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1.
Micromachines (Basel) ; 15(3)2024 Mar 14.
Artigo em Inglês | MEDLINE | ID: mdl-38542642

RESUMO

The three-point bending test is a valuable method for evaluating the mechanical properties of 3D-printed biomaterials, which can be used in various applications. The use of 3D printing in specimen preparation enables precise control over material composition and microstructure, facilitating the investigation of different printing parameters and advanced materials. The traditional approach to analyzing the mechanical properties of a material using a three-point bending test has the disadvantage that it provides only global information about the material's behavior. This means that it does not provide detailed insight into the local strain distribution within the material. However, the 2D Digital Image Correlation (DIC) method offers additional insight, especially in terms of strain localization. DIC is an optical technique that measures full-field displacements and strains on the surface of a sample. PLA and enhanced PLA-X material were utilized to create three-point bending samples. The aim of this paper was to analyze and compare the influence of aging on the mechanical properties of PLA and enhanced PLA-X materials using three-point bending coupled with the DIC method. The results showed statistically significant differences between the PLA and PLA-X, for both the new and aged materials. The aged PLA samples had the highest average value of maximal force around 68 N, which was an increase of 8.8% compared to the new PLA samples. On the other hand, the aged PLA-X material had an increase of 7.7% in the average maximal force compared to the new PLA-X samples. When comparing the two materials, the PLA samples had higher maximal force values, 6.2% for the new samples, and 7.3% for the aged samples. The DIC results showed that both the new PLA and PLA-X samples endured higher strain values at Points 1 and 2 than the aged ones, except for the aged PLA-X sample at Point 2, where the new sample had higher strain values. However, for the first 5 min of the experiment, both materials exhibited identical behavior, after which point significant differences started to occur for both materials, as well as at Points 1 and 2. A more profound comprehension of the biomechanical characteristics of both PLA and PLA-X material is essential to enhance the knowledge for potential biomedical applications. The DIC method was found to be a powerful tool for analyzing the deformation and failure behavior of samples and for complementing the traditional approach to material testing.

2.
Polymers (Basel) ; 15(21)2023 Oct 24.
Artigo em Inglês | MEDLINE | ID: mdl-37959878

RESUMO

Additive manufacturing technologies have developed rapidly in recent decades, pushing the limits of known manufacturing processes. The need to study the properties of the different materials used for these processes comprehensively and in detail has become a primary goal in order to get the best out of the manufacturing itself. The widely used thermoplastic polymer material acrylonitrile butadiene styrene (ABS) was selected in the form of both filaments and ABS-like resins to investigate and compare the mechanical properties through a series of different tests. ABS-like resin material is commercially available, but it is not a sufficiently mechanically studied form of the material, which leads to the rather limited literature. Considering that ABS resin is a declared material that behaves like the ABS filament but in a different form, the objective of this study was to compare these two commercially available materials printed with three different 3D printers, namely Fused Deposition Modelling (FDM), Stereolithography (SLA) and Digital Light Processing (DLP). A total of 45 test specimens with geometries and test protocols conforming to the relevant standards were subjected to a series of tensile, three-point bending and compression tests to determine their mechanical properties. Characterization also included evaluation of morphology with 2D and 3D microscopy, dimensional accuracy of 3D scans, and Shore A hardness of each material and 3D printing process. Tensile testing results have shown that FDM toughness is 40% of the value for DLP. FDM elongation at break is 37% of DLP, while ultimate tensile stress for SLA is 27% higher than FDM value. Elastic modulus for FDM and SLA coincide. Flexure testing results indicate that value of DLP flexural modulus is 54% of the FDM value. SLA strain value is 59% of FDM, and DLP ultimate flexure stress is 77% of the value for FDM. Compression test results imply that FDM specimens absorb at least twice as much energy as vat polymerized specimens. Strain at break for SLA is 72% and strain at ultimate stress is 60% of FDM values. FDM yield stress is 32% higher than DLP value. SLA ultimate compressive stress is half of FDM, while value for DLP compressive modulus is 69% of the FDM value. The results obtained are beneficial and give a more comprehensive picture of the behavior of the ABS polymers used in different forms and different AM processes.

