Pilot Study of Acute Behavioral Effects of Pallidal Burst Stimulation in Parkinson's Disease.

BACKGROUND: Burst-patterned pallidal deep brain stimulation (DBS) in an animal model of Parkinson's disease (PD) yields significantly prolonged therapeutic benefit compared to conventional continuous DBS, but its value in patients remains unclear. OBJECTIVES: The aims were to evaluate the safety and tolerability of acute (<2 hours) burst DBS in PD patients and to evaluate preliminary clinical effectiveness relative to conventional DBS. METHODS: Six PD patients were studied with DBS OFF, conventional DBS, and burst DBS. Unified Parkinson's Disease Rating Scale III (UPDRS-III) and proactive inhibition (using stop-signal task) were evaluated for each condition. RESULTS: Burst and conventional DBS were equally tolerated without significant adverse events. Both stimulation patterns provided equivalent significant UPDRS-III reduction and increased proactive inhibition relative to DBS OFF. CONCLUSIONS: This pilot study supports the safety and tolerability of burst DBS, with acute effects similar to conventional DBS. Further larger-scale studies are warranted given the potential benefits of burst DBS due to decreased total energy delivery. © 2024 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Epidemiological Survey of Congenital Heart Disease Among Children Aged from 2 to 18 in Suo County, Nagqu, Tibet.

Lin, Tian, Huaping Jia, Yunming Li, Yongxing Xu, Bei Zhao, Dong Zheng, Hongfeng Yan, Meihui Zhao, Yanlei Li, Liping Xia, Fengxia Zhou, Cuiping Liu, Ke Ma, Ma Mi, and Jianwen Gu. Epidemiological survey of congenital heart disease among children aged from 2 to 18 in Suo County, Nagqu, Tibet. High Alt Med Biol. 00:000-000, 2024. Background: Studies have reported the prevalence of congenital heart disease (CHD) in parts of Tibet, but relative epidemiological surveys are rare. We aimed to explore the prevalence of CHD in children and its relationship with family history in Suo County, Nagqu, Tibet, an altitude of 3,980 meters. Methods: We recruited 4,002 children aged 2-18 years. Subjects underwent a family history investigation, cardiac auscultation, and clinical manifestation examination and then received echocardiographic screening. Results: The prevalence of CHD among children in Suo County was 0.97% (39 cases), much higher than the prevalence at sea level. The most common subtype was atrial septal defect, accounting for 53.9% of CHD, followed by patent ductus arteriosus (33.3%) and ventricular septal defect (12.8%). We also found that children whose mothers had previously borne children with CHD had a higher risk of CHD than those without (p = 0.002); other factors related to CHD during pregnancy, such as smoking, drinking, drug use, and viral infection, showed no statistical differences between children with and without CHD. Conclusions: The prevalence of CHD in children in Suo County is much higher than at low altitude, consisting mostly of simple forms with left-to-right shunt, with rare complex CHD. These results support implementing diagnostic and treatment plans to prevent CHD in Suo County.

Long non-coding RNA-NONMMMUT004552.2 regulates the unloading-induced bone loss through the miRNA-15b-5p/Syne1 in mice.

Exercise-induced mechanical loading can increase bone strength whilst mechanical unloading enhances bone-loss. Here, we investigated the role of lncRNA NONMMUT004552.2 in unloading-induced bone-loss. Knockout of lncRNA NONMMUT004552.2 in hindlimb-unloaded mice caused an increase in the bone formation and osteoblast activity. The silencing of lncRNA NONMMUT004552.2 also decreased the osteoblast apoptosis and expression of Bax and cleaved caspase-3, increased Bcl-2 protein expression in MC3T3-E1 cells. Mechanistic investigations demonstrated that NONMMUT004552.2 functions as a competing endogenous RNA (ceRNA) to facilitate the protein expression of spectrin repeat containing, nuclear envelope 1 (Syne1) by competitively binding miR-15b-5p and subsequently inhibits the osteoblast differentiation and bone formation in the microgravity unloading environment. These data highlight the importance of the lncRNA NONMMUT004552.2/miR-15b-5p/Syne1 axis for the treatment of osteoporosis.

The potential beneficial effects of Lactobacillus plantarum GM11 on rats with chronic unpredictable mild stress- induced depression.

