Genetics behind Cerebral Disease with Ocular Comorbidity: Finding Parallels between the Brain and Eye Molecular Pathology.

Cerebral visual impairments (CVIs) is an umbrella term that categorizes miscellaneous visual defects with parallel genetic brain disorders. While the manifestations of CVIs are diverse and ambiguous, molecular diagnostics stand out as a powerful approach for understanding pathomechanisms in CVIs. Nevertheless, the characterization of CVI disease cohorts has been fragmented and lacks integration. By revisiting the genome-wide and phenome-wide association studies (GWAS and PheWAS), we clustered a handful of renowned CVIs into five ontology groups, namely ciliopathies (Joubert syndrome, Bardet-Biedl syndrome, Alstrom syndrome), demyelination diseases (multiple sclerosis, Alexander disease, Pelizaeus-Merzbacher disease), transcriptional deregulation diseases (Mowat-Wilson disease, Pitt-Hopkins disease, Rett syndrome, Cockayne syndrome, X-linked alpha-thalassaemia mental retardation), compromised peroxisome disorders (Zellweger spectrum disorder, Refsum disease), and channelopathies (neuromyelitis optica spectrum disorder), and reviewed several mutation hotspots currently found to be associated with the CVIs. Moreover, we discussed the common manifestations in the brain and the eye, and collated animal study findings to discuss plausible gene editing strategies for future CVI correction.

Ginkgo biloba extract inhibits oxidized low-density lipoprotein (oxLDL)-induced matrix metalloproteinase activation by the modulation of the lectin-like oxLDL receptor 1-regulated signaling pathway in human umbilical vein endothelial cells.

BACKGROUND: The overexpression of matrix metalloproteinases (MMPs) induced by oxidized low-density lipoprotein (oxLDL) has been found in atherosclerotic lesions. Previous reports have identified that oxLDL, via the upregulation of lectin-like ox-LDL receptor 1 (LOX-1), modulates the expression of MMPs in endothelial cells. Ginkgo biloba extract (GbE), from Ginkgo biloba leaves, has often been considered as a therapeutic compound for cardiovascular and neurologic diseases. However, further investigation is needed to ascertain the probable molecular mechanisms underlying the antiatherogenic effects of GbE. The aim of this study was to investigate the effects of GbE on oxLDL-activated MMPs of human endothelial cells and to test the involvement of LOX-1 and protein kinase C (PKC)-α, extracellular signal-regulated kinase (ERK), and peroxisome proliferator-activated receptor-γ (PPAR-γ). METHODS: Human umbilical vein endothelial cells were stimulated with oxLDL, with or without GbE treatment. LOX-1 signaling and MMPs expression were tested by Western blotting or activity assay. Further, protein expression levels of PKC-α, ERK, nuclear factor-κB, and PPAR-γ were investigated by Western blotting. RESULTS: GbE inhibited the oxLDL-caused upregulation of MMP-1, MMP-2, and MMP-3. Pretreating with GbE reduced oxLDL-activated LOX-1 expression. Furthermore, pharmacologic inhibitors of free radicals, Ca(++), PKC, and GbE, inhibited the oxLDL-induced ERK and nuclear factor-κB activation. Lastly, GbE ameliorated the oxLDL-inhibited PPAR-γ function. CONCLUSIONS: Data obtained in this study indicate that GbE actives its protective effects by regulating the LOX-1-mediated PKC-α/ERK/PPAR-γ/MMP pathway, resulting in the suppression of reactive oxygen species formation and, ultimately, the reduction of MMPs expression in endothelial cells treated with oxLDL.

Ultrasound-Guided Hyaluronic Acid Injections for Trigger Finger: A Double-Blinded, Randomized Controlled Trial.

OBJECTIVES: To investigate the effects of ultrasound-guided injections of hyaluronic acid (HA) versus steroid for trigger fingers in adults. DESIGN: Prospective, double-blinded, randomized controlled study. SETTING: Tertiary care center. PARTICIPANTS: Subjects with a diagnosis of trigger finger (N=36; 39 affected digits) received treatment and were evaluated. INTERVENTIONS: Subjects were randomly assigned to HA and steroid injection groups. Both study medications were injected separately via ultrasound guidance with 1 injection. MAIN OUTCOME MEASURES: The classification of trigger grading, pain, functional disability, and patient satisfaction were evaluated before the injection and 3 weeks and 3 months after the injection. RESULTS: At 3 months, 12 patients (66.7%) in the HA group and 17 patients (89.5%) in the steroid group exhibited no triggering of the affected fingers (P=.124). The treatment results at 3 weeks and 3 months showed similar changes in the Quinnell scale (P=.057 and .931, respectively). A statistically significant interaction effect between group and time was found for visual analog scale (VAS) and Michigan Hand Outcome Questionnaire (MHQ) evaluation (P<.05). The steroid group had a lower VAS at 3 months after injection (steroid 0.5±1.1 vs HA 2.7±2.4; P<.001). The HA group demonstrated continuing significant improvement in MHQ at 3 months (change from 3wk: steroid -2.6±14.1 vs HA 19.1±37.0; P=.023; d=.78). CONCLUSIONS: Ultrasound-guided injection of HA demonstrated promising results for the treatment of trigger fingers. The optimal frequency, dosage, and molecular weight of HA injections for trigger fingers deserve further investigation for future clinical applications.

