Transgenic viral expression of PH-20, IL-12, and sPD1-Fc enhances immune cell infiltration and anti-tumor efficacy of an oncolytic virus.

Oncolytic viruses are of significant clinical interest due to their ability to directly infect and kill tumors and enhance the anti-tumor immune response. Previously, we developed KLS-3010, a novel oncolytic virus derived from the International Health Department-White (IHD-W) strain vaccinia virus, which has robust tumoricidal effects. In the present study, we generated a recombinant oncolytic virus, KLS-3020, by inserting three transgenes (hyaluronidase [PH-20], interleukin-12 [IL-12], and soluble programmed cell death 1 fused to the Fc domain [sPD1-Fc]) into KLS-3010 and investigated its anti-tumor efficacy and ability to induce anti-tumor immune responses in CT26.WT and B16F10 mouse tumor models. A single injection of KLS-3020 significantly decreased tumor growth. The roles of the transgenes were investigated using viruses expressing each single transgene alone and KLS-3020. PH-20 promoted virus spread and tumor immune cell infiltration, IL-12 activated and reprogrammed T cells to inflammatory phenotypes, and sPD1-Fc increased intra-tumoral populations of activated T cells. The tumor-specific systemic immune response and the abscopal tumor control elicited by KLS-3020 were demonstrated in the CT26.WT tumor model. The insertion of transgenes into KLS-3020 increased its anti-tumor efficacy, supporting further clinical investigation of KLS-3020 as a novel oncolytic immunotherapy.

Structural Integrity of the Cerebellar Outflow Tract Predicts Long-Term Motor Function After Middle Cerebral Artery Ischemic Stroke.

BACKGROUND: The cerebellum plays a crucial role in functional movement by influencing sensorimotor coordination and learning. However, the effects of cortico-cerebellar connectivity on the recovery of upper extremity motor function after stroke have not been investigated. We hypothesized that the integrity of the cortico-cerebellar connections would be reduced in patients with a subacute middle cerebral artery (MCA) stroke, and that this reduction may help to predict chronic upper extremity motor function. METHODS: We retrospectively analyzed the diffusion-tensor imaging of 25 patients with a subacute MCA stroke (mean age: 62.2 ± 2.7 years; 14 females) and 25 age- and sex-matched healthy controls. We evaluated the microstructural integrity of the corticospinal tract (CST), dentatothalamocortical tract (DTCT), and corticopontocerebellar tract (CPCT). Furthermore, we created linear regression models to predict chronic upper extremity motor function based on the structural integrity of each tract. RESULTS: In stroke patients, the affected DTCT and CST showed significantly impaired structural integrity compared to unaffected tracts and the tracts in controls. When all models were compared, the model that used the fractional anisotropy (FA) asymmetry indices of CST and DTCT as independent variables best predicted chronic upper extremity motor function (R2 = .506, P = .001). The extent of structural integrity of the CPCT did not significantly differ between hemispheres or groups and was not predictive of motor function. CONCLUSIONS: We found evidence that microstructural integrity of the DTCT in the subacute phase of an MCA stroke helped to predict chronic upper extremity motor function, independent of CST status.

Changes in Trunk Muscle Activity during Unilateral Weight Bearing and Abnormal Postural Gait in Healthy Individuals.

Background and Objectives: Many people tend to carry their bags or baggage on only one side of their body. Due to smartphone use, people also tend to walk bent forward in a kyphotic posture. In this study, we aimed to assess trunk muscle activity changes due to weight-bearing, carried in the left or right hand, and using three different gait postures. Materials and Methods: We recruited 27 healthy participants (aged 19−75 years) with no history of LBP within the last 6 months before study participation. Electromyographic activities of the lower back and the abdominal muscles of the participants were evaluated using four-channel surface electromyography (EMG). Surface EMG recordings were obtained from four trunk muscles, including the flexor (rectus abdominis (RA), external oblique (EO)) and extensor muscles (lumbar erector spinae (LE), and the superficial lumbar multifidus (LM)), during unilateral weight-bearing tasks and with different gait postures (normal gait, with a sway back, and thoracic kyphosis). Results: In the "unilateral weight-bearing task", there was a significant difference in the activity of all the trunk muscles between the weight-bearing limb side and the opposite side (p < 0.05). The activation of the left trunk muscle was greater than that of the right trunk muscle when the dumbbell was lifted using the right hand. The other side showed the same result. In the "gait posture task" performed by the participants using a sway-back posture, the RA and EO had a higher level of activity in the stance and swing phases compared with that in a neutral gait (p < 0.05). Moreover, in the participants with a thoracic kyphosis posture, the LE and LM had a higher level of activity compared with that in a neutral gait (p < 0.05). Conclusions: Our results indicate that abnormal gait posture and unilateral weight-bearing tasks may impair the balance of trunk muscles, increasing the incidence of LBP. However, further large-scale, prospective, controlled studies are warranted to corroborate our results.