OBJECTIVE: The main purpose of the present study was to assess the beneficial effect of Lactobacillus plantarum GM11 (LacP GM11), screened from Sichuan traditional fermented food, in depressive rats induced by chronic unpredictable mild stress (CUMS). METHODS: Male SPF SD rats were randomly assigned to 3 groups: the control group, CUMS group and CUMS + LacP GM11 group (n = 10). The rats in the CUMS and LacP GM11 groups received CUMS stimulation for 42 d. The behavioral tests and levels of monoamine neurotransmitter, glucocorticoid hormone and brain-derived neurotrophic factor (BDNF) in the serum and hippocampus were measured. The effects of LacP GM11 on the mRNA and protein expression of BDNF and cAMP response element binding protein (CREB) in the hippocampus were also investigated. RESULTS: After supplementation for 21 d, LacP GM11 was associated with alleviation of depressive-like behavior, not anxiety-like behavior, in depressive rats. LacP GM11 increased the levels of 5-hydroxytryptamine (5-HT) and BDNF and decreased the level of cortisol (CORT) in the serum and hippocampus in depressed rats. In addition, treatment with LacP GM11 also increased the mRNA and protein expression of BDNF and CREB in the hippocampus. CONCLUSIONS: This work has revealed that LacP GM11 has potential beneficial effects on depression. This effect might be related to alleviating monoamine neurotransmitter deficiency, HPA axis hyperfunction and CREB-BDNF signaling pathway downregulation. This study demonstrates that LacP GM11 could be a potential therapeutic approach to treat depression and other mental health problems.

[Design and validation of a novel knee biomechanical test method].

A novel structural dynamics test method and device were designed to test the biomechanical effects of dynamic axial loading on knee cartilage and meniscus. Firstly, the maximum acceleration signal-to-noise ratio of the experimental device was calculated by applying axial dynamic load to the experimental device under unloaded condition with different force hammers. Then the experimental samples were divided into non-specimen group (no specimen loaded), sham specimen group (loaded with polypropylene samples) and bovine knee joint specimen group (loaded with bovine knee joint samples) for testing. The test results show that the experimental device and method can provide stable axial dynamic load, and the experimental results have good repeatability. The final results confirm that the dynamic characteristics of experimental samples can be distinguished effectively by this device. The experimental method proposed in this study provides a new way to further study the biomechanical mechanism of knee joint structural response under axial dynamic load.

Rapid Segmentation and Diagnosis of Breast Tumor Ultrasound Images at the Sonographer Level Using Deep Learning.

BACKGROUND: Breast cancer is one of the most common malignant tumors in women. A noninvasive ultrasound examination can identify mammary-gland-related diseases and is well tolerated by dense breast, making it a preferred method for breast cancer screening and of significant clinical value. However, the diagnosis of breast nodules or masses via ultrasound is performed by a doctor in real time, which is time-consuming and subjective. Junior doctors are prone to missed diagnoses, especially in remote areas or grass-roots hospitals, due to limited medical resources and other factors, which bring great risks to a patient's health. Therefore, there is an urgent need to develop fast and accurate ultrasound image analysis algorithms to assist diagnoses. METHODS: We propose a breast ultrasound image-based assisted-diagnosis method based on convolutional neural networks, which can effectively improve the diagnostic speed and the early screening rate of breast cancer. Our method consists of two stages: tumor recognition and tumor classification. (1) Attention-based semantic segmentation is used to identify the location and size of the tumor; (2) the identified nodules are cropped to construct a training dataset. Then, a convolutional neural network for the diagnosis of benign and malignant breast nodules is trained on this dataset. We collected 2057 images from 1131 patients as the training and validation dataset, and 100 images of the patients with accurate pathological criteria were used as the test dataset. RESULTS: The experimental results based on this dataset show that the MIoU of tumor location recognition is 0.89 and the average accuracy of benign and malignant diagnoses is 97%. The diagnosis performance of the developed diagnostic system is basically consistent with that of senior doctors and is superior to that of junior doctors. In addition, we can provide the doctor with a preliminary diagnosis so that it can be diagnosed quickly. CONCLUSION: Our proposed method can effectively improve diagnostic speed and the early screening rate of breast cancer. The system provides a valuable aid for the ultrasonic diagnosis of breast cancer.

Low-Dose Ketamine-Induced Deficits in Arbitrary Visuomotor Mapping in Monkeys.

