International Journal of Technology Assessment in Health Care
INTRODUCTION:Urothelial Bladder Cancer (UBC) is the ninth worldwide most common cancer. In Italy ... more INTRODUCTION:Urothelial Bladder Cancer (UBC) is the ninth worldwide most common cancer. In Italy the prevalence of the disease is about 10 percent, representing the third most prevalent cancer with 180,775 cases in men and 42,757 cases in women. The increase in the incidence requires continuous surveillance and care, resulting in a significant burden on Italian Healthcare System, making any improvement to the strategy for diagnosing and treating this disease important to the medical and scientific community. The aim of this study was to evaluate the burden of UBC in the Italian context, collecting and measuring the total costs of the disease.METHODS:An economic analysis in the National Health Service perspective was carried out, evaluating in six centers direct costs in terms of outpatient, inpatient and emergency care, pharmaceuticals and follow up procedures and indirect costs in terms of productivity losses. Data were collected through aggregated form reports, focusing on patient...
ClinicoEconomics and outcomes research : CEOR, 2017
Urothelial bladder cancer (UBC) is the ninth most common cancer worldwide. In Italy, the prevalen... more Urothelial bladder cancer (UBC) is the ninth most common cancer worldwide. In Italy, the prevalence of the disease is approximately 10%, making it the fourth most prevalent cancer in the country. The increase in prevalence requires continuous surveillance and care, resulting in a significant burden on Italian National Health Service, making any improvement to the strategy for diagnosing and treating this disease important to the medical and scientific community. The aim of this study was to evaluate the UBC cost of illness in the Italian context, collecting the total costs of the disease. An economic analysis was carried out in the context of the National Health Service, using data collected from six centers, in order to evaluate direct costs in terms of outpatient, inpatient, and emergency care; pharmaceuticals and follow-up procedures; and indirect costs in terms of productivity losses. Data were collected through aggregated form reports, focusing on patients with an existing diag...
European neuropsychopharmacology : the journal of the European College of Neuropsychopharmacology, Apr 1, 2017
Antipsychotics (APDs) are divided into first-generation antipsychotics (FGAs) and second-generati... more Antipsychotics (APDs) are divided into first-generation antipsychotics (FGAs) and second-generation antipsychotics (SGAs) based on the concept that SGAs have reduced motor side effects. With this premise, this study examined in HeLa and other cell lines the effects of different APDs on the activation of ERK1/2 (Extracellular signal-regulated kinases) and AKT (Protein Kinase B) kinases, which may be affected in schizophrenia and bipolar disorder. Among the SGAs, Clozapine clearly resulted as the most effective drug inducing ERK1/2 phosphorylation with potency in the low micromolar range. Quetiapine and Olanzapine showed a maximal response of about 50% compared to Clozapine, while FGAs such as Haloperidol and Sulpiride did not have any relevant effect. Among FGAs, Chlorpromazine was able to partially activate ERK1/2 at 30% compared to Clozapine. Referring to AKT activation, Clozapine, Quetiapine and Olanzapine demonstrated a similar efficacy, while FGAs, besides Chlorpromazine, were i...
