Radiotherapy of T4 squamous cell carcinoma of the skin of nasal pyramid.
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Aged↗
Biomedical subjects
R Brambilla
Publications and source records attributed to R Brambilla.
Cerebellar neurons and glial cells are transducible by lentiviral vectors without decrease of cerebellar functions.
Due to the profuse connections of the cerebellum to the rest of the central nervous system, cerebellar dysfunction impacts tremendously on movement coordination, maintenance of equilibrium, muscle tone and motor memory. Efficient gene transfer of therapeutic genes to this central nervous system structure would constitute a relevant step ahead the design of treatments to ameliorate cerebellar dysfunction. Lentiviral vectors (LVs) have been used as efficient vehicles to integrate transgenes into dividing and non-dividing cells, such as postmitotic adult neurons, with minimal toxicity and immune response. This study aimed to use LVs carrying green fluorescent protein (GFP) cDNA for transduction of cerebellar cells in vivo without compromising neurological cerebellar functions. Our results indicate that LVs, injected in the lobulus simplex, transduced different cerebellar neurons including stellate, Purkinje cells, granular neurons and glial cells such as astrocytes, oligodendrocytes, and that this gene transfer approach was not accompanied by cerebellar deficits.
Animals↗
Targeting Ras/ERK signaling in the striatum: will it help?
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Alzheimer Disease↗
Alveolar--capillary membrane gas conductance: a novel prognostic indicator in chronic heart failure.
AIMS: Lung dysfunction occurring in chronic heart failure worsens clinical status and exercise performance. The prognostic value of airway and alveolar function measurements in chronic heart failure has not been explored. We aimed to evaluate the prognostic value of lung function tests in a population of patients with stable chronic heart failure. METHODS AND RESULTS: One hundred and six stable chronic heart failure patients (whose left ventricular ejection fraction averaged 33 +/- 1%) underwent echocardiography, metabolic stress testing, assessment of pulmonary function at rest (by spirometry), of alveolar diffusing capacity (DLco) (with carbon monoxide technique) and of its membrane (DM) and capillary blood volume (Vc) components. Prognostic relevance of pulmonary variables was assessed by the Kaplan-Meier approach with log-rank testing and by Cox regression analysis. Cut-off values of lung parameters were based on the 33rd and 66th centiles. Seventeen patients died for cardiac reasons. Non-survivors compared to survivors showed lower forced expiratory volume in 1 s (2 X 1 +/- 0 X 1 vs 2 X 4 +/- 0 X 1 l; P<0 X 01), forced vital capacity (2 X 6 +/- 0 X 1 vs 2 X 9 +/- 0 X 1 l; P<0 X 01), maximal voluntary ventilation (80 X 7 +/- 2 X 5 vs 95 X 4 +/- 2 X 7 l; P<0 X 01), DLco (16 X 5 +/- 1 X 1 vs 19 X 3 +/- 0 X 6 ml . min(-1) . mmHg(-1); P<0 X 01) and DM (25 X 1 +/- 1 X 8 vs 31 X 9 +/- 1 X 5 ml . min(-1) . mmHg(-1); P<0 X 01). They also exhibited a smaller peak VO2 (14 X 6 +/- 0 X 7 vs 15 X 9 +/- 0 X 6 ml . min(-1) . kg(-1); P<0 X 05) and a steeper VE/VCO2 slope (45 X 0 +/- 1 X 7 vs 41 X 9 +/- 1 X 5; P<0 X 01). Multivariate analysis revealed that DM was the only independent predictor of cardiac death. Cases at high risk for adverse outcome were identified by a DM<24 X 7 ml . min(-1) . mmHg(-1). Patients receiving ACE-inhibitors presented with a higher DM (32 X 1 +/- 1 X 7 vs 27 X 9 +/- 1 X 7 ml . min(-1) . mmHg(-1), P<0 X 05) as well as a better Cox estimated survival rate. CONCLUSIONS: Impaired DM is a powerful independent predictor of worse prognosis in stable chronic heart failure and may be considered an additional index of disease severity, as well as a specific therapeutic target.
Angiotensin-Converting Enzyme Inhibitors↗
Cellular mechanisms of striatum-dependent behavioral plasticity and drug addiction.