Ketamine, an NMDA antagonist, is widely used in clinical settings. Recently, low-dose ketamine has gained attention because of its promising role as a rapid antidepressant. However, the effects of low-dose ketamine on brain function, particularly higher cognitive functions of primate brains, are not fully understood. In this study, we used two macaques as subjects and found that acute low-dose ketamine administration significantly impaired the ability for arbitrary visuomotor mapping (AVM), a form of associative learning (AL) essential for flexible behaviors, including executions of learned stimuli-response contingency or learning of new contingencies. We conducted in-depth analyses and identified intrinsic characteristics of these ketamine-induced functional deficits, including lowered accuracy, prolonged time for planning and movement execution, increased tendency to make errors when visual cues are changed from trial to trial, and stronger impact on combining associative learning and another key higher cognitive function, working memory (WM). Our results shed new light on how associative learning relies on the NMDA-mediated synaptic transmission of the brain and contribute to a better understanding of the potential acute side effects of low-dose ketamine on cognition, which can help facilitate its safe usage in medical practice.

Curcumin Alleviates Oxidative Stress, Neuroinflammation, and Promotes Behavioral Recovery After Traumatic Brain Injury.

BACKGROUND: Neuroinflammation and oxidative stress after traumatic brain injury (TBI) can further lead to neuronal apoptosis, which plays a crucial role in the process of neuron death. Curcumin, which is derived from the rhizome of the Curcuma longa plant, has multiple pharmacological effects. OBJECTIVE: The objective of this study was to investigate whether curcumin treatment has neuroprotective effects after TBI, and to elucidate the underlying mechanism. METHODS: A total of 124 mice were randomly divided into 4 groups: Sham group, TBI group, TBI+Vehicle group, and TBI+Curcumin group. The TBI mice model used in this study was constructed with TBI device induced by compressed gas, and 50 mg/kg curcumin was injected intraperitoneally 15 minutes after TBI. Then, the blood-brain barrier permeability, cerebral edema, oxidative stress, inflammation, apoptosis-related protein, and behavioral tests of neurological function were utilized to evaluate the protective effect of curcumin after TBI. RESULTS: Curcumin treatment markedly alleviated post-trauma cerebral edema and blood-brain barrier integrity, and suppressed neuronal apoptosis, reduced mitochondrial injury and the expression of apoptosis-related proteins. Moreover, curcumin also attenuates TBI-induced inflammatory response and oxidative stress in brain tissue and improves cognitive dysfunction after TBI. CONCLUSION: These data provide substantial evidence that curcumin has neuroprotective effects in animal TBI models, possibly through the inhibition of inflammatory response and oxidative stress.

Modulating Brain Activity with Invasive Brain-Computer Interface: A Narrative Review.

Brain-computer interface (BCI) can be used as a real-time bidirectional information gateway between the brain and machines. In particular, rapid progress in invasive BCI, propelled by recent developments in electrode materials, miniature and power-efficient electronics, and neural signal decoding technologies has attracted wide attention. In this review, we first introduce the concepts of neuronal signal decoding and encoding that are fundamental for information exchanges in BCI. Then, we review the history and recent advances in invasive BCI, particularly through studies using neural signals for controlling external devices on one hand, and modulating brain activity on the other hand. Specifically, regarding modulating brain activity, we focus on two types of techniques, applying electrical stimulation to cortical and deep brain tissues, respectively. Finally, we discuss the related ethical issues concerning the clinical application of this emerging technology.

Post-COVID pain and quality of life in COVID-19 patients: protocol for a meta-analysis and systematic review.

INTRODUCTION: During the COVID-19 pandemic, approximately 10%-35% of COVID-19 infected patients experience post-COVID sequela. Among these sequelae, pain symptoms should not be neglected. In addition, the sequelae of COVID-19 also decrease the quality of life of these populations. However, meta-analyses that systematically evaluated post-COVID pain are sparse. METHODS AND ANALYSIS: A comprehensive screening will be performed by searching MEDLINE and Embase without language restriction from inception to August 2021. Cohort studies, case-control studies, cross-sectional studies and case series will be included. Case report and interventional studies will be excluded. Studies with less than 20 participants will be also excluded. We aim to investigate the prevalence of pain-related symptoms in patients after the acute phase of COVID-19. The impact of COVID-19 on the quality of life and pain symptoms among these populations in the post-acute phase will also be evaluated. ROBINS-I tool will be used to assess the risk of bias of cohort studies. The risk of bias tool developed by Hoy et al will be used to assess the risk of bias of prevalence studies. Metaprop command in Stata will be used to estimate the pooled prevalence of pain symptoms. DerSimonian and Laird random-effects models will be used to calculate the pooled relative risks. All analyses will be calculated using Stata software (V.15.0; StataCorp) ETHICS AND DISSEMINATION: Ethics approval is not required. Results of our study will be submitted to a peer-review journal. PROSPERO REGISTRATION NUMBER: CRD42021272800.