3.
Biomed Res Int ; 2022: 7943609, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35178455

RESUMO

After primary treatment of localized prostate carcinoma (PC), up to a third of patients have disease recurrence. Different predictive models have already been used either for initial stratification of PC patients or to predict disease recurrence. Recently, artificial intelligence has been introduced in the diagnosis and management of PC with a potential to revolutionize this field. The aim of this study was to analyze machine learning (ML) classifiers in order to predict disease progression in the moment of prostate-specific antigen (PSA) elevation during follow-up. The study cohort consisted of 109 PC patients treated with external beam radiotherapy alone or in combination with androgen deprivation therapy. We developed and evaluated the performance of two ML algorithms based on artificial neural networks (ANN) and naïve Bayes (NB). Of all patients, 72.5% was randomly selected for a training set while the remaining patients were used for testing of the models. The presence/absence of disease progression was defined as the output variable. The input variables for models were conducted from the univariate analysis preformed among two groups of patients in the training set. They included two pretreatment variables (UICC stage and Gleason's score risk group) and five posttreatment variables (nadir PSA, time to nadir PSA, PSA doubling time, PSA velocity, and PSA in the moment of disease reevaluation). The area under the receiver operating characteristic curve, sensitivity, specificity, positive predictive value, negative predictive value, and predictive accuracy was calculated to test the models' performance. The results showed that specificity was similar for both models, while NB achieved better sensitivity then ANN (100.0% versus 94.4%). The ANN showed an accuracy of 93.3%, and the matching for NB model was 96.7%. In this study, ML classifiers have shown potential for application in routine clinical practice during follow-up when disease progression was suspected.


Assuntos
Carcinoma , Neoplasias da Próstata , Antagonistas de Androgênios/uso terapêutico , Inteligência Artificial , Teorema de Bayes , Carcinoma/tratamento farmacológico , Progressão da Doença , Humanos , Aprendizado de Máquina , Masculino , Recidiva Local de Neoplasia/tratamento farmacológico , Próstata/patologia , Antígeno Prostático Específico , Neoplasias da Próstata/patologia
4.
Z Gerontol Geriatr ; 54(5): 507-512, 2021 Aug.
Artigo em Alemão | MEDLINE | ID: mdl-32676737

RESUMO

INTRODUCTION: Pain is highly prevalent in older persons and has a variety of causes. In geriatric patients, especially in patients with dementia, pain is often not sufficiently recognized and therefore frequently remains untreated. For the affected patient group this can have far-reaching consequences for their functional and cognitive abilities and may consequently lead to loss of autonomy. OBJECTIVE: Existing deficits of pain assessment for geriatric patients are described, with a primary focus on those patients suffering from cognitive impairments and pain. In addition, the influence of multimorbidity on pain management in old age is considered in detail. METHODS: The diagnostics and measurement of pain in older individuals are described based on recent literature and corresponding instruments used in the assessment of pain are outloned. The authors pay special attention to the possibilities of pain measurement in patients with higher grade cognitive impairments and non-communicative patients. CONCLUSION: A standardized pain assessment should be an integral component in the care and treatment of geriatric patients and individuals suffering from dementia. Validated instruments for pain measurement exist for both groups and should be integrated into daily clinical practice.


