had reduced fluency, impaired visual naming, paranoia, loss of interest in activities, and psychomotor retardation, but showed a rather mild vegetative syndrome. Depressive symptomatology, and especially psychomotor retardation and loss of interest in activities, contributed to disability in DED patients, whereas paranoia was associated with disability independently of executive dysfunction. These findings may aid clinicians in identifying patients needing vigilant follow-up, because depression with executive dysfunction was found to be associated with disability, poor treatment response, relapse, and recurrence.     

A dose-escalation study of irinotecan (CPT-11) in combination with gemcitabine in patients with advanced non-small cell lung cancer previously treated with a cisplatin-based front line chemotherapy

PURPOSE: CPT-11 and gemcitabine are both active agents against non-small cell lung cancer (NSCLC). We conducted a phase I study to determine the maximum-tolerated dose (MTD) and the dose-limiting toxicities (DLTs) of their combination in patients with previously treated advanced NSCLC. PATIENTS AND METHODS: Twenty-seven patients with histologically confirmed NSCLC, who had failed cisplatin-based front-line chemotherapy, were enrolled. The patients' median age was 56 years, 24 were male and 22 had a performance status (WHO) 0-1. Gemcitabine was administered on days 1 and 8, as a 30-minute i.v. infusion, at escalated doses ranging from 900 to 1200 mg/m2. CPT-11 was given over a 60-minute i.v. infusion on day 8 at escalated doses ranging from 200 to 350 mg/m2, following gemcitabine administration. The treatment was repeated every three weeks. RESULTS: The MTD was exceeded at dose-level 7 with CPT-11 350 mg/m2 and gemcitabine 1200 mg/m2, where all three enrolled patients presented DLTs (one patient grade 4 thrombocytopenia, one grade 3 diarrhea and one grade 3 asthenia). The recommended doses for future phase II studies are CPT-11 300 mg/m2 on day 8 and gemcitabine 1200 mg/m2 on days 1 and 8. A total of 107 treatment cycles were administered. Grade 3/4 neutropenia was observed in 13 (13%) cycles, febrile neutropenia in 3 (3%) and grade 3/4 thrombocytopenia in 2 (2%). Grade 2/3 diarrhea was seen in 6 (6%) cycles, grade 2/3 nausea and vomiting in 13 (13%) and grade 2/3 asthenia in 8 (8%). Other toxicities were mild. Among 23 patients evaluable for response, PR was achieved in one (4.5%), SD in 12 (52.5%) and PD in 10 (43%). CONCLUSION: The results of this phase I study clearly demonstrate that gemcitabine and CPT-11 can be efficiently combined in a low-toxicity regimen with doses equal or near monotherapy levels. Further studies are needed to evaluate the efficacy of this combination in both chemotherapy-naive and pre-treated patients with advanced NSCLC.