RESUMO
Prostaglandin E receptor EP4, a G-protein-coupled receptor, is involved in disorders such as cancer and autoimmune disease. Here, we report the crystal structure of human EP4 in complex with its antagonist ONO-AE3-208 and an inhibitory antibody at 3.2 Å resolution. The structure reveals that the extracellular surface is occluded by the extracellular loops and that the antagonist lies at the interface with the lipid bilayer, proximal to the highly conserved Arg316 residue in the seventh transmembrane domain. Functional and docking studies demonstrate that the natural agonist PGE2 binds in a similar manner. This structural information also provides insight into the ligand entry pathway from the membrane bilayer to the EP4 binding pocket. Furthermore, the structure reveals that the antibody allosterically affects the ligand binding of EP4. These results should facilitate the design of new therapeutic drugs targeting both orthosteric and allosteric sites in this receptor family.
Assuntos
Receptores de Prostaglandina E Subtipo EP4/química , Receptores de Prostaglandina E Subtipo EP4/metabolismo , Regulação Alostérica , Animais , Anticorpos Monoclonais/química , Anticorpos Monoclonais/metabolismo , Sítios de Ligação , Caprilatos/química , Caprilatos/metabolismo , Cristalografia por Raios X , Epoprostenol/análogos & derivados , Epoprostenol/química , Epoprostenol/metabolismo , Humanos , Ligantes , Bicamadas Lipídicas , Simulação de Acoplamento Molecular , Naftalenos/química , Naftalenos/metabolismo , Éteres Fenílicos/química , Éteres Fenílicos/metabolismo , Fenilbutiratos/química , Fenilbutiratos/metabolismo , Receptores de Prostaglandina E Subtipo EP4/antagonistas & inibidores , Receptores de Prostaglandina E Subtipo EP4/genética , Spodoptera/genéticaRESUMO
BACK GROUND: Patients with spinal kyphosis were radiographically evaluated while standing. However, the spino-pelvic alignment during walking is different. This study examined the spino-pelvic-lower extremity alignment during walking by a three-dimensional (3D) motion analysis. METHODS: Twenty-six patients with a sagittal vertical axis of ≥4 cm (male: female, 5:21; average age, 66 years) were evaluated. Using a 3D motion capture system, the trunk and pelvic anterior inclination angles, hip and knee joint angles were measured during a 3-min walk. The correlation coefficient between the change of the trunk anterior inclination angle and each parameter at the beginning of walking was calculated, and those parameters were compared with radiographic measurements. RESULTS: The patients were divided into two groups according to the change of the trunk anterior inclination angle: the large change group included 14 patients with an increase of ≥5° between the beginning and end of the 3-min walk; the small change group included 12 patients with an increase of <5°. The pelvic anterior inclination angle showed a significant difference between the two groups at the first gait cycles. The pelvic anterior inclination angle and the hip joint angle in the large change group showed a significant difference between the first and last cycles. The correlation coefficient revealed a significant association between the change in the trunk anterior inclination angle and the pelvic anterior inclination angle at the beginning of walking. There were no significant differences between the two groups in any radiographic spino-pelvic parameters. CONCLUSIONS: There were two types of patients with spinal kyphosis: patients with a small pelvic anterior inclination angle at the beginning of walking showed slight progression in their trunk anterior inclination, whereas those with a large pelvic angle showed a large degree of progression in their pelvic and trunk inclination during walking.