Assuntos
Manejo da Dor , Dor , Idoso , Idoso de 80 Anos ou mais , Avaliação Geriátrica , Humanos , Dor/diagnóstico , Dor/epidemiologia , Medição da Dor
5.
Z Gerontol Geriatr ; 54(6): 605-610, 2021 Oct.
Artigo em Alemão | MEDLINE | ID: mdl-32681466

RESUMO

BACKGROUND: For geriatric patients with chronic pain, a comprehensive well-coordinated pain management is pivotal to ensure the best possible pain relief and to minimize as far as possible preventable negative side effects of treatment. OBJECTIVE: Description of the difficulties in pain management of geriatric patients with respect to general basic rules that are worth paying attention to and presentation of pharmacological and non-pharmacological treatment options. METHODS: This article describes the special features of pain management in older patients and gives recommendations on the use of analgesics and potential drug interactions in geriatric patients with organ dysfunction. Furthermore, individual substance groups are described with respect to their use in geriatric patients based on the recent literature. CONCLUSION: The aim of an individualized pain treatment in older and multimorbid patients is the relief of pain to an appropriate level, preservation of mobility, self-reliance and autonomy of each individual. The ability to participate in social activities as well as improvement in the quality of life need to be the focus of pharmacological and non-pharmacological treatment.


Assuntos
Dor Crônica , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos , Idoso , Analgésicos/uso terapêutico , Analgésicos Opioides , Dor Crônica/diagnóstico , Dor Crônica/tratamento farmacológico , Humanos , Manejo da Dor , Qualidade de Vida
6.
Biomed Res Int ; 2019: 2041348, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31828093

RESUMO

The introduction of resin-based cements and an adhesive-bonding system in daily dental practice has given the opportunity to increase the retention of previously conventional cemented restorations and the optimal results in esthetic. This experimental study employed the 3D Digital Image Correlation Method (3D-DIC) for detecting shrinkage strain in four dual cured composite cements. The aim was to visualize measure, analyze, and compare strain fields in four resin-based cements using the 3D-DIC method. A total of 72 samples were divided into 4 groups considering variations in sample types, diameter, and thickness. Four types of composite cements: RelyX U200 (3 M ESPE, St. Paul, MN, USA), MaxCem Elite (Kerr, Orange, CA, USA), Multilink Automix (Ivoclar Vivadent, Schaan, Liechtenstein), and SeT PP (SDI, Australia) were used. Each type had diameters of 3 mm, 4 mm, and 5 mm, respectively, combined with two different values of thickness: 1 mm and 2 mm. Thickness had an important role on strain detected in all tested materials showing higher strain in samples with 2 mm thickness compared to 1 mm samples. Shrinkage strain values were the highest in Set PP samples indicated the possibility of undesirable de-bonding.


Assuntos
Cimentos Dentários/química , Resinas Acrílicas/química , Austrália , Resinas Compostas/química , Colagem Dentária/métodos , Análise do Estresse Dentário/métodos , Humanos , Teste de Materiais/métodos , Poliuretanos/química , Cimentos de Resina/química , Resistência à Tração
7.
Dent Mater ; 32(11): 1441-1451, 2016 11.
Artigo em Inglês | MEDLINE | ID: mdl-27686259

RESUMO

OBJECTIVE: To compare strain and displacement of sculptable bulk-fill, low-shrinkage and conventional composites as well as dye penetration along the dentin-restoration interface. METHODS: Modified Class II cavities (N=5/group) were filled with sculptable bulk-fill (Filtek Bulk Fill Posterior, 3M ESPE; Tetric EvoCeram Bulk Fill, Ivoclar Vivadent; fiber-reinforced EverX Posterior, GC; giomer Beautifil Bulk, Schofu), low-shrinkage (Kalore, GC), nanohybrid (Tetric EvoCeram, Ivoclar Vivadent) or microhybrid (Filtek Z250, 3M ESPE) composites. Strain and displacement were determined using the 3D digital image correlation method based on two cameras with 1µm displacement sensitivity and 1600×1200 pixel resolution (Aramis, GOM). Microleakage along dentin axial and gingival cavity walls was measured under a stereomicroscope using a different set of teeth (N=8/group). Data were analyzed using analyses of variance with Tukey's post-test, Pearson correlation and paired t-test (α=0.05). RESULTS: Strain of TEC Bulk, Filtek Bulk, Beautifil Bulk and Kalore was in the range of 1-1.5%. EverX and control composites showed 1.5-2% strain. Axial displacements were between 5µm and 30µm. The least strain was identified at 2mm below the occlusal surface in 4-mm but not in 2-mm layered composites. Greater microleakage occurred along the gingival than axial wall (p<0.05). No correlation was found between strain/displacements and microleakage axially (r2=0.082, p=0.821; r2=-0.2, p=0.605, respectively) or gingivally (r2=-0.126, p=0.729, r2=-0.278, p=0.469, respectively). SIGNIFICANCE: Strain i.e. volumetric shrinkage of sculptable bulk-fill and low-shrinkage composites was comparable to control composites but strain distribution across restoration depth differed. Marginal integrity was more compromised along the gingival than axial dentin wall.


