Lysosome positioning and mTOR activity in Lowe syndrome.

Lowe syndrome is a rare, developmental disorder caused by mutations in the phosphatase, OCRL. A study in this issue of EMBO Reports shows that OCRL is required for microtubule nucleation and that mutations in this protein lead to an inability to activate mTORC1 signaling and consequent cell proliferation in the presence of nutrients. These defects are the result of impaired microtubule-dependent lysosomal trafficking to the cell periphery and are independent of OCRL phosphatase activity.

Ultrasound Measurement of the Transverse Abdominis, Internal Oblique, and External Oblique Muscles Associated with Forward Head Posture and Reduced Cranio-Vertebral Angle.

BACKGROUND Abnormal posture can affect the alignment of the cervical spine, which can lead to various physical problems. There are many ways to solve the problem by limiting the area around the neck to restore abnormal neck condition. However, there is a need to look at these problems from an enlarged perspective through the relationship between the cervical spine and trunk. This study aimed to investigate the significance of the thickness of the transverse abdominis, internal oblique, and external oblique muscles in patients with forward head posture and reduced cranio-vertebral angle. MATERIAL AND METHODS We included 24 healthy adult males in their 20s without lower back pain. The cranio-vertebral angle (CVA) in all the subjects was measured with the help of pictures taken in the sagittal plane using a digital camera. The thickness of muscles, including transverse abdominis (TrA), internal oblique (IO), and external oblique (EO), was measured using a diagnostic ultrasound device. Pearson's correlation analysis was used to identify the correlation between the variables measured. RESULTS CVA showed a statistically significant correlation with TrA thickness (r=0.506/p=0.012), and among the abdominal muscles, there was a significant correlation between IO and EO thickness (r=0.663/p=0.000). CONCLUSIONS A reduced CVA due to FHP was significantly associated with reduced TrA thickness. Therefore, increasing the bulk of the abdominal muscles with restoration of the abnormal CVA is a potential treatment approach and requires further study.

Pelvic Belt Wearing during Exercise Improves Balance of Patients with Stroke: A Randomized, Controlled, Preliminary Trial.

OBJECTIVES: To investigate whether wearing a pelvic belt during a trunk stability exercise program positively affects balance in patients with stroke. MATERIALS AND METHODS: Twenty-four patients with stroke were randomly allocated to the experimental or control group and performed a 60-min general physical therapy and an additional 30-min trunk stability exercise (five times/week for 6 weeks). Those in the experimental and control groups performed the trunk stability exercises with and without wearing the pelvic belt, respectively. RESULTS: The experimental group showed a significantly greater magnitude of improvements in balance than the control group (Postural Assessment Scale for Stroke: +18.3%, F (1, 22)=14.350, p=.001, η2=.395; Berg Balance Scale: +11%, F (1, 22)=19.062, p=.000, η2=.464; Timed Up and Go Test: -10.5%, F (1, 22)=8.562, p=.008, η2=.280; center of pressure path length with eyes open: -15.1%, F (1, 22)=6.770, p=.016, η2=.235; center of pressure path length with eyes closed: -19.5%, F (1, 22)=9.256, p=.006, η2=.296; center of pressure path velocity with eyes open: -22.6%, F (1, 22)=37.747, p=.000, η2=.632; center of pressure path velocity with eyes closed: -13.9%, F (1, 22)=6.511, p=.018, η2=.228, respectively). CONCLUSIONS: Wearing a pelvic belt while performing trunk stability exercise programs could be a more effective approach for improving balance in patients with stroke.

Deficit of Motor Skill Acquisition on the Upper Limb Ipsilesional to the Injured Hemisphere in Individuals with Stroke.