Assuntos
Cifose/fisiopatologia , Extremidade Inferior/fisiopatologia , Vértebras Lombares/fisiopatologia , Pelve/fisiopatologia , Postura , Teste de Caminhada , Idoso , Fenômenos Biomecânicos , Feminino , Humanos , Imageamento Tridimensional , Cifose/diagnóstico por imagem , Extremidade Inferior/diagnóstico por imagem , Vértebras Lombares/diagnóstico por imagem , Masculino , Pelve/diagnóstico por imagem , RadiografiaRESUMO
OBJECTIVE: Intermittent claudication aggravates physical function and is associated with an increased risk of death in patients with peripheral arterial disease (PAD). Previous studies on kinetic parameters (joint moment and power) of lower limbs in these patients have largely focused on the decline in the ankle plantar flexor moment and power at self-selected (SS) walking speed, which may not be an optimal condition to induce claudication pain. In the present study, we investigated the abnormalities in joint kinetic parameters in patients with PAD at both SS and at fast walking speeds. METHODS: We recruited 16 patients with aortoiliac PAD (4 unilateral and 12 bilateral) and 10 healthy controls. The participants were instructed to walk at SS and fast speeds along a 7-meter walkway embedded with a force plate. Spatiotemporal parameters and joint kinetic parameters of the lower limbs during the stance phase were recorded using a three-dimensional motion analysis device. RESULTS: Compared with the controls, patients with PAD showed a significant reduction in their walking speed, step length, stride length, and cadence. Further, a reduction in peak hip flexor moment at fast walking speed and in peak hip flexor generation power was observed in both modes of walking. However, no significant between-group differences were observed for the peak ankle plantar flexor moment or power at either walking speed. Multiple regression analysis showed peak hip flexor generation power was a strong contributor to reduction at both SS and fast walking speeds in patients with PAD. CONCLUSIONS: Patients with aortoiliac PAD walk slowly and show reduced kinetic parameters of the hip joint at both SS and fast walking speeds. Our results suggest that hip flexor muscles may be a useful target for exercise training in patients with aortoiliac PAD.
Assuntos
Doenças da Aorta/fisiopatologia , Articulação do Quadril/fisiopatologia , Artéria Ilíaca/fisiopatologia , Músculo Esquelético/fisiopatologia , Doença Arterial Periférica/fisiopatologia , Velocidade de Caminhada , Idoso , Doenças da Aorta/diagnóstico por imagem , Fenômenos Biomecânicos , Estudos de Casos e Controles , Estudos Transversais , Teste de Esforço , Feminino , Humanos , Artéria Ilíaca/diagnóstico por imagem , Japão , Masculino , Pessoa de Meia-Idade , Força Muscular , Doença Arterial Periférica/diagnóstico por imagem , Estudos Prospectivos , Fluxo Sanguíneo Regional , Análise de Regressão , Fatores de TempoRESUMO
PURPOSE: The aim of this study was to compare the stiffness of the dorsal scapular muscles before and after computer work between individuals with and without neck and shoulder complaints. METHODS: Thirty subjects were divided into patient (n = 18) and control (n = 12) groups. The stiffness of the upper trapezius, levator scapulae, and rhomboid major was measured using ultrasound elastography before and after a 30-min typing task. The strain ratio of the muscle to an acoustic coupler was calculated (a lower strain ratio value indicates greater muscle stiffness). RESULTS: At baseline, the strain ratio of the upper trapezius in the patient group (3.762 ± 1.679) (mean ± SD) was significantly lower than that of the control group (7.763 ± 5.921) (p = 0.041). No significant change in the strain ratio of the upper trapezius after the typing task was observed in the patient group (4.158 ± 3.465) (p = 0.549). A significant decrease in the strain ratio of the levator scapulae after the typing task was observed in the patient group (before: 9.006 ± 7.079, after: 5.718 ± 2.847) (p = 0.022), whereas there was no significant change in the control group (p = 0.436). CONCLUSIONS: The increase in stiffness of the upper trapezius is an objective finding and may be a persistently altered condition in individuals with neck and shoulder complaints. The patterns of change in stiffness of the levator scapulae are different between individuals with and without neck and shoulder complaints.
Assuntos
Elasticidade , Cervicalgia/diagnóstico por imagem , Doenças Profissionais/diagnóstico por imagem , Dor de Ombro/diagnóstico por imagem , Músculos Superficiais do Dorso/diagnóstico por imagem , Adulto , Estudos de Casos e Controles , Feminino , Humanos , Masculino , Cervicalgia/etiologia , Doenças Profissionais/etiologia , Dor de Ombro/etiologia , Carga de TrabalhoRESUMO
Sensory impairments caused by neurological or physical disorders hamper kinesthesia, making rehabilitation difficult. In order to overcome this problem, we proposed and developed a novel biofeedback prosthesis called Auditory Foot for transforming sensory modalities, in which the sensor prosthesis transforms plantar sensations to auditory feedback signals. This study investigated the short-term effect of the auditory feedback prosthesis on walking in stroke patients with hemiparesis. To evaluate the effect, we compared four conditions of auditory feedback from plantar sensors at the heel and fifth metatarsal. We found significant differences in the maximum hip extension angle and ankle plantar flexor moment on the affected side during the stance phase, between conditions with and without auditory feedback signals. These results indicate that our sensory prosthesis could enhance walking performance in stroke patients with hemiparesis, resulting in effective short-term rehabilitation.