Assuntos
Resinas Compostas , Cárie Dentária , Dentina , Corantes/farmacocinética , Materiais Dentários , Humanos , Teste de Materiais
8.
Mater Sci Eng C Mater Biol Appl ; 58: 487-94, 2016 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-26478336

RESUMO

This study investigated the degree of conversion, depth of cure, Vickers hardness, flexural strength, flexural modulus and volumetric shrinkage of experimental composite containing a low shrinkage monomer FIT-852 (FIT; Esstech Inc.) and photoinitiator 2,4,6-trimethylbenzoyldiphenylphosphine oxide (TPO; Sigma Aldrich) compared to conventional composite containing Bisphenol A-glycidyl methacrylate (BisGMA) and camphorquinone-amine photoinitiator system. The degree of conversion was generally higher in FIT-based composites (45-64% range) than in BisGMA-based composites (34-58% range). Vickers hardness, flexural strength and modulus were higher in BisGMA-based composites. A polywave light-curing unit was generally more efficient in terms of conversion and hardness of experimental composites than a monowave unit. FIT-based composite containing TPO showed the depth of cure below 2mm irrespective of the curing light. The depth of cure of FIT-based composite containing CQ and BisGMA-based composites with either photoinitiator was in the range of 2.8-3.0mm. Volumetric shrinkage of FIT-based composite (0.9-5.7% range) was lower than that of BisGMA-based composite (2.2-12% range). FIT may be used as a shrinkage reducing monomer compatible with the conventional CQ-amine system as well as the alternative TPO photoinitiator. However, the depth of cure of FIT_TPO composite requires boosting to achieve clinically recommended thickness of 2mm.


Assuntos
Resinas Compostas/química , Lâmpadas de Polimerização Dentária , Luz , Teste de Materiais , Metacrilatos/química , Óxidos/química , Fosfinas/química , Bis-Fenol A-Glicidil Metacrilato/química , Módulo de Elasticidade , Dureza , Polietilenoglicóis/química , Polimerização , Ácidos Polimetacrílicos/química , Espectrometria de Fluorescência , Espectroscopia de Infravermelho com Transformada de Fourier
10.
Dent Mater ; 31(2): 171-81, 2015 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-25541508