BACKGROUND Movement deficits in limbs ipsilesional to the damaged hemisphere in individuals with stroke have been established through various motor tasks. Nevertheless, there has been little evidence regarding hindrance of motor skill acquisition on the ipsilesional limb in patients with stroke. Therefore, we attempted to demonstrate whether the characteristics of ipsilesional deficits involved motor learning insufficiency in stroke survivors with unilateral brain damage. MATERIAL AND METHODS Thirty-six participants (18 patients with stroke and 18 normal individuals) were recruited. Patients with stroke performed a visuo-spatial tracking task in the upper limb ipsilesional to the injured hemisphere, and normal participants did the same task with the upper limb matched for the same side. The participants were required to track a target sine wave as accurately as possible while the wave was displayed on the computer screen for 15 seconds. An accuracy index was calculated for each of the trials. RESULTS We found that motor skill learning improved in both stroke and normal groups with repetitive practice. However, the normal group exhibited greater motor skill acquisition than in comparison the stroke group for motor skill improvement. Statistical analyses revealed significant differences in time effects and time x group interactions. CONCLUSIONS Our findings provide evidence that individuals with stroke might have difficulty in performing visuo-spatial movements and acquiring motor skills with the ipsilateral upper limb. Improvement of ipsilesional limb function increases self-care activity in daily life. Therefore, we recommend that clinicians adopt remedial strategies for ipsilesional limbs.

Changes of gait parameters following constrained-weight shift training in patients with stroke.

[Purpose] This study aimed to investigate the effects of training involving compelled weight shift on the paretic lower limb on gait parameters and plantar pressure distribution in patients with stroke. [Subjects and Methods] Forty-five stroke patients participated in the study and were randomly divided into: group with a 5-mm lift on the non-paretic side for constrained weight shift training (5: constrained weight shift training) (n=15); group with a 10-mm lift on the non-paretic side for constrained weight shift training (10: constrained weight shift training) (n=15); or the control group (n=15). Both, the 5 constrained weight shift training and 10 constrained weight shift training groups underwent constrained weight shift training 5 times per week for 4 weeks, whereas the control group performed ergometer exercises for lower limb muscle strengthening. [Results] The 10 constrained weight shift training group showed a significant increase in the contact surface and impulse of the hindfoot compared to the control group, and the step length and walking speed were significantly longer and faster. [Conclusion] We found that constrained weight shift training on the paretic lower limb is an effective treatment method for improving normal gait pattern in stroke patients.

Microglia contributes to plaque growth by cell death due to uptake of amyloid ß in the brain of Alzheimer's disease mouse model.

Pathological hallmarks of Alzheimer's disease (AD) include extracellularly accumulated amyloid ß (Aß) plaques and intracellular neurofibrillary tangles in the brain. Activated microglia, brain-resident macrophages, are also found surrounding Aß plaques. The study of the brain of AD mouse models revealed that Aß plaque formation is completed by the consolidation of newly generated plaque clusters in vicinity of existed plaques. However, the dynamics of Aß plaque formation, growth and the mechanisms by which microglia contribute to Aß plaque formation are unknown. In the present study, we confirmed how microglia are involved in Aß plaque formation and their growth in the brain of 5XFAD mice, the Aß-overexpressing AD transgenic mouse model, and performed serial intravital two-photon microscopy (TPM) imaging of the brains of 5XFAD mice crossed with macrophage/microglia-specific GFP-expressing CX3CR1GFP/GFP mice. We found that activated microglia surrounding Aß plaques take up Aß, which are clusters developed inside activated microglia in vivo and this was followed by microglial cell death. These dying microglia release the accumulated Aß into the extracellular space, which contributes to Aß plaque growth. This process was confirmed by live TPM in vivo imaging and flow cytometry. These results suggest that activated microglia can contribute to formation and growth of Aß plaques by causing microglial cell death in the brain. GLIA 2016;64:2274-2290.

Changes of kinematic parameters of lower extremities with gait speed: a 3D motion analysis study.

