Epidemiological studies have demonstrated that patients with diabetes mellitus have an increased ... more Epidemiological studies have demonstrated that patients with diabetes mellitus have an increased risk of developing Alzheimer disease, but the relationship between the 2 entities is not clear. Both diseases exhibit similar metabolic abnormalities: disordered glucose metabolism, abnormal insulin receptor signalling and insulin resistance, oxidative stress, and structural abnormalities in proteins and β-amyloid deposits. Different hypotheses have emerged from experimental work in the last two decades. One of the most comprehensive relates the microvascular damage in diabetic polyneuritis with the central nervous system changes occurring in Alzheimer disease. Another hypothesis considers that cognitive impairment in both diabetes and Alzheimer disease is linked to a state of systemic oxidative stress. Recently, attenuation of cognitive impairment and normalisation of values in biochemical markers for oxidative stress were found in patients with Alzheimer disease and concomitant diabete...
In this brief theoretical work, a new conceptual model is proposed to explain the psychosis of Am... more In this brief theoretical work, a new conceptual model is proposed to explain the psychosis of American chess player Bobby Fischer. Based on the pioneering work of psychoanalysts, we introduce the concept of sinthome, taken from the Lacanian topology of the Borromean knot, with its three registers: real, symbolic and imaginary [RSI], and its fourth stabilizer knot at the breaking of the symbolic. Here we call it chess-sinthome to designate the antipsychotic role fulfilled the ultra-competitive chess, in life and in the minds of some great players.
Gastrocnemius muscle biopsies were performed in 7 subjects with chronic Chagas' disease. On c... more Gastrocnemius muscle biopsies were performed in 7 subjects with chronic Chagas' disease. On clinical and laboratory grounds the selected patients were judged to be healthy, being the only abnormality found the presence of positive serum tests for Chagas' disease. Fibre type grouping of either type I or type II was observed in 5 of the 7 patients. Furthermore, in 2 of the 5 patients showing muscle fibre groupings, angular fibres reacting with NADH and non-specific sterase were also found. These observations strongly suggest denervation associated with reinervation. This picture often can be observed in the skeletal muscle of patients with well compensated denervatory conditions who do not show clinical evidences of denervation.
Charles Morin, MD,* Jacques Dubé, MD,† Brian H. Robinson, PhD,‡ Jacques Lacroix, MD,† Jean Michau... more Charles Morin, MD,* Jacques Dubé, MD,† Brian H. Robinson, PhD,‡ Jacques Lacroix, MD,† Jean Michaud, MD,† Marc De Braekeleer, MD, PhD,§ Guy Geoffroy, MD,† Anne Lortie, MD,† Christine Blanchette, MD, Marie A. ...
Sensory motor multifocal acquired demyelinating neuropathy (SMMADN) is a variant of the chronic m... more Sensory motor multifocal acquired demyelinating neuropathy (SMMADN) is a variant of the chronic multifocal neuropathies. Several reports have been published about the clinical and electrophysiological progression in motor multifocal neuropathy (MMN) prior to and following immunoglobulin (Ig) therapy, but we have found no reports that deal with SMMADN. We describe a case of SMMADN in which we conducted a clinical and electrophysiological evaluation before and after therapy with Ig UNC Hemoderivados. Female, 40 years of age, who presented asymmetrical weakness in all four limbs which she had been suffering for 12 years. We observed distal muscular atrophies, notable weakness and paresthesias in the four limbs. Electrophysiological studies revealed demyelinating neuropathy with secondary axonal involvement. Intravenous Ig was indicated. We observed a clear improvement in muscular strength, and changes in motor and sensory conduction speeds, but not in the amplitudes of the respective p...