RESUMO

OBJECTIVE: To determine the shear bond strength (SBS) between synthetic controlled porous hydroxyapatite (HAP) inserts and restorative materials and dimensional changes of insert-containing restorations during curing. METHODS: Cylinder-shaped HAP inserts (4mm in diameter, 1.6mm thick) were cemented in dentin discs (5mm×1.6mm), cut mid-coronally from human third molars, using one of the following materials: universal microhybrid composite Filtek Z250, flowable composite Filtek Ultimate or glass-ionomer Vitrebond (all 3M ESPE). SBS of the same materials to HAP inserts was tested in a universal testing machine. Three-dimensional digital image correlation system Aramis (GOM) was used to measure strains and displacements. Data were statistically analyzed using one-way ANOVA with Tukey's post-test (α=0.05). RESULTS: SBS of restorative materials to HAP inserts ranged between 12.2±2.1MPa (Filtek Z250) and 0.7±0.4MPa (Filtek Z250 without an adhesive). The 'total-etch' approach of adhesive application significantly increased SBS of both Filtek Z250 (12.2±2.1MPa) and Filtek Ultimate flowable (9.5±2.5MPa) compared to the 'self-etch' approach (8.2±1.6MPa and 4.4±0.9MPa, respectively) (p<0.05). HAP inserts reduced polymerization shrinkage to below 0.5% as well as displacements in the central region of the restorations. Peripheral shrinkage of restorative materials was similar with and without HAP inserts as were displacements of Filtek Z250 and Vitrebond. SIGNIFICANCE: Replacing major part of dentin clinically, especially in large cavities, HAP inserts may shorten clinical working time, improve dimensional stability of the restoration by reducing central shrinkage and displacements and provide adhesive bonding to universal composites following a 'total-etch' approach.


Assuntos
Resinas Compostas/química , Materiais Dentários/química , Restauração Dentária Permanente/métodos , Adesivos Dentinários/química , Durapatita/química , Cimentos de Ionômeros de Vidro/química , Silicatos de Alumínio/química , Colagem Dentária , Porcelana Dentária/química , Análise do Estresse Dentário , Humanos , Técnicas In Vitro , Cura Luminosa de Adesivos Dentários , Dente Molar , Polimerização , Propriedades de Superfície
11.
Coll Antropol ; 36(1): 173-8, 2012 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-22816217

RESUMO

The aim of this study was to register and measure any deformation of mandible models under load. The method for full field measurement of strain is done by using the ARAMIS three-dimensional image correlation system. The system uses two digital cameras that provide a synchronized stereo view of the specimen and the results show the complete strain field during the tests. The biggest deformation values were just under the working force of the biggest intensity 500 N, and for the region of the lower second premolar the deformation is 625 microm. The following study is presented that highlight the use of stereometric measuring system for modern research. It is shown that this measuring methodology can capture the trends of the experiments.


Assuntos
Dente Pré-Molar/fisiologia , Dentaduras , Mandíbula/fisiologia , Óptica e Fotônica/métodos , Falha de Prótese , Suporte de Carga/fisiologia , Adulto , Fenômenos Biomecânicos/fisiologia , Força de Mordida , Humanos , Masculino , Teste de Materiais/métodos
12.
Biomech Model Mechanobiol ; 11(6): 751-8, 2012 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-21918835

RESUMO

It was the purpose of this study to determine and analyse strains in the bone of posterior mandible below the removable and fixed partial dentures using Digital Image Correlation Method. Dried mandible with shortened dental arch (Kennedy Class 1) was used in the experiment. The mandible model was prepared for accepting two types of restorations for bilaterally missing molars conventional therapy, and removable and fixed partial dentures were manufactured following standard prosthetic protocol. The models with prosthetic restorations placed in situ were subjected to loading of 50-300 N, and photographed using two digital cameras as part of the digital image correlation method equipment. Afterwards, the obtained data for strains within restored mandible during loading ciclus were analysed in the software Aramis and graphically presented. Percentage size of the mandible strains within the line section are from 0.14 to 0.19% for the removable partial denture experimental model and 0-0.14% for the fixed partial denture experimental model. The study has demonstrated that Digital Image Correlation method can be used to measure strain on the mandible surface and replacements during loading and that from biomechanical perspective both therapeutic modalities can be equally useful for the restoration of the mandible with bilaterally distal edentulous spaces.


