CYP17 and CYP19 genetic polymorphisms in endometrial cancer: association with intratumoral aromatase activity

Excessive estrogenic influence is known to be associated with initiation/promotion of endometrial cancer (EC). Allelic polymorphisms of the genes involved in steroidogenesis/steroid metabolism may contribute to EC susceptibility. It is important to know endocrine mechanisms by which such susceptibility is acquired. Here, we compared CYP19 (aromatase) and CYP17 (17alpha-hydroxylase/17,20-lyase) gene polymorphisms correspondingly in 136 and 165 EC patients and in 116 and 188 non-affected women primarily of postmenopausal age. In these expanded studies we confirmed our previous observations that genotypes with longest alleles of CYP19 (A6 or A7) are over-represented (64.7+/-4.0 vs. 49.1+/-4.6%, P = 0.04, and 11.0+/-2.7 vs. 1.7+/-1.2%, P = 0.01)) and A2/A2 CYP17 genotype is under-represented (12.1+/-2.5 vs. 25.0+/-3.2%, P = 0.001) in patients as compared to controls. Additionally, aromatase activity was studied by tritiated water release assay in tumor tissues of 32 EC patients. In carriers of A2/A2 CYP17 genotype this activity was significantly lower than in carriers of A1/A1 genotype or in combined group of A1/A1 and A1/A2 CYP17 carriers (P = 0.04 in both cases). On the other side, intratumoral aromatase activity demonstrated tendency to higher values in carriers of longest CYP19 alleles (A6A6 and A6A7) than in carriers of all other CYP19 allele variants (P = 0.066). Thus, specific set of genetic polymorphisms (carrying of CYP17 A1 allele and combination of longest A6 or A7 CYP19 alleles) may predispose to the induction of higher rate of local estrogen biosynthesis in malignant endometrium, that in its turn may support growth of the latter. Further studies are warranted to connect revealed regularities with the type I or II of EC.     

Deficits in the evolution of hand preshaping in Parkinson's disease

Parkinson's disease (PD) results in various types of motor impairments including bradykinesia, tremor and rigidity. Recent research has implicated more fundamental processes at the source of the observed motor deficits. Among these, problems in the sequencing and/or timing of complex movements and in the execution of internally-guided tasks. Furthermore, PD patients exhibit procedural learning deficits which may complicate the interpretation of experimental results of studies involving novel sensorimotor tasks. The reach-to-grasp movement is a complex, overlearned sensorimotor task consisting of two semi-independent components, a relatively simple reach or transport phase and a more complex manipulation or prehension phase. In the present study, we used a novel technique in order to study the evolution of hand preshaping during the reach-to-grasp movement of PD patients and age-matched controls to objects of different shapes in three different spatial locations. Our results indicate that while PD patients are able to specify movement direction as well as controls, their hand preshaping exhibits substantial impairments. Other prehension measures, such as the time to peak aperture (TPA), indicate that PD patients delayed execution of the grasp until visual feedback of their hand was available. Overall, our results suggest that PD patients' internal guidance processes are severely disrupted, having to rely on visual feedback in order to modulate their hand shape to fit the contours of the target objects during a reach-to-grasp movement.     

Evaluation of humoral response to tumor antigens using recombinant expression-based serological mini-arrays (SMARTA)

Screening of expression cDNA libraries derived from human neoplasms with autologous sera (SEREX) is an established method for defining antigens immunogenic in individual cancer patients. Although the majority of SEREX-derived cDNA clones encode autoantigens, some of them represent shared cancer antigens with cancer-related serological profiles. Routine evaluation of multiple SEREX-derived clones in serological assays using panels of allogeneic sera from cancer patients is an important step towards defining disease parameters of diagnostic and prognostic significance. Here we show how the seroreactivity of multiple SEREX-derived antigens can be simultaneously evaluated using a rapid semi-quantitative protocol of allogeneic screening, which we call SMARTA (serological mini-arrays of recombinant tumor antigens).     

Pregnancy, delivery and puerperium in patients after liver transplantation

We report two cases of successful pregnancies in women after liver transplantation for end-stage liver dysfunction caused in one case by Wilson disease and in the second one by lupoid hepatitis. For woman with the Wilson disease it was a second pregnancy and for woman with lupoid hepatitis it was the first pregnancy. Mothers continued immunosuppressive therapy during their pregnancies. Labours started spontaneously at 39th and 36th week's of gestation. As a result the healthy two female infants weighing 3600 g and 2420 g respectively were born. The first woman with her baby was discharged from hospital on the third day after delivery and the second one and her baby on the sixth day after delivery. Both were in good condition.     

