Biomedical subjects

M Colucci

Publications and source records attributed to M Colucci.

At least 19 recordsLinked to original sources

PubMed2007

Tissue factor and vascular endothelial growth factor expression in colorectal cancer: relation with cancer recurrence.

OBJECTIVE: This study was undertaken to quantify tissue factor (TF) and vascular endothelial growth factor (VEGF) in colorectal cancer and to evaluate their possible relationship with recurrence. METHOD: TF and VEGF were measured by enzyme-linked immunosorbent assay in surgical tumour specimens and normal mucosa from 50 consecutive patients with colorectal cancer who were followed up for 3 years for the assessment of disease recurrence. RESULTS: TF and VEGF antigens were detected in all tumour samples. VEGF, but not TF, was much higher in tumour than in normal mucosa (P < 0.0001), as also confirmed by measurement of specific mRNAs. There was a strong correlation between TF and VEGF antigens (P < 0.0005) in tumour tissue but not in normal mucosa. Neither protein was related to tumour stage, grade or size. Local or distant recurrence was statistically related to pTNM stage. High VEGF, but not TF, levels in tumour extracts were associated with an increased risk of recurrence both by univariate (RR, 4.00, 95% CI: 1.45-11.0) and multivariate analyses (RR, 3.65, 95% CI: 1.33-10.0). CONCLUSION: These findings suggest that VEGF content in colorectal cancer is an independent risk factor for tumour recurrence and might help select patients who might benefit from adjuvant therapy.

Colorectal Neoplasms↗

PubMed2006

Variability among polysulphone calibration curves.

Within an epidemiological study regarding the correlation between skin pathologies and personal ultraviolet (UV) exposure due to solar radiation, 14 field campaigns using polysulphone (PS) dosemeters were carried out at three different Italian sites (urban, semi-rural and rural) in every season of the year. A polysulphone calibration curve for each field experiment was obtained by measuring the ambient UV dose under almost clear sky conditions and the corresponding change in the PS film absorbance, prior and post exposure. Ambient UV doses were measured by well-calibrated broad-band radiometers and by electronic dosemeters. The dose-response relation was represented by the typical best fit to a third-degree polynomial and it was parameterized by a coefficient multiplying a cubic polynomial function. It was observed that the fit curves differed from each other in the coefficient only. It was assessed that the multiplying coefficient was affected by the solar UV spectrum at the Earth's surface whilst the polynomial factor depended on the photoinduced reaction of the polysulphone film. The mismatch between the polysulphone spectral curve and the CIE erythemal action spectrum was responsible for the variability among polysulphone calibration curves. The variability of the coefficient was related to the total ozone amount and the solar zenith angle. A mathematical explanation of such a parameterization was also discussed.

Biocompatible Materials↗

PubMed2006

The number of pregnancies is a risk factor for Alzheimer's disease.

Epidemiological data show a higher prevalence of late-onset Alzheimer's disease (AD) in women. The estrogenic deficiency in the post-menopausal period is suspected to be the cause of the gender-related risk of the disease, but studies on the estrogenic therapy and occurrence of AD were not consistent and sometimes contradicting. The aim of this study is to investigate whether a higher exposure to endogenous estrogens is associated with lower risk of dementia or not. Two hundred and four AD patients and 201 control women were considered. By interviews, we evaluated different variables, indirectly correlated to estrogenic natural exposure, as well as educational level and head trauma. These data were correlated in the AD group with the disease progression, as well as with the age at onset. Unexpectedly, we found a significant higher number of pregnancies in the AD than in the control group. Within the AD cases, the number of lifetime pregnancies is related to an earlier onset of the disease. As previously reported, we confirmed that the educational level is a protective factor and that major head trauma represents a risk factor in developing AD. The higher number of pregnancies and a less frequency of nulliparous women, indirectly relate the AD group to a higher estro-progestinic exposure. These findings suggest that it is the increase of progesterone or estrogens level--and not the estrogens decrease, as previously indicated by other authors--that could play a role in the Alzheimer's pathology.

Aged↗

PubMed2005

Changes in coagulation-fibrinolysis balance in blood mononuclear cells and in gastric mucosa from patients with Helicobacter pylori infection.

