Supplemental material, Spplementary_figure for Interleukin-6 Disrupts Synaptic Plasticity and Imp... more Supplemental material, Spplementary_figure for Interleukin-6 Disrupts Synaptic Plasticity and Impairs Tissue Damage Compensation in Multiple Sclerosis by Mario Stampanoni Bassi, Ennio Iezzi, Francesco Mori, Ilaria Simonelli, Luana Gilio, Fabio Buttari, Francesco Sica, Nicla De Paolis, Georgia Mandolesi, Alessandra Musella, Francesca De Vito, Ettore Dolcetti, Antonio Bruno, Roberto Furlan, Annamaria Finardi, Girolama A. Marfia, Diego Centonze and Francesca Romana Rizzo in Neurorehabilitation and Neural Repair
The increasing number and quality of randomized controlled trials (RCTs) employing transcranial d... more The increasing number and quality of randomized controlled trials (RCTs) employing transcranial direct current stimulation (tDCS) denote the rising awareness of neuroscientific community about its electroceutical potential and opening to include these treatments in the framework of medical therapies under the indications of the international authorities. The purpose of this quantitative review is to estimate the recommendation strength applying the Grading of Recommendations, Assessment, Development and Evaluations (GRADE) criteria and PICO (population, intervention, comparison, outcome) model values for effective tDCS treatments on no-structural diseases, and to provide an estimate of Sham effect for future RCTs. Applying GRADE evaluation pathway, we searched in literature the tDCS-based RCTs in psychophysical diseases displaying a major involvement of brain electrical activity imbalances. Three independent authors agreed on Class 1 RCTs (18 studies) and meta-analyses were carried ...
In multiple sclerosis (MS), activated T and B lymphocytes and microglial cells release various pr... more In multiple sclerosis (MS), activated T and B lymphocytes and microglial cells release various proinflammatory cytokines, promoting neuroinflammation and negatively affecting the course of the disease. The immune response homeostasis is crucially regulated by the activity of the enzyme adenosine deaminase (ADA), as evidenced in patients with genetic ADA deficiency and in those treated with cladribine tablets. We investigated in a group of patients with MS the associations of a single nucleotide polymorphism (SNP) of ADA gene with disease characteristics and cerebrospinal fluid (CSF) inflammation. The SNP rs244072 of the ADA gene was determined in 561 patients with MS. Disease characteristics were assessed at the time of diagnosis; furthermore, in 258 patients, proinflammatory and anti-inflammatory molecules were measured in the CSF. We found a significant association between rs244072 and both clinical characteristics and central inflammation. In C-carriers, significantly enhanced di...
In multiple sclerosis (MS), inflammation alters synaptic transmission and plasticity, negatively ... more In multiple sclerosis (MS), inflammation alters synaptic transmission and plasticity, negatively influencing the disease course. In the present study, we aimed to explore the influence of the proinflammatory cytokine IL-1β on peculiar features of associative Hebbian synaptic plasticity, such as input specificity, using the paired associative stimulation (PAS). In 33 relapsing remitting-MS patients and 15 healthy controls, PAS was performed on the abductor pollicis brevis (APB) muscle. The effects over the motor hot spot of the APB and abductor digiti minimi (ADM) muscles were tested immediately after PAS and 15 and 30 min later. Intracortical excitability was tested with paired-pulse transcranial magnetic stimulation (TMS). The cerebrospinal fluid (CSF) levels of IL-1β were calculated. In MS patients, PAS failed to induce long-term potentiation (LTP)-like effects in the APB muscle and elicited a paradoxical motor-evoked potential (MEP) increase in the ADM. IL-1β levels were negative...