The striatum has long been known to be involved in the control of motor behavior, since disruption of dopamine-mediated function in this brain structure is directly linked to Parkinson's disease and other disorders of movement. However, it is now accepted that both dorsal and ventral striatal nuclei are also essential for a variety of cognitive processes, which depend on reward-based stimulus-response learning. Since the neuroanatomical and neurochemical organization of dorsal and ventral striatum is only partially overlapping, it is likely that both common and nucleus-specific cellular and molecular events contribute to synaptic plasticity, learning and memory processes mediated by these cerebral structures. Alterations in cell signaling in the striatum may be particularly important in the response to both acute and chronic administration of drugs of abuse, resulting in maladaptive changes in the reward-based associative learning involved in addiction, withdrawal and relapse.
Animals↗
Inhibition of gap-junctional communication induces the trans-differentiation of osteoblasts to an adipocytic phenotype in vitro.
Osteoblasts and adipocytes are thought to differentiate from a common stromal progenitor cell. These two phenotypically mature cell types show a high degree of plasticity, which can be observed when cells are grown under specific culture conditions. Gap junctions are abundant among osteoblastic cells in vivo and in vitro, whereas they are down-regulated during adipogenesis. Gap junctional communication (GJC) modulates the expression of genes associated with the mature osteoblastic phenotype. Inhibition of GJC utilizing 18-alpha-glycyrrhetinic acid (AGRA) blocks the maturation of pre-osteoblastic cells in vitro. Moreover, cytoplasmic lipid droplets are detectable at the end of the culture period, suggesting that GJC inhibition may favor an adipocytic phenotype. We used several human osteoblastic cell lines, as well as bone-derived primary osteoblastic cells, to show that confluent cultures of human osteoblastic cells grown under osteogenic conditions developed an adipocytic phenotype after 3 days of complete inhibition of GJC using AGRA or oleamide, two dissimilar nontoxic reversible inhibitors. Development of an adipogenic phenotype was confirmed by the accumulation of triglyceride droplets and the increase in mRNA expression of the adipocytic markers peroxisome proliferator-activated receptor gamma2 and lipoprotein lipase. Glycyrrhizic acid, a noninhibitory AGRA analog, or alpha-bromopalmitate, a nondegradable fatty acid, had no effect. Modulation of skeletal GJC may represent a new pharmacological target by which inhibition of marrow adipogenesis can take place with the parallel enhancement of osteoblastogenesis, thus providing a novel therapeutic approach to the treatment of human age-related osteopenic diseases and postmenopausal osteoporosis.
3T3 Cells↗
Involvement of CDC25Mm/Ras-GRF1-dependent signaling in the control of neuronal excitability.
Ras-GRF1 is a neuron-specific guanine nucleotide exchange factor for Ras proteins. Mice lacking Ras-GRF1 (-/-) are severely impaired in amygdala-dependent long-term synaptic plasticity and show higher basal synaptic activity at both amygdala and hippocampal synapses (Brambilla et al., 1997). In the present study we investigated the effects of Ras-GRF1 deletion on hippocampal neuronal excitability. Electrophysiological analysis of both primary cultured neurons and adult hippocampal slices indicated that Ras-GRF1-/- mice displayed neuronal hyperexcitability. Ras-GRF1-/- hippocampal neurons showed increased spontaneous activity and depolarized resting membrane potential, together with a higher firing rate in response to injected current. Changes in the intrinsic excitability of Ras-GRF1-/- neurons can entail these phenomena, suggesting that Ras-GRF1 deficiency might alter the balance between ionic conductances. In addition, we showed that mice lacking Ras-GRF1 displayed a higher seizure susceptibility following acute administration of convulsant drugs. Taken together, these results demonstrated a role for Ras-GRF1 in neuronal excitability.
Action Potentials↗
Influence of ACE-inhibition on salt-mediated worsening of pulmonary gas exchange in heart failure.