Physical activity, quality of life and parenting stress in children with cerebral palsy.

BACKGROUND: Children with cerebral palsy (CP) are less physically active than their typically developing peers. The effects of decreased physical activity on children's quality of life (QOL) or caregiver's lives are not well understood. This study aimed to investigate the association between physical activity, QOL, and parenting stress in children with CP. METHODS: A prospective cross-sectional study was done in children with CP. Daily physical activity was measured over 7 days using an accelerometer (ActiGraph™). Caregivers completed the Child Health Questionnaire - Parent Form 50 and Parenting Stress Index - Short Form. Multiple regression analysis was used. RESULTS: In total, data from 65 children with Gross Motor Function Classification System (GMFCS) levels I-V, aged 4-13 years, were analyzed. Non-ambulatory (GMFCS IV-V) children had significantly lower activity counts and moderate to vigorous physical activity (MVPA) in comparison with ambulatory (GMFCS I-II) and marginally ambulatory (GMFCS III) children. The ambulatory group had better physical QOL than the non-ambulatory group. Caregivers of the non-ambulatory or marginally ambulatory children with CP reported higher parenting stress levels than those of the ambulatory group. Time spent in MVPA and activity counts were positively associated with physical QOL in children with CP. Low activity counts and low amounts of MVPA of children with CP were significant predictors of high parenting stress. CONCLUSIONS: Physical activity in children with CP is associated with children's QOL and parenting stress. These results suggest that clinicians should conduct physical activity assessment and counseling to promote physical activity.

Clinical Course of Dysphagia in Patients with Nemaline Myopathy.

Nemaline myopathy (NM) is a rare congenital myopathy, a group of disorders that are clinically and genetically heterogeneous. Infants and children with NM often suffer from recurrent pulmonary infections and swallowing difficulty, leading to malnutrition. However, knowledge about the clinical course and prognosis of dysphagia is limited. In this study, we reported the clinical course of two NM patients suffering from dysphagia. Although tube feeding was required for several months after birth, it was eventually possible to obtain sufficient nutrition with an oral diet. Therefore, dysphagia rehabilitation therapy through a series of evaluations should be considered even in children with severe oral motor dysfunction. Through these cases, physicians should be convinced that the symptoms of dysphagia in children with NM can be improved and be able to encourage their parents by explaining this progress. They have the potential to show improvements in swallowing function and will finally be able to take food slowly but fully orally.

Factors Influencing the Progression and Direction of Scoliosis in Children with Neurological Disorders.

(1) Background: scoliosis is highly prevalent in children with neurological disorders, however, studies predicting the progression and affecting the direction of scoliosis have been insufficient. We investigated the factors associated with the progression and direction of scoliosis in children with neurological disorders. (2) Method: retrospectively, 518 whole spine radiographs from 116 patients were used for analysis. Factors affecting the progression of scoliosis over time were analyzed using linear mixed-effects model. Factors associated with the apex direction of the scoliosis were analyzed. (3) Results: pelvic obliquity (PO) ≥ 2.5°, gross motor function classification system level V, vertebral rotation, and female sex significantly affect the progression of scoliosis (p = 0.04, <0.001, <0.001, 0.005, respectively). The higher side of PO and the apex side of scoliosis were interrelated (χ² = 14.58, p < 0.001), but the asymmetrical neurological upper extremity involvement was not. (4) Conclusions: severely impaired gross motor function, PO, vertebral rotation, and female sex were significantly related to the progression of scoliosis. The higher side of PO was opposite to the apex side of scoliosis. By identifying the factors that influence the progression of scoliosis, patients at high risk could be more actively intervened to minimize the severe complications.