[Purpose] The purpose of this study was to investigate the changes in hip, knee and ankle kinematic variables of the lower extremities at different gait speeds. [Subjects and Methods] Forty healthy subjects who had no previous history of neurological, musculo-skeletal or other medical conditions that could affect gait were recruited. The subjects were asked to walk 10 m down a walkway at three different gait speeds: normal gait speed, and self-selected fast, and slow speeds. The experimental order was randomly chosen across these gaits. The hip, knee and ankle kinematic data were evaluated using a VICON 3D motion analysis system and force plates. [Results] The flexion peak and external rotation peak of the knee joint significantly increased with the increase of gait speed. The plantarflexion peaks of the ankle joint significantly increased with increase of gait speed. However, none of the kinematic data of the hip joint were significantly dependent on increase of gait speed. [Conclusion] The relationship of the knee and ankle joint can be described as coupling motion which is dependent on gait speed. Our present findings suggest that coupling motion of the knee joint and plantarflexion of the ankle joint significantly increase with increase of gait speed. These results will provide important insight into gait mechanisms for the evaluation of pathological populations.

The effect of aging on respiratory synergy.

[Purpose] The purpose of this study was to investigate the effect of aging on respiratory synergy, through the comparison of an elderly group and a young group, to help further understanding of postural control in the elderly. [Subjects and Methods] Ten community-dwelling elderly subjects and ten young subjects performed standing under two different respiratory conditions: quiet breathing and apnea. Center of foot pressure displacement and joint angular movements of the head, trunk, pelvis, hips, knees and ankles were measured. [Results] The results of this study showed that the elderly group had a respiratory synergy different from that of the young group. The elderly group in quiet stance used significantly more hip and pelvis movements when compensating for respiratory disturbance than standing with apnea, while the young group used significantly more whole body segments. There were no differences in angular displacements in the quiet stance between the elderly and the young groups. [Conclusion] The elderly group demonstrated a respiratory synergy pattern different from that of the young group. The findings indicate that aging changes the respiratory synergy pattern and this change is not due to decreased functioning of the ankle joint alone.

Changes in upper-extremity muscle activities due to head position in subjects with a forward head posture and rounded shoulders.

[Purpose] This study investigated upper-extremity muscle activities in natural, ideal, and corrected head positions. [Subjects and Methods] Forty subjects with a forward head posture and rounded shoulder were recruited and randomly assigned to the natural head position group (n = 13), ideal head position group (n = 14), or corrected head position group (n = 13). Muscle activities were measured using a four-channel surface electromyography system at the sternocleidomastoideus, upper and lower trapezius, and serratus anterior muscles on the right side during an overhead reaching task. [Results] The muscle activities of the upper trapezius and serratus anterior differed significantly among head positions. Post hoc tests revealed significant differences between natural and ideal head positions, and natural and ideal head positions for both the upper trapezius and serratus anterior. [Conclusion] Recovery of normal upper trapezius and serratus anterior muscle functions plays an important role in correcting forward head posture and rounded shoulders.

Effect of constrained weight shift on the static balance and muscle activation of stroke patients.

[Purpose] The purpose of this study was to evaluate the effects of constrained weight shift induced by shoe lift beneath the unaffected lower extremity, on balance functions and electromyography of the affected lower extremity of stroke patients. [Subjects and Methods] Twelve patients with unilateral stroke were recruited as volunteers for this study. The subjects were repeatedly measured in a randomized order under three conditions: no-shoe lift, and shoe lifts of 5 mm and 10 mm heights beneath the unaffected lower extremity. [Results] Standing with a 10 mm shoe lift for the unaffected lower extremity decreased the mean velocity of mediolateral sway compared to no-shoe lift. Regarding the velocity of anteroposterior sway, standing with 5 mm and 10 mm shoe lifts decreased the mean velocity of anteroposterior sway. The muscle activation of the affected lower extremity was not significantly different among the no-shoe lift, 5 mm shoe lift and 10 mm shoe lift conditions; however, the muscle activities of the rectus femoris, biceps femoris, tibialis anterior, and medial gastrocnemius of the affected lower extremity progressively improved with increasing height of the shoe lift. [Conclusion] A constrained weight shift to the affected side elicited by a shoe insole of 10 mm height on the unaffected side can improve the static standing balance of stroke patients, and it resulted in 14-24% increases in the muscle activities of the affected leg.