AIMS: In congestive heart failure (CHF), pulmonary gas exchange, as evaluated by carbon monoxide diffusion (DLCO), is impaired. ACE-inhibition improves DLCO. Infusion of saline worsens DLCO, because of upregulated sodium and water transport to the alveolar interstitium, which thickens the alveolar-capillary interface and lengthens the diffusion path for gas exchange. We investigated whether enalapril can readjust the capillary permeability to sodium. METHODS: In 10 NYHA class II-III CHF patients, we measured DLCO, its two subcomponents (VC, capillary blood volume available for gas exchange, and DM, alveolar-capillary membrane diffusion), left and right ventricular filling pressures, plasma noradrenaline, aldosterone and renin activity, at baseline and following saline infusion in the main pulmonary artery stem, before and after 1 week enalapril treatment (20 mg daily). RESULTS: Saline (150 ml) significantly reduced DLCO (-9.1%) and DM (-9.8%) and augmented VC (+ 10.7%). Responses to 750 ml saline were somewhat greater and qualitatively similar. Enalapril produced a significant improvement of DLCO and DM at rest as well as after saline, that was not associated with variations in ventricular filling pressures, cardiac output and left ventricular ejection fraction, and was not accounted for by humoral changes. CONCLUSIONS: In CHF, ACE-inhibition attenuates the deterioration of pulmonary gas transfer produced by saline infusion, suggesting an ability to readjust the upregulated sodium transport across the pulmonary microvascular endothelium.
Angiotensin-Converting Enzyme Inhibitors↗
Modulation of cyclooxygenase-2 and brain reactive astrogliosis by purinergic P2 receptors.
Astroglial cells respond to trauma and ischemia with reactive gliosis, a reaction characterized by increased astrocytic proliferation and hypertrophy. Although beneficial to a certain extent, excessive gliosis may be detrimental, contributing to neuronal death in neurodegenerative diseases. We have tested the hypothesis that ATP may act as a trigger of reactive gliosis in an in vitro model (rat brain primary astrocytes) where reactive astrogliosis can be quantified as elongation of astrocytic processes. Challenge of cells with the ATP analog alpha,beta methyleneATP (alpha,beta meATP) resulted in concentration dependent elongation of astrocytic processes, an effect that was fully counteracted by the non-selective ATP/P2 receptor antagonists suramin and pyridoxalphosphate-6-azophenyl-2',4'-disulphonic acid (PPADS). Signalling studies revealed that alpha,beta meATP-induced gliosis is mediated by a novel G-protein-coupled receptor (a P2Y receptor) coupled to an early release of arachidonic acid. Challenge of cells with alpha,beta meATP also resulted in an increase of inducible cyclooxygenase-2 (COX-2), the activity of which has been reported to be pathologically increased in a variety of neurodegenerative diseases characterized by inflammation and astrocytic activation. Induction of COX-2 by alpha,beta meATP was causally related to reactive astrogliosis, since the selective COX-2 inhibitor NS-398 prevented both the purine-induced elongation of astrocytic processes and the associated COX-2 increase. Preliminary data on the putative receptor-to-nucleus pathways responsible for purine-induced gliosis suggest that induction of the COX-2 gene may occur through the protein kinase C/mitogen activated protein kinase system, and may involve the formation of activated AP-1 transcription complexes. We speculate that antagonists selective at this novel P2Y receptor subtype may represent a novel class of neuroprotective agents able to slow down neurodegeneration by counteracting the inflammatory events contributing to neuronal cell death.
Adenosine Triphosphate↗
A novel gliotic P2 receptor mediating cyclooxygenase-2 induction in rat and human astrocytes.
In astrocytic cultures maintained in vitro, a brief challenge with the ATP analog alpha,beta methyleneATP (alpha,betameATP) results, 3 days later, in marked elongation of astrocytic processes, an event that resembles the astrocytic hypertrophy known to occur in vivo during reactive astrogliosis. alpha,beta meATP-induced effects were observed in primary astrocytes obtained from both rat striatum and cortex (a brain area highly involved in chronic neurodegenerative pathologies), as well as in human astrocytoma cells (ADF cells). Purine-induced gliosis could be reversed by the non-selective P2X/P2Y receptor antagonist pyridoxalphosphate-6-azophenyl-2', 4'-disulphonic acid (PPADS), but not by oxidized ATP (an antagonist of the P2X(7) receptor), in line with previous studies of our laboratory suggesting the involvement of a P2Y receptor subtype. Induction of reactive gliosis was preceded by increased expression of cyclooxygenase-2 (COX-2), an enzyme whose excessive activation has been implicated in both acute and chronic neurodegenerative diseases. The selective COX-2 inhibitor NS-398 prevented both purine-induced astrogliosis and the associated COX-2 induction, suggesting that inhibition of the transcription of the COX-2 gene may also contribute to the anti-inflammatory properties of this agent. Significant blockade of both alpha,beta meATP-mediated reactive gliosis and COX-2 induction was also observed with PPADS. These data suggest that COX-2 mediates P2Y receptor-induced reactive astrogliosis, and that antagonists selective for this receptor subtype may represent a novel class of anti-inflammatory agents of potential interest in acute and chronic neurological disorders characterized by an inflammatory component and reactive gliosis.