Evidence indicates that patients with Alzheimer’s dementia (AD) show signs of copper (Cu) dyshome... more Evidence indicates that patients with Alzheimer’s dementia (AD) show signs of copper (Cu) dyshomeostasis. This study aimed at evaluating the potential of Cu dysregulation as an AD susceptibility factor. We performed a meta-analysis of 56 studies investigating Cu biomarkers in brain specimens (pooled total of 182 AD and 166 healthy controls, HC) and in serum/plasma (pooled total of 2929 AD and 3547 HC). We also completed a replication study of serum Cu biomarkers in 97 AD patients and 70 HC screened for rs732774 and rs1061472 ATP7B, the gene encoding for the Cu transporter ATPase7B. Our meta-analysis showed decreased Cu in AD brain specimens, increased Cu and nonbound ceruloplasmin (Non-Cp) Cu in serum/plasma samples, and unchanged ceruloplasmin. Serum/plasma Cu excess was associated with a three to fourfold increase in the risk of having AD. Our replication study confirmed meta-analysis results and showed that carriers of the ATP7B AG haplotype were significantly more frequent in th...
Background: Synaptic plasticity helps in reducing the clinical expression of brain damage and rep... more Background: Synaptic plasticity helps in reducing the clinical expression of brain damage and represents a useful mechanism to compensate the negative impact of new brain lesions in multiple sclerosis (MS). Inflammation, altering synaptic plasticity, could negatively influence the disease course in relapsing-remitting MS (RR-MS). Objective: In the present study, we explored whether interleukin (IL)-6, a major proinflammatory cytokine involved in MS pathogenesis, alters synaptic plasticity and affects the ability to compensate for ongoing brain damage. Methods: The effect of IL-6 incubation on long-term potentiation (LTP) induction was explored in vitro, in mice hippocampal slices. We also explored the correlation between the cerebrospinal fluid (CSF) levels of this cytokine and the LTP-like effect induced by the paired associative stimulation (PAS) in a group of RR-MS patients. Finally, we examined the correlation between the CSF levels of IL-6 at the time of diagnosis and the prosp...
The Journal of clinical endocrinology and metabolism, Jan 23, 2018
Somatostatin analogs (SSAs) effectivelycontrol growth hormone secretion in first and second line ... more Somatostatin analogs (SSAs) effectivelycontrol growth hormone secretion in first and second line treatmentof acromegaly. Their effect onglucose metabolism is still debated. to address the following questions: 1) Do SSAs affect fasting plasma glucose (FPG), fasting plasma insulin (FPI), glycosylated hemoglobin (HbA1c), glucose load (2h-OGTT), HOMA-I, HOMA-β, triglycerides (TGD), weight (W) or body mass index (BMI)? 2) Do lanreotide (LAN) and octreotide LAR (OCT) affect metabolism differently? 3)Does their effect depend on disease control? We performed a meta-analysis of prospective interventional trialstreating acromegaly with SSAs. Inclusion criteria: all studies reporting glyco-metabolic outcomes before and after SSAs with a minimum 6-month follow-up. The inclusion criteria were met by 47 studies treating 1297 subjects (631 F). SSA treatment effectively lowered FPI (effect size [ES] -6.67 mU/L, 95%CI: -8.38 to -4.95mU/L; p<0.001), HOMA-I (ES -1.57, CI: -2.42 to -0.72; p<0.001...
The Journal of clinical endocrinology and metabolism, Mar 1, 2017
Hirsutism is frequently expressed in women affected by polycystic ovary syndrome (PCOS). The effi... more Hirsutism is frequently expressed in women affected by polycystic ovary syndrome (PCOS). The efficacy of oral contraceptive pill (OC) plus anti-androgens in the treatment of its severe expression is controversial due to the lack of randomized double-blind long-term studies. The primary outcome was the reduction of hirsutism in PCOS women objectively measured by videodermoscopy (VD) on the androgen-sensitive skin areas assessed by the modified Ferriman&Gallwey (mF&G) total score, after 12 months of therapy with OC+Bicalutamide (BC) versus OC plus placebo (P). The secondary outcomes were to evaluate tolerability of bicalutamide and body composition as well as the occurrence of adverse events. This was an experimental, phase III, prospective, multicenter, randomized, double-blind, placebo-controlled trial. Patients were evaluated at the baseline visit, at the sixth and twelfth month during treatment and six months after its end. 70 women with classic PCOS (severe hirsutism, oligo-anovu...