Could DOAC Be a Better Choice Than Warfarin in Low Compliance Patients with Fontan Procedure?

Background and Objectives: After the Fontan procedure, thromboembolic events need to be prevented. We present a young patient with a history of Fontan procedure and poor adherence to warfarin who developed systemic thromboembolism. He was changed to maintenance dabigatran, which is one of the available direct oral anticoagulants (DOACs). Case presentation: A 20-year-old man was diagnosed with cerebral infarct, pulmonary thromboembolism (PTE), and renal infarcts. He was prescribed warfarin to prevent thromboembolic events after the Fontan procedure. Based on his poor adherence to warfarin, we decided to change the anticoagulant therapy from warfarin to dabigatran 150 mg bid. One month later, his pulmonary thromboembolism regressed. Conclusion: Our case report showed a young adult with low compliance to warfarin who developed cerebral, pulmonary, and renal thromboembolic events. Thus, in our opinion, the change from warfarin to a DOAC was necessary for further prevention and treatment of PTE. A change from warfarin to a DOAC should be considered in patients with poor compliance who are at high risk of thromboembolic events, for example, after the Fontan procedure.

Alteration of White Matter in Patients with Central Post-Stroke Pain.

A stroke may be followed by central post-stroke pain (CPSP), which is characterized by chronic neuropathic pain. The exact mechanism has not yet been fully uncovered. We investigated alterations in the white matters in patients with CPSP, compared with stroke patients without CPSP and normal controls. Our retrospective cross-sectional, case-control study participants were assigned to three groups: CPSP (stroke patients with CPSP (n = 17)); stroke control (stroke patients without CPSP (n = 26)); and normal control (normal subjects (n = 34)). The investigation of white matter for CPSP was focused on the values of fiber numbers (FN) and fractional anisotrophy (FA) for spinothalamic tract (STT), anterior thalamic radiation (ATR), superior thalamic radiation (STR) and posterior thalamic radiation (PTR), and corticospinal tract (CST) was measured. The FA for the STT and STR of the CPSP group were lower than those for the stroke control and normal control groups. The FA of CST and ATR did not differ between the CPSP and stroke groups, but both differed from the normal control. The FA of PTR in the stroke control group differed from the normal control group, but not from the CPSP group. The FN of CST, STT, ATR, and STR for the CPSP and stroke control groups did not differ from each other, but both differed from those of normal controls. FN of PTR did not differ between the CPSP and normal control groups. The alterations in the spinothalamic tract and superior thalamic radiation after stroke would play a role in the pathogenesis of CPSP.

Periodic Fluctuations in the Incidence of Gastrointestinal Cancer.

PURPOSE: Native stem cells can be periodically replaced during short and long epigenetic intervals. Cancer-prone new stem cells might bring about periodic (non-stochastic) carcinogenic events rather than stochastic events. We investigated the epigenetic non-stochastic carcinogenesis by analyzing regular fluctuations in lifelong cancer incidence. MATERIALS AND METHODS: Korean National Cancer Screening Program data were collected between 2009 and 2016. Non-linear and log-linear regression models were applied to comparatively evaluate non-stochastic and stochastic increases in cancer incidence. Prediction performances of regression models were measured by calculating the coefficient of determination, R2. RESULTS: The incidence of gastric and colorectal cancers fluctuated regularly during both short (8 years) and long (20 years) intervals in the non-linear regression model and increased stochastically in the log-linear regression model. In comparison between the 20-year interval fluctuation model and the stochastic model, R2 values were higher in the 20-year interval fluctuation model of men with gastric cancer (0.975 vs. 0.956), and in the stochastic model of men with colorectal cancer (0.862 vs. 0.877) and women with gastric cancer (0.837 vs. 0.890) and colorectal cancer (0.773 vs. 0.809). Men with gastric cancer showed a high R2 value (0.973) in the 8-year interval fluctuation model as well. CONCLUSION: Lifelong incidence of gastrointestinal cancer tended to fluctuate during short and long intervals, especially in men with gastric cancer, suggesting the influence of an epigenetic schedule.

Generation of a Novel Oncolytic Vaccinia Virus Using the IHD-W Strain.

Oncolytic viruses are promising cancer therapies due to their selective killing of tumor cells and ability to stimulate the host immune system. As an oncolytic virus platform, vaccinia virus has unique advantages, including rapid replication, a broad range of host targets, and a large capacity for transgene incorporation. In this study, we developed a novel oncolytic vaccinia virus with high potency and a favorable safety profile. We began with the International Health Department-White (IHD-W) strain, which had the strongest cytotoxicity against tumor cells among the four vaccinia virus strains tested. Next, several candidate viruses were constructed by deleting three viral genes (C11R, K3L, and J2R) in various combinations, and their efficacy and safety were compared. The virus ultimately selected, named KLS-3010, exhibited strong antitumor activity against broad targets in vitro and in vivo. Furthermore, KLS-3010 showed a favorable safety profile in mice, as determined by the biodistribution and body weight change. More promisingly, KLS-3010 was able to shift the tumor microenvironment to a proinflammatory state, as evidenced by an increase in activated lymphocytes after KLS-3010 administration, suggesting that this strain may elicit an oncolytic virus-mediated immune response. The KLS-3010 strain thus represents a promising platform for the further development of oncolytic virus-based cancer therapies.

Twelve Weeks of Strengthening Exercise for Patients with Rheumatoid Arthritis: A Prospective Intervention Study.

Rheumatoid arthritis (RA) patients may benefit from exercise for several reasons. However, whole-limb strengthening exercises for such patients remain poorly studied. We hypothesized that systemic strength training that includes the upper and lower extremities would improve strength per se and enhance the quality of life. Here, we investigated the effects of 12 weeks of upper- and lower-limb strengthening exercise on the strength and quality of life of RA patients using the International Classification of Functioning, Disability, and Health model. This was a prospective, interventional controlled trial. Forty female RA patients were recruited and assigned to two groups not based on willingness to exercise, with 20 patients in the exercise group and 20 in the control group. All patients in the exercise group received once-weekly training sessions of 60 min over 12 weeks. All participants were assessed before and after the 12-week intervention period. We measured the hand grip strength and isometric quadriceps contraction, the cross-sectional area of the rectus femoris (CSA-RF) (via ultrasonography), and performed the 30 s sit-to-stand test and the 6 min walk test (6MWT). We derived the Borg scale score after the 6MWT and assessed the extent of social participation and quality of life using a Korean version of the 36-Item Short Form Health Survey (SF-36). A total of 35 subjects completed the experiment (18 in the exercise group, 17 in the control group). After the 12-week intervention period, the lower-limb strength and the CSA-RF were significantly increased in the exercise group. The activity level did not change significantly in either group. The exercise group exhibited significant improvements in the SF-36 mental health domain scores. Thus, strengthening exercise is useful for patients with RA.

Effects of Age on Long-Term Functional Recovery in Patients with Stroke.

Background and objectives: Age might be a determinant that limits functional recovery in patients with stroke. Here, we investigated the effect of age on functional recovery within 30 months after stroke onset. Materials and Methods: This retrospective longitudinal study enrolled 111 patients with first-ever stroke. Functional recovery was assessed at 2 weeks and at 1, 6, and 30 months after stroke onset using the modified Barthel Index (MBI), modified Rankin Score (mRS), functional ambulation category (FAC), muscle strength, and Mini-Mental State Examination (MMSE). A generalized estimating equation analysis was performed. Results: With the MBI, function improved until 6 months after stroke onset in patients aged <70 years and until 1 month after stroke onset in patients ≥70 years. At 30 months after stroke, there was no significant change of MBI in patients aged <70 years, whereas there was a significant decline in older patients. With the mRS and FAC, function improved until 30 months after stroke onset in patients aged <70 years and until 1 month after stroke onset in older patients. Motor deficit, assessed using the Medical Research Council (MRC), improved significantly until 6 months after stroke onset in patients aged <70 years. There was a significant improvement in cognition (assessed using the MMSE) until 6 months after stroke onset in patients aged <70 years and until 1 month after stroke onset in older patients. Conclusions: Long-term functional recovery occurred for up to 30 months after stroke. Patients aged ≥70 years showed functional decline between 6 and 30 months after onset. These findings could be useful when measuring functional recovery after stroke.

Association Between the Severity of Dysphagia and Various Parameters of the Cervical Spine; Videofluoroscopic Analysis in Neutral and Retraction Position of the Normal Volunteers.

STUDY DESIGN: Videoflurographic swallowing study in asymptomatic volunteers. OBJECTIVE: The purpose of this study was to investigate the relationship between the severity of dysphagia and various parameters of the subjects. SUMMARY OF BACKGROUND DATA: Occipitocervical fixation is associated with several potential complications. Malalignment of craniovertebral junction and associated dysphagia have been well described in the literature. However, there has been little attention given to investigate the association between the degree of swallowing dysfunction and various patient's parameters. METHODS: Thirty-nine healthy asymptomatic volunteers, 18 males and 21 females, were enrolled in this study. Based on videofluorographic swallowing study (VFSS), two scoring systems of swallowing dysfunction (dysphagia rating scale [DRS], dysphagia outcome and severity scale [DOSS]) were measured in neutral and retraction position. Multiple linear regression analysis was performed to evaluate the relationship between the degree of swallowing dysfunction and various factors of the subjects such as radiological and clinical parameters. RESULTS: There was statistically significant correlation between DRS and DOSS (r = -0.354, P < 0.05). Multiple regression analysis showed that there was a significant association of the dysphagia severity (DRS and DOSS) with the percentile change of the narrowest oropharyngeal diameter (OD) (%dn OD) (r = 0.121, P < 0.01 and r = 0.020, P < 0.01, respectively). Percentile change of OD (neutral and retraction position) was positively associated with the difference of C0-2 angle (r = 1.676, P < 0.01). None of the other variables such as age, sex, C0-1 angle, C1-2 angle, and C2-7 angle were significantly associated with the degree of dysphagia or %dn OD. CONCLUSION: This study demonstrated that the severity of dysphagia is significantly associated with the percentile change of OD and the C0-2 angle has considerable effect on the OD after O-C fusion. Therefore, C0-2 angle could be the most critical radiological parameter not only for predicting the stricture of oropharyngeal space but also for preventing postoperative dysphagia. LEVEL OF EVIDENCE: 4.

The Role of Regular Physical Therapy on Spasticity in Children With Cerebral Palsy.

OBJECTIVE: To investigate the effect of physical therapy (PT) intervention on spasticity in patients with cerebral palsy (CP), and to assess the degree of deterioration of spasticity when regular PT is interrupted in those patients. METHODS: We recruited 35 children with spastic CP who visited our hospital for PT, and whose Modified Tardieu Scale (MTS) scores were serially recorded including before and after a 10-day public holiday time frame period. The outcome measures were the angle of range of motion (ROM) of dorsiflexion of the ankle joint (R1 and R2) in the knee flexion and extension positions as assessed using the MTS. RESULTS: The range of dorsiflexion of the ankle joint (R1 and R2) after the holiday period was significantly decreased as compared with that measured ROM noted before the holiday period, regardless of the knee position, age, or gross motor function. The dynamic component of the MTS (R2-R1) showed a slight decrease in the knee flexion position. CONCLUSION: Interruption of regular PT aggravated spasticity and decreased ankle joint ROM in children with spastic CP. Our findings suggest that regular PT in the care continuum for children with CP is crucial for the maintenance of ROM in the spastic ankle joints.

Sinking Skin Flap Syndrome or Syndrome of the Trephined: A Report of Two Cases.

Decompressive craniectomy (DC) is commonly performed in patients with intracranial hypertension or brain edema due to traumatic brain injury. Infrequently, neurologic deteriorations accompanied by sunken scalp may occur after DC. We report two patients with traumatic subdural hemorrhage who had neurologic deteriorations accompanied by sunken scalp after DC. Neurologic function improved dramatically in both patients after cranioplasty. Monitoring for neurologic deterioration after craniectomy is advised. For patients showing neurologic deficit with a sunken scalp, early cranioplasty should be considered.

Modification of Cerebellar Afferent Pathway in the Subacute Phase of Stroke.