Effect of handrail use while performing treadmill walking on the gait of stroke patients.

[Purpose] The purpose of this study was to investigate how the use of handrails during treadmill walking affects the gait parameters of stroke patients. [Subjects and Methods] The participants, 30 hemiplegic stroke patients, were randomly allocated to one of three groups: the NHG group (No Handrail group, n=10), the FHG group (Front handrail group, n=10), and BHG group (Bilateral Handrail group, n=10). All the subjects' performed treadmill walking for 30 min, five days a week, for a period of eight weeks. Gait parameters were evaluated using the RS-scan system. [Results] A statistically significant difference in the HM (heel-medial) area of plantar foot pressure was observed between BHG and NHG. Statistically significant difference in the HL (heel-lateral) area of plantar foot pressure was observed between BHG and NHG, and between FHG and NHG. A statistically significant difference in contact area of the rear foot was observed between BHG and NHG. [Conclusion] The results of this study show that holding handrails during treadmill training may enhance the improvement in the quality of patients' gait (plantar foot pressure, contact area of foot).

Prevalence and determinants of pain in the ipsilateral upper limb of stroke patients.

This study investigated the prevalence of pain in the ipsilateral upper-limb in stroke patients. 229 stroke patients (133 men, 96 women; M age = 59.0 yr., SD = 12.4) were assessed with the Pain Behaviors Scales and their motor weakness was measured with the Motricity Index. Results indicated that over 27% of patients experienced pain in at least one joint of the ipsilateral upper limb. Shoulder pain was the most common. Further analysis indicated that the occurrence of pain in the ipsilateral upper limb was higher among women, among patients who used a cane, and among patients with a greater weakness of the affected lower limb.

Comparison of Spatiotemporal Gait Parameters between Children with Normal Development and Children with Diplegic Cerebral Palsy.

[Purpose] The purpose of this study was to determine the differences in spatiotemporal gait parameters between children with spastic diplegic CP and children with normal development (ND). [Subjects and Methods] Sixteen children (eight children with spastic diplegic CP and eight ND children) were recruited for participation as volunteers in this study. The children with CP had a Gross Motor Function Classification (GMFC) System level of between I and II. [Results] Walking velocity, cadence, stride length, and step width of children with CP with a GMFC of between I and II were a level of 60%, 77%, 73%, and 160%, respectively, of those of ND children. The percentages of right and left double-limb support were 188% and 179% higher, respectively, and the proportion of single limb support was shorter by 83% and 82%. [Conclusion] Our results provide objective evidence of distinct differences in spatiotemporal gait parameters between children with spastic diplegic CP with a GMFC level I or II and ND children and would be helpful to persons involved in the care of these children.

Comparison of the plantar pressure distributions at different degrees of tilting: a preliminary report.

[Purpose] The purpose of this study was to investigate the amount of plantar pressures on the lower limb during tilt table standing and to indicate the ideal degree of tilting for partial weight bearing. [Subjects and Methods] Fifteen healthy subjects between the ages of 20 and 30 were recruited as volunteers for this study. All the measurements were taken while standing on a tilt table according to different inclination angles. [Results] The plantar pressures for 60° tilt table standing were lower by 7-9% of total body weight than the pressures during tilt table standing at 90°, and the pressures for 30° tilt table standing were lower by 18-20% of total body weight than the pressures for tilt table standing at 90°. [Conclusion] Standing training on a 60° tilt table might be equivalent to 80% of full weight bearing training, and tilt table standing training at 30° might be equivalent to 60% of full weight bearing training.

