Percutaneous nephrolithotomy guided by 5G-powered robot-assisted teleultrasound diagnosis system: first clinical experience with a novel tele-assistance approach (IDEAL stage 1).

BACKGROUND: To demonstrate the technical feasibility of percutaneous nephrolithotomy (PCNL) guided by 5G-powered robot-assisted teleultrasound diagnosis system (RTDS) in a complex kidney-stone (CKS) cohort and present our preliminary outcomes. PCNL is highly skill-required, which hinders it popularization in primary medical units of remote regions. We designed an innovative tele-assistance approach to make PCNL easy to be operated by inexperienced surgeons. METHODS: This was a prospective proof-of-concept study (IDEAL phase 1) on intraoperative tele-assistance provided by online urological experts via a 5G-powered RTDS. Total 15 CKS patients accepted this technology. Online experts manipulated a simulated probe to assist unskilled local operators by driving a patient-side robot-probe to guide and monitor the steps of access establishment and finding residual stones. RESULTS: Median total delay was 177ms despite one-way network-connecting distance > 5,800 km. No perceptible delay of audio-visual communication, driving robot-arm or dynamic ultrasound images was fed back. Successful tele-assistance was obtained in all cases. The first-puncture access-success rate was 78.6% with a one-session SF rate of 71.3% and without complications of grade III-V. CONCLUSIONS: The current technology based on 5G-powered RTDS can provide high-quality intraoperative tele-assistance, which has preliminarily shown satisfactory outcomes and reliable safety. It will break down a personal competence-based barrier to endow PCNL with more popular utilization. TRIAL REGISTRATION: The study was approved by ethics committee of the Xinjiang Kezhou People's Hospital and ethics committee of the First Affiliated Hospital of Nanjing Medical University and was registered on http://www.chictr.org.cn (ChiCTR2200065849, 16/11/2022).

[Ultra-remote robot-assisted laparoscopic surgery for varicocele through 5G network: Report of two cases and review of the literature].

OBJECTIVE: At present, the longest network transmission distance (NTD) for 5G remote endoscopic surgery is reportedly only about 229 km, and the NTD longer than 5 000 km has not yet been reported in clinical application. In this study, we attempted the clinical application of 5G ultra-remote robot-assisted laparoscopic surgery in spermatic vein ligation. METHODS: This retrospective study included two cases of 5G ultra-remote robot-assisted laparoscopic spermatic vein ligation using the home-made Tumai Surgical Robot System. The operation table was located in Xinjiang Kezhou People's Hospital, with an NTD of about 5 800 km (a linear distance of about 3 800 km) from the surgeon's console in the Telemedical Center of the First Affiliated Hospital of Nanjing Medical University, the apparatuses connected through the public 5G network. We observed the network connection delay, network fluctuation, and data packet loss rate of the devices at both ends of the loop through the feedback value of the Ping command by real-time monitoring. RESULTS: The total operation time of the two cases was 45 and 40 minutes respectively, with a mean blood loss of < 5 ml. The patients resumed a liquid diet and out-of-bed activity on the first day, the abdominal drainage tubes removed on the second, and both discharged from the hospital on the third day. The intraoperative average two-way network delay was 130 ms, and the average continuous data packet loss rate was 1.4%. No adverse network events, such as network interruption, occurred during the operation. CONCLUSION: Through the public 5G network and home-made Tumai Surgical Robot System, ultra-remote robot-assisted laparoscopic surgery was performed safely and successfully.

LncRNA HOTAIR Promotes Neuronal Damage Through Facilitating NLRP3 Mediated-Pyroptosis Activation in Parkinson's Disease via Regulation of miR-326/ELAVL1 Axis.