Assuntos
Articulação do Tornozelo/fisiopatologia , Pé/fisiopatologia , Paresia/fisiopatologia , Próteses e Implantes , Acidente Vascular Cerebral/fisiopatologia , Caminhada/fisiologia , Adulto , Idoso , Eletromiografia/métodos , Retroalimentação Sensorial/fisiologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Músculo Esquelético/fisiopatologia , Acidente Vascular Cerebral/terapia , Fatores de TempoRESUMO
OBJECTIVE: To compare scapular kinematics and muscle activity among various scapular muscle exercises. DESIGN: A cross-sectional study. SETTING: A university research laboratory. PARTICIPANTS: Eighteen healthy men participated in this study. MAIN OUTCOME MEASURES: Three-dimensional scapular kinematics was measured with an electromagnetic motion capture system. Activities of the upper trapezius (UT), lower trapezius (LT), and serratus anterior (SA) were measured by using surface electromyography (EMG). In addition, the ratio of LT to the UT (LT/UT) and SA to the UT (SA/UT) was calculated. A repeated one-way analysis of variance and Shaffer's post-hoc analysis were used to detect the differences in each outcome during five exercises. RESULTS: The scapula was rotated upwardly during all exercises except push-up plus. The LT/UT ratio during side-lying external rotation and side-lying flexion were significantly higher than that for scapular plane elevation (P < .05), although the highest activity of the lower trapezius was produced during scapular plane elevation. The activities of the serratus anterior and SA/UT ratio during horizontal adducted elevation and push-up plus were significantly higher than that during scapular plane elevation (P < .05). CONCLUSION: Horizontal adducted elevation might be more appropriate for increasing scapular upward rotation with high serratus anterior activity and SA/UT ratio than push-up plus.
Assuntos
Eletromiografia , Escápula , Músculos Superficiais do Dorso , Humanos , Masculino , Escápula/fisiologia , Fenômenos Biomecânicos/fisiologia , Estudos Transversais , Músculos Superficiais do Dorso/fisiologia , Adulto Jovem , Adulto , Músculo Esquelético/fisiologia , Amplitude de Movimento Articular/fisiologia , Exercício Físico/fisiologiaRESUMO
The differences in kinetic mechanisms of decreased gait speed across brain lesion sides have not been elucidated, including the arrangement of motor modules reflected by kinetic interjoint coordination. The purpose of this study was to elucidate the differences in the kinetic factors of slow gait speed in patients with stroke on the lesion sides. A three-dimensional motion analysis system was employed to assess joint moment in the lower limb and representative gait parameters in 32 patients with right hemisphere brain damage (RHD) and 38 patients with left hemisphere brain damage (LHD) following stroke as well as 20 healthy controls. Motor module composition and timing were determined using principal component analysis based on the three joint moments in the lower limb in the stance phase, which were the variances accounted for principal components (PCs) and the peak timing in the time series of PCs. A stepwise multiple linear regression analysis was performed to identify the most significant joint moment and PC-associated parameter in explaining gait speed. A negligible difference was observed in age, weight, height, and gait speed among patients with RHD and LHD and controls. The following factors contributed to gait speed: in patients with RHD, larger ankle plantarflexion moment on the paretic (p = 0.001) and nonparetic (p = 0.002) sides and ankle dorsiflexion moment on the nonparetic side (p = 0.004); in patients with LHD, larger ankle plantarflexion moment (p < 0.001) and delayed peak timing of the first PC (p = 0.012) on the paretic side as well as ankle dorsiflexion moment on the nonparetic side (p < 0.001); in the controls, delayed peak timing of the first PC (p = 0.002) on the right side and larger ankle dorsiflexion moment (p = 0.001) as well as larger hip flexion moment on the left side (p = 0.023). The findings suggest that the kinetic mechanisms of gait speed may differ among patients with RHD following patients with stroke with LHD, and controls.
RESUMO
BACKGROUND: Reduced ankle quasi-joint stiffness affects propulsion in the paretic side of patients with hemiparesis, contributing to gait asymmetry. We investigated whether the use of an ankle-foot orthosis with dorsiflexion resistance to compensate for reduced stiffness would increase quasi-joint stiffness and spatiotemporal symmetry in patients with hemiparesis. METHODS: Seventeen patients walked along a 7-m walkway in both ankle-foot orthosis with dorsiflexion resistance and control (i.e., ankle-foot orthosis) conditions. Dorsiflexion resistance by spring and cam was set to increase linearly from zero-degree ankle dorsiflexion. Gait data were analyzed using a three-dimensional motion analysis system. FINDINGS: Ankle-foot orthosis with dorsiflexion resistance significantly increased the quasi-joint stiffness in the early and middle stance phase (P = 0.028 and 0.040). Furthermore, although ankle power generation in the ankle-foot orthosis with dorsiflexion resistance condition was significantly lower than in the control condition (P = 0.003), step length symmetry significantly increased in the ankle-foot orthosis with dorsiflexion resistance condition (P = 0.016). There was no significant difference in swing time ratio between conditions. INTERPRETATION: Applying dorsiflexion resistance in the paretic stance phase increased quasi-joint stiffness but did not lead to an increase in ankle power generation. On the other hand, applying dorsiflexion resistance also resulted in a more symmetrical step length, even though the ankle joint power generation on the paretic side did not increase as expected. Future research should explore whether modifying the magnitude and timing of dorsiflexion resistance, considering the biomechanical characteristics of each patients' ankle joint during gait, enhances ankle joint power generation.
Assuntos
Articulação do Tornozelo , Órtoses do Pé , Marcha , Paresia , Humanos , Articulação do Tornozelo/fisiopatologia , Paresia/fisiopatologia , Paresia/reabilitação , Paresia/etiologia , Masculino , Feminino , Pessoa de Meia-Idade , Idoso , Transtornos Neurológicos da Marcha/fisiopatologia , Transtornos Neurológicos da Marcha/reabilitação , Transtornos Neurológicos da Marcha/etiologia , Amplitude de Movimento Articular , Fenômenos Biomecânicos , AdultoRESUMO
BACKGROUND: Knee osteoarthritis negatively affects the gait of patients, especially that of elderly people. However, the assessment of wearable sensors in knee osteoarthritis patients has been under-researched. During clinical assessments, patients may change their gait patterns under the placebo effect, whereas wearable sensors can be used in any environment. METHODS: Sixty patients with knee osteoarthritis and 20 control subjects were included in the study. Wearing shoes with an IMU sensor embedded in the insoles, the participants were required to walk along a walkway. The sensor data were collected during the gait. To discriminate between healthy and knee osteoarthritis patients and to classify different subgroups of knee osteoarthritis patients (patients scheduled for surgery vs. patients not scheduled for surgery; bilateral knee osteoarthritis diagnosis vs. unilateral knee osteoarthritis diagnosis), we used a machine learning approach called the support vector machine. A total of 88 features were extracted and used for classification. FINDINGS: The patients vs. healthy participants were classified with 71% accuracy, 85% sensitivity, and 56% specificity. The "patients scheduled for surgery" vs. "patients not scheduled for surgery" were classified with 83% accuracy, 83% sensitivity, and 81% specificity. The bilateral knee osteoarthritis diagnosis vs. unilateral knee osteoarthritis diagnosis was classified with 81% accuracy, 75% sensitivity, and 79% specificity. INTERPRETATION: Gait analysis using wearable sensors and machine learning can discriminate between healthy and knee osteoarthritis patients and classify different subgroups with reasonable accuracy, sensitivity, and specificity. The proposed approach requires no complex gait factors and is not limited to controlled laboratory settings.