ABSTRACT Background. Parkinson?s disease is the second most common neurodegenerative disease. The... more ABSTRACT Background. Parkinson?s disease is the second most common neurodegenerative disease. The transplantation of stem cells has emerged as a promising approach to replace lost neurons in order to restore dopamine levels in the striatum. Post Mortem Neural Precursor Cells (PM-NPCs) are a subclass of SVZ-derived neural progenitors, capable of surviving hours after donor death. Their in vitro differentiation yields 30%of neurons. Aims. The potential of PM-NPCs in terms of replacement therapy was investigated in a mouse model of Parkinson disease. Methods. The degeneration of dopaminergic neurons was obtained with MPTP administration. PM-NPCs were administered by stereotaxic injection unilaterally in the striatum. The effects of transplanted cells were determined by means of performance tests aimed at detecting behavioral improvements. Results. Animals treated with GFP-PM-NPCs had a rapid behavioral improvement of starting within the third day after cells transplantation. By means of immunofluorescence staining we observed that the majority of transplanted GFP-PM-NPCs were vital and able to migrate ventrally and caudally from the injection site, and could reach the ipsilateral and contralateral substantia nigra pars compacta. Morphological analyses revealed that transplanted cells in the striatum can differentiate into dopaminergic (40%), cholinergic (40%), and gabaergic neurons (20%). Moreover, by means of HPLC we determined cathecolamines and their metabolites levels into the striata of GFP-PM-NPCs or saline injected mice without finding any significant variation. Conclusions. Our findings suggest how these stem cells may represent a liable source for cellular therapy in neurodegenerative disorders such as Parkinson Disease.
Spinal cord injury (SCI) is a debilitating clinical condition, characterized by a complex of neur... more Spinal cord injury (SCI) is a debilitating clinical condition, characterized by a complex of neurological dysfunctions. Adult neural stem cells (NSCs) from the subventricular zone of the forebrain have been considered a potential tool for cell replacement therapies. We have recently isolated a subclass of neural progenitors from the cadaver of mouse donors. These cells, named Post Mortem Neural Precursor Cells (PM-NPCs), express both erythropoietin and its receptor and their EPO-dependent differentiation abilities produce a significantly higher percentage of neurons than regular NSCs. The aim of the present study was to compare the reparative properties of PM-NPCs and those expressed by NSCs in a mouse model of traumatic spinal cord injury. PM-NPCs and NSCs were administered intravenously, and then functional recovery and fate of transplanted cells were studied. Animals transplanted with PM-NPCs showed a more remarkably improved recovery of hind limb function than NSCs treated anima...
Background. Parkinson?s disease is the second most common neurodegenerative disease. The transpla... more Background. Parkinson?s disease is the second most common neurodegenerative disease. The transplantation of stem cells has emerged as a promising approach to replace lost neurons in order to restore dopamine levels in the striatum. Post Mortem Neural Precursor Cells (PM-NPCs) are a subclass of SVZ-derived neural progenitors, capable of surviving hours after donor death. Their in vitro differentiation yields 30%of neurons. Aims. The potential of PM-NPCs in terms of replacement therapy was investigated in a mouse model of Parkinson disease. Methods. The degeneration of dopaminergic neurons was obtained with MPTP administration. PM-NPCs were administered by stereotaxic injection unilaterally in the striatum. The effects of transplanted cells were determined by means of performance tests aimed at detecting behavioral improvements. Results. Animals treated with GFP-PM-NPCs had a rapid behavioral improvement of starting within the third day after cells transplantation. By means of immunof...
Autism spectrum disorder (ASD) is a congenital neurodevelopmental behavioral disorder that appear... more Autism spectrum disorder (ASD) is a congenital neurodevelopmental behavioral disorder that appears in early childhood. Recent human genetic studies identified the homeobox transcription factor, Engrailed 2 (EN2), as a possible ASD susceptibility gene. En2 knockout mice (En2-/-) display subtle cerebellar neuropathological changes and reduced levels of tyrosine hydroxylase, noradrenaline and serotonin in the hippocampus and cerebral cortex similar to those ones which have been observed in the ASD brain. Furthermore other similarities link En2 knockout mice to ASD patients. Several lines of evidence suggest that serotonin may play an important role in the pathophysiology of the disease. In the present study we measured, by using an HPLC, the 5-HT levels in different brain areas and at different ages in En2-/- mice. In the frontal and occipital cortex, the content of 5HT was reduced in En2-/- 1 and 3 months old mice; in 6 month old mice, the difference was still present, but it was not statistically significant. The 5-HT content of cerebellar cortex was significantly reduced at 1 month old but significantly high when the KO mice reached 3 months of age. The increase was present even at 6 months of age. A similar trend was highlighted by SERT immunolabeling in En2-/- mice compared to control in the same areas and age analyzed. Our findings, in agreement with the current knowledge on the 5-HT system alterations in ASD, confirm the early neurotransmitter deficit with a late compensatory recovery in En2 KO-mice further suggesting that this experimental animal may be considered a good predictive model for the human disease.