Cognitive deficits are frequently observed in multiple sclerosis (MS), mainly involving processin... more Cognitive deficits are frequently observed in multiple sclerosis (MS), mainly involving processing speed and episodic memory. Both demyelination and gray matter atrophy can contribute to cognitive deficits in MS. In recent years, neuroinflammation is emerging as a new factor influencing clinical course in MS. Inflammatory cytokines induce synaptic dysfunction in MS. Synaptic plasticity occurring within hippocampal structures is considered as one of the basic physiological mechanisms of learning and memory. In experimental models of MS, hippocampal plasticity is profoundly altered by proinflammatory cytokines. Although mechanisms of inflammation-induced hippocampal pathology in MS are not completely understood, alteration of Amyloid-β (Aβ) metabolism is emerging as a key factor linking together inflammation, synaptic plasticity and neurodegeneration in different neurological diseases. We explored the correlation between concentrations of Aβ1-42 and the levels of some proinflammatory ...
The clinical complexity of Internal Medicine patients is a daily challenge for clinicians. Althou... more The clinical complexity of Internal Medicine patients is a daily challenge for clinicians. Although clinical complexity cannot be directly measured, several scores describe the variability of clinical severity and comorbidity. The aim of this study was to analyze staff workload by assessing the nursing and medical complexity of patients admitted to an Internal Medicine ward. We included 40 consecutive inpatients [52.5% females, mean age 71.2 (18.2) years] classified according to the index of clinical complexity (ICC, type A: very high; type B: high; type C: moderate) and the cumulative illness rating scale (CIRS) severity and comorbidity index. Patient outcomes, hospitalization duration, tests performed, number of daily medications and time to perform standard nursing tasks were analysed across groups. Mean duration of hospitalization was 15.6 (10.1) days; in-hospital mortality was 15%. Mean CIRS severity index (SI) was 1.03 (0.31) and median CIRS comorbidity index (CI) was 2 (range...
Supplemental material, Spplementary_figure for Interleukin-6 Disrupts Synaptic Plasticity and Imp... more Supplemental material, Spplementary_figure for Interleukin-6 Disrupts Synaptic Plasticity and Impairs Tissue Damage Compensation in Multiple Sclerosis by Mario Stampanoni Bassi, Ennio Iezzi, Francesco Mori, Ilaria Simonelli, Luana Gilio, Fabio Buttari, Francesco Sica, Nicla De Paolis, Georgia Mandolesi, Alessandra Musella, Francesca De Vito, Ettore Dolcetti, Antonio Bruno, Roberto Furlan, Annamaria Finardi, Girolama A. Marfia, Diego Centonze and Francesca Romana Rizzo in Neurorehabilitation and Neural Repair
The increasing number and quality of randomized controlled trials (RCTs) employing transcranial d... more The increasing number and quality of randomized controlled trials (RCTs) employing transcranial direct current stimulation (tDCS) denote the rising awareness of neuroscientific community about its electroceutical potential and opening to include these treatments in the framework of medical therapies under the indications of the international authorities. The purpose of this quantitative review is to estimate the recommendation strength applying the Grading of Recommendations, Assessment, Development and Evaluations (GRADE) criteria and PICO (population, intervention, comparison, outcome) model values for effective tDCS treatments on no-structural diseases, and to provide an estimate of Sham effect for future RCTs. Applying GRADE evaluation pathway, we searched in literature the tDCS-based RCTs in psychophysical diseases displaying a major involvement of brain electrical activity imbalances. Three independent authors agreed on Class 1 RCTs (18 studies) and meta-analyses were carried ...