Assuntos
Força Compressiva/fisiologia , Prótese Parcial Fixa , Prótese Parcial Removível , Processamento de Imagem Assistida por Computador/métodos , Estresse Mecânico , Humanos , Arcada Parcialmente Edêntula/patologia , Masculino , Mandíbula , Pessoa de Meia-Idade , Modelos Biológicos
13.
Gerodontology ; 29(2): e851-7, 2012 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-22004157

RESUMO

BACKGROUND: Understanding of the biomechanical consequences of the stresses generated to the supporting bone during occlusal loading is significant for improving the design and clinical planning process in partial edentulism therapy. OBJECTIVE: The aim of this study was to analyse the distribution of strain and displacement on the partially dentate lower jaw rehabilitated with an partial denture (RPD) and to compare it to the strain and displacement distribution on a partially dentate lower jaw rehabilitated with a cantilever fixed partial denture (FPD). MATERIAL AND METHODS: The experimental models were a partially dentate mandible with full-arch PFM crowns and RPD and a partially dentate mandible rehabilitated with a full-arch cantilever FPD. Strains and displacement were measured using the Digital Image Correlation Method. RESULTS: Displacement values of the first experimental model ranged from 0.31 to 0.54 mm with strains from 1.35 to 2.34%. Analysis of the second experimental model results showed displacement values from 0 to 0.34 mm, while strains were in the range of 0-1.40%. CONCLUSION: Higher displacements and strains of bone tissue were observed below the RPD, especially in the region of the distal abutment and distal portion of the free-end saddle. Strains within bone and the bone-denture contact area were mostly influenced by the teeth and denture vertical displacement.


Assuntos
Prótese Parcial Fixa , Prótese Parcial Removível , Arcada Parcialmente Edêntula/fisiopatologia , Mandíbula/fisiopatologia , Idoso , Fenômenos Biomecânicos , Força de Mordida , Coroas , Dente Suporte , Grampos Dentários , Análise do Estresse Dentário/instrumentação , Planejamento de Dentadura , Humanos , Processamento de Imagem Assistida por Computador , Imageamento Tridimensional , Arcada Parcialmente Edêntula/reabilitação , Masculino , Fotografação , Software , Estresse Mecânico , Resistência à Tração
14.
Pflugers Arch ; 447(1): 71-7, 2003 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-12898257

RESUMO

The loop connecting domains II and III of the sodium channel alpha-subunit is not known to have a major effect on channel gating. Recently mutations in the II-III loop of various sodium channel isoforms have been reported to cause channelopathies suggesting the functional importance of this region. In the II-III loop of the skeletal muscle isoform Na(v)1.4, we found a Ser-to-Thr substitution at position 906 in 5% of patients with dyskalemic periodic paralysis but also in 4% of healthy human individuals. To investigate whether this position is important for channel gating, we characterized the following amino acids at 906 by whole-cell patch-clamp experiments: Gln, Ser, Thr, Cys, Pro, Val, ordered according to their hydrophobicity. All substitutions mainly affected slow inactivation. For example, Gln caused a +13-mV right-shift of the steady-state slow inactivation curve, and entry into slow inactivation was 6 times slower compared with Ser, leading to a destabilization of the slow inactivated state; in contrast, Val, at the other end of the hydrophobicity spectrum, shifted the steady-state slow inactivation curve by -6 mV and slowed the recovery from the slow inactivated state threefold compared with Ser, resulting in an enhancement of slow inactivation. Recovery from the slow inactivated state was also slowed by Pro, Cys and Thr. Our results suggest that (1) a benign polymorphism affects channel function, (2) the II-III loop is important for slow inactivation, and (3) the effects on slow inactivation may depend on the hydrophobicity of the residue at position 906.


Assuntos
Substituição de Aminoácidos/genética , Proteínas Musculares/genética , Polimorfismo Genético , Serina/genética , Canais de Sódio/genética , Humanos , Ativação do Canal Iônico/genética , Canal de Sódio Disparado por Voltagem NAV1.4 , Estrutura Secundária de Proteína
15.
J Physiol ; 547(Pt 3): 691-8, 2003 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-12562902

