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1.
Eur J Health Law ; 30(5): 507-532, 2023 05 26.
Article in English | MEDLINE | ID: mdl-37582521

ABSTRACT

The AI presence in healthcare (e.g., telemedicine platforms and Software as Medical Devices) is uncontroversial by now. Beyond the Big Tech already for some time large investors in this field, the States, repeatedly accused to be unable keeping pace with the exponential technological development, are growingly called upon to deal with it. Taking the distance from those who perceive the US as a regulatory model to oppose in order to assert the EU digital sovereignty, the present analysis will prove that a glimpse across the Atlantic could only help the EU legislator. With a specific focus on the SaMD regulation, it will be shown how the choices made in the US appear to be grounded on a fair balance between patient and economic operators' rights. Building on it, a new balancing formula needs to be put forward to guide the EU intensive legislative activity for the digital world.


Subject(s)
Software , Telemedicine , Humans
2.
Int J Oral Maxillofac Implants ; 37(5): 891-904, 2022.
Article in English | MEDLINE | ID: mdl-36170303

ABSTRACT

PURPOSE: To evaluate the role of different healing abutment designs in compensating for the buccolingual volumetric tissue change that occurs following flapless single-tooth immediate extraction placement in the molar area. MATERIALS AND METHODS: Patients in need of extraction and replacement of a first or second molar in the mandible or maxilla were consecutively recruited. Immediately after extraction and implant placement, an abutment was connected. Five different types of abutments were randomly selected to be used for each case. The study population was divided into five categories according to abutment design: 5-mm diameter healing abutment (group 1); 6-mm diameter healing abutment (group 2); 7.5-mm diameter healing abutment (group 3); provisional restoration (group 4); and customized healing abutment (group 5). The buccopalatal dimension (BPD) was measured on the study casts at 1, 3, and 5 mm apical to the free gingival margin, and horizontal volumetric changes were compared between baseline and 2, 4, and 6 months. RESULTS: A total of 267 implants were inserted in 246 patients. The breakdown of placed implants for each group was as follows: 67 implants in group 1; 64 in group 2; 71 in group 3; 33 in group 4; and 32 in group 5. Changes in the mean horizontal ridge dimension were as follows. After 6 months in group 1, BPD diminished at 1-, 3-, and 5-mm distance from the free gingival margin, respectively, by 4.21 ± 0.158, 3.38 ± 0. 178 and 2.35 ± 0.178 mm. In group 2, BPD diminished at 1-, 3-, and 5-mm distance from the free gingival margin, respectively, by 3.16 ± 0.198, 2.56 ± 0.198, and 1.62 ± 0.198 mm. In group 3, BPD diminished at 1-, 3-, and 5-mm distance from the free gingival margin, respectively, by 2.53 ± 0.138, 2.16 ± 0.144, and 1.56 ± 0.144 mm. In group 4, BPD diminished at 1-, 3-, and 5-mm distance from the free gingival margin, respectively, by 1.11 ± 0.179, 1.23 ± 0.179, and 1.12 ± 0.179 mm. In group 5, BPD diminished at 1-, 3-, and 5-mm distance from the free gingival margin, respectively, by 0.25 ± 0.225, 0.30 ± 0.225, and 0.19 ± 0.225 mm. Mixed-effect regression and post hoc means comparisons were used to model the impact of the restoration technique, height of measurement, and time on BPD using a significance reference level of .05. Statistical analysis showed that the type of abutment, the height of measurement, and the time significantly influenced the BPD and that there were complex interaction effects between these variables. CONCLUSION: The observed volumetric soft tissue changes in the 6-month short-term follow-up appeared to vary based on the use of different healing abutment sizes that were connected to implants placed immediately after tooth extraction in the molar area. In particular, the use of a customized healing abutment resulted in preservation of the original horizontal dimension of the molar soft tissue.


Subject(s)
Dental Implants, Single-Tooth , Dental Implants , Immediate Dental Implant Loading , Humans , Molar/surgery , Tooth Extraction/adverse effects , Tooth Socket/surgery
3.
Neurosci Lett ; 506(1): 94-9, 2012 Jan 06.
Article in English | MEDLINE | ID: mdl-22056484