The beneficial effects of genetically engineered Escherichia coli Nissle 1917 in obese C57BL/6J mice.

BACKGROUND: Genetically modified probiotics have potential for use as a novel approach to express bioactive molecules for the treatment of obesity. The objective of the present study was to investigate the beneficial effect of genetically modified Escherichia coli Nissle 1917 (EcN-GM) in obese C57BL/6J mice. METHODS: First, an obesity model in C57BL/6J mice was successfully established. Then, the obese mice were randomly assigned into three groups: obese mice (OB), obese mice + EcN-GM (OB + EcN-GM), and obese mice + orlistat (OB + orlistat) (n = 10 in each group). The three groups were gavaged with 0.3 ml of 1010 CFU/ml control EcN, EcN-GM (genetically engineered EcN) and 10 ml/kg orlistat. Body weight, food consumption, fat pad and organ weight, hepatic biochemistry and hepatic histopathological alterations were measured. The effects of EcN-GM on the levels of endocrine peptides and the intestinal microbiota were also analyzed. RESULTS: After supplementation for 8 weeks, EcN-GM was associated with decreases in body weight gain, food intake, fat pad and liver weight, and alleviation hepatocyte steatosis in obese mice. EcN-GM also increased the level of GLP-1 in serum and alleviated leptin and insulin resistance. Moreover, supplementation with EcN-GM increased the α-diversity of the intestinal microbiota but did not significantly influence the relative abundance of Firmicutes and Bacteroidetes. CONCLUSIONS: These results indicated that EcN-GM, a genetically modified E. coli strain, may be a potential therapeutic approach to treat obesity. The beneficial effect of EcN-GM may be independent of the alteration of the diversity and composition of the intestinal microbiota in obese mice.

Establishment and Evaluation of a Novel High-Efficiency Model of Graded Traumatic Brain Injury in Mice.

BACKGROUND: Although previous studies have made significant contributions to establishing animal traumatic brain injury (TBI) models for simulation of human TBI, the accuracy, controllability, and modeling efficiency of animal TBI models need to be further improved. This study established a novel high-efficiency graded mouse TBI model induced by shock wave. METHODS: A total of 125 mice were randomly divided into sham, 0.7 mm, 0.6 mm, and 0.5 mm groups according to the depth of the cross groove of the aluminum sheets. The stability and repeatability of apparatus were evaluated, and the integrity of the blood-brain barrier, cerebral edema, neuropathologic immunohistochemistry, apoptosis-related protein, and behavioral tests of neurologic function were used to validate this new model. RESULTS: The results showed that 4 mice were injured simultaneously in 1 experiment. They received the same intensity of shock waves. Moreover, the mortality rates caused by 3 different aluminum sheets were consistent with the mortality rates of mild TBI, moderate TBI, and severe TBI. Compared with the sham group, mice in different injured groups significantly increased brain water content, blood-brain barrier permeability, and neuronal apoptosis. And the mice in all injured groups showed poor motor ability, balancing, spatial learning, and memory abilities. CONCLUSIONS: The novel TBI apparatus has advantages in its small size, simple operation, high repeatability, high efficiency, and graded severity. Our TBI apparatus provides a novel tool to investigate the neuropathologic changes and underlying mechanisms of TBI with various levels of severities.

Is liver involvement overestimated in COVID-19 patients? A meta-analysis.

Background: Considering transaminase more than the upper limit of normal value as liver injury might overestimate the prevalence of liver involvement in COVID-19 patients. No meta-analysis has explored the impact of varied definitions of liver injury on the reported prevalence of liver injury. Moreover, few studies reported the extent of hypertransaminasemia stratified by COVID-19 disease severity. Methods: A literature search was conducted using PubMed and Embase. The pooled prevalence of liver injury and hypertransaminasemia was estimated. Results: In total, 60 studies were included. The overall prevalence of liver injury was 25%. Compared to subgroups with the non-strict definition of liver injury (33%) and subgroups without giving detailed definition (26%), the subgroup with a strict definition had a much lower prevalence of liver injury (9%). The overall prevalence of alanine aminotransferase (ALT) and aspartate aminotransferase (AST) elevation was 19% and 22%. The prevalence of elevated ALT and AST were significantly higher in severe COVID-19 cases compare to non-severe cases (31% vs 16% and 44% vs 11%). In critically ill and fatal cases, no difference was found in the prevalence of elevated ALT (24% vs 30%) or AST (54% vs 49%). Sensitivity analyses indicated that the adjusted prevalence of ALT elevation, AST elevation, and liver injury decreased to 14%, 7%, and 12%. Conclusion: The overall prevalence of liver injury and hypertransaminasemia in COVID-19 patients might be overestimated. Only a small fraction of COVID-19 patients have clinically significant liver injury. The prevalence of hypertransaminasemia was significantly higher in severe COVID-19 cases compare to non-severe cases. Hence, in severe COVID-19 patients, more attention should be paid to liver function tests.