Spinal cord injury (SCI) is a debilitating clinical condition, characterized by a complex of neur... more Spinal cord injury (SCI) is a debilitating clinical condition, characterized by a complex of neurological dysfunctions. Neural stem cells from the subventricular zone of the forebrain have been considered a potential tool for cell replacement therapies. We isolated recently a subclass of neural progenitors from the cadaver of mouse donors. These cells, named Post Mortem Neural Precursor Cells (PM-NPCs), express both erythropoietin and its receptor and their EPO-dependent differentiation abilities produce a significantly higher percentage of neurons than regular NSCs. The cholinergic yield is also higher. The aim of the present study was to evaluate the potential repair properties of PM-NPCs in a mouse model of traumatic spinal cord injury. Labeled PM-NPCs, were administered intravenously, then the functional recovery and the fate of transplanted cells were studied. Animals transplanted with PM-NPCs showed a remarkable improved recovery of hind limb function that was evaluated up to ...
Spinal cord injury is a devastating clinical condition, characterized by a complex of neurologica... more Spinal cord injury is a devastating clinical condition, characterized by a complex of neurological dysfunctions. Animal models of spinal cord injury can be used both to investigate the biological responses to injury and to test potential therapies. Contusion or compression injury delivered to the surgically exposed spinal cord are the most widely used models of the pathology. In this report the experimental contusion is performed by using the Infinite Horizon (IH) Impactor device, which allows the creation of a reproducible injury animal model through definition of specific injury parameters. Stem cell transplantation is commonly considered a potentially useful strategy for curing this debilitating condition. Numerous studies have evaluated the effects of transplanting a variety of stem cells. Here we demonstrate an adapted method for spinal cord injury followed by tail vein injection of cells in CD1 mice. In short, we provide procedures for: i) cell labeling with a vital tracer, ii) pre-operative care of mice, iii) execution of a contusive spinal cord injury, and iv) intravenous administration of post mortem neural precursors. This contusion model can be utilized to evaluate the efficacy and safety of stem cell transplantation in a regenerative medicine approach.
Autism spectrum disorder (ASD) is a congenital neurodevelopmental behavioral disorder that appear... more Autism spectrum disorder (ASD) is a congenital neurodevelopmental behavioral disorder that appears in early childhood. Recent human genetic studies identified the homeobox transcription factor, Engrailed 2 (EN2), as a possible ASD susceptibility gene. En2 knockout mice (En2-/-) display subtle cerebellar neuropathological changes and reduced levels of tyrosine hydroxylase, noradrenaline and serotonin in the hippocampus and cerebral cortex similar to those ones which have been observed in the ASD brain. Furthermore other similarities link En2 knockout mice to ASD patients. Several lines of evidence suggest that serotonin may play an important role in the pathophysiology of the disease. In the present study we measured, by using an HPLC, the 5-HT levels in different brain areas and at different ages in En2-/- mice. In the frontal and occipital cortex, the content of 5HT was reduced in En2-/- 1 and 3 months old mice; in 6 month old mice, the difference was still present, but it was not ...