We investigated the prevalence of overweight and obesity and their relationships with the main ca... more We investigated the prevalence of overweight and obesity and their relationships with the main cardiovascular risk factors in the population of Ventimiglia di Sicilia, a rural village in Southern Italy characterized by low cholesterol levels and by a low incidence of early coronary heart disease mortality. We related all deaths to body weight and fat distribution during an 8 y follow-up. DESIGN: Cross-sectional and prospective observational study. SUBJECTS: A total of 835 free-living individuals, 363 males and 472 females, of age between 20 and 69 y. MEASUREMENTS: In all participants body weight, waist-to-hip ratio (WHR), cardiovascular risk factors and plasma lipids were measured. During the follow-up, total and cardiovascular deaths were registered. RESULTS: We found a high overall prevalence of subjects with overweight or obesity (respectively 45.0% and 27.7%), with great differences among classes of age. As expected, body weight and fat distribution were associated with diabetes, hypertension, dyslipidemia and with a worsening of lipid pro®le. During the follow-up we registered 37 total and 11 cardiovascular deaths. All-cause and cardiovascular mortality risks were, respectively, 1.64 (95% CI 0.65 ± 4.15) and 2.71 (95% CI 0.29 ± 25.26) in subjects with a body mass index (BMI) of 27 ± 29.99 kgam 2 and 2.45 (95% CI 1.03 ± 5.87) and 5.36 (95% CI 1.41 ± 62.01) in subjects with a BMI of ! 30 kgam 2 in comparison with participants with a BMI of`27 kgam 2 , and 3.48 (95% CI 1.46 ± 8.30) and 4.55 (95% CI 1.12 ± 18.40) in subjects with a WHR higher than the median in comparison with individuals with a WHR lower than the median. CONCLUSION: The Ventimiglia di Sicilia Study highlights the great importance of overweight and obesity as a public health issue in a rural population and indicates that it is necessary to consider the impact of body weight and fat distribution on both total and CHD mortality.
This paper documents aggregate trends in the foreign listings of companies, and analyzes their di... more This paper documents aggregate trends in the foreign listings of companies, and analyzes their distinctive pre-listing characteristics and post-listing performance. In 1986-97, many European companies listed abroad, mainly on U.S. exchanges, while the number of U.S. companies listed in Europe decreased. The characteristics and performance of European companies differ sharply depending on whether they cross-list in the U.S. or within Europe. In the first case, companies tend to be high-tech and export-oriented, and pursue a strategy of rapid expansion with no significant leveraging.
Entrepreneurs may be legally bound to bequeath a minimal stake to non-controlling heirs. The size... more Entrepreneurs may be legally bound to bequeath a minimal stake to non-controlling heirs. The size of this stake can reduce investment in family firms, by reducing the future income they can pledge to external financiers. Using a purpose-built indicator of the permissiveness of inheritance law and data for 10,004 firms from 38 countries in 1990-2006, we find that stricter inheritance law is associated with lower investment in family firms, but does not affect investment in non-family firms. Moreover, as the model predicts, inheritance law affects investment only in family firms that experience a succession.
To assess the histological features of in vivo toluidine blue (TB) uptake in potentially malignan... more To assess the histological features of in vivo toluidine blue (TB) uptake in potentially malignant oral lesions (PML) and to determine whether any were related to clinical Dark versus Pale Royal Blue stain and/or to the malignant/dysplastic nature of the lesions. Frozen sections were used to evaluate TB extra-and intra-epithelial distribution, depth of penetration and nuclear or extra-nuclear uptake. Eighteen lesions were studied. The clinical appearance of a Dark Royal Blue stain was significantly related to the nuclear uptake of the dye. Conversely Pale Royal Blue staining was unrelated to any histological feature. Dark Royal Blue-malignant lesions had more nuclear uptake than benign lesions. The results suggest that Dark Royal Blue staining is the true positive outcome of a TB test and showed that Dark Royal Blue-malignant and Dark Royal Blue-benign lesions have a different histological pattern of uptake.
The most important complication of oral lichen planus (OLP) is the development of oral squamous c... more The most important complication of oral lichen planus (OLP) is the development of oral squamous cell carcinoma (OSCC) but this is a very controversial matter. The aim of the study was to estimate in a Northern Italian cohort of OLP patients the risk for OSCC. Four hundred and two patients with histologically confirmed OLP diagnosed from January 1988 to July 1999, were followed-up to the end of February 2001. The standardized incidence ratio (SIR) of OSCC was calculated for the entire cohort and specific for gender, type of OLP, therapy for OLP and hepatitis C virus (HCV) infection. The relative risk (RR) of OSCC according to HCV infection was also estimated in the cohort. During the follow-up period, two men (1.3%) and seven women (2.9%) developed an OSCC. The SIR was 44.9 (95% CI: 20.5-85.2), being higher among women, but statistically significant in both genders. The RR of OSCC for patients with HCV as compared with those without HCV infection was 3.16 (0.8-12.5). Patients with OLP had a significantly increased risk of OSCC, irrespective of the clinical type of OLP and therapy. HCV infection apparently increased the risk for OSCC although this result could reflect the role of confounders, such as liver cirrhosis. #
Ubiquitin-specific proteases (USPs) are a subclass of cysteine proteases that catalyze the remova... more Ubiquitin-specific proteases (USPs) are a subclass of cysteine proteases that catalyze the removal of ubiquitin (either monomeric or chains) from substrates, thus counteracting the activity of E3 ubiquitin ligases. Although the importance of USPs in a multitude of processes, from hereditary cancer to neurodegeneration, is well established, our knowledge on their mode of regulation, substrate specificity and biological function is quite limited. In this study we identify USP47 as a novel interactor of the E3 ubiquitin ligase, Skp1/Cul1/ F-box protein b-transducin repeat-containing protein (SCF b-Trcp ). We found that both b-Trcp1 and b-Trcp2 bind specifically to USP47, and point mutations in the b-Trcp WD-repeat region completely abolished USP47 binding, indicating an E3-substrate-type interaction. However, unlike canonical b-Trcp substrates, USP47 protein levels were neither affected by silencing of b-Trcp nor modulated in a variety of processes, such as cell-cycle progression, DNA damage checkpoint responses or tumor necrosis factor (TNF) pathway activation. Notably, genetic or siRNA-mediated depletion of USP47 induced accumulation of Cdc25A, decreased cell survival and augmented the cytotoxic effects of anticancer drugs. In conclusion, we showed that USP47, a novel b-Trcp interactor, regulates cell growth and survival, potentially providing a novel target for anticancer therapies.