In multiple sclerosis (MS), activated T and B lymphocytes and microglial cells release various pr... more In multiple sclerosis (MS), activated T and B lymphocytes and microglial cells release various proinflammatory cytokines, promoting neuroinflammation and negatively affecting the course of the disease. The immune response homeostasis is crucially regulated by the activity of the enzyme adenosine deaminase (ADA), as evidenced in patients with genetic ADA deficiency and in those treated with cladribine tablets. We investigated in a group of patients with MS the associations of a single nucleotide polymorphism (SNP) of ADA gene with disease characteristics and cerebrospinal fluid (CSF) inflammation. The SNP rs244072 of the ADA gene was determined in 561 patients with MS. Disease characteristics were assessed at the time of diagnosis; furthermore, in 258 patients, proinflammatory and anti-inflammatory molecules were measured in the CSF. We found a significant association between rs244072 and both clinical characteristics and central inflammation. In C-carriers, significantly enhanced di...
In multiple sclerosis (MS), inflammation alters synaptic transmission and plasticity, negatively ... more In multiple sclerosis (MS), inflammation alters synaptic transmission and plasticity, negatively influencing the disease course. In the present study, we aimed to explore the influence of the proinflammatory cytokine IL-1β on peculiar features of associative Hebbian synaptic plasticity, such as input specificity, using the paired associative stimulation (PAS). In 33 relapsing remitting-MS patients and 15 healthy controls, PAS was performed on the abductor pollicis brevis (APB) muscle. The effects over the motor hot spot of the APB and abductor digiti minimi (ADM) muscles were tested immediately after PAS and 15 and 30 min later. Intracortical excitability was tested with paired-pulse transcranial magnetic stimulation (TMS). The cerebrospinal fluid (CSF) levels of IL-1β were calculated. In MS patients, PAS failed to induce long-term potentiation (LTP)-like effects in the APB muscle and elicited a paradoxical motor-evoked potential (MEP) increase in the ADM. IL-1β levels were negative...
Evidence indicates that patients with Alzheimer’s dementia (AD) show signs of copper (Cu) dyshome... more Evidence indicates that patients with Alzheimer’s dementia (AD) show signs of copper (Cu) dyshomeostasis. This study aimed at evaluating the potential of Cu dysregulation as an AD susceptibility factor. We performed a meta-analysis of 56 studies investigating Cu biomarkers in brain specimens (pooled total of 182 AD and 166 healthy controls, HC) and in serum/plasma (pooled total of 2929 AD and 3547 HC). We also completed a replication study of serum Cu biomarkers in 97 AD patients and 70 HC screened for rs732774 and rs1061472 ATP7B, the gene encoding for the Cu transporter ATPase7B. Our meta-analysis showed decreased Cu in AD brain specimens, increased Cu and nonbound ceruloplasmin (Non-Cp) Cu in serum/plasma samples, and unchanged ceruloplasmin. Serum/plasma Cu excess was associated with a three to fourfold increase in the risk of having AD. Our replication study confirmed meta-analysis results and showed that carriers of the ATP7B AG haplotype were significantly more frequent in th...
Background: Synaptic plasticity helps in reducing the clinical expression of brain damage and rep... more Background: Synaptic plasticity helps in reducing the clinical expression of brain damage and represents a useful mechanism to compensate the negative impact of new brain lesions in multiple sclerosis (MS). Inflammation, altering synaptic plasticity, could negatively influence the disease course in relapsing-remitting MS (RR-MS). Objective: In the present study, we explored whether interleukin (IL)-6, a major proinflammatory cytokine involved in MS pathogenesis, alters synaptic plasticity and affects the ability to compensate for ongoing brain damage. Methods: The effect of IL-6 incubation on long-term potentiation (LTP) induction was explored in vitro, in mice hippocampal slices. We also explored the correlation between the cerebrospinal fluid (CSF) levels of this cytokine and the LTP-like effect induced by the paired associative stimulation (PAS) in a group of RR-MS patients. Finally, we examined the correlation between the CSF levels of IL-6 at the time of diagnosis and the prosp...