The present review update the relationship between acetaldehyde (ACE) and parkinsonism with a spe... more The present review update the relationship between acetaldehyde (ACE) and parkinsonism with a specific focus on the role of P450 system and CYP 2E1 isozyme particularly. We have indicated that ACE is able to enhance the parkinsonism induced in mice by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine, a neurotoxin able to damage the nigrostriatal dopaminergic pathway. Similarly diethyldithiocarbamate, the main metabolite of disulfiram, a drug widely used to control alcoholism, diallylsulfide (DAS) and phenylisothiocyanate also markedly enhance the toxin-related parkinsonism. All these compounds are substrate/inhibitors of CYP450 2E1 isozyme. The presence of CYP 2E1 has been detected in the dopamine (DA) neurons of rodent Substantia Nigra (SN), but a precise function of the enzyme has not been elucidated yet. By treating CYP 2E1 knockout (KO) mice with the neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine, the SN induced lesion was significantly reduced when compared with the lesion observed in wild-type animals. Several in vivo and in vitro studies led to the conclusion that CYP 2E1 may enhance the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine toxicity in mice by increasing free radical production inside the dopaminergic neurons. ACE is a good substrate for CYP 2E1 enzyme as the other substrate-inhibitors and by this way may facilitate the susceptibility of dopaminergic neurons to toxic events. The literature suggests that ethanol and/or disulfiram may be responsible for toxic parkinsonism in human and it indicates that basal ganglia are the major targets of disulfiram toxicity. A very recent study reports that there are a decreased methylation of the CYP 2E1 gene and increased expression of CYP 2E1 mRNA in Parkinson's disease (PD) patient brains. This study suggests that epigenetic variants of this cytochrome contribute to the susceptibility, thus confirming multiples lines of evidence which indicate a link between environmental toxins and PD.
The possibility to visualize and image the arrangement of proteins within the cell at the molecul... more The possibility to visualize and image the arrangement of proteins within the cell at the molecular level has always been an attraction for scientists in biological research. In particular, for signalling molecules such as GPCRs (G-protein-coupled receptors), the existence of protein aggregates such as oligomers or clusters has been the topic of extensive debate. One of the reasons for this lively argument is that the molecular size is below the diffraction-limited resolution of the conventional microscopy, precluding the direct visualization of protein super-structures. On the other hand, new super-resolution microscopy techniques, such as the PALM (photoactivated localization microscopy), allow the limit of the resolution power of conventional optics to be broken and the localization of single molecules to be determined with a precision of 10-20 nm, close to their molecular size. The application of super-resolution microscopy to study the spatial and temporal organization of GPCRs has brought new insights into receptor arrangement on the plasma membrane. Furthermore, the use of this powerful microscopy technique as a quantitative tool opens up the possibility for investigating and quantifying the number of molecules in biological assemblies and determining the protein stoichiometry in signalling complexes.
Autism spectrum disorder (ASD) is a congenital neurodevelopmental behavioral disorder that appear... more Autism spectrum disorder (ASD) is a congenital neurodevelopmental behavioral disorder that appears in early childhood. Recent human genetic studies identified the homeobox transcription factor, Engrailed 2 (EN2), as a possible ASD susceptibility gene. En2 knockout mice (En2-/-) display subtle cerebellar neuropathological changes and reduced levels of tyrosine hydroxylase, noradrenaline and serotonin in the hippocampus and cerebral cortex similar to those ones which have been observed in the ASD brain. Furthermore other similarities link En2 knockout mice to ASD patients. Several lines of evidence suggest that serotonin may play an important role in the pathophysiology of the disease. In the present study we measured, by using an HPLC, the 5-HT levels in different brain areas and at different ages in En2-/- mice. In the frontal and occipital cortex, the content of 5HT was reduced in En2-/- 1 and 3 months old mice; in 6 month old mice, the difference was still present, but it was not statistically significant. The 5-HT content of cerebellar cortex was significantly reduced at 1 month old but significantly high when the KO mice reached 3 months of age. The increase was present even at 6 months of age. A similar trend was highlighted by SERT immunolabeling in En2-/- mice compared to control in the same areas and age analyzed. Our findings, in agreement with the current knowledge on the 5-HT system alterations in ASD, confirm the early neurotransmitter deficit with a late compensatory recovery in En2 KO-mice further suggesting that this experimental animal may be considered a good predictive model for the human disease.