ABSTRACT

The purpose of this study was to investigate the microglia-driven apoptosis and the Aß deposits triggered generation of new microglial cells in the neocortex of TgCRND8 mice. Three- and seven-month-old TgCRND8 mice, displaying an early and widespread amyloid deposition, respectively, were used. In 7-month-old TgCRND8 mice the Aß-associated glial reaction was accompanied by an intense immunoreactivity of both TNF-α and inducible nitric oxide synthase, increased immunoreactivity of the pro-apoptotic protein Bax and a decrease in levels of the anti-apoptotic protein Bcl-2.Cortical and hippocampal neurons of TgCRND8 mice displayed higher immunoreactivity and higher nuclear expression of the transcription factor NF-kB than controls. It is possible that such an increase could represent a defence/compensatory response to degeneration. These findings indicate that Aß deposits activate brain-resident microglia population and astrocytes, and induce overproduction of inflammatory mediators that enhance pro- and anti-apoptotic cascades. In both 3- and 7-month-old TgCRND8 mice apparent gliogenesis was present in the vicinity of Aß plaques in the neocortex, indicating that microglia have a high proliferative rate which might play a more complex role than previously acknowledge.


Subject(s)
Alzheimer Disease/pathology , Alzheimer Disease/physiopathology , Apoptosis/genetics , Cerebral Cortex/pathology , Neuroglia/physiology , Plaque, Amyloid/pathology , Age Factors , Alzheimer Disease/genetics , Amyloid beta-Protein Precursor/genetics , Animals , Bromodeoxyuridine/metabolism , Calcium-Binding Proteins/metabolism , Cell Proliferation , Disease Models, Animal , Gene Expression Regulation/genetics , Glial Fibrillary Acidic Protein/metabolism , Humans , Mice , Mice, Transgenic , Microfilament Proteins/metabolism , Mutation/genetics , Neurons/physiology , Nitric Oxide Synthase Type II/metabolism
4.
PLoS One ; 5(12): e14382, 2010 Dec 20.
Article in English | MEDLINE | ID: mdl-21187954

ABSTRACT

BACKGROUND: Alzheimer's disease (AD) is a neurodegenerative disorder characterized by progressive deterioration of cognitive functions, extracellular ß-amyloid (Aß) plaques and intracellular neurofibrillary tangles within neocortex and hippocampus. Adult hippocampal neurogenesis plays an important role in learning and memory processes and its abnormal regulation might account for cognitive impairments associated with AD. METHODOLOGY/PRINCIPAL FINDINGS: The double transgenic (Tg) CRND8 mice (overexpressing the Swedish and Indiana mutations in the human amyloid precursor protein), aged 2 and 6 months, were used to examine in vivo the effects of 5 weeks lithium treatment. BrdU labelling showed a decreased neurogenesis in the subgranular zone of Tg mice compared to non-Tg mice. The decrease of hippocampal neurogenesis was accompanied by behavioural deficits and worsened with age and pathology severity. The differentiation into neurons and maturation of the proliferating cells were also markedly impaired in the Tg mice. Lithium treatment to 2-month-old Tg mice significantly stimulated the proliferation and neuron fate specification of newborn cells and fully counteracted the transgene-induced impairments of cognitive functions. The drug, by the inhibition of GSK-3ß and subsequent activation of Wnt/ß-catenin signalling promoted hippocampal neurogenesis. Finally, the data show that the lithium's ability to stimulate neurogenesis and cognitive functions was lost in the aged Tg mice, thus indicating that the lithium-induced facilitation of neurogenesis and cognitive functions declines as brain Aß deposition and pathology increases. CONCLUSIONS: Lithium, when given on time, stimulates neurogenesis and counteracts AD-like pathology.


Subject(s)
Amyloid beta-Protein Precursor/genetics , Amyloid beta-Protein Precursor/metabolism , Cerebral Cortex/drug effects , Hippocampus/drug effects , Lithium/pharmacology , Neurons/metabolism , Animals , Antipsychotic Agents/pharmacology , Cell Survival , Cerebral Cortex/metabolism , Cognition/drug effects , Dentate Gyrus/metabolism , Female , Hippocampus/metabolism , Male , Mice , Mice, Transgenic , Mutation , Wnt Proteins/metabolism
5.
J Neurochem ; 112(6): 1539-51, 2010 Mar.
Article in English | MEDLINE | ID: mdl-20050968

ABSTRACT

To investigate the role of the Wnt inhibitor Dickkopf-1 (DKK-1) in the pathophysiology of neurodegenerative diseases, we analysed DKK-1 expression and localization in transgenic mouse models expressing familial Alzheimer's disease mutations and a frontotemporal dementia mutation. A significant increase of DKK-1 expression was found in the diseased brain areas of all transgenic lines, where it co-localized with hyperphosphorylated tau-bearing neurons. In TgCRND8 mice, DKK-1 immunoreactivity was detected in neurons surrounding amyloid deposits and within the choline acetyltransferase-positive neurons of the basal forebrain. Active glycogen synthase kinase-3 (GSK-3) was found to co-localize with DKK-1 and phospho-tau staining. Downstream to GSK-3, a significant reduction in beta-catenin translocation to the nucleus, indicative of impaired Wnt signaling functions, was found as well. Cumulatively, our findings indicate that DKK-1 expression is associated with events that lead to neuronal death in neurodegenerative diseases and support a role for DKK-1 as a key mediator of neurodegeneration with therapeutic potential.