BACKGROUND: This study aims to identify the relationship between corticopontocerebellar tract (CPCT) and corticospinal tract (CST) integrity as well as motor function after stroke. MATERIALS AND METHODS: A total of 33 patients with stroke (18 left, 15 right hemispheric lesions) who underwent diffusion tensor imaging within 2 months of stroke onset and 17 age- and sex-matched healthy controls were retrospectively enrolled. Tract volume and the asymmetry index based on tract volume (AITV) of the CST and CPCT were used to identify structural changes in individual tracts and the correlation between those tracts. Motor function was assessed using the Medical Research Council (MRC) muscle scale, manual function test (MFT), functional ambulation category, and modified Barthel index. RESULTS: The volume of the affected CPCT was lower, and that of the unaffected CPCT was higher than the volumes in the control group (P < .001, P = .001, respectively). The CPCT AITV showed a strong positive correlation with the CST AITV in patients with either left or right hemispheric lesions (rs = .779, P < .001; rs = .732, P = .003, respectively). The CPCT AITV negatively correlated with the MRC muscle scale of the shoulder, wrist, and ankle muscles (r = -.490, -.490, -.416; P = .004, .004, .016, respectively). A higher unaffected CPCT volume was indicative of less affected upper extremity function, as assessed by MFT (rs = -.546, P = .029). CONCLUSIONS: Modification of the CPCT depended on CST integrity and was associated with the severity of hemiplegia and hemiplegic upper extremity function. The CPCT may complement the role of the CST and help to predict the motor function.

Cardiovascular Autonomic Dysfunction Predicts Diabetic Foot Ulcers in Patients With Type 2 Diabetes Without Diabetic Polyneuropathy.

We investigated the factors that might influence the development of diabetic foot ulcers (DFUs) in type 2 diabetes patients without diabetic polyneuropathy (DPN).From January 2000 to December 2005, a total of 595 patients who had type 2 diabetes without DPN between the ages of 25 and 75 years, and had no prior history of DFUs were consecutively enrolled in the study. A cardiovascular autonomic function test was performed to diagnose cardiovascular autonomic neuropathy (CAN) using heart rate variability parameters.The median follow-up time was 13.3 years. Among the 449 (75.4%) patients who completed the follow-up evaluation, 22 (4.9%) patients developed new ulcers, and 6 (1.3%) patients underwent the procedure for lower extremity amputations. The patients in the DFUs group had a longer duration of diabetes, higher baseline HbA1c levels, higher rates of nephropathy, and CAN. A Cox hazard regression analysis results revealed that the development of DFUs was significantly associated with the presence of CAN (normal vs definite CAN; HR, 4.45; 95% confidence interval, 1.29-15.33) after adjusting for possible confounding factors.The development of DFUs was independently associated with CAN in patients with type 2 diabetes without DPN. We suggested the importance of CAN as a predictor of DFUs even in the patients without DPN, and the need to pay attention to patients with definite CAN and type 2 diabetes.

Cervical Meningomyelitis After Lumbar Epidural Steroid Injection.

Epidural steroid injections (ESI) are a common treatment for back pain management. ESI-related complications have increased with the growing number of procedures. We report a case of cervical meningomyelitis followed by multiple lumbar ESI. A 60-year-old male with diabetes mellitus presented to our hospital with severe neck pain. He had a history of multiple lumbar injections from a local pain clinic. After admission, high fever and elevated inflammatory values were detected. L-spine magnetic resonance imaging (MRI) revealed hematoma in the S1 epidural space. Antibiotic treatment began under the diagnosis of a lumbar epidural abscess. Despite the treatment, he started to complain of weakness in both lower extremities. Three days later, the weakness progressed to both upper extremities. C-spine MRI revealed cervical leptomeningeal enhancement in the medulla oblongata and cervical spinal cord. Removal of the epidural abscess was performed, but there was no neurological improvement.

Walking through doorways causes forgetting: Younger and older adults.

Previous research on event cognition has found that walking through doorways can cause forgetting. The explanation for this finding is that there is a competition between event models, producing interference, and depressing performance. The current study explored the degree to which this might be affected by the natural aging process. This is of interest because there is some evidence that older adults have trouble coordinating sources of interference, which is what is thought to underlie this effect. This would suggest that older adults should do worse on this task. Alternatively, there is also evidence that older adults are typically not disrupted at the event level of processing per se. This would suggest that older adults should perform similarly to younger adults on this task. In the study reported here, younger and older participants navigated through a virtual environment, and memory was tested with probes either before or after a shift and for objects that were associated with the participant (i.e., just picked up). In general, both younger and older adults had memory disrupted after walking through a doorway. Importantly, the magnitude of this disruption was similar in the 2 age groups. This is consistent with the idea that processing at the event level is relatively unaffected by the natural aging process. (PsycINFO Database Record