International Journal of Technology Assessment in Health Care
INTRODUCTION:Urothelial Bladder Cancer (UBC) is the ninth worldwide most common cancer. In Italy ... more INTRODUCTION:Urothelial Bladder Cancer (UBC) is the ninth worldwide most common cancer. In Italy the prevalence of the disease is about 10 percent, representing the third most prevalent cancer with 180,775 cases in men and 42,757 cases in women. The increase in the incidence requires continuous surveillance and care, resulting in a significant burden on Italian Healthcare System, making any improvement to the strategy for diagnosing and treating this disease important to the medical and scientific community. The aim of this study was to evaluate the burden of UBC in the Italian context, collecting and measuring the total costs of the disease.METHODS:An economic analysis in the National Health Service perspective was carried out, evaluating in six centers direct costs in terms of outpatient, inpatient and emergency care, pharmaceuticals and follow up procedures and indirect costs in terms of productivity losses. Data were collected through aggregated form reports, focusing on patient...
ClinicoEconomics and outcomes research : CEOR, 2017
Urothelial bladder cancer (UBC) is the ninth most common cancer worldwide. In Italy, the prevalen... more Urothelial bladder cancer (UBC) is the ninth most common cancer worldwide. In Italy, the prevalence of the disease is approximately 10%, making it the fourth most prevalent cancer in the country. The increase in prevalence requires continuous surveillance and care, resulting in a significant burden on Italian National Health Service, making any improvement to the strategy for diagnosing and treating this disease important to the medical and scientific community. The aim of this study was to evaluate the UBC cost of illness in the Italian context, collecting the total costs of the disease. An economic analysis was carried out in the context of the National Health Service, using data collected from six centers, in order to evaluate direct costs in terms of outpatient, inpatient, and emergency care; pharmaceuticals and follow-up procedures; and indirect costs in terms of productivity losses. Data were collected through aggregated form reports, focusing on patients with an existing diag...
European neuropsychopharmacology : the journal of the European College of Neuropsychopharmacology, Apr 1, 2017
Antipsychotics (APDs) are divided into first-generation antipsychotics (FGAs) and second-generati... more Antipsychotics (APDs) are divided into first-generation antipsychotics (FGAs) and second-generation antipsychotics (SGAs) based on the concept that SGAs have reduced motor side effects. With this premise, this study examined in HeLa and other cell lines the effects of different APDs on the activation of ERK1/2 (Extracellular signal-regulated kinases) and AKT (Protein Kinase B) kinases, which may be affected in schizophrenia and bipolar disorder. Among the SGAs, Clozapine clearly resulted as the most effective drug inducing ERK1/2 phosphorylation with potency in the low micromolar range. Quetiapine and Olanzapine showed a maximal response of about 50% compared to Clozapine, while FGAs such as Haloperidol and Sulpiride did not have any relevant effect. Among FGAs, Chlorpromazine was able to partially activate ERK1/2 at 30% compared to Clozapine. Referring to AKT activation, Clozapine, Quetiapine and Olanzapine demonstrated a similar efficacy, while FGAs, besides Chlorpromazine, were i...
ABSTRACT Background. Parkinson?s disease is the second most common neurodegenerative disease. The... more ABSTRACT Background. Parkinson?s disease is the second most common neurodegenerative disease. The transplantation of stem cells has emerged as a promising approach to replace lost neurons in order to restore dopamine levels in the striatum. Post Mortem Neural Precursor Cells (PM-NPCs) are a subclass of SVZ-derived neural progenitors, capable of surviving hours after donor death. Their in vitro differentiation yields 30%of neurons. Aims. The potential of PM-NPCs in terms of replacement therapy was investigated in a mouse model of Parkinson disease. Methods. The degeneration of dopaminergic neurons was obtained with MPTP administration. PM-NPCs were administered by stereotaxic injection unilaterally in the striatum. The effects of transplanted cells were determined by means of performance tests aimed at detecting behavioral improvements. Results. Animals treated with GFP-PM-NPCs had a rapid behavioral improvement of starting within the third day after cells transplantation. By means of immunofluorescence staining we observed that the majority of transplanted GFP-PM-NPCs were vital and able to migrate ventrally and caudally from the injection site, and could reach the ipsilateral and contralateral substantia nigra pars compacta. Morphological analyses revealed that transplanted cells in the striatum can differentiate into dopaminergic (40%), cholinergic (40%), and gabaergic neurons (20%). Moreover, by means of HPLC we determined cathecolamines and their metabolites levels into the striata of GFP-PM-NPCs or saline injected mice without finding any significant variation. Conclusions. Our findings suggest how these stem cells may represent a liable source for cellular therapy in neurodegenerative disorders such as Parkinson Disease.