Overcoming the challenges of scalable iPSC generation in translation medicine.

BACKGROUND: The potential of induced pluripotent stem cells (iPSCs) in revolutionizing regenerative medicine cannot be overstated. iPSCs offer a profound opportunity for therapies involving cell replacement, disease modeling, and cell transplantation. However, the widespread application of iPSC cellular therapy faces hurdles, including the imperative to regulate iPSC differentiation rigorously and the inherent genetic disparities among individuals. To address these challenges, the concept of iPSC super donors emerges, holding exceptional genetic attributes and advantageous traits. These super donors serve as a wellspring of standardized, high-quality cell sources, mitigating inter-individual variations and augmenting the efficacy of therapy. METHODS: In pursuit of this goal, our study embarked on the establishment of iPSC cell lines specifically sourced from donors possessing the HLA type (A33:03-B58:01-DRB1*03:01). The reprogramming process was meticulously executed, resulting in the successful generation of iPSC lines from these carefully selected donors. Subsequently, an extensive characterization was conducted to comprehensively understand the features and attributes of these iPSC lines. RESULTS: The outcomes of our research were highly promising. The reprogramming efforts culminated in the generation of iPSC lines from donors with the specified HLA type. These iPSC lines displayed a range of distinctive characteristics that were thoroughly examined and documented. This successful generation of iPSC lines from super donors possessing advantageous genetic traits represents a significant stride towards the realization of their potential in therapeutic applications. CONCLUSION: In summary, our study marks a crucial milestone in the realm of regenerative medicine. The establishment of iPSC lines from super donors with specific HLA types signifies a paradigm shift in addressing challenges related to iPSC cellular therapy. The standardized and high-quality cell sources derived from these super donors hold immense potential for various therapeutic applications. As we move forward, these findings provide a solid foundation for further research and development, ultimately propelling the field of regenerative medicine toward new horizons of efficacy and accessibility.

Body constitutions of traditional Chinese medicine caused a significant effect on irritable bowel syndrome.

BACKGROUND: According to the theory of traditional Chinese medicine (TCM), all types of body constitutions, except for the Gentleness (ie, the control group in our study), have disease susceptibility and affect the disease development process. This study attempted to investigate the relationship between TCM body constitutions and irritable bowel syndrome (IBS). METHODS: This cross-sectional study was based on Taiwan Biobank (TWB) and collected clinical data from 13 941 subjects aged 30 to 70. The results of the study showed that subjects with Yang-deficiency (N = 3161 subjects, odds ratio [OR] = 2.654, 95% CI = 1.740-3.910), Ying-deficiency (N = 3331 subjects, OR = 1.096, 95% CI = 0.627-1.782) or Stasis (N = 2335 subjects, OR = 1.680, 95% CI = 0.654-3.520) were more likely to have IBS. RESULTS: If the subjects with two or more TCM body constitutions: Yang-deficiency + Ying-deficiency (OR = 3.948, 95% CI = 2.742-5.560), Yang-deficiency + Stasis (OR = 2.312, 95% CI = 1.170-4.112), Ying-deficiency + Stasis (OR = 1.851, 95% CI = 0.828-3.567), or Yang-deficiency + Ying-deficiency + Stasis (OR = 3.826, 95% CI = 2.954-4.932) were also prone to IBS. CONCLUSION: These results confirmed the high correlation between TCM body constitutions and IBS. Because the current treatment for IBS is not entirely satisfactory, integrated traditional Chinese and Western medicine might provide patients with an alternative treatment option to alleviate IBS.

Frontier review of the roles of exosomes in osteoarthritis.

Osteoarthritis (OA) is a common degenerative disease; however, its exact pathophysiology and early diagnosis are still a challenge. Growing attention to the exosomes may inspire innovations that would make the current management of OA more effective. The exosomes in synovial fluid are relatively stable, and they can be easily isolated by the relatively noninvasive procedure of liquid biopsy to provide diagnostic and monitoring value. Some miRNAs (miR-504, miR-146a, miR-26a, miR-200c, and miR-210) have been known to be secreted in exosomes of OA patients. On the other hand, intraarticular injection of platelet-rich plasma (PRP) is becoming a popular therapy for OA patients. PRP is also a source of exosomes and their numerous contents. It is evident from the literature that PRP-derived exosomes can induce chondrogenic gene expression in OA chondrocytes. Here, we review the latest findings on the roles of exosomes in OA with the emphasis on PRP-derived exosomes and their potential applications for treating OA.