Subject(s)
Gene Expression Regulation/physiology , Intercellular Signaling Peptides and Proteins/metabolism , Neurodegenerative Diseases/metabolism , Age Factors , Amyloid beta-Peptides/metabolism , Amyloid beta-Protein Precursor/genetics , Analysis of Variance , Animals , Antibodies, Monoclonal/metabolism , Brain/cytology , Brain/metabolism , Choline O-Acetyltransferase/metabolism , Disease Models, Animal , Gene Expression Regulation/genetics , Glycogen Synthase Kinase 3/metabolism , Humans , Intercellular Signaling Peptides and Proteins/genetics , LDL-Receptor Related Proteins/genetics , LDL-Receptor Related Proteins/metabolism , Low Density Lipoprotein Receptor-Related Protein-5 , Mice , Mice, Inbred C57BL , Mice, Transgenic , Mutation/genetics , Neurodegenerative Diseases/genetics , Neurodegenerative Diseases/pathology , Neurons/metabolism , Peptide Fragments/metabolism , Phosphopyruvate Hydratase/metabolism , Presenilin-1/genetics , beta Catenin/metabolism , tau Proteins/metabolism
6.
J Alzheimers Dis ; 17(2): 423-40, 2009.
Article in English | MEDLINE | ID: mdl-19363260

ABSTRACT

Clioquinol (CQ) is a "metal protein attenuating compound" that crosses the blood-brain barrier and binds, with high affinity, copper(II) and zinc(II), two metal ions critically involved in amyloid-beta aggregation and toxicity. CQ was recently proposed for the treatment of Alzheimer's disease, but controversial data have been reported so far concerning its real therapeutic advantages. We describe here results of chronic CQ treatment in the TgCRND8 mouse model of Alzheimer's disease. Remarkably, based on classical behavioral tests, CQ treatment was found to reverse, to a large extent, the working memory impairments that are characteristic of this mouse model. Pairwise, a significant reduction of amyloid-beta plaque burden, both in the cortex and in the hippocampus, was detected as well as an attenuation of astrogliosis. MALDI Mass Spectrometry Imaging technique revealed a specific localization of CQ in the above mentioned brain areas. Modest but significant effects on the absolute and relative brain concentrations of the three most important biometals (i.e., copper, zinc, and iron) were highlighted following CQ treatment. The pharmacological and mechanistic implications of the above findings are thoroughly discussed.


Subject(s)
Alzheimer Disease/drug therapy , Amyloid beta-Peptides/metabolism , Clioquinol/pharmacology , Clioquinol/therapeutic use , Memory Disorders/drug therapy , Memory, Short-Term/drug effects , Alzheimer Disease/complications , Alzheimer Disease/metabolism , Alzheimer Disease/pathology , Amyloid beta-Protein Precursor/genetics , Analysis of Variance , Animals , Body Weight/drug effects , Cerebral Cortex/metabolism , Cerebral Cortex/pathology , Disease Models, Animal , Glial Fibrillary Acidic Protein/metabolism , Hippocampus/metabolism , Hippocampus/pathology , Humans , Maze Learning/drug effects , Memory Disorders/etiology , Metals/analysis , Mice , Mice, Inbred C57BL , Mice, Transgenic , Reaction Time/drug effects , Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization/methods
7.
Neurobiol Dis ; 31(1): 145-58, 2008 Jul.
Article in English | MEDLINE | ID: mdl-18571100

ABSTRACT

In a comprehensive proteomics study aiming at the identification of proteins associated with amyloid-beta (Abeta)-mediated toxicity in cultured cortical neurons, we have identified Thimet oligopeptidase (THOP1). Functional modulation of THOP1 levels in primary cortical neurons demonstrated that its overexpression was neuroprotective against Abeta toxicity, while RNAi knockdown made neurons more vulnerable to amyloid peptide. In the TgCRND8 transgenic mouse model of amyloid plaque deposition, an age-dependent increase of THOP1 expression was found in brain tissue, where it co-localized with Abeta plaques. In accordance with these findings, THOP1 expression was significantly increased in human AD brain tissue as compared to non-demented controls. These results provide compelling evidence for a neuroprotective role of THOP1 against toxic effects of Abeta in the early stages of AD pathology, and suggest that the observed increase in THOP1 expression might be part of a compensatory defense mechanism of the brain against an increased Abeta load.


