Expression of insulin-like growth factor II (IGF–II) in human hepatocellular carcinomas: An immunohistochemical study

Recent results obtained using molecular biology techniques have suggested a possible role for insulin-like growth factor II (IGF-II) in the pathogenesis of hepatocellular carcinoma (HCC). To investigate this phenomenon, a monoclonal anti-body was used against IGF-II to study 54 patients with HCC. The presence of HBsAg was also tested both in serum and liver tissue. A positive immunoreaction was found in 9/15 (60%) of the HCC arising in cirrhotic livers of patients who had serum markers for HBV (HBV+ positive patients). These results provide further evidence that HBV might play a role in the expression of IGF-II. In HCC of patients without any markers of HBV infection (HBV- negative patients), IGF–II was detected in 10/39 (25.6%) of the tumors, and in some benign neoplastic lesions. It was found not only in neoplastic cells but also in some dysplastic nodules. The speculation arises that IGF–II expression may play a role in some steps of hepato-carcinogenesis.     

Modulating parameters of excitability during and after transcranial direct current stimulation of the human motor cortex

Weak transcranial direct current stimulation (tDCS) of the human motor cortex results in excitability shifts which occur during and after stimulation. These excitability shifts are polarity-specific with anodal tDCS enhancing excitability, and cathodal reducing it. To explore the origin of this excitability modulation in more detail, we measured the input–output curve and motor thresholds as global parameters of cortico-spinal excitability, and determined intracortical inhibition and facilitation, as well as facilitatory indirect wave (I-wave) interactions. Measurements were performed during short-term tDCS, which elicits no after-effects, and during other tDCS protocols which do elicit short- and long-lasting after-effects. Resting and active motor thresholds remained stable during and after tDCS. The slope of the input–output curve was increased by anodal tDCS and decreased by cathodal tDCS. Anodal tDCS of the primary motor cortex reduced intracortical inhibition and enhanced facilitation after tDCS but not during tDCS. Cathodal tDCS reduced facilitation during, and additionally increased inhibition after its administration. During tDCS, I-wave facilitation was not influenced but, for the after-effects, anodal tDCS increased I-wave facilitation, while cathodal tDCS had only minor effects. These results suggest that the effect of tDCS on cortico-spinal excitability during a short period of stimulation (which does not induce after-effects) primarily depends on subthreshold resting membrane potential changes, which are able to modulate the input-output curve, but not motor thresholds. In contrast, the after-effects of tDCS are due to shifts in intracortical inhibition and facilitation, and at least partly also to facilitatory I-wave interaction, which is controlled by synaptic activity.     

Linkage analysis of anorexia and bulimia nervosa cohorts using selected behavioral phenotypes as quantitative traits or covariates.

To increase the likelihood of finding genetic variation conferring liability to eating disorders, we measured over 100 attributes thought to be related to liability to eating disorders on affected individuals from multiplex families and two cohorts: one recruited through a proband with anorexia nervosa (AN; AN cohort); the other recruited through a proband with bulimia nervosa (BN; BN cohort). By a multilayer decision process based on expert evaluation and statistical analysis, six traits were selected for linkage analysis (1): obsessionality (OBS), age at menarche (MENAR), and anxiety (ANX) for quantitative trait locus (QTL) linkage analysis; and lifetime minimum body mass index (BMI), concern over mistakes (CM), and food-related obsessions (OBF) for covariate-based linkage analysis. The BN cohort produced the largest linkage signals: for QTL linkage analysis, four suggestive signals: (for MENAR, at 10p13; for ANX, at 1q31.1, 4q35.2, and 8q13.1); for covariate-based linkage analyses, both significant and suggestive linkages (for BMI, one significant [4q21.1] and three suggestive [3p23, 10p13, 5p15.3]; for CM, two significant [16p13.3, 14q21.1] and three suggestive [4p15.33, 8q11.23, 10p11.21]; and for OBF, one significant [14q21.1] and five suggestive [4p16.1, 10p13.1, 8q11.23, 16p13.3, 18p11.31]). Results from the AN cohort were far less compelling: for QTL linkage analysis, two suggestive signals (for OBS at 6q21 and for ANX at 9p21.3); for covariate-based linkage analysis, five suggestive signals (for BMI at 4q13.1, for CM at 11p11.2 and 17q25.1, and for OBF at 17q25.1 and 15q26.2). Overlap between the two cohorts was minimal for substantial linkage signals.     