Establishment of vestibular function multimodality platform.

BACKGROUND: The technology of using inertial measurement units (IMUs) to detect motions in different body segments has drawn enormous attention to research and industry. In our previous research, we have applied IMUs in evaluating and treating patients with vestibular hypofunction. Furthermore, according to the research, when a person's head rotates over 60° on either side in the horizontal plane, and desires to focus vision on any targets, then the function of gaze shift comes in to operation. Herein, we aimed to use IMUs to build up a system to evaluate vestibular ocular reflex (VOR) during gaze shifting maneuver. METHODS: In this study, we developed a platform, which combines the features of gaze shift and computerized dynamic visual acuity (cDVA), called the gaze shift DVA (gsDVA) platform. The gsDVA platform measures the orientations of the subject's head by IMU, and executed the evaluation according to the algorithm that was developed by us. Finally, we used the VICON system to validate the performance of gsDVA platform. RESULTS: The performance of the accuracy was 2.41° ± 1.08°, the maximal sensor error was within 4.25°, and highly correlated between our platform and VICON (p < 0.05, R = 0.99). The intraclass correlation coefficient (ICC) of between-day and within-day was 0.984 and 0.999, respectively. Furthermore, the platform not only executed the evaluation automatically but also recorded other information besides the head orientation, such as rotation speed, rotation time, reaction time, and visual acuity. CONCLUSION: In this study, we demonstrated the utility of vestibular evaluation, and this platform can help to clarify the relationship between gaze shift and VOR. This methodology is useful and can be applied efficiently to different disease groups for interactive evaluation and rehabilitation programs.

Age-Related Increases in Benign Paroxysmal Positional Vertigo Are Reversed in Women Taking Estrogen Replacement Therapy: A Population-Based Study in Taiwan.

Benign paroxysmal positional vertigo (BPPV) is the most common cause of peripheral vertigo. Numerous investigations have reported an increased BPPV incidence in females and in the aged population. The hormonal characteristics of BPPV patients have not been previously investigated. This study aimed to determine the risk of BPPV in relation to menopause in a population-based study. Materials and Methods: This retrospective population-based study was designed to use a nationwide longitudinal health insurance database to follow and analyze the incidence of and protective factors against BPPV in a Taiwanese population. Data Analyses: Univariate and multivariate analyses were performed to calculate the adjusted hazard ratio (aHR) for the incidence of BPPV using Cox-proportional regression models. Results: In the multivariate analyses, we found that older people (older than 65 years old) were more prone to develop BPPV (aHR: 5.37, 95% CI: 0 4.83-5.97, p < 0.001). The risk of BPPV was analyzed in two specific age subgroups of elderly females. Results revealed that in both age groups (45-65 years old and >65 years old), patients who took estrogen for menopausal syndromes had a significantly lower incidence of BPPV (aHR; 0.01, 95% CI: 0.06-0.23, p < 0.001). Conclusion: Our study provides a novel etiology and possible treatment method for the prevention of BPPV. Further studies may focus on the pathophysiological mechanism of estrogen in BPPV patients and the development of new drugs for the prevention and treatment of BPPV.

Investigating the role of Sirt1-modulated oxidative stress in relation to benign paroxysmal positional vertigo and Parkinson's disease.

Benign paroxysmal positional vertigo (BPPV) is one of the most frequently encountered primary complaints in dizziness clinics. The incidence of BPPV has been proven to increase with age. The relationship between BPPV and another neurodegenerative disease, Parkinson's disease (PD), has not been previously discussed. This study aimed to investigate the relationship of BPPV and PD with oxidative stress. A total of 30,811 subjects participated in our cohort study. The study cohort comprised 5057 BPPV patients and a comparison cohort of 25,754 nonBPPV patients. SIRT1 axis gene expression was investigated in BPPV patient blood samples and a PD cell model of 6-hydroxydopamine (6-OHDA)-treated PC-12 cells to elucidate the potential in vitro and in vivo mechanisms of degeneration in PD and BPPV. Our data suggest that BPPV patients with histories of head injuries show a significantly higher hazard to develop subsequent PD (hazard ratio, 3.942; confidence interval, 1.523-10.205, p = 0.005). We also observed that oxidative status is increased in blood samples from patients with BPPV. Our in vitro study suggests that SIRT1 function is inhibited by oxidative stress, which thereby promotes 6-hydroxydopamine-induced cell death. We conclude that BPPV is independently associated with an increased risk of PD. This finding may be attributed to oxidative stress-mediated inhibition of SIRT1 expression levels.

SIRT1-related inhibition of pro-inflammatory responses and oxidative stress are involved in the mechanism of nonspecific low back pain relief after exercise through modulation of Toll-like receptor 4.

Low back pain is a common clinical problem that causes disability and impaired quality of life. While the reason behind low back pain was largely considered to be of musculoskeletal origin, the contribution of inflammatory cytokines and oxidative stress could never be overlooked. Exercise has been proven to be an effective approach to treat low back pain. However, the mechanism of the exercise effect on the inflammatory cytokines and oxidative stress is still largely unknown. In this study, we revealed that exercise intervention reduces Toll-like receptor 4 (TLR-4) pathway and enhances Sirtuin 1 (SIRT1) expression in low back pain patients. We also confirmed that exercise up-regulates the expression of peroxisome proliferator-activated receptor-gamma, PPAR-γ coactivator-1 and FoxOs family proteins and also increases the activity of catalase and superoxide dismutase in patients with low back pain. Furthermore, we found that exercise intervention attenuates the oxidative stress, pro-inflammatory cytokine concentrations and p53 expression in patients with low back pain. This study demonstrates that exercise intervention improves low back pain symptoms through regulation of the SIRT1 axis with repression of oxidative stress and TLR-4 inhibition.

Plantar pressure analysis of accommodative insole in older people with metatarsalgia.

Foot pain frequently reduces physical activity and increases the risk of falls in older people. In current orthotic management of forefoot pain, metatarsal padding is the main strategy to reduce metatarsal pressure. However, pressure reductions are usually diverse and limited. The multi-step accommodative insole is fabricated by sequential foam padding on Plastazote under dynamic accommodation in daily walking. The aims of this study were to investigate the effectiveness and mechanisms of accommodative insole on plantar pressure redistribution in older people with metatarsalgia. The study was conducted on 21 old outpatients with moderate to severe metatarsalgia, using the ethylene vinyl acetate control, 9-mm flat Plastazote, and accommodative insoles with and without metatarsal and arch support. Outcome measures included pressure-related variables measured by a Pedar-X system, and pain scores assessed with a 0-10 Visual Analog Scale. The accommodative insole significantly decreased peak pressure under the metatarsal heads by 47.2% (p<0.001) and the pain scores from 8.2 to 1.1 (p<0.001). Plantar pressure analyses indicated that the effects of dynamic metatarsal contouring and cushioning on reducing peak pressure were greater than those of metatarsal padding. The temporo-spatial relationships between the toe and metatarsal head can assist in explaining an elevated metatarsal pressure and higher risk of falls in older people with toe deformities. The multi-step insole is simple in orthotic fabrication and ensures an even distribution of plantar pressure loading in walking. It can effectively relieve metatarsalgia and help to preserve regular walking activity for older people with metatarsalgia.

Can sit-to-stand lower limb muscle power predict fall status?

Sit-to-stand (STS) movements are essential for daily activities. Failure to perform STS movements efficiently and smoothly may lead to falls. In this study, we developed a forceplate to analyze vertical ground reaction force (VGRF), STS duration and generated muscle power to investigate which parameters were fall status predictors. A total of 105 participants were included in this study and were grouped into those (1) aged between 20 and 30 years (Young), (2) aged above 65 years without a history of falling (Non-fallers) and (3) aged above 65 with a history of falling in the past 12 months (Fallers). The results indicated a significantly higher maximal lower limb muscle power (MP) for the Young (9.05 ± 3.66 W/kg), followed by Non-fallers (5.50 ± 2.02W/kg) and Fallers (3.66 ± 1.45 W/kg) as well as higher modified falls efficacy scale (MFES) scores for the Young (Young: 9.88 ± 0.10; Non-fallers: 6.27 ± 1.40; Fallers: 4.83 ± 0.89) and shorter times for the five times sit-to-stand test (FSTST) for the young (Young: 6.09 ± 2.20 s; Non-fallers: 15.65 ± 3.30s; Fallers: 19.82 ± 4.46 s). There was a significant difference between the Young group and the Non-fallers in the maximal vertical ground reaction force (VGRF) (138.79 ± 24.20 N/BW in Young, 117.51 ± 8.57 N/BW in old Non-fallers, p < 0.01), and there was a significant difference between the Non-fallers and the Fallers in the duration of the STS movement (2.74 ± 0.87 s for the Non-fallers, 4.27 ± 2.56 s for the Fallers, p < 0.01). The regression analysis results further indicated that only MP and the STS stabilization phase could differentiate individuals who had past fall events. Therefore, the equipment we developed could potentially be useful in the assessment and monitoring of balance and the risk of falling in older people.