Spinal cord injury (SCI) is a debilitating clinical condition, characterized by a complex of neur... more Spinal cord injury (SCI) is a debilitating clinical condition, characterized by a complex of neurological dysfunctions. Adult neural stem cells (NSCs) from the subventricular zone of the forebrain have been considered a potential tool for cell replacement therapies. We have recently isolated a subclass of neural progenitors from the cadaver of mouse donors. These cells, named Post Mortem Neural Precursor Cells (PM-NPCs), express both erythropoietin and its receptor and their EPO-dependent differentiation abilities produce a significantly higher percentage of neurons than regular NSCs. The aim of the present study was to compare the reparative properties of PM-NPCs and those expressed by NSCs in a mouse model of traumatic spinal cord injury. PM-NPCs and NSCs were administered intravenously, and then functional recovery and fate of transplanted cells were studied. Animals transplanted with PM-NPCs showed a more remarkably improved recovery of hind limb function than NSCs treated anima...
Background. Parkinson?s disease is the second most common neurodegenerative disease. The transpla... more Background. Parkinson?s disease is the second most common neurodegenerative disease. The transplantation of stem cells has emerged as a promising approach to replace lost neurons in order to restore dopamine levels in the striatum. Post Mortem Neural Precursor Cells (PM-NPCs) are a subclass of SVZ-derived neural progenitors, capable of surviving hours after donor death. Their in vitro differentiation yields 30%of neurons. Aims. The potential of PM-NPCs in terms of replacement therapy was investigated in a mouse model of Parkinson disease. Methods. The degeneration of dopaminergic neurons was obtained with MPTP administration. PM-NPCs were administered by stereotaxic injection unilaterally in the striatum. The effects of transplanted cells were determined by means of performance tests aimed at detecting behavioral improvements. Results. Animals treated with GFP-PM-NPCs had a rapid behavioral improvement of starting within the third day after cells transplantation. By means of immunof...
Autism spectrum disorder (ASD) is a congenital neurodevelopmental behavioral disorder that appear... more Autism spectrum disorder (ASD) is a congenital neurodevelopmental behavioral disorder that appears in early childhood. Recent human genetic studies identified the homeobox transcription factor, Engrailed 2 (EN2), as a possible ASD susceptibility gene. En2 knockout mice (En2-/-) display subtle cerebellar neuropathological changes and reduced levels of tyrosine hydroxylase, noradrenaline and serotonin in the hippocampus and cerebral cortex similar to those ones which have been observed in the ASD brain. Furthermore other similarities link En2 knockout mice to ASD patients. Several lines of evidence suggest that serotonin may play an important role in the pathophysiology of the disease. In the present study we measured, by using an HPLC, the 5-HT levels in different brain areas and at different ages in En2-/- mice. In the frontal and occipital cortex, the content of 5HT was reduced in En2-/- 1 and 3 months old mice; in 6 month old mice, the difference was still present, but it was not statistically significant. The 5-HT content of cerebellar cortex was significantly reduced at 1 month old but significantly high when the KO mice reached 3 months of age. The increase was present even at 6 months of age. A similar trend was highlighted by SERT immunolabeling in En2-/- mice compared to control in the same areas and age analyzed. Our findings, in agreement with the current knowledge on the 5-HT system alterations in ASD, confirm the early neurotransmitter deficit with a late compensatory recovery in En2 KO-mice further suggesting that this experimental animal may be considered a good predictive model for the human disease.