The Journal of clinical endocrinology and metabolism, Jan 23, 2018
Somatostatin analogs (SSAs) effectivelycontrol growth hormone secretion in first and second line ... more Somatostatin analogs (SSAs) effectivelycontrol growth hormone secretion in first and second line treatmentof acromegaly. Their effect onglucose metabolism is still debated. to address the following questions: 1) Do SSAs affect fasting plasma glucose (FPG), fasting plasma insulin (FPI), glycosylated hemoglobin (HbA1c), glucose load (2h-OGTT), HOMA-I, HOMA-β, triglycerides (TGD), weight (W) or body mass index (BMI)? 2) Do lanreotide (LAN) and octreotide LAR (OCT) affect metabolism differently? 3)Does their effect depend on disease control? We performed a meta-analysis of prospective interventional trialstreating acromegaly with SSAs. Inclusion criteria: all studies reporting glyco-metabolic outcomes before and after SSAs with a minimum 6-month follow-up. The inclusion criteria were met by 47 studies treating 1297 subjects (631 F). SSA treatment effectively lowered FPI (effect size [ES] -6.67 mU/L, 95%CI: -8.38 to -4.95mU/L; p<0.001), HOMA-I (ES -1.57, CI: -2.42 to -0.72; p<0.001...
The Journal of clinical endocrinology and metabolism, Mar 1, 2017
Hirsutism is frequently expressed in women affected by polycystic ovary syndrome (PCOS). The effi... more Hirsutism is frequently expressed in women affected by polycystic ovary syndrome (PCOS). The efficacy of oral contraceptive pill (OC) plus anti-androgens in the treatment of its severe expression is controversial due to the lack of randomized double-blind long-term studies. The primary outcome was the reduction of hirsutism in PCOS women objectively measured by videodermoscopy (VD) on the androgen-sensitive skin areas assessed by the modified Ferriman&Gallwey (mF&G) total score, after 12 months of therapy with OC+Bicalutamide (BC) versus OC plus placebo (P). The secondary outcomes were to evaluate tolerability of bicalutamide and body composition as well as the occurrence of adverse events. This was an experimental, phase III, prospective, multicenter, randomized, double-blind, placebo-controlled trial. Patients were evaluated at the baseline visit, at the sixth and twelfth month during treatment and six months after its end. 70 women with classic PCOS (severe hirsutism, oligo-anovu...
Cognitive deficits are frequently observed in multiple sclerosis (MS), mainly involving processin... more Cognitive deficits are frequently observed in multiple sclerosis (MS), mainly involving processing speed and episodic memory. Both demyelination and gray matter atrophy can contribute to cognitive deficits in MS. In recent years, neuroinflammation is emerging as a new factor influencing clinical course in MS. Inflammatory cytokines induce synaptic dysfunction in MS. Synaptic plasticity occurring within hippocampal structures is considered as one of the basic physiological mechanisms of learning and memory. In experimental models of MS, hippocampal plasticity is profoundly altered by proinflammatory cytokines. Although mechanisms of inflammation-induced hippocampal pathology in MS are not completely understood, alteration of Amyloid-β (Aβ) metabolism is emerging as a key factor linking together inflammation, synaptic plasticity and neurodegeneration in different neurological diseases. We explored the correlation between concentrations of Aβ1-42 and the levels of some proinflammatory ...
The clinical complexity of Internal Medicine patients is a daily challenge for clinicians. Althou... more The clinical complexity of Internal Medicine patients is a daily challenge for clinicians. Although clinical complexity cannot be directly measured, several scores describe the variability of clinical severity and comorbidity. The aim of this study was to analyze staff workload by assessing the nursing and medical complexity of patients admitted to an Internal Medicine ward. We included 40 consecutive inpatients [52.5% females, mean age 71.2 (18.2) years] classified according to the index of clinical complexity (ICC, type A: very high; type B: high; type C: moderate) and the cumulative illness rating scale (CIRS) severity and comorbidity index. Patient outcomes, hospitalization duration, tests performed, number of daily medications and time to perform standard nursing tasks were analysed across groups. Mean duration of hospitalization was 15.6 (10.1) days; in-hospital mortality was 15%. Mean CIRS severity index (SI) was 1.03 (0.31) and median CIRS comorbidity index (CI) was 2 (range...
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