Improvement in cognitive dysfunction following blast induced traumatic brain injury by thymosin α1 in rats: Involvement of inhibition of tau phosphorylation at the Thr205 epitope.

Cognitive impairment is a significant sequela of traumatic brain injury (TBI) especially blast induced traumatic brain injury (bTBI), which is characterized by rapid impairments of learning and memory ability. Although several neuroprotective agents have been postulated as promising drugs for bTBI in animal studies, very few ideal therapeutic options exist to improve cognitive impairment following bTBI. Thymosin α1(Tα1), a 28-amino-acid protein that possesses immunomodulatory functions, has exhibited beneficial effects in the treatment of infectious diseases, immunodeficiency diseases and cancers. However, it remains unclear whether Tα1 has a therapeutic role in bTBI. Thus, we hypothesized that Tα1 administration could reverse the outcomes of bTBI. The blast induced TBI (bTBI) rat model was established with the compressed gas driven blast injury model system. A consecutive Tα1 therapy (in 1 ml saline, twice a day) at a dose of 200 µg/kg or normal saline (NS) (1 ml, twice a day) for 3 days or 2 weeks was performed. Utilizing our newly designed bTBI model, we investigated the beneficial effects of Tα1 therapy on rats exposed to bTBI including: cognitive functions, general histology, regulatory T (Treg) cells, edema, inflammation reactions and the expression and phosphorylation level of tau via Morris Water Maze test (MWM test), HE staining, flow cytometry, brain water content (BWC) calculation, IL-6 assay and Western blotting, respectively. Tα1 treatment seemed to reduce the 24-hour mortality, albeit with no statistical significance. Moreover, Tα1 treatment markedly improved cognitive dysfunction by decreasing the escape latency in the acquisition phase, and increasing the crossing numbers in the probe phase of MWM test. More interestingly, Tα1 significantly inhibited tau phosphorylation at the Thr205 epitope, but not at the Ser404 and Ser262 epitopes. Tα1 increased the percentage of Treg cells and inhibited plasma IL-6 production on 3d post bTBI. Moreover, Tα1 suppressed brain edema as demonstrated by decrease of BWC. However, there was a lack of obvious change in histopathology in the brain upon Tα1 treatment. This is the first study showing that Tα1 improves neurological deficits after bTBI in rats, which is potentially related to the inhibition of tau phosphorylation at the Thr205 epitope, increased Treg cells and decreased inflammatory reactions and brain edema.

SIRT2, a direct target of miR-212-5p, suppresses the proliferation and metastasis of colorectal cancer cells.

The aberrant expression of human sirtuin 2 (SIRT2) has been detected in various types of cancer; however, the biological roles, underlying mechanisms and clinical significance of SIRT2 dysregulation in human colorectal cancer (CRC) remain unclear. The results of this study demonstrate that compared with paired normal tissues, SIRT2 expression is significantly decreased in CRC tissues. SIRT2 loss has been correlated with clinicopathological characteristics, including distant metastasis, lymph node metastasis and American Joint Committee on Cancer (AJCC) stage; this loss serves as an independent factor that indicates a poor prognosis for patients with CRC. Further gain- and loss-of-function analyses have demonstrated that SIRT2 suppresses CRC cell proliferation and metastasis both in vivo and in vitro. Mechanistically, miR-212-5p was identified to directly target the SIRT2 3'-untranslated region (3'-UTR), leading to SIRT2 down-regulation. The ectopic expression of SIRT2 reverses the effect of miR-212-5p overexpression on CRC cell colony formation, invasion, migration and proliferation. Clinically, an inverse correlation was found between miR-212-5p and SIRT2 expression. High miR-212-5p expression has been found to result in a poor prognosis and aggressive clinicopathological characteristics in patients with CRC. Taken together, these results suggest that SIRT2, targeted by miR-212-5p, acts as a tumour suppressor in CRC and that the miR-212-5p/SIRT2 axis is a promising prognostic factor and potential therapeutic target in CRC.