Spinal cord injury (SCI) is a debilitating clinical condition, characterized by a complex of neur... more Spinal cord injury (SCI) is a debilitating clinical condition, characterized by a complex of neurological dysfunctions. Neural stem cells from the subventricular zone of the forebrain have been considered a potential tool for cell replacement therapies. We isolated recently a subclass of neural progenitors from the cadaver of mouse donors. These cells, named Post Mortem Neural Precursor Cells (PM-NPCs), express both erythropoietin and its receptor and their EPO-dependent differentiation abilities produce a significantly higher percentage of neurons than regular NSCs. The cholinergic yield is also higher. The aim of the present study was to evaluate the potential repair properties of PM-NPCs in a mouse model of traumatic spinal cord injury. Labeled PM-NPCs, were administered intravenously, then the functional recovery and the fate of transplanted cells were studied. Animals transplanted with PM-NPCs showed a remarkable improved recovery of hind limb function that was evaluated up to ...
Spinal cord injury is a devastating clinical condition, characterized by a complex of neurologica... more Spinal cord injury is a devastating clinical condition, characterized by a complex of neurological dysfunctions. Animal models of spinal cord injury can be used both to investigate the biological responses to injury and to test potential therapies. Contusion or compression injury delivered to the surgically exposed spinal cord are the most widely used models of the pathology. In this report the experimental contusion is performed by using the Infinite Horizon (IH) Impactor device, which allows the creation of a reproducible injury animal model through definition of specific injury parameters. Stem cell transplantation is commonly considered a potentially useful strategy for curing this debilitating condition. Numerous studies have evaluated the effects of transplanting a variety of stem cells. Here we demonstrate an adapted method for spinal cord injury followed by tail vein injection of cells in CD1 mice. In short, we provide procedures for: i) cell labeling with a vital tracer, ii) pre-operative care of mice, iii) execution of a contusive spinal cord injury, and iv) intravenous administration of post mortem neural precursors. This contusion model can be utilized to evaluate the efficacy and safety of stem cell transplantation in a regenerative medicine approach.
Autism spectrum disorder (ASD) is a congenital neurodevelopmental behavioral disorder that appear... more Autism spectrum disorder (ASD) is a congenital neurodevelopmental behavioral disorder that appears in early childhood. Recent human genetic studies identified the homeobox transcription factor, Engrailed 2 (EN2), as a possible ASD susceptibility gene. En2 knockout mice (En2-/-) display subtle cerebellar neuropathological changes and reduced levels of tyrosine hydroxylase, noradrenaline and serotonin in the hippocampus and cerebral cortex similar to those ones which have been observed in the ASD brain. Furthermore other similarities link En2 knockout mice to ASD patients. Several lines of evidence suggest that serotonin may play an important role in the pathophysiology of the disease. In the present study we measured, by using an HPLC, the 5-HT levels in different brain areas and at different ages in En2-/- mice. In the frontal and occipital cortex, the content of 5HT was reduced in En2-/- 1 and 3 months old mice; in 6 month old mice, the difference was still present, but it was not ...