Parkinson's disease (PD) seriously threatens human's health. Researches have shown a close correlation between long non-coding RNAs (lncRNAs) and PD. However, the biological function of lncRNA homeobox transcript antisense RNA (HOTAIR) in PD remains largely unknown. In this study, we established PD models in vivo and in vitro by using 1-methyl-4-phenyl-2, 3, 6-tetrahydropyridine (MPTP) and 1-methyl-4-phenylpyridinium (MPP+) to assess the role of HOTAIR in pyroptotic cell death and neuronal damage. RNA immunoprecipitation (RIP) and dual luciferase reporter assay were used to verify the interaction between miR-326 and HOTAIR or ELAV like RNA binding protein 1 (ELAVL1). LncRNA HOTAIR was upregulated in PD mice and MPP+ induced SH-SY5Y cells. Additionally, knockdown of HOTAIR notably attenuated the symptom of PD in vivo. Downregulation of HOTAIR could obviously promoted cell viability and suppressed NLR family pyrin domain containing 3 (NLRP3) mediated pyroptotic cell death of SH-SY5Y cells in the presence of MPP+. Further, lncRNA HOTAIR positively regulated ELAVL1 expression by targeting miR-326, and downregulation of HOTAIR or ELAVL1 notably suppressed promotive effects of miR-326 inhibitor on MPP+ induced pyroptosis via activation of NLRP3 inflammasome. Collectively, HOTAIR silencing significantly inhibits neuronal damage through repressing NLRP3 mediated pyroptosis activation via regulation of miR-326/ELAVL1 axis in PD, which may contribute to a better understanding of PD pathogenesis and provide new treatment strategies for this disease.

LncRNA MALAT1 facilitates inflammasome activation via epigenetic suppression of Nrf2 in Parkinson's disease.

The goal of the present study was to elucidate the mechanism by which long non-coding RNA metastasis-associated lung adenocarcinoma transcript 1 (lncRNA MALAT1) promotes inflammation in Parkinson's disease (PD). 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) was used to induce PD development in C57BL/6 mice, and tyrosine hydroxylase (TH) expression was analysed by immunohistochemical analysis. Western blot and qPCR analyses were conducted to assess the expression of protein and mRNA levels, respectively. Lipopolysaccharide/adenosine triphosphate (LPS/ATP) was used to activate microglia in vitro. Chromatin immunoprecipitation (ChIP), RNA pull-down and RNA immunoprecipitation chip (RIP) assays were performed to investigate the interaction among specific molecules. The 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay was used to evaluate cell viability and proliferation. Flow cytometry was performed to analyse cell apoptosis after staining. The dichlorofluorescein diacetate (DCFH-DA) assay was used to measure the generation of reactive oxygen species (ROS) in cells. The results showed that MALAT1 was highly expressed in the brains of MPTP-induced PD model mice and in LPS/ATP-induced microglia cells. Knockdown of MALAT1 inhibited elevated nuclear factor (erythroid-derived 2)-like-2 factor (NRF2) expression, thereby inhibiting inflammasome activation and ROS production. MALAT1 was shown to promote neuroinflammation by recruiting enhancer of zeste homologue 2 (EZH2) to the promoter of NRF2, suppressing Nrf2 expression. In summary, MALAT1 epigenetically inhibits NRF2, thereby inducing inflammasome activation and reactive oxygen species (ROS) production in PD mouse and microglial cell models.

Neuroprotection of GLP-1/GIP receptor agonist via inhibition of mitochondrial stress by AKT/JNK pathway in a Parkinson's disease model.

OBJECTIVES: To investigate the effect of glucagon-like peptide-1 (GLP-1) receptor and glucose dependent insulinotrophic polypeptide (GIP) receptor dual agonist DA-JC4 on alleviating Parkinson's disease (PD) and unveil related cellular mechanisms. METHODS: Rotenone was injected to generate a rat PD model, on which the effect of DA-JC4 on motor functions was evaluated by rotational behavioral assay and open field test. The survival of dopaminergic neurons was analyzed, in addition to assays for mitochondrial stress and quantification of neurotransmitter levels using high performance liquid chromatography (HPLC). In cultured hippocampal neurons, the effect of DA-JC4 on mitochondrial stress and related cellular mechanism was analyzed by Flow cytometry, western blotting and reactive oxygen species (ROS). RESULTS: DA-JC4 significantly improved motor functions in PD rats, and elevated levels of major neurotransmitters. By histological analysis, DA-JC4 protected dopaminergic neurons from rotenone-induced cell death, which was associated with reduced mitochondrial stress. Experiments in cultured rat hippocampal neurons validated the neuroprotective role of DA-JC4 against cell apoptosis and mitochondrial stress induced by rotenone. The protective effect of DA-JC4 was later found to be dependent on AKT/JNK signal pathway, as treatment using AKT inhibitor or JNK activator abolished such effects. CONCLUSION: Our results showed that the dual agonist of GLP-1/GIP receptor could ameliorate motor dysfunctions of PD by protecting dopaminergic neurons which was mediated by relieved mitochondrial stress and apoptosis via AKT/JNK signal pathway.