Assuntos
Marcha , Osteoartrite do Joelho , Sapatos , Humanos , Osteoartrite do Joelho/fisiopatologia , Osteoartrite do Joelho/diagnóstico , Osteoartrite do Joelho/classificação , Feminino , Masculino , Pessoa de Meia-Idade , Idoso , Análise da Marcha/métodos , Análise da Marcha/instrumentação , Dispositivos Eletrônicos Vestíveis , Aprendizado de Máquina , Máquina de Vetores de Suporte , Sensibilidade e Especificidade , Reprodutibilidade dos TestesRESUMO
BACKGROUND: An inertial measurement unit is small and lightweight, allowing patient measurements without physical constraints. This study aimed to determine the differences in kinematic parameters during gait using an insole with a single inertial measurement unit in healthy controls and on both sides in patients with knee osteoarthritis. METHODS: Twenty patients with knee osteoarthritis and 13 age-matched controls were included in this study. The participants walked at a self-selected speed and foot kinematics were measured during gait using an insole with a single inertial measurement unit. The right side of the healthy controls and both the affected and contralateral sides of patients with KOA were analyzed separately. FINDINGS: The foot extension angular velocity at toe-off was significantly reduced on the affected side than on the contralateral side (P < 0.001) and in healthy controls (P < 0.001). During the swing phase, foot posterior-anterior acceleration was significantly lower on the affected side than on the healthy controls (P = 0.005). Furthermore, despite a decrease in walking speed, foot superior-inferior acceleration at initial contact in patients was significantly lower on the contralateral side than in healthy controls (P = 0.0167), but not on the affected side (P = 0.344). INTERPRETATION: An insole with a single inertial measurement unit can detect differences in foot kinematics during gait between healthy controls and patients with knee osteoarthritis. Our findings indicate that patients with knee osteoarthritis exhibit dysfunction of push-off at toe-off and shock absorption at initial contact on the affected side.
Assuntos
Osteoartrite do Joelho , Humanos , Articulação do Joelho , Fenômenos Biomecânicos , Estudos de Casos e Controles , Marcha , CaminhadaRESUMO
Psychosis is a distressing symptom commonly occurring in people with dementia. To treat Parkinson's disease psychosis, pimavanserin (1), a 5-HT2A receptor inverse agonist having minimal 5-HT2C receptor affinity and no dopamine D2 receptor affinity, was approved in the United States, but not for dementia-related psychosis due to limited efficacy issues. Herein, we report on the identification of a potent and dual 5-HT2A and 5-HT2C receptor inverse agonist 8 having minimal hERG inhibition, after having demonstrated the involvement of both 5-HT2A and 5-HT2C receptors to deliver antipsychotic efficacy in an MK-801-induced locomotor model and having conducted 5-HT2A and 5-HT2C occupancy studies including a surrogate method. The introduction of a spirocyclopropyl group boosting 5-HT2C affinity in 1 followed by further optimization to control lipophilicity resulted in balanced dual potency and metabolic stability, and mitigating hERG inhibition led to 8 that showed significant antipsychotic efficacy due to the involvement of both receptors.
Assuntos
Antipsicóticos , Demência , Transtornos Psicóticos , Receptor 5-HT2A de Serotonina , Receptor 5-HT2C de Serotonina , Agonistas do Receptor 5-HT2 de Serotonina , Antipsicóticos/farmacologia , Antipsicóticos/uso terapêutico , Antipsicóticos/química , Antipsicóticos/síntese química , Animais , Receptor 5-HT2A de Serotonina/metabolismo , Humanos , Transtornos Psicóticos/tratamento farmacológico , Agonistas do Receptor 5-HT2 de Serotonina/farmacologia , Agonistas do Receptor 5-HT2 de Serotonina/uso terapêutico , Agonistas do Receptor 5-HT2 de Serotonina/química , Receptor 5-HT2C de Serotonina/metabolismo , Demência/tratamento farmacológico , Relação Estrutura-Atividade , Masculino , Agonismo Inverso de Drogas , Canal de Potássio ERG1/metabolismo , Canal de Potássio ERG1/antagonistas & inibidores , Ratos , Camundongos , Piperidinas/farmacologia , Piperidinas/uso terapêutico , Piperidinas/química , Ratos Sprague-Dawley , Canais de Potássio Éter-A-Go-Go/antagonistas & inibidores , Canais de Potássio Éter-A-Go-Go/metabolismo , Ureia/análogos & derivadosRESUMO
The Ser/Thr kinase CK2 consists of two catalytic subunits (CK2α) and a dimer of the regulatory subunits (CK2ß), and is a ubiquitous enzyme that regulates growth, proliferation and the survival of cells. CK2 is a remarkable drug target for potentially treating a wide variety of tumours and glomerulonephritis. The purified CK2α protein was crystallized using ethylene glycol as a precipitant. The crystal structure of CK2α with 21 loci of alternative conformations, including a niacin, 19 ethylene glycols and 346 waters, was determined at 1.06 Å resolution to an Rwork of 14.0% (Rfree = 16.5%). The alternative ensemble in the internal hydrophobic core underpins the plasticity of the αD-helix responsible for the regulation of ATP/GTP binding. The clear density map indicates that a niacin molecule, contained in the Escherichia coli culture medium, binds to the ATP binding site. An ethylene glycol molecule binds in the hydrophobic pocket lateral to the αD-helix forming the rim of the active site. The other ethylene glycol molecules occupy physiologically significant sites, including the CK2ß binding interface and substrate binding site, as well as the gap in the crystal packing. Together with water molecules in the active site, these structural insights should facilitate drug discovery.