INTRODUCTION: Helicobacter pylori and some of its virulence factors stimulate human blood mononuclear cells (MNC) in vitro to produce tissue factor (TF) and plasminogen activator inhibitor-2 (PAI-2). In this study we investigated the procoagulant-fibrinolytic potential of blood MNC in patients with H. pylori infection. In the same patients we also evaluated the coagulation-fibrinolysis profile in gastric tissue and in plasma. METHODS AND RESULTS: The production of TF and PAI-2 was evaluated in 61 patients with dyspepsia, 31 positive and 30 negative for H. pylori infection. TF expressed by MNC and PAI-2 accumulation in cell culture medium after incubation for 20 h at 37 degrees C were significantly higher in H. pylori(+) than in H. pylori(-) patients and were significantly correlated. TF and PAI-2 content in extracts of gastric mucosa was similar in the two groups whereas lower levels of tissue plasminogen activator (t-PA) and thrombomodulin (TM) antigens were found in the antrum of H. pylori(+) patients. No difference between the groups was observed in plasma thrombus precursor protein, prothrombin fragment 1+2, D-dimer, t-PA, PAI-1, TM and thrombin activatable fibrinolysis inhibitor. CONCLUSIONS: H. pylori infection is associated with functional abnormalities of blood MNC resulting in the coordinate expression of TF and antifibrinolytic activity. Changes in cell coagulation-fibrinolysis balance may represent a link between H. pylori infection and ischemic heart disease.

Adult↗

PubMed2005

A novel nitric oxide-releasing statin derivative exerts an antiplatelet/antithrombotic activity and inhibits tissue factor expression.

BACKGROUND: NO-releasing statins are new chemical entities, combining HMG-CoA reductase inhibition and slow NO release, that possess stronger anti-inflammatory and antiproliferative activities than the native statins. OBJECTIVE: We evaluated the antithrombotic effects of nitropravastatin (NCX-6550) by assessing its activity on platelet activation and tissue factor (TF) expression by mononuclear cells in vitro and in vivo. METHODS AND RESULTS: In vitro, NCX-6550 inhibited (1) U46619- and collagen-induced platelet aggregation in buffer and plasma; (2) collagen-induced P-selectin expression in whole blood and (3) platelet adhesion to collagen-coated coverslips under high shear stress. These effects were displayed at concentrations of NCX-6550 ranging from 25 to 100 mum, and were totally reverted by the guanylylcyclase inhibitor ODQ (10 microm). Equimolar concentrations of pravastatin had no influence on these parameters of platelet function. LPS- and PMA-induced TF expression by blood mononuclear cells was also inhibited by NCX-6550 (IC50 13 microm), but not by pravastatin, as assessed by functional and immunological assays and by real-time PCR. In a mouse model of platelet pulmonary thromboembolism, induced by the i.v. injection of collagen plus epinephrine, pretreatment with NCX-6550 (24-48 mg kg(-1)) significantly reduced platelet consumption, lung vessel occlusion and mortality. Moreover, nitropravastatin markedly inhibited the generation of procoagulant activity by spleen mononuclear cells and peritoneal macrophages in mice treated with LPS. In these in vivo models too, pravastatin failed to affect platelet activation and monocyte/macrophage procoagulant activity. CONCLUSIONS: Our results show that nitropravastatin exerts strong antithrombotic effects in vitro and in vivo, and may represent an interesting antiatherothrombotic agent for testing in acute coronary syndromes.

Animals↗

PubMed2004

Plasma levels of amyloid beta-protein 42 are increased in women with mild cognitive impairment.

BACKGROUND: Accumulation in the brain of small aggregates of amyloid beta-protein 42 (Abeta42) is the major pathogenic event of Alzheimer disease (AD). In familial early-onset AD this event is likely the result of Abeta42 overproduction; in the most common sporadic late-onset form of the disease the mechanisms of Abeta42 accumulation are unknown. METHODS: To address this issue the authors analyzed plasma levels of Abeta42 in 88 elderly patients with amnestic mild cognitive impairment (MCI), chosen as paradigm of preclinical sporadic AD. RESULTS: The authors found a significant increase of Abeta42 plasma levels in women with MCI, in comparison to the affected men and 72 cognitively normal age-matched subjects. The levels were independent of variables in education, apolipoprotein E genotype, cholesterol, and creatinine plasma concentrations, as well as hemoglobin content. CONCLUSIONS: The elevation of Abeta42 plasma levels in women with MCI may represent a biologic explanation for the sex-dependent increased incidence of late-onset AD in women identified by epidemiologic studies.

Age of Onset↗

PubMed2004

Sensitivity of 14-3-3 protein test varies in subtypes of sporadic Creutzfeldt-Jakob disease.

BACKGROUND: The increase of the 14-3-3 protein in CSF is used as a diagnostic test in Creutzfeldt-Jakob disease (CJD), but the sensitivity and specificity of the 14-3-3 test are disputed. One reason for the dispute may be the recently established heterogeneity of sporadic CJD. The relationship between CSF 14-3-3 protein and sporadic CJD subtypes, distinguished by electrophoretic mobility of proteinase K-resistant prion protein (PrP(Sc)) and genotype at codon 129 of the prion protein gene, has not been elucidated. METHODS: The authors examined the 14-3-3 protein test in 90 patients with sporadic CJD. PrP(Sc) type (type 1 or type 2) and the genotype at polymorphic codon 129 were determined in each patient. Mutations were excluded by prion gene sequencing. RESULTS: The authors' findings indicate that the sensitivity of the 14-3-3 test is higher in patients with molecular features of the classic sporadic CJD than in patients with the nonclassic CJD subtypes. The difference appears to be related to the PrP(Sc) type and not to the codon 129 genotype. Disease duration before 14-3-3 testing might also have an influence because it was shorter in classic sporadic CJD. CONCLUSION: The Creutzfeldt-Jakob disease clinical subtype should be considered when interpreting results of the 14-3-3 test.

14-3-3 Proteins↗

PubMed2004

The 14-3-3 protein in multiple sclerosis: a marker of disease severity.

CONTEXT: In multiple sclerosis (MS) axonal damage is an early event and is probably to be considered the most relevant cause of permanent and progressive disability. OBJECTIVES: To investigate the value of the increase of 14-3-3 and tau proteins in the cerebrospinal fluid (CSF) as peripheral markers of axonal pathology and predictors of disease evolution. PATIENTS AND METHODS: In the CSF samples obtained from 63 patients with demyelinating diseases (DD), including 20 clinically isolated syndromes (CIS) and 43 clinically defined MS, as well as from 56 controls, we analysed the presence of 14-3-3 reactivity by immunoblot analysis along with the concentration of tau protein by sandwich ELISA. RESULTS: The percentage of DD subjects showing a positive 14-3-3 protein CSF reactivity (38%) was significantly higher than the one previously detected, and was correlated in the MS patients with a more severe clinical phenotype in terms of degree of disability and rate of disease progression, during a 10-month mean clinical follow-up. On the contrary, the levels of the CSF-tau protein were highly variable in DD and control subjects, and the mean CSF-tau concentration was similar in both groups. CONCLUSIONS: The immunoblot analysis of 14-3-3 protein in the CSF could be a useful marker to identify a subgroup of DD patients with high risk of developing severe disability.

14-3-3 Proteins↗

PubMed2001

Effectiveness of hepatitis B vaccination in babies born to hepatitis B surface antigen-positive mothers in Italy.

This study examined 522 children born to hepatitis B surface antigen (HBsAg)-positive mothers from 1985 through 1994 and evaluated the protection provided by anti-hepatitis B virus (HBV) immunization at birth. Babies were given hepatitis B immunoglobulin and hepatitis B vaccine at birth. At 5-14 years after immunization, 17 children (3.3%) were anti-HB core antigen positive, and 3 also were HBsAg positive. One carrier child had a double mutation, with substitution of proline-->serine at codons 120 (P120S) and 127 (P127S) within the a determinant of HBsAg. Of the 522 children, 400 (79.2%) of 505 still had protective anti-HBsAg titers > or =10 mIU/mL. Thus, HBV vaccination of children born to HBsAg-positive mothers is effective and confers long-term immunity. There is no evidence that the emergence of HBV escape mutants secondary to the immune pressure against wild-type HBV is of concern.