RESUMO

Missense mutations of the human skeletal muscle voltage-gated Na+ channel (hSkM1) cause a variety of neuromuscular disorders. The mutation R1448H results in paramyotonia congenita and causes cold-induced myotonia with subsequent paralysis. The mutation M1360V causes an overlapping syndrome with both K+-induced muscle weakness and cold-induced myotonia. The molecular mechanisms of the temperature dependence of these disorders are not well understood. Therefore we investigated physiological parameters of these Na+ channel mutations at different temperatures. Channel proteins were recombinantly expressed in human embryonic kidney cells and studied electrophysiologically, using the whole-cell patch-clamp technique. We compared the wild-type (WT) channel with both mutants at different temperatures. Both mutations had slower inactivation and faster recovery from inactivation compared to WT channels. This effect was more pronounced at the R1448H mutation, leading to a larger depolarization of the cell membrane causing myotonia and paralysis. The voltage dependence of activation of R1448H was shifted to more negative membrane potentials at lower temperature but not at the M1360V mutation or in the WT. The window current by mutation R1448H was increased at lower temperatures. The results of this study may explain the stronger cold-induced clinical symptoms resulting from the R1448H mutation in contrast to the M1360V mutation.


Assuntos
Temperatura Baixa , Músculo Esquelético/fisiologia , Mutação de Sentido Incorreto , Transtornos Miotônicos/fisiopatologia , Canais de Sódio/genética , Linhagem Celular , Humanos , Ativação do Canal Iônico/fisiologia , Rim/citologia , Potenciais da Membrana/fisiologia , Transtornos Miotônicos/genética , Técnicas de Patch-Clamp , Sódio/metabolismo , Canais de Sódio/metabolismo
16.
Brain ; 125(Pt 4): 835-43, 2002 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-11912116

RESUMO

Hypokalaemic periodic paralysis (hypoPP) is a dominantly inherited muscle disorder characterized by episodes of flaccid weakness. Previous genetic studies revealed mutations in the voltage-gated calcium channel alpha1-subunit (CACNA1S gene) in families with hypoPP (type I). Electrophysiological studies on these mutants in different expression systems could not explain the pathophysiology of the disease. In addition, several mutations (Arg669His, Arg672His, Arg672Gly and Arg672Ser) in the voltage sensor of the skeletal muscle sodium channel alpha-subunit (SCN4A gene) have been found in families with hypoPP (type II). For Arg672Gly/His a fast inactivation defect was described, and for Arg669His an impairment of slow inactivation was reported. Except for the substitution for serine, we have now expressed all mutants in a human cell-line and studied them electrophysiologically. Patch-clamp recordings show an enhanced fast inactivation for all three mutations, whereas two of them reveal enhanced slow inactivation. This may reduce the number of functional sodium channels at resting membrane potential and contribute to the long-lasting periods of paralysis experienced by hypoPP patients. The gating of both histidine mutants (Arg669His, Arg672His) can be modulated by changes of extra- or intracellular pH. The inactivation defects of Arg669His and Arg672His can be alleviated by low pH to a significant degree, suggesting that the decrease of pH in muscle cells (e.g. during muscle work) might lead to an auto-compensation of functional defects. This may explain a delay or prevention of paralytic attacks in patients by slight physical activity. Moreover, the histidine residues may be the target for a potential therapeutic action by acetazolamide.


Assuntos
Arginina/genética , Glicina/genética , Histidina/genética , Paralisia Periódica Hipopotassêmica/metabolismo , Músculo Esquelético/metabolismo , Mutação/genética , Canais de Sódio/genética , Canais de Sódio/metabolismo , Arginina/metabolismo , Células Cultivadas , Glicina/metabolismo , Histidina/metabolismo , Humanos , Concentração de Íons de Hidrogênio , Paralisia Periódica Hipopotassêmica/tratamento farmacológico , Paralisia Periódica Hipopotassêmica/fisiopatologia , Potenciais da Membrana/genética , Músculo Esquelético/fisiopatologia , Canal de Sódio Disparado por Voltagem NAV1.4 , Potássio/metabolismo , Potássio/farmacologia
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