Assuntos
Trifosfato de Adenosina/metabolismo , Caseína Quinase II/química , Domínio Catalítico , Cristalografia por Raios X , Escherichia coli/química , Etilenoglicol/química , Guanosina Trifosfato/metabolismo , Humanos , Modelos Moleculares , Conformação ProteicaRESUMO
Background: Balanced postural control of the body is associated with two mechanisms: anticipatory postural adjustment and compensatory postural adjustment. Previous studies reported changes in body postural control under unpredictable conditions (interference with closed eyes). Research question: To ascertain whether in contrast with predictable disturbances, there is a difference in muscle activity and center of pressure displacement changes when the direction of the disturbance is unpredictable. Methods: Three examiners stood at 45° to the left, the front, and 45° to the right of the participant to throw the ball to him. 11 healthy young participants were required to maintain their balance in the standing position after receiving the ball in conditions with and without known catching directions. The anticipatory postural adjustment and compensatory postural adjustment integral changes of the muscle activity in the lower limbs and trunk bilaterally and at the center of pressure displacement in the known and unknown conditions were observed. Two-way ANOVA was used to compare the differences in muscle activity and displacement changes. Results: Results showed that the center of pressure in the anticipatory postural adjustment and compensatory postural adjustment in the posterior direction with known catching direction was significantly shorter than those without. Integration of electromyogram in anticipatory postural adjustment of the right soleus (p = 0.023) was associated with higher muscle activities in the unknown than known conditions. Integration of electromyogram in compensatory postural adjustment of the right tibial anterior (p = 0.004), right rectus femoris (p = 0.023) and left rectus abdominis (p = 0.038) in unknown catching direction had significantly greater muscle activity than those without. When the direction of the perturbation is unpredictable, the central nervous system may initiate and induce greater center of pressure changes in the posterior direction with changes in several muscular activities to ensure postural control.
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Wearing loose footwear, such as slippers, poses a risk factor for tripping. Previous studies have examined obstacle crossing to find strategies to avoid tripping. However, the effect of wearing slippers on the likelihood of tripping remains unclear. Therefore, this study aimed to determine whether wearing slippers while level walking and obstacle crossing affects kinematic characteristics and muscle activity. Sixteen healthy, young adults performed two tasks (a) while wearing slippers and (b) while barefoot: (1) level walking and (2) crossing a 10-cm obstacle. Toe clearance, joint angles, muscle activity, and cocontraction were measured for both the leading and trailing lower limbs. In the slipper-wearing condition, knee flexion and hip flexion angles were significantly increased in the swing phase for the leading limb (p < .001 and p < .001, respectively) and trailing limb (p < .001 and p = .004, respectively) compared with the barefoot condition. Tibialis anterior activity (p = .01) and muscle cocontraction of the tibialis anterior and the medial head of the gastrocnemius (p = .047) were significantly increased in the swing phase of the trailing limb for the slipper-wearing condition compared with the barefoot condition in the obstacle crossing task. Wearing slippers increased knee and hip flexion angles, and muscle cocontraction of the tibialis anterior and medial head of gastrocnemius increased during obstacle crossing. The results revealed that obstacle crossing while wearing slippers would require foot fixation adjustment in addition to increased knee and hip flexion to avoid toe collision.