Adolescent↗

PubMed2001

Novel differences between two human prion strains revealed by two-dimensional gel electrophoresis.

The phenotype of human sporadic prion diseases is affected by patient genotype at codon 129 of the prion protein (PrP) gene, the site of a common methionine/valine polymorphism, and by the type of the scrapie PrP (PrP(Sc)), which likely reflects the prion strain. However, two distinct disease phenotypes, identified as sporadic Creutzfeldt-Jakob disease (M/M2 sCJD) and sporadic fatal insomnia (sFI), share methionine homozygosity at codon 129 and PrP(Sc) type 2. One-dimensional gel electrophoresis and immunoblotting reveal no difference between the M/M2 sCJD and sFI species of PrP(Sc) in gel mobility and glycoform ratio. In contrast, the two-dimensional immunoblot demonstrates that in M/M2 sCJD the full-length PrP(Sc) form is overrepresented and carries glycans that are different from those present in the PrP(Sc) of sFI. Because the altered glycans are detectable only in the PrP(Sc) and not in the normal or cellular PrP (PrP(C)), they are likely to result from preferential conversion to PrP(Sc) of rare PrP(C) glycoforms. This is the first evidence that a qualitative difference in glycans contributes to prion diversity.

Electrophoresis, Gel, Two-Dimensional↗

PubMed2001

Helicobacter pylori neutrophil-activating protein stimulates tissue factor and plasminogen activator inhibitor-2 production by human blood mononuclear cells.

Helicobacter pylori neutrophil-activating protein (HP-NAP) is a virulence factor that activates phagocytic NADPH-oxidase. The effect of HP-NAP on the production of tissue factor (TF), plasminogen activator inhibitor-2 (PAI-2), and urokinase-type plasminogen activator (u-PA) by human blood mononuclear cells (MNC) was evaluated by using functional and immunological assays and mRNA analysis. HP-NAP induced time- and dose-dependent increases in TF and PAI-2, with a maximal effect at 300 nmol/L (>15-fold increase in antigens). No changes in u-PA were observed. When whole bacteria were used, an H. pylori mutant lacking HP-NAP was significantly less active than the wild-type strain. MNC from a patient with chronic granulomatous disease behaved as do normal cells, which indicates that HP-NAP effects can occur independently of NADPH-oxidase. HP-NAP, by inducing the coordinate expression of cell procoagulant and antifibrinolytic activities, might favor fibrin deposition and contribute to the inflammatory reaction of gastric mucosa elicited by H. pylori.

Bacterial Proteins↗

PubMed2001

Monocytes, but not endothelial cells, downregulate the anticoagulant activity of activated protein C.

Activated protein C (APC) is a natural anticoagulant and inhibits thrombin generation by degrading factors Va and VIIIa. We evaluated the ability of APC to inhibit blood coagulation triggered by lipopolysaccharide (LPS)-stimulated [tissue factor (TF)-expressing] human mononuclear cells (MNCs) or umbilical vein endothelial cells (HUVECs). Using a plasma recalcification assay, we found that APC (up to 53.3 nmol/l final concentration) had a poor anticoagulant effect in the presence of LPS-stimulated MNCs, whereas it caused a marked prolongation of clotting time in the presence of LPS-stimulated HUVECs. A poor response to APC was also observed when platelet-free MNCs, monocyte-enriched preparations or the monocytoid cell line U937 were tested. Using a TF-independent (FXa-induced) thrombin generation assay, we demonstrated that both LPS-stimulated and unstimulated MNCs negated the inhibitory activity of APC. Direct determination of FVa activity indicated that MNCs were less efficient than HUVECs in promoting FVa inactivation by APC. Together, our results suggest that MNCs, at variance with HUVECs, protect factor Va from inactivation by APC, probably through the expression of a membrane component not present on endothelial cells. These strengthen the importance of monocytes in fibrin deposition associated with pathological conditions characterized by monocyte recruitment and activation.

Anticoagulants↗

PubMed2001

Human immunodeficiency virus type 1 Tat protein decreases cyclic AMP synthesis in rat microglia cultures.