The present review update the relationship between acetaldehyde (ACE) and parkinsonism with a spe... more The present review update the relationship between acetaldehyde (ACE) and parkinsonism with a specific focus on the role of P450 system and CYP 2E1 isozyme particularly. We have indicated that ACE is able to enhance the parkinsonism induced in mice by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine, a neurotoxin able to damage the nigrostriatal dopaminergic pathway. Similarly diethyldithiocarbamate, the main metabolite of disulfiram, a drug widely used to control alcoholism, diallylsulfide (DAS) and phenylisothiocyanate also markedly enhance the toxin-related parkinsonism. All these compounds are substrate/inhibitors of CYP450 2E1 isozyme. The presence of CYP 2E1 has been detected in the dopamine (DA) neurons of rodent Substantia Nigra (SN), but a precise function of the enzyme has not been elucidated yet. By treating CYP 2E1 knockout (KO) mice with the neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine, the SN induced lesion was significantly reduced when compared with the lesion observed in wild-type animals. Several in vivo and in vitro studies led to the conclusion that CYP 2E1 may enhance the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine toxicity in mice by increasing free radical production inside the dopaminergic neurons. ACE is a good substrate for CYP 2E1 enzyme as the other substrate-inhibitors and by this way may facilitate the susceptibility of dopaminergic neurons to toxic events. The literature suggests that ethanol and/or disulfiram may be responsible for toxic parkinsonism in human and it indicates that basal ganglia are the major targets of disulfiram toxicity. A very recent study reports that there are a decreased methylation of the CYP 2E1 gene and increased expression of CYP 2E1 mRNA in Parkinson's disease (PD) patient brains. This study suggests that epigenetic variants of this cytochrome contribute to the susceptibility, thus confirming multiples lines of evidence which indicate a link between environmental toxins and PD.
The possibility to visualize and image the arrangement of proteins within the cell at the molecul... more The possibility to visualize and image the arrangement of proteins within the cell at the molecular level has always been an attraction for scientists in biological research. In particular, for signalling molecules such as GPCRs (G-protein-coupled receptors), the existence of protein aggregates such as oligomers or clusters has been the topic of extensive debate. One of the reasons for this lively argument is that the molecular size is below the diffraction-limited resolution of the conventional microscopy, precluding the direct visualization of protein super-structures. On the other hand, new super-resolution microscopy techniques, such as the PALM (photoactivated localization microscopy), allow the limit of the resolution power of conventional optics to be broken and the localization of single molecules to be determined with a precision of 10-20 nm, close to their molecular size. The application of super-resolution microscopy to study the spatial and temporal organization of GPCRs has brought new insights into receptor arrangement on the plasma membrane. Furthermore, the use of this powerful microscopy technique as a quantitative tool opens up the possibility for investigating and quantifying the number of molecules in biological assemblies and determining the protein stoichiometry in signalling complexes.
Autism spectrum disorder (ASD) is a congenital neurodevelopmental behavioral disorder that appear... more Autism spectrum disorder (ASD) is a congenital neurodevelopmental behavioral disorder that appears in early childhood. Recent human genetic studies identified the homeobox transcription factor, Engrailed 2 (EN2), as a possible ASD susceptibility gene. En2 knockout mice (En2-/-) display subtle cerebellar neuropathological changes and reduced levels of tyrosine hydroxylase, noradrenaline and serotonin in the hippocampus and cerebral cortex similar to those ones which have been observed in the ASD brain. Furthermore other similarities link En2 knockout mice to ASD patients. Several lines of evidence suggest that serotonin may play an important role in the pathophysiology of the disease. In the present study we measured, by using an HPLC, the 5-HT levels in different brain areas and at different ages in En2-/- mice. In the frontal and occipital cortex, the content of 5HT was reduced in En2-/- 1 and 3 months old mice; in 6 month old mice, the difference was still present, but it was not statistically significant. The 5-HT content of cerebellar cortex was significantly reduced at 1 month old but significantly high when the KO mice reached 3 months of age. The increase was present even at 6 months of age. A similar trend was highlighted by SERT immunolabeling in En2-/- mice compared to control in the same areas and age analyzed. Our findings, in agreement with the current knowledge on the 5-HT system alterations in ASD, confirm the early neurotransmitter deficit with a late compensatory recovery in En2 KO-mice further suggesting that this experimental animal may be considered a good predictive model for the human disease.
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Papers by Claudio Gerace