Assuntos
Extremidade Inferior , Caminhada , Humanos , Adulto Jovem , Caminhada/fisiologia , Pé , Articulação do Joelho/fisiologia , Dedos do Pé , Fenômenos Biomecânicos , Marcha/fisiologiaRESUMO
Deep-squat movement is one of the most important activities for independent living. Although a large range of motion of lower extremity joints in the sagittal plane is required for deep-squat movement, older individuals exhibit reduced mobility of lower limb joints. However, the effect of aging on deep-squat movement remains unclear. The purpose of this study was to investigate the age-related changes in the whole-body movement and lower extremity joint kinematics and kinetics during deep-squat movement. Twelve older and nineteen younger individuals performed the deep-squat movement, with knee flexion exceeding 100 degrees, and a motion analysis system and force plates collected their motion data. The median (interquartile range) age of older and younger individuals was 76.5 (3.3) and 30.0 (9.0) years, respectively. The deep-squat depth was significantly shallower in older individuals than in younger individuals (P < 0.05). Furthermore, older individuals exhibited smaller ankle dorsiflexion and knee flexion angles, larger trunk flexion angles, and greater forward displacement of the whole-body center of mass during deep-squat movement (P < 0.05). In terms of kinetic variables, older individuals exhibited smaller contributions of knee extension moment and larger contributions of hip extension moment to the support moment in the timing of the maximum support moment during deep-squat movement (P < 0.05). Our results indicated that older individuals have greater difficulty with deeper-squat movement and smaller contribution of knee extension moment to support body weight using trunk, hip, and ankle movements during deep-squat movement.
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Articulação do Joelho , Extremidade Inferior , Idoso , Envelhecimento , Articulação do Tornozelo , Fenômenos Biomecânicos , Articulação do Quadril , Humanos , Cinética , Movimento , Amplitude de Movimento ArticularRESUMO
The detailed understanding of the molecular features of a ligand binding to a target protein, facilitates the successful design of potent and selective inhibitors. We present a case study of ATP-competitive kinase inhibitors that include a pyradine moiety. These compounds have similar chemical structure, except for distinct terminal hydrophobic cyclopentyl or isopropyl groups, and block kinase activity of casein kinase 2 subunit α (CK2α), which is a target for several diseases, such as cancer and glomerulonephritis. Although these compounds display similar inhibitory potency against CK2α, the crystal structures reveal that the cyclopentyl derivative gains more favorable interactions compared with the isopropyl derivative, because of the additional ethylene moiety. The structural observations and biological data are consistent with the thermodynamic profiles of these inhibitors in binding to CK2α, revealing that the enthalpic advantage of the cyclopentyl derivative is accompanied with a lower entropic loss. Computational analyses indicated that the relative enthalpic gain of the cyclopentyl derivative arises from an enhancement of a wide range of van der Waals interactions from the whole complex. Conversely, the relative entropy loss of the cyclopentyl derivative arises from a decrease in the molecular fluctuation and higher conformational restriction in the active site of CK2α. These structural insights, in combination with thermodynamic and computational observations, should be helpful in developing potent and selective CK2α inhibitors.