We have studied the modulation of cyclic AMP (cAMP) accumulation by the human immunodeficiency virus type 1 (HIV 1) protein Tat in microglia and astrocyte cultures obtained from neonatal rat brain. Pretreatment of microglia with recombinant Tat resulted in a dose- and time-dependent decrease of cAMP accumulation induced by subsequent exposure to isoproterenol (1 microM). The inhibitory action of 100 ng/mL Tat approached 50% after 4 h of preincubation and reached a maximum of 70% after 24 h. The Tat-induced time- and dose-dependent decrease of cAMP accumulation was observed also when microglial cultures were stimulated with the adenylyl cyclase activator forskolin (100 microM). In both cases, Tat inhibitory action was 70% reverted by a specific monoclonal anti-Tat antibody, but was not prevented either by the phosphodiesterase inhibitor 3-isobutyl-1-methyl-xantine (100 microM) or by a 16-h pretreatment of microglial cultures with the Gi protein inhibitor pertussis toxin (10 ng/mL). All these results suggested that the viral protein acts at a step of the cAMP transduction pathway other than receptors, G proteins and phosphodiesterases. The target of Tat appeared to be adenylyl cyclase, whose activity was markedly reduced (up to 60%) in membranes prepared from Tat-treated microglial cells, both in basal conditions and after stimulation with isoproterenol and forskolin. The inability of the competitive inhibitor of nitric oxide synthase N(G)-monometyl- L-arginine (20 and 200 microM) to revert Tat action on forskolin-induced cAMP accumulation, and of two potent nitric oxide donors, PAPA and DETA (0.1-2 m M), to alter forskolin-induced cAMP accumulation, excluded an involvement of nitric oxide in Tat-induced adenylyl cyclase inhibition. On the contrary, two inhibitors of nuclear factor kappaB activation, N-tosyl-( L)-phenylalanine chloromethyl ketone (10 microM) and SN50 (25 microM), markedly prevented the reduction of forskolin-evoked cAMP accumulation by Tat, suggesting a possible role for this nuclear transcriptional factor in the regulation of adenylyl cyclase by Tat in microglia. This assumption was strengthened by the ability of lipopolysaccharide (100 ng/mL, 4 h) to mimic the inhibitory effect of the viral protein. Conversely, astrocyte cAMP accumulation was unaffected by the viral protein, as tested at various concentrations and time points. Finally, Tat inhibition of microglial adenylyl cyclase was not due to non-specific cytotoxicity. As cAMP has been reported to exert a neuroprotective role in several in vivo and in vitro models of brain pathologies, and microglia is believed to mediate Tat-induced neurotoxicity, these results suggest that the ability of Tat to inhibit cAMP synthesis in microglia may contribute to neuronal degeneration and cell death associated with HIV infection.

1-Methyl-3-isobutylxanthine↗

PubMed2001

Aberrant metal binding by prion protein in human prion disease.

Human prion diseases are characterized by the conversion of the normal prion protein (PrP(C)) into a pathogenic isomer (PrP(Sc)). Distinct PrP(Sc) conformers are associated with different subtypes of prion diseases. PrP(C) binds copper and has antioxidation activity. Changes in metal-ion occupancy can lead to significant decline of the antioxidation activity and changes in conformation of the protein. We studied the trace element status of brains from patients with sporadic Creutzfeldt-Jakob disease (sCJD). We found a decrease of up to 50% of copper and an increase in manganese of approximately 10-fold in the brain tissues from sCJD subjects. We have also studied the metal occupancy of PrP in sCJD patients. We observed striking elevation of manganese and, to a lesser extent, of zinc accompanied by significant reduction of copper bound to purified PrP in all sCJD variants, determined by the PrP genotype and PrP(Sc) type, combined. Both zinc and manganese were undetectable in PrP(C) preparations from controls. Copper and manganese changes were pronounced in sCJD subjects homozygous for methionine at codon 129 and carrying PrP(Sc) type-1. Anti-oxidation activity of purified PrP was dramatically reduced by up to 85% in the sCJD variants, and correlated with increased in oxidative stress markers in sCJD brains. These results suggest that altered metal-ion occupancy of PrP plays a pivotal role in the pathogenesis of prion diseases. Since the metal changes differed in each sCJD variants, they may contribute to the diversity of PrP(Sc) and disease phenotype in sCJD. Finally, this study also presented two potential approaches in the diagnosis of CJD; the significant increase in brain manganese makes it potentially detectable by MRI, and the binding of manganese by PrP in sCJD might represent a novel diagnostic marker.