Whereas most SCF substrates require phosphorylation to interact with their F-box proteins, phosph... more Whereas most SCF substrates require phosphorylation to interact with their F-box proteins, phosphorylation of p85β on Tyr 655, which is adjacent to the degron, inhibits p85β binding to FBXL2. Dephosphorylation of phospho-Tyr-655 by PTPL1 stimulates p85β binding to and degradation through FBXL2. Finally, defects in the FBXL2-mediated degradation of p85β inhibit the binding of p110 subunits to IRS1, attenuate the PI(3)K signalling cascade and promote autophagy. We propose that FBXL2 and PTPL1 suppress p85β levels, preventing the inhibition of PI(3)K by an excess of free p85 that could compete with p85-p110 heterodimers for IRS1.
Ubiquitin-mediated proteolysis is involved in the turnover of many short-lived regulatory protein... more Ubiquitin-mediated proteolysis is involved in the turnover of many short-lived regulatory proteins. This pathway leads to the covalent attachment of one or more multiubiquitin chains to target substrates which are then degraded by the 26S multicatalytic proteasome complex. Multiple classes of regulatory enzymes have been identified that mediate either ubiquitin conjugation or ubiquitin deconjugation from target substrates.
Epidemiological studies have demonstrated that patients with diabetes mellitus have an increased ... more Epidemiological studies have demonstrated that patients with diabetes mellitus have an increased risk of developing Alzheimer disease, but the relationship between the 2 entities is not clear. Both diseases exhibit similar metabolic abnormalities: disordered glucose metabolism, abnormal insulin receptor signalling and insulin resistance, oxidative stress, and structural abnormalities in proteins and β-amyloid deposits. Different hypotheses have emerged from experimental work in the last two decades. One of the most comprehensive relates the microvascular damage in diabetic polyneuritis with the central nervous system changes occurring in Alzheimer disease. Another hypothesis considers that cognitive impairment in both diabetes and Alzheimer disease is linked to a state of systemic oxidative stress. Recently, attenuation of cognitive impairment and normalisation of values in biochemical markers for oxidative stress were found in patients with Alzheimer disease and concomitant diabete...
In this brief theoretical work, a new conceptual model is proposed to explain the psychosis of Am... more In this brief theoretical work, a new conceptual model is proposed to explain the psychosis of American chess player Bobby Fischer. Based on the pioneering work of psychoanalysts, we introduce the concept of sinthome, taken from the Lacanian topology of the Borromean knot, with its three registers: real, symbolic and imaginary [RSI], and its fourth stabilizer knot at the breaking of the symbolic. Here we call it chess-sinthome to designate the antipsychotic role fulfilled the ultra-competitive chess, in life and in the minds of some great players.
Gastrocnemius muscle biopsies were performed in 7 subjects with chronic Chagas' disease. On c... more Gastrocnemius muscle biopsies were performed in 7 subjects with chronic Chagas' disease. On clinical and laboratory grounds the selected patients were judged to be healthy, being the only abnormality found the presence of positive serum tests for Chagas' disease. Fibre type grouping of either type I or type II was observed in 5 of the 7 patients. Furthermore, in 2 of the 5 patients showing muscle fibre groupings, angular fibres reacting with NADH and non-specific sterase were also found. These observations strongly suggest denervation associated with reinervation. This picture often can be observed in the skeletal muscle of patients with well compensated denervatory conditions who do not show clinical evidences of denervation.