Interaction between a peroxisome proliferator-activated receptor gamma gene polymorphism and dietary fat intake in relation to body mass

The peroxisome proliferator-activated receptor gamma (PPAR gamma) is a critical regulator of adipogenesis. PPAR gamma+/- mice are resistant to high-fat diet-induced obesity and thus PPAR gamma may mediate physiological responses to dietary fat in other mammals. The aim of this study was to determine whether the human PPAR gamma proline to alanine substitution polymorphism (Pro12Ala) modifies the association between dietary fat and adiposity and plasma lipids. Subjects (n=2141) were controls selected for three case-control studies nested within the Nurses' Health Study, a large ongoing prospective cohort study. Associations between intake of total fat, fat subtypes and BMI were different in PPAR gamma 12Ala variant allele-carriers compared with non-carriers. Among homozygous wild-type Pro/Pro individuals, those in the highest quintile of total fat intake, had significantly higher mean body mass index (BMI) compared with those in the lowest quintile (27.3 versus 25.4 kg/m2, respectively; P-trend<0.0001) whereas among 12Ala variant allele-carriers there was no significant trend observed between dietary fat intake and BMI (P-trend=0.99; P-interaction=0.003). In contrast, intake of monounsaturated fat was not associated with BMI among homozygous wild-type women but was inversely associated with BMI among 12Ala variant allele-carriers (mean in lowest quintile=27.6 versus mean in highest quintile=25.5 kg/m2; P-trend=0.006; P-interaction=0.003). The relationship between dietary fat intake and plasma lipid concentrations also differed according to PPAR gamma genotype. These data suggest that PPAR gamma genotype is an important factor in physiological responses to dietary fat in humans.     

Use of ecarin clotting time in whole blood for monitoring recombinant hirudine treatment during cardiopulmonary bypass in patients with heparin-induced thrombocytopenia

Lepirudin (Refludan is a recombinant hirudin, approved for anticoagulation treatment of heparin-induced thrombocytopenia patients with thrombosis. We report here our method for laboratory monitoring with ecarin clotting time (ECT) of hirudin therapy as anticoagulation for cardiac surgery. Ecarin is extracted from the Echis carinatus snake venom and directly converts prothrombin to its intermediate, meizothrombin. This one binds in a stoechiometric way to hirudin to be proportioned in whole blood. The activation of coagulation starts up only when the totality of the hirudin is bound to the meizothrombin. To minimize the effect of dilution related to the CEC on the prothrombin and fibrinogen levels, thus lengthening the ECT, the specimen to be tested is diluted with normal whole blood. In 1997, when we have performed our first surgery with cardiopulmonary bypass, only one team (P?tzsch et al., 1997) had described the use of the ECT in whole blood. We describe in this work our assay to dose hirudin with ECT after dilution in whole blood. This assay was used during 8 CEC among 7 patients affected with HIT (n = 6) or potentially sensitized with heparin (n = 1). Experimental conditions and interpretation of the assay are reported here. This test is fast enough to provide useful information for adjusting the dose during cardiopulmonary bypass.     

Preprocessor Adapts Cardiovascular Signals to a Minicomputer

A laboratory-developed analog signal processor, driven by a conventional polygraph recorder and associated signal conditioning devices, provides automatic heart beat-by-heart beat preprocessing of various cardiovascular functions for input to a laboratory-type minicomputer. The technique of preprocessing individual functions, integrated with the minicomputer system which includes an A/D converter and teletype as input-output peripherals, provides a low-cost data acquisition and reduction system for the on-line computation and analysis of cardiovascular functions in experimental research applications. Such preprocessing more efficiently uses the minicomputer's memory to handle large amounts of information since the digitized data is in the form of one data sample, per function, per heart beat. Preprocessing analog data provides a low density data format and simplified software programs that are ideally suited for the utilization of a minicomputer in this on-line application.     

Impaired signal transduction in mitogen activated rat splenic lymphocytes during aging

Mitogen activated protein kinases (MAPK) are activated by a wide variety of signals leading to cell proliferation and differentiation in different cell types. With aging, there is a marked decrease in proliferation of T-lymphocytes in response to a variety of mitogens. Several age-related changes in the activation of MAPK pathways in T-lymphocytes activated via the T-cell receptor (TCR) have been described in different species. This way, some TCR proximal defects in tyrosine kinase activity have been delineated. In this study, we have used rat splenic lymphocytes to measure the effect of aging on the activation of two MAP kinase families: ERK and JNK. In order to bypass the receptor-proximal age-dependent defects previously described, we used phorbol ester (PMA) and Ca2+ ionophore (A23187) as co-mitogens. Our results demonstrate that splenic lymphocytes from old rats have a disturbance in the activation of the ERK and JNK MAPK signal transduction pathways, that are located downstream of the receptor-proximal events. At least part of the age-related defect leading to decreased ERK activity appears to be located upstream of ERK itself, since activation of MEK is also impaired. On the other hand, the observed defects in MAPK activation do result in decreased activation of downstream events, such as c-Jun phosphorylation. Thus, we conclude that aging of splenic lymphocytes results in a functional decline in signal transduction, and at least some of these defects are located downstream of the receptor-proximal events previously described by others. The impaired activity of these two MAP kinase pathways is likely to play a role in the diminished lymphoproliferation observed in old individuals.