Adenosine Triphosphate↗
Ras-related and MAPK signalling in neuronal plasticity and memory formation.
Ras-related guanosine triphosphatases (GTPases) couple receptor activity to a number of intracellular signalling events culminating in the control of cell morphology and gene transcription. In culture cells, the best-understood Ras-dependent signalling pathway involves the mitogen-activated protein kinase/extracellular-regulated kinase (MAPK/ERK) cascade. A growing body of evidence has recently been accumulating to suggest a crucial role of Ras and MAPK signalling in neuronal functions connected to synaptic plasticity. In the present review article we discuss the experimental basis supporting the notion that the Ras/MAPK pathway interacts with other synaptic mechanisms to regulate invertebrate and vertebrate behavioural responses such as those implicated in learning and memory processes.
Animals↗
Activation of the A3 adenosine receptor affects cell cycle progression and cell growth.
The A3 adenosine receptor has been implicated in modulation of cell growth. As a first step to the characterization of the underlying mechanisms, we exposed Chinese hamster ovary (CHO) cells transfected with the human A3 receptor (A3R-CHO) to selective A3 receptor ligands. At micromolar concentrations, the A3 agonists N6-(3-iodobenzyl)-adenosine-5'-N-methyluronamide (IB-MECA) and its 2-chloro derivative Cl-IB-MECA reduced cell number, with no effects on either parental CHO cells (not expressing any adenosine receptor), or CHO cells transfected with the human A1 receptor. Cl-IB-MECA also reduced cell number in the human HEK293 cell line transfected with the human A3 receptor cDNA as opposed to the respective untransfected wild-type cells. In A3R-CHO, agonist-induced effects were antagonized by nanomolar concentrations of A3 antagonists, including the triazoloquinazoline derivative MRS 1220, the dihydropyridine derivative MRS 1191, and the triazolonaphthyridine derivative L-249,313. A3 agonist-induced effects were not due to modulation of cell adhesion, nor to necrosis or apoptosis. Growth curves revealed highly impeded growth, and flow-cytometric analysis showed markedly reduced bromodeoxyuridine incorporation into nuclei. The effect on cell cycle was completely antagonized by MRS1191. Hence, activation of the human A3 receptor in A3R-CHO results in markedly impaired cell cycle progression, suggesting an important role for this adenosine receptor subtype in cell cycle regulation and cell growth.
Adenosine↗
Celsior solution and clinical liver transplantation.
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Adolescent↗
CDC25(Mm)/Ras-GRF1 regulates both Ras and Rac signaling pathways.
The Ras-GRF1 exchange factor molecule contains in addition to the catalytic domain two pleckstrin homology (PH1 and PH2), one IQ and one Dbl homology (DH) domains. In this study we investigated the role of such additional domains. We found that a Ras-GRF1 mutant lacking PH1 and IQ domains is sufficient to activate c-fos promoter in response to lysophosphatidic acid (LPA). The same mutant did not increase external stimuli-regulated kinase (ERK) activity, suggesting an additional mechanism for the induction of gene transcription. Isolated DH-PH2 module activates c-Jun NH(2)-terminal kinase and the c-fos promoter in response to LPA, providing the basis for an ERK-independent mechanism. These results provide evidence that Ras-GRF1 acts as a bifunctional molecule on both ERK-dependent and independent pathways.
3T3 Cells↗
Signalling mechanisms involved in P2Y receptor-mediated reactive astrogliosis.
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Animals↗
Sustained bronchoprotection, bronchodilatation, and symptom control during regular formoterol use in asthma of moderate or greater severity. The Canadian FO/OD1 Study Group.