Charles Morin, MD,* Jacques Dubé, MD,† Brian H. Robinson, PhD,‡ Jacques Lacroix, MD,† Jean Michau... more Charles Morin, MD,* Jacques Dubé, MD,† Brian H. Robinson, PhD,‡ Jacques Lacroix, MD,† Jean Michaud, MD,† Marc De Braekeleer, MD, PhD,§ Guy Geoffroy, MD,† Anne Lortie, MD,† Christine Blanchette, MD, Marie A. ...
Sensory motor multifocal acquired demyelinating neuropathy (SMMADN) is a variant of the chronic m... more Sensory motor multifocal acquired demyelinating neuropathy (SMMADN) is a variant of the chronic multifocal neuropathies. Several reports have been published about the clinical and electrophysiological progression in motor multifocal neuropathy (MMN) prior to and following immunoglobulin (Ig) therapy, but we have found no reports that deal with SMMADN. We describe a case of SMMADN in which we conducted a clinical and electrophysiological evaluation before and after therapy with Ig UNC Hemoderivados. Female, 40 years of age, who presented asymmetrical weakness in all four limbs which she had been suffering for 12 years. We observed distal muscular atrophies, notable weakness and paresthesias in the four limbs. Electrophysiological studies revealed demyelinating neuropathy with secondary axonal involvement. Intravenous Ig was indicated. We observed a clear improvement in muscular strength, and changes in motor and sensory conduction speeds, but not in the amplitudes of the respective p...
We investigated the prevalence of overweight and obesity and their relationships with the main ca... more We investigated the prevalence of overweight and obesity and their relationships with the main cardiovascular risk factors in the population of Ventimiglia di Sicilia, a rural village in Southern Italy characterized by low cholesterol levels and by a low incidence of early coronary heart disease mortality. We related all deaths to body weight and fat distribution during an 8 y follow-up. DESIGN: Cross-sectional and prospective observational study. SUBJECTS: A total of 835 free-living individuals, 363 males and 472 females, of age between 20 and 69 y. MEASUREMENTS: In all participants body weight, waist-to-hip ratio (WHR), cardiovascular risk factors and plasma lipids were measured. During the follow-up, total and cardiovascular deaths were registered. RESULTS: We found a high overall prevalence of subjects with overweight or obesity (respectively 45.0% and 27.7%), with great differences among classes of age. As expected, body weight and fat distribution were associated with diabetes, hypertension, dyslipidemia and with a worsening of lipid pro®le. During the follow-up we registered 37 total and 11 cardiovascular deaths. All-cause and cardiovascular mortality risks were, respectively, 1.64 (95% CI 0.65 ± 4.15) and 2.71 (95% CI 0.29 ± 25.26) in subjects with a body mass index (BMI) of 27 ± 29.99 kgam 2 and 2.45 (95% CI 1.03 ± 5.87) and 5.36 (95% CI 1.41 ± 62.01) in subjects with a BMI of ! 30 kgam 2 in comparison with participants with a BMI of`27 kgam 2 , and 3.48 (95% CI 1.46 ± 8.30) and 4.55 (95% CI 1.12 ± 18.40) in subjects with a WHR higher than the median in comparison with individuals with a WHR lower than the median. CONCLUSION: The Ventimiglia di Sicilia Study highlights the great importance of overweight and obesity as a public health issue in a rural population and indicates that it is necessary to consider the impact of body weight and fat distribution on both total and CHD mortality.
This paper documents aggregate trends in the foreign listings of companies, and analyzes their di... more This paper documents aggregate trends in the foreign listings of companies, and analyzes their distinctive pre-listing characteristics and post-listing performance. In 1986-97, many European companies listed abroad, mainly on U.S. exchanges, while the number of U.S. companies listed in Europe decreased. The characteristics and performance of European companies differ sharply depending on whether they cross-list in the U.S. or within Europe. In the first case, companies tend to be high-tech and export-oriented, and pursue a strategy of rapid expansion with no significant leveraging.
Entrepreneurs may be legally bound to bequeath a minimal stake to non-controlling heirs. The size... more Entrepreneurs may be legally bound to bequeath a minimal stake to non-controlling heirs. The size of this stake can reduce investment in family firms, by reducing the future income they can pledge to external financiers. Using a purpose-built indicator of the permissiveness of inheritance law and data for 10,004 firms from 38 countries in 1990-2006, we find that stricter inheritance law is associated with lower investment in family firms, but does not affect investment in non-family firms. Moreover, as the model predicts, inheritance law affects investment only in family firms that experience a succession.