Antioxidants↗

PubMed2001

Low molecular weight heparins prevent thrombin-induced thrombo-embolism in mice despite low anti-thrombin activity. Evidence that the inhibition of feed-back activation of thrombin generation confers safety advantages over direct thrombin inhibition.

BACKGROUND AND OBJECTIVES: Thrombin-induced thromboembolism in mice is a model in which the feed-back clotting activation produced by the injected enzyme greatly contributes to fibrin accumulation in lungs and to mortality. Using this model we have previously shown that activated human protein C (aPC), by interrupting endogenous clotting activation at a high level (factors Va and VIIIa), prevents mortality inducing only a minor hemostatic impairment. With the same model we have now compared the antithrombotic and prohemorrhagic effects of two low molecular weight heparins (LMWHs), reviparin and tinzaparin, which are expected to inhibit preferentially the positive feed-back triggered by thrombin (anti Xa activity), with those of unfractionated heparin (UFH) and PEG-hirudin, which inhibit mainly or exclusively thrombin activity (anti IIa activity). DESIGN AND METHODS: Pulmonary thromboembolism was induced in mice by i.v. injection of bovine thrombin (1,000U/kg). Drugs (from 0.12 to 1.2 mg/kg) were given as bolus injection 2 min prior to thrombin challenge and mortality was assessed within 15 min. The bleeding time was assessed by a tail tip transection model. Activated partial thromboplastin time (aPTT), thrombin clotting time (TcT), fibrinogen assay and anti Xa activity determination were performed in citrated plasma from saline- or drug-treated animals. RESULTS: All drugs protected mice from thrombin-induced mortality in a dose-dependent way. At comparable antithrombotic dosages, the anti IIa activity generated in plasma (assessed by TcT) was highest with UFH, intermediate with tinzaparin and very low with reviparin. Accordingly, the fibrinogen drop, which is caused mainly by the injected thrombin, was prevented by the heparins to an extent that was fairly well related to their anti IIa activity. aPTT and bleeding time, used as measures of hemorrhagic risk, were markedly more prolonged by UFH than by reviparin. Tinzaparin, instead, had an intermediate effect. Interestingly, PEG-hirudin, at equipotent antithrombotic dosages, caused a prolongation of bleeding time comparable to that observed with UFH. INTERPRETATIONS AND CONCLUSIONS: Our data show that, in our model, drugs acting at a high level of the blood clotting cascade, like LMWHs with a high anti Xa/anti IIa ratio, display a better antithrombotic/prohemorrhagic profile than drugs acting prevalently on thrombin.

Animals↗

PubMed2001

Thrombin activatable fibrinolysis inhibitor (TAFI) does not inhibit in vitro thrombolysis by pharmacological concentrations of t-PA.

TAFI (thrombin activatable fibrinolysis inhibitor) is a plasma procarboxypeptidase that upon activation inhibits the fibrinolytic process by removing the C-terminal lysines from partially degraded fibrin. The generation of activated TAFI (TAFIa) has been suggested to represent a mechanism of thrombus resistance to thrombolytic therapy. However, the ability of TAFI to inhibit fibrinolysis by pharmacological concentrations of t-PA has not been properly investigated. We used an in vitro model consisting of 125I-fibrin blood clots submerged in autologous defibrinated plasma. Upon addition of t-PA (125-5,000 ng/ml) and CaCl2 (25 mM), samples were incubated at 37 degrees C, and clot lysis was measured at intervals from the radioactivity released into solution. The role of TAFI was assessed either by neutralizing the generated TAFIa with the specific inhibitor PTI (50 microg/ml) or by enhancing TAFI activation through the addition of recombinant soluble thrombomodulin (solulin, 1 microg/ml). In our clot lysis model, activation of TAFI amounted to about 20% of inducible carboxypeptidase activity. Addition of PTI, however, produced a significant increase in the extent of lysis only at concentrations of t-PA equal to or lower than 250 ng/ml. When solulin was added to the plasma surrounding the clot, about 70% of TAFI was activated within 15 min. Under these conditions, inhibition of clot lysis was very marked in samples containing 125 or 250 ng/ml of t-PA, but negligible in those containing pharmacological concentrations of the activator (1,000 and 5,000 ng/ml). Additional experiments suggest that loss of fibrin-dependence by elevated concentrations of t-PA may be one of the mechanisms explaining the lack of effect of TAFIa. Our data indicate that, under our experimental conditions, clot lysis by pharmacological concentrations of t-PA is not influenced by TAFIa even after maximal activation of this procarboxy-peptidase.