Influence of Resistance Exercise Training to Strengthen Muscles across Multiple Joints of the Lower Limbs on Dynamic Balance Functions of Stroke Patients.

[Purpose] The objective of this study was to evaluate the effects of resistance exercise training for strengthening muscles across multiple joints on the dynamic balance function of stroke patients. [Subjects and Methods] Subjects in the training group (n=14) and the control group (n=14) received conservative physical therapy for 30 minutes per day, five days per week, for a period of six weeks. The training group additionally performed three sets (eight to 10 repetitions per set) of resistance exercise at 70% of the 1-repetition maximum (1RM) to strengthen muscles across multiple joints. The control group did the same exercises for the same duration but without resistance. To assess dynamic balance function, before and after the intervention, we measured antero-posterior (A-P) and medio-lateral (M-L) sway distances, the Berg balance scale (BBS), and the timed up and go (TUG) times. [Results] Compared to pre-intervention values, the BBS score showed significant increases in both groups, and A-P and M-L sway distances and TUG times showed significant decreases in both groups. Changes in A-P and M-L sway distances, BBS scores, and TUG times were significantly different between the muscle training group and the control group. [Conclusion] Training involving muscle strength across multiple joints is an effective intervention for improvement of dynamic balance function of stroke patients.

p300 nucleocytoplasmic shuttling underlies mTORC1 hyperactivation in Hutchinson-Gilford progeria syndrome.

The mechanistic target of rapamycin complex 1 (mTORC1) is a master regulator of cell growth, metabolism and autophagy. Multiple pathways modulate mTORC1 in response to nutrients. Here we describe that nucleus-cytoplasmic shuttling of p300/EP300 regulates mTORC1 activity in response to amino acid or glucose levels. Depletion of these nutrients causes cytoplasm-to-nucleus relocalization of p300 that decreases acetylation of the mTORC1 component raptor, thereby reducing mTORC1 activity and activating autophagy. This is mediated by AMP-activated protein kinase-dependent phosphorylation of p300 at serine 89. Nutrient addition to starved cells results in protein phosphatase 2A-dependent dephosphorylation of nuclear p300, enabling its CRM1-dependent export to the cytoplasm to mediate mTORC1 reactivation. p300 shuttling regulates mTORC1 in most cell types and occurs in response to altered nutrients in diverse mouse tissues. Interestingly, p300 cytoplasm-nucleus shuttling is altered in cells from patients with Hutchinson-Gilford progeria syndrome. p300 mislocalization by the disease-causing protein, progerin, activates mTORC1 and inhibits autophagy, phenotypes that are normalized by modulating p300 shuttling. These results reveal how nutrients regulate mTORC1, a cytoplasmic complex, by shuttling its positive regulator p300 in and out of the nucleus, and how this pathway is misregulated in Hutchinson-Gilford progeria syndrome, causing mTORC1 hyperactivation and defective autophagy.

Effects of Transcranial Direct Current Stimulation on Clinical Features of Dizziness and Cortical Activation in a Patient with Vestibular Migraine.

BACKGROUND: Vestibular migraine (VM) is common migraine that occurs in patients with dizziness. Vestibular rehabilitation for managing VM generally remains unclear. Recently, it has been reported that transcranial direct current stimulation (tDCS) has positive effects in alleviating dizziness. This study investigated the effects of tDCS on dizziness and cortical activation in a patient with VM. METHODS: We recruited a male patient aged 31 years with no dizziness. The patient watched a video to induce dizziness using a virtual reality device. The study applied the intervention using tDCS for 4 weeks and measured 4 assessments: functional near-infrared spectroscopy (fNIRS), quantitative electroencephalography (qEEG), dizziness handicap inventory, and visual vertigo analog scale. RESULTS: We showed the activation in the middle temporal gyrus and inferior temporal gyrus (ITG) of the left hemisphere and in the superior temporal gyrus and ITG of the right hemisphere in the pre-intervention. After the intervention, the activation of these areas decreased. In the results of qEEG, excessive activation of C3, P3, and T5 in the left hemisphere and C4 in the right hemisphere before intervention disappeared after the intervention. CONCLUSIONS: This study indicated that tDCS-based intervention could be considered a viable approach to treating patients with vestibular dysfunction and dizziness caused by VM.