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Caseína Quinase II/metabolismo , Ciclopentanos/química , Pentanos/química , Inibidores de Proteínas Quinases/metabolismo , Trifosfato de Adenosina/metabolismo , Sítios de Ligação , Caseína Quinase II/antagonistas & inibidores , Caseína Quinase II/química , Colorimetria , Cristalografia por Raios X , Descoberta de Drogas , Entropia , Humanos , Ligação Proteica/efeitos dos fármacos , Inibidores de Proteínas Quinases/química , Inibidores de Proteínas Quinases/farmacologiaRESUMO
Real-world walking activity is important for poststroke patients because it leads to their participation in the community and physical activity. Walking activity may be related to adaptability to different surface conditions of the ground. The purpose of this study was to clarify whether walking adaptability on an uneven surface by step is related to daily walking activity in patients after stroke. We involved 14 patients who had hemiparesis after stroke (age: 59.4 ± 8.9 years; post-onset duration: 70.7 ± 53.5 months) and 12 healthy controls (age: 59.5 ± 14.2 years). The poststroke patients were categorized as least limited community ambulators or unlimited ambulators. For the uneven surface, the study used an artificial grass surface (7 m long, 2-cm leaf length). The subjects repeated even surface walking and the uneven surface walking trials at least two times at a comfortable speed. We collected spatiotemporal and kinematic gait parameters on both the even and uneven surfaces using a three-dimensional motion analysis system. After we measured gait, the subjects wore an accelerometer around the waist for at least 4 days. We measured the number of steps per day using the accelerometer to evaluate walking activity. Differences in gait parameters between the even and uneven surfaces were calculated to determine how the subjects adapted to an uneven surface while walking. We examined the association between the difference in parameter measurements between the two surface properties and walking activity (number of steps per day). Walking activity significantly and positively correlated with the difference in paretic step length under the conditions of different surface properties in the poststroke patients (r = 0.65, p = 0.012) and step width in the healthy controls (r = 0.68, p = 0.015). The strategy of increasing the paretic step length, but not step width, on an uneven surface may lead to a larger base of support, which maintains stability during gait on an uneven surface in poststroke patients, resulting in an increased walking activity. Therefore, in poststroke patients, an increase in paretic step length during gait on an uneven surface might be more essential for improving walking activity.
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Walking rehabilitation is challenging in stroke patients with sensory impairments. In this study, we examined the two-week effect of an auditory biofeedback prosthesis, Auditory Foot (AF), on the change in the frontal whole body angular momentum (WBAM) range, before and after a two-week walking rehabilitation. We conducted a pilot randomized controlled trial (RCT). We employed statistical Bayesian modeling to understand the mechanism of the rehabilitation effect and predict the expected effect in new patients. The best-performing model indicated that the frontal WBAM range was reduced in the AF group by 12.9-28.7%. This suggests that the use of kinesthetic biofeedback in gait rehabilitation contributes to the suppression of frontal WBAM, resulting in an improved walking balance function in stroke patients.
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Categorization based on quasi-joint stiffness (QJS) may help clinicians select appropriate ankle foot orthoses (AFOs). The objectives of the present study were to classify the gait pattern based on ankle joint stiffness, also called QJS, of the gait in patients after stroke and to clarify differences in the type of AFO among 72 patients after stroke. Hierarchical cluster analysis was used to classify gait patterns based on QJS at least one month before the study, which revealed three distinct subgroups (SGs 1, 2, and 3). The proportion of use of AFOs, articulated AFOs, and non-articulated AFOs were significantly different among SGs 1-3. In SG1, with a higher QJS in the early and middle stance, the proportion of the patients using articulated AFOs was higher, whereas in SG3, with a lower QJS in both stances, the proportion of patients using non-articulated AFOs was higher. In SG2, with a lower QJS in the early stance and higher QJS in the middle stance, the proportion of patients using AFOs was lower. These findings indicate that classification of gait patterns based on QJS in patients after stroke may be helpful in selecting AFO. However, large sample sizes are required to confirm these results.
RESUMO
Sit-to-stand (STS) movements from low seat height are not easily executed by older individuals. Although young individuals increase their lower limb muscle power (LLMP) based on the product of the ground reaction force (GRF) and center of mass velocity (CoMv) during STS movement from a low seat height, it remains unclear whether seat height has an effect on LLMP during STS movement in older individuals. The present study aimed to investigate differences in the LLMP during STS movements when seat height is lowered between young and older individuals. Twelve older and twelve height-matched young individuals were instructed to perform STS movements from low (20 cm), middle (40 cm), and high (60 cm) seat heights. STS movement and GRF were obtained by a motion analysis system and force plates. In the low-seat-height condition, the forward and upward LLMPs and the upward CoMv were significantly lower in older individuals than those in young individuals, but the forward CoMv was not. The completion time of STS movement from a low seat height was significantly longer in older individuals than in young individuals. Our findings suggest that the slower upward CoMv due to the lower upward LLMP extends the completion time of STS movement from a low seat height in older individuals. Furthermore, in the low-seat-height condition, older individuals may move their center of mass (CoM) forward in a different way when compared with young individuals, and they may not use forward LLMP for moving CoM forward.