Effect of exercise to exhaustion on myeloperoxidase and lysozyme release from blood neutrophils

Exercise sessions (swimming in rats and treadmill running in humans) resulted in stimulation of neutrophil degranulation in the experiments with animals and in the human study. Myeloperoxidase (MPO) (+67%) and lysozyme (+51%) quantities in the plasma of rats increased significantly immediately after exercise. The blood plasma lysozyme concentration was increased by 41% at the 6th min of treadmill exercise in athletes. The blood concentrations of neutrophil proteins normalized both in humans and animals at rest. The neutrophil protein concentrations in blood increased in parallel with the decrease of their level in leukocytes. The neutrophil capacity for an oxidative burst was not changed by the exercise, but decreased for 3–6 h in the post-exercise period. Such dynamics of the oxidative burst activity suggest a lack of association between this parameter and the degranulation process. The neutrophil proteins that appear in blood during degranulation can be involved in enhancing the bactericidal potency of blood, the activation of granulopoiesis, neutrophil efflux from bone marrow, and the conditioning of blood endothelium for leukocyte extravasation. Electronic Publication     

Inter-bouton variability of synaptic strength correlates with heterogeneity of presynaptic Ca(2+) signals

The elevation of presynaptic calcium concentration is a crucial step in excitation-secretion coupling. However, the amplitudes of action-potential-induced presynaptic calcium transients can display high variability among different terminals. The aim of this study was to clarify whether, at individual boutons, synaptic strength correlates with the average amplitude of presynaptic calcium transients. Low-density collicular cultures were loaded with the calcium indicator Oregon Green bis-(o-aminophenoxy)-N,N,N',N'-tetraacetic acid (BAPTA) 1. Action potentials were blocked with tetrodotoxin. Presynaptic terminals were identified with FM4-64, a use-dependent vesicle marker. Presynaptic calcium influx was elicited by a focal electrical stimulation of single boutons. Whole cell patch-clamp and calcium imaging techniques were used to record GABAergic evoked inhibitory postsynaptic currents (eIPSCs) and presynaptic fluorescence changes in the stimulated terminal. To make the eIPSCs from different boutons comparable, they were normalized to the mean value of miniature IPSCs (mIPSCs) of the postsynaptic cell. Records from 47 boutons showed that eIPSCs varied between 0.5 and 3.0 and presynaptic calcium transients varied between 0.1 and 1.3. However, there was a strong correlation between the mean amplitudes of eIPSCs and presynaptic calcium responses. The eIPSC-[Ca(2+)](pre) relationship allows to use the amplitudes of presynaptic calcium transients as an indicator of release efficacy and, in a set of contacts made by one axon, to predict the relative impact of individual terminals.     

Association of lipoprotein(a) excess with early vein graft occlusions in middle-aged men undergoing coronary artery bypass surgery

OBJECTIVE: To assess the relationship of lipoprotein(a) to early vein graft occlusions in patients after coronary artery bypass grafting. METHODS: We studied 102 male patients (mean age 52.3 +/- 8.6 years) with chest pain occurrence during the first year (mean time 5.3 +/- 3.0 months) after surgical myocardial revascularization. Graft patency was examined by electron-beam computed tomography (n = 102) and quantitative coronary angiography (n = 31). RESULTS: Patients were divided into 2 groups according to graft patency data: 66 (65%) with occlusions and 36 (35%) without occlusions at follow-up. No significant differences were found between the groups concerning age, smoking, family history of coronary heart disease, previous myocardial infarction, hypertension, serum lipids, and apolipoprotein B. Lipoprotein(a) level was significantly higher in patients with occluded grafts with a median (95% confidence intervals) of 24 mg/dL (17-42 mg/dL) versus 12 mg/dL (6-24 mg/dL) in patients with patent grafts, P <.01. More patients with nonoccluded grafts were taking statins postoperatively: 42% versus 18% of patients with occluded grafts, P <.05. The sensitivity and specificity of electron-beam computed tomography in revealing vein graft occlusion was close to 100%. CONCLUSION: There is an association between high lipoprotein(a) level and vein graft occlusions in middle-aged men during the first year after coronary artery bypass grafting. Use of statins is associated with a lower rate of vein graft occlusion. Electron-beam tomography could be useful for assessing graft occlusions.     

Correlation of regenerable opsin with rod ERG signal in Rpe65-/- mice during development and aging

PURPOSE: RPE65 has been shown to be essential for the production of 11-cis retinal by the retinal pigment epithelium. Mutations in RPE65 are known to be associated with severe forms of early-onset retinal dystrophy. This project was designed to determine the amount of regenerable opsin in Rpe65-/- mice during development and aging, and to examine the function of this rhodopsin by electroretinography (ERG). METHODS: Young and aged Rpe65-/- and wild-type (WT) mice were dark adapted. Endogenous rhodopsin and regenerable opsin were measured using absorption-difference spectrophotometry. Photoreceptor function was assessed with scotopic single-flash ERGs and photoreceptors were counted in histologic sections. Opsin's primary structure was analyzed by mass-spectrometric mapping. RESULTS: Unlike WT mice, amounts of regenerable opsin in Rpe65-/- mice decreased significantly with age, which correlated with a decrease in the number of photoreceptors and a decline in ERG amplitudes. Opsin structure, however, did not change. No endogenous levels of rhodopsin were measurable in the Rpe65-/- mice (detection limit: 0.225 pmol). 11-cis Retinal injections resulted in the regeneration of similar amounts of rhodopsin and improved rod function in a comparable way, irrespective of age. CONCLUSIONS: In the aged Rpe65-/- mouse, opsin levels decrease because of the loss of photoreceptors. The remaining opsin is structurally intact, and the components of the phototransduction cascade and the retinal circuitry remain functional, despite the absence of normal photoreceptor activity.