BACKGROUND: Recent studies have raised concern that regular inhalation of beta2 -agonists may cause a worsening of asthma control compared with on-demand dosing regimens. OBJECTIVE: The objective of this study was to compare the effect of twice daily formoterol (Foradil), 4 times daily albuterol, and on-demand albuterol on bronchial hyperresponsiveness (BHR), lung function measurements, symptoms, and other indicators of disease control over 6 months inpatients with asthma of moderate or greater severity receiving concomitant inhaled corticosteroids. We also looked for occurrence of rebound BHR on discontinuation of treatment. METHODS: This was a multicenter, parallel-group, double-blind, clinical trial. Methacholine PC20 was the primary outcome variable. Other outcome variables included symptom scores, use of rescue medication, morning peak expiratory flow (PEF), serial FEV1 measurements, and asthma exacerbations. RESULTS: Of the 271 randomized patients, 217 completed the study. Formoterol was significantly superior to on-demand albuterol with regard to methacholine PC20, FEV1, PEF, symptom scores, and use of rescue medication at each measured time point/interval. Regular albuterol was superior to on-demand albuterol with regard to PC20 and FEV1, but not PEF or various clinical scores. After a small drop in the magnitude of bronchoprotection and bronchodilatation occurring shortly after randomization, there was no evidence of progressive tolerance to either regular treatment for any of the measured variables or of rebound increase in BHR 2 days after the end of treatment. The formoterol group had the lowest number of exacerbation days, as defined by high intake of rescue bronchodilator and/or symptom scores, whereas the number of exacerbations requiring increased corticosteroid coverage was similar in the 3 groups. CONCLUSION: In patients with asthma of moderate or greater severity receiving inhaled corticosteroids, formoterol taken twice daily resulted in superior bronchoprotection, bronchodilatation, and clinical control compared with on-demand albuterol over 6 months. Four times daily albuterol was superior to on-demand albuterol for only some of the end points. Progressive tolerance and a rebound increase in BHR on discontinuation of beta-agonists were not found
Adolescent↗
Is the Ras-MAPK signalling pathway necessary for long-term memory formation?
Genetic and pharmacological experiments have recently implicated several protein kinase cascades in LTP and memory formation. The small GTPases of the Ras subfamily are activated by multiple extracellular stimuli and, via a complex array of downstream effectors, they control a variety of cellular events that culminate in gene transcription. In the well-characterized Aplysia gill-withdrawal reflex, activation of the Ras-dependent mitogen-activated protein kinase (MAPK) cascade is essential for the long-term, but not the short-term, facilitation process. In addition, in the rodent hippocampus, specific inhibition of the MAPK pathway significantly impairs the induction of LTP, which implicates this signalling cascade in hippocampal-dependent behaviour. Mice that lack the neuronal-specific Ras regulator, Ras-GRF (guanine-releasing factor), have severely impaired LTP in the amygdala and a corresponding deficit in long-term memory for aversive events. The results obtained from these different systems demonstrate the involvement of Ras-dependent signalling in neuronal plasticity and behaviour and raise a number of intriguing questions.
Animals↗
Cyclo-oxygenase-2 mediates P2Y receptor-induced reactive astrogliosis.
Excessive cyclo-oxygenase-2 (COX-2) induction may play a role in chronic neurological diseases characterized by inflammation and astrogliosis. We have previously identified an astroglial receptor for extracellular nucleotides, a P2Y receptor, whose stimulation leads to arachidonic acid (AA) release, followed, 3 days later, by morphological changes resembling reactive astrogliosis. Since COX-2 may be upregulated by AA metabolites, we assessed a possible role for COX-2 in P2Y receptor-mediated astrogliosis. A brief challenge of rat astrocytes with the ATP analogue alpha,beta-methylene ATP (alpha,beta(me)ATP) resulted, 24 h later, in significantly increased COX-2 expression. The selective COX-2 inhibitor NS-398 completely abolished alpha,beta(me)ATP-induced astrocytic activation. Constitutive astroglial COX-1 or COX-2 did not play any role in purine-induced reactive astrogliosis. PGE2, a main metabolite of COX-2, also induced astrocytic activation. These data suggest that a P2Y receptor mediates reactive astrogliosis via induction of COX-2. Antagonists selective for this receptor may counteract excessive COX-2 activation in both acute and chronic neurological diseases.
Adenosine Triphosphate↗