To assess the histological features of in vivo toluidine blue (TB) uptake in potentially malignan... more To assess the histological features of in vivo toluidine blue (TB) uptake in potentially malignant oral lesions (PML) and to determine whether any were related to clinical Dark versus Pale Royal Blue stain and/or to the malignant/dysplastic nature of the lesions. Frozen sections were used to evaluate TB extra-and intra-epithelial distribution, depth of penetration and nuclear or extra-nuclear uptake. Eighteen lesions were studied. The clinical appearance of a Dark Royal Blue stain was significantly related to the nuclear uptake of the dye. Conversely Pale Royal Blue staining was unrelated to any histological feature. Dark Royal Blue-malignant lesions had more nuclear uptake than benign lesions. The results suggest that Dark Royal Blue staining is the true positive outcome of a TB test and showed that Dark Royal Blue-malignant and Dark Royal Blue-benign lesions have a different histological pattern of uptake.
The most important complication of oral lichen planus (OLP) is the development of oral squamous c... more The most important complication of oral lichen planus (OLP) is the development of oral squamous cell carcinoma (OSCC) but this is a very controversial matter. The aim of the study was to estimate in a Northern Italian cohort of OLP patients the risk for OSCC. Four hundred and two patients with histologically confirmed OLP diagnosed from January 1988 to July 1999, were followed-up to the end of February 2001. The standardized incidence ratio (SIR) of OSCC was calculated for the entire cohort and specific for gender, type of OLP, therapy for OLP and hepatitis C virus (HCV) infection. The relative risk (RR) of OSCC according to HCV infection was also estimated in the cohort. During the follow-up period, two men (1.3%) and seven women (2.9%) developed an OSCC. The SIR was 44.9 (95% CI: 20.5-85.2), being higher among women, but statistically significant in both genders. The RR of OSCC for patients with HCV as compared with those without HCV infection was 3.16 (0.8-12.5). Patients with OLP had a significantly increased risk of OSCC, irrespective of the clinical type of OLP and therapy. HCV infection apparently increased the risk for OSCC although this result could reflect the role of confounders, such as liver cirrhosis. #
Ubiquitin-specific proteases (USPs) are a subclass of cysteine proteases that catalyze the remova... more Ubiquitin-specific proteases (USPs) are a subclass of cysteine proteases that catalyze the removal of ubiquitin (either monomeric or chains) from substrates, thus counteracting the activity of E3 ubiquitin ligases. Although the importance of USPs in a multitude of processes, from hereditary cancer to neurodegeneration, is well established, our knowledge on their mode of regulation, substrate specificity and biological function is quite limited. In this study we identify USP47 as a novel interactor of the E3 ubiquitin ligase, Skp1/Cul1/ F-box protein b-transducin repeat-containing protein (SCF b-Trcp ). We found that both b-Trcp1 and b-Trcp2 bind specifically to USP47, and point mutations in the b-Trcp WD-repeat region completely abolished USP47 binding, indicating an E3-substrate-type interaction. However, unlike canonical b-Trcp substrates, USP47 protein levels were neither affected by silencing of b-Trcp nor modulated in a variety of processes, such as cell-cycle progression, DNA damage checkpoint responses or tumor necrosis factor (TNF) pathway activation. Notably, genetic or siRNA-mediated depletion of USP47 induced accumulation of Cdc25A, decreased cell survival and augmented the cytotoxic effects of anticancer drugs. In conclusion, we showed that USP47, a novel b-Trcp interactor, regulates cell growth and survival, potentially providing a novel target for anticancer therapies.
Whereas most SCF substrates require phosphorylation to interact with their F-box proteins, phosph... more Whereas most SCF substrates require phosphorylation to interact with their F-box proteins, phosphorylation of p85β on Tyr 655, which is adjacent to the degron, inhibits p85β binding to FBXL2. Dephosphorylation of phospho-Tyr-655 by PTPL1 stimulates p85β binding to and degradation through FBXL2. Finally, defects in the FBXL2-mediated degradation of p85β inhibit the binding of p110 subunits to IRS1, attenuate the PI(3)K signalling cascade and promote autophagy. We propose that FBXL2 and PTPL1 suppress p85β levels, preventing the inhibition of PI(3)K by an excess of free p85 that could compete with p85-p110 heterodimers for IRS1.
Ubiquitin-mediated proteolysis is involved in the turnover of many short-lived regulatory protein... more Ubiquitin-mediated proteolysis is involved in the turnover of many short-lived regulatory proteins. This pathway leads to the covalent attachment of one or more multiubiquitin chains to target substrates which are then degraded by the 26S multicatalytic proteasome complex. Multiple classes of regulatory enzymes have been identified that mediate either ubiquitin conjugation or ubiquitin deconjugation from target substrates.
Uploads
Papers by M. Pagano