Subject(s)
Alzheimer Disease/enzymology , Amyloid beta-Peptides/toxicity , Cerebral Cortex/enzymology , Metalloendopeptidases/biosynthesis , Neurons/enzymology , Aged , Aged, 80 and over , Alzheimer Disease/pathology , Animals , Blotting, Western , Cells, Cultured , Cerebral Cortex/pathology , Female , Gene Expression , Humans , Immunohistochemistry , Male , Mice , Mice, Transgenic , Microscopy, Confocal , Middle Aged , Neurons/pathology , Plaque, Amyloid/metabolism , RNA, Small Interfering , Rats , Rats, Sprague-Dawley , Reverse Transcriptase Polymerase Chain Reaction , Transfection
8.
Mol Immunol ; 45(4): 1056-62, 2008 Feb.
Article in English | MEDLINE | ID: mdl-17850871

ABSTRACT

In vitro and in vivo studies indicate that Alzheimer's Disease (AD) could be prevented or treated by active immunization against self-peptide beta-amyloid. In this study, we compared the immunogenicity of different regions of beta-amyloid, displayed on filamentous phages. We established that a filamentous phage displaying epitope 2-6 (AEFRH) of beta-amyloid at the N-terminus of Major Capside Protein (phage fdAD(2-6)) is more immunogenic than a phage displaying epitope 1-7 (DAEFRHD) that differs only in flanking residues. Monthly injections of fdAD(2-6) trigger a robust anti-beta-amyloid antibody response, and afford a significant reduction of plaque pathology in a mouse model of AD, whereas the same treatment, performed with phage fdAD(1-7), induces a lower anti-beta-amyloid titer and does not protect from amyloid deposition. "Memory" anti-amyloid antibodies induced by a single prime-boost cycle with vaccine fdAD(2-6), that have a lower titer compared to antibodies induced by monthly restimulations, do not prevent plaque pathology. Our data show that optimization of epitope display is essential in vaccine design, and suggest that the titer of the anti-amyloid response is the crucial parameter to obtain therapeutic efficacy in vivo.


Subject(s)
Alzheimer Disease/therapy , Amyloid beta-Peptides/immunology , Antibodies/immunology , Coliphages/immunology , Peptide Fragments/immunology , Alzheimer Disease/immunology , Alzheimer Disease/pathology , Animals , Antibodies/therapeutic use , Coliphages/metabolism , Epitopes , Immunotherapy , Mice , Mice, Transgenic , Peptide Fragments/therapeutic use , Peptide Library , Plaque, Amyloid/pathology
9.
Neurobiol Dis ; 27(3): 328-38, 2007 Sep.
Article in English | MEDLINE | ID: mdl-17656099

ABSTRACT

Amyloid plaques and neurofibrillary tangles are the main histopathological hallmarks of Alzheimer's disease (AD). In the neocortex and hippocampus of aged TgCRND8 mice, tau is hyperphosphorylated at different sites recognized by PHF-1, AT100, AT8 and CP13 antibodies. Phospho-SAPK/JNK levels were increased in the tg mouse brain, where activated SAPK/JNK co-localizes with PHF-1-positive cells. Phosphorylated tau-positive cells showed Bielschowsky- and Thioflavine S-positive intraneuronal deposits. PHF-1 and nitrotyrosine immunoreactivity merged within neurons surrounding amyloid deposits in cortical and hippocampal areas and immunoprecipitation studies confirmed that tau is nitrosylated. Our findings, demonstrating the presence of hyperphosphorylated and nitrosylated tau protein as well as of insoluble aggregates after the onset of amyloid deposition in the TgCRND8 mouse brain, indicate that the abnormal processing of tau may occur subsequently to cerebral amyloidosis and that activation of SAPK/JNK and induction of nitrosative stress are the more likely connecting factors between amyloidosis and tauopathy in AD.


Subject(s)
Aging , Brain/metabolism , Brain/pathology , tau Proteins/metabolism , Animals , Female , Humans , Immunoblotting , Immunohistochemistry , Immunoprecipitation , Inclusion Bodies/metabolism , Inclusion Bodies/pathology , MAP Kinase Kinase 4/metabolism , Male , Mice , Mice, Transgenic , Phosphorylation , Plaque, Amyloid/metabolism , Plaque, Amyloid/pathology , Tyrosine/analogs & derivatives , Tyrosine/metabolism
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