Animals↗

PubMed2000

Absence of hemispheric dominance for mental rotation ability: a transcranial Doppler study.

Mean blood flow velocity (MFV) of the middle cerebral arteries was monitored in 19 healthy, adult, right-handed subjects during the resting phase and the execution of a series of neuropsychological tests: two right/left discrimination tasks, two mental rotation paradigms (the Ratcliff's test and a cube comparison test) and a phonemic fluency task, which was utilised as an internal control. In the group as a whole, the Ratcliff's test was associated with a significant bilateral increase in MFV versus both the resting state (right: p < .000001, left: p < .000001) and right/left discrimination tasks (task 1: right: p = .003, left: p = .005; task 2: right: p = .001, left: p = .001). The cube comparison in turn produced a significant increase in MFV versus both the baseline conditions (right: p < .000001, left: p < .000001) and the Ratcliff's test (right: p = .01, left: p = .002). As expected, the fluency task was associated with a significant asymmetric increase in cerebral perfusion (left > right: p = .0001). Increasing task difficulty (right/left discrimination < Ratcliffs test < cube comparison) was paralleled by a roughly proportional rise in MFV values (right: r = .424, p < .01; left: r = .331, p = .01). In conclusion, we were able to demonstrate that (1) in addition to the amount of MFV variation due to right/left discrimination (when required), mental rotation per se causes a bihemispheric activation irrespective of the experimental paradigm; (2) the MFV variation is proportional to the difficulty of the tasks.

Adult↗

PubMed2000

Protein kinase C activation reduces microglial cyclic AMP response to prostaglandin E2 by interfering with EP2 receptors.

We studied the modulation by protein kinase C (PKC) of the cyclic AMP (cAMP) accumulation induced by prostaglandin (PG) E2 in rat neonatal microglial cultures. Short pretreatment of microglia with phorbol 12-myristate 13-acetate (PMA) or 4beta-phorbol 12,13-didecanoate, which activate PKC, but not with the inactive 4alpha-phorbol 12,13-didecanoate, substantially reduced cAMP accumulation induced by 1 microM PGE2. The action of PMA was dose and time dependent, and the maximal inhibition (approximately 85%) was obtained after 10-min preincubation with 100 nM PMA. The inhibitory effect of PMA was mimicked by diacylglycerol and was prevented by the PKC inhibitor calphostin C. As PMA did not affect isoproterenol- or forskolin-stimulated cAMP accumulation, we investigated whether activation of PKC decreased cAMP production by acting directly at PGE2 EP receptors. Neither sulprostone (10(-9)-10(-5) M), a potent agonist at EP3 receptors (coupled to adenylyl cyclase inhibition), nor 17-phenyl-PGE2 (10(-6)-10(-5) M), an agonist of EP1 receptors, modified cAMP accumulation induced by forskolin. On the contrary, 11-deoxy-16,16-dimethyl PGE2, which does not discriminate between EP2 and EP4 receptors, both coupled to the activation of adenylyl cyclase, and butaprost, a selective EP2 agonist, induced a dose-dependent elevation of cAMP that was largely reduced by PMA pretreatment, as in the case of PGE2. These results indicated EP2 receptors as a possible target of PKC and suggest that PKC-activating agents present in the pathological brain may prevent the cAMP-mediated microglia-deactivating function of PGE2.

Animals↗