Nuclear proteasomes buffer cytoplasmic proteins during autophagy compromise.

Autophagy is a conserved pathway where cytoplasmic contents are engulfed by autophagosomes, which then fuse with lysosomes enabling their degradation. Mutations in core autophagy genes cause neurological conditions, and autophagy defects are seen in neurodegenerative diseases such as Parkinson's disease and Huntington's disease. Thus, we have sought to understand the cellular pathway perturbations that autophagy-perturbed cells are vulnerable to by seeking negative genetic interactions such as synthetic lethality in autophagy-null human cells using available data from yeast screens. These revealed that loss of proteasome and nuclear pore complex components cause synergistic viability changes akin to synthetic fitness loss in autophagy-null cells. This can be attributed to the cytoplasm-to-nuclear transport of proteins during autophagy deficiency and subsequent degradation of these erstwhile cytoplasmic proteins by nuclear proteasomes. As both autophagy and cytoplasm-to-nuclear transport are defective in Huntington's disease, such cells are more vulnerable to perturbations of proteostasis due to these synthetic interactions.

The Intra- and Inter-rater Reliabilities of the Forward Head Posture Assessment of Normal Healthy Subjects.

[Purpose] Assessment of posture is an important goal of physical therapy interventions for preventing the progression of forward head posture (FHP). The purpose of this study was to determine the inter- and intra-rater reliabilities of the assessment of FHP. [Subjects and Methods] We recruited 45 participants (20 male subjects, 25 female subjects) from a university student population. Two physical therapists assessed FHP using images of head extension. FHP is characterized by the measurement of angles and distances between anatomical landmarks. Forward shoulder angle of 54° or less was defined as FHP. Intra- and inter-rater reliabilities were estimated using Kendall's Taub correlation coefficients. [Results] Intra-class correlation of intra-rater measurements indicated an excellent level of reliability (0.91), and intra-class correlation of inter-rater measurements showed a good level of reliability in the assessment of FHP (0.75). [Conclusion] Assessment of FHP is an important component of evaluation and affects the design of the treatment regimen. The assessment of FHP was reliably measured by two physical therapists. It could therefore become a useful method for assessing FHP in the clinical setting. Future studies will be needed to provide more detailed quantitative data for accurate assessment of posture.

Deficits of Movement Accuracy and Proprioceptive Sense in the Ipsi-lesional Upper Limb of Patients with Hemiparetic Stroke.

[Purpose] Previous studies have reported on motor deficits in the ipsilateral upper limbs (UL) of a damaged brain hemisphere in motor tasks. However, little is known about sensory deficits on the ipsilateral side. Therefore, we investigated whether both motor and sensory function of the ipsilateral UL are affected in patients with stroke. [Subjects and Methods] Fifty patients with unilateral stroke and 40 age- and sex- matched normal subjects participated in this study. Subjects were evaluated on performance of a tracking task for motor function, and by the joint reposition test for integrity of proprioceptive sense in the ipsilateral UL. [Result] The comparison of the stroke group and the control group showed significant differences in performance of the tracking task and the joint reposition test. The accuracy index for the tracking task showed significant correlation with the error score for the joint reposition test in the stroke group. [Conclusion] These results suggest that the ipsilateral UL of stroke patients has impairment in sensory function which is related to proprioceptive sense, along with motor deficits. Therefore, we think that the difficulty stroke patients experience with motor tasks for the ipsilateral UL is induced by diminished integrity of sensorimotor function due to both sensory and motor deficits.