Up-regulation of microRNA-375 ameliorates the damage of dopaminergic neurons, reduces oxidative stress and inflammation in Parkinson's disease by inhibiting SP1.

BACKGROUND: This study is conducted to investigate the protective role of elevated microRNA-375 (miR-375) in dopaminergic neurons in Parkinson's disease through down-regulating transcription factor specificity protein 1 (SP1). RESULTS: The successfully modeled rats with Parkinson's disease showed aggregated neurobehavioral change, increased neuroinflammatory response and oxidative stress, and lowered dopamine content. Parkinson's disease rats treated with overexpressed miR-375 displayed improved neurobehavioral change, ameliorated neuroinflammatory response and oxidative stress, heightened dopamine content and abated neuronal apoptosis by down-regulating SP1. Up-regulation of SP1 reversed the protective effect of upregulated miR-375 on Parkinson's disease. CONCLUSION: Up-regulation of miR-375 ameliorated the damage of dopaminergic neurons, reduced oxidative stress and inflammation in Parkinson's disease by inhibiting SP1. METHODS: Parkinson's disease rat model was established by targeted injection of 6-hydroxydopamine to damage the substantia nigra striatum. The successfully modeled Parkinson's disease rats were intracerebroventricularly injected with miR-375 mimics or pcDNA3.1-SP1. The functions of miR-375 and SP1 in neurobehavioral change, neuroinflammatory response, oxidative stress, dopamine content and expression of apoptosis-related proteins in the substantia nigra of Parkinson's disease rats were evaluated. The target relation of miR-375 and SP1 was confirmed by bioinformatics analysis and dual luciferase reporter gene assay.

Neuroprotective effect and mechanism of baicalin on Parkinson's disease model induced by 6-OHDA.

OBJECTIVE: This research was aimed to investigate the effects of baicalin on 6-hydroxydopamine (6-OHDA)-induced rat model of Parkinson's disease (PD) and the main mechanism of baicalin based on metabolomics. METHODS: The rat model of PD was induced by 6-OHDA. The protective effects of baicalin on rat model of PD were evaluated by open field test and rotarod test. The anti-PD efficacy of baicalin was evaluated by examining the morphologic changes of neurons and the level of monoamine neurotransmitters in the striatum, the number and morphology of tyrosine hydroxylase (TH)-positive neurons, and oxidative stress. Combined with metabolomics methods, the pharmacodynamic mechanism of baicalin on PD pathogenesis was also explored. RESULTS: Baicalin treatment improved the rod time and voluntary movement in rat model of PD (P<0.05) by the open field test and rotarod test. In addition, baicalin also protected from oxidative stress injury (P<0.05), and regulated the content of monoamine neurotransmitters dopamine, 3,4-dihydroxyphenylacetic acid, 5-hydroxytryptamine, and 5-hydroxyindoleacetic acid (P<0.05) and the number and morphology of TH-positive cells in 6-OHDA-induced PD model rats. By metabolomics, multivariate statistical analysis, and receiver operating characteristic curve analysis, we found that two metabolites N-acetyl aspartic acid and glutamic acid had a good diagnostic value. Quantitative analysis of metabolites showed a regulatory function of baicalin. CONCLUSION: Baicalin has significant protective effect on 6-OHDA-induced PD rats, which may play a protective role through an antioxidant, promoting the release of neurotransmitters and regulating the metabolism of N-acetyl aspartate and glutamate.

Bexarotene attenuates early brain injury via inhibiting micoglia activation through PPARγ after experimental subarachnoid hemorrhage.

Objectives Early brain injury (EBI) is considered to be one of the main causes of poor outcome in subarachnoid hemorrhage (SAH) patients. Bexarotene is an agonist of retinoid X receptor and plays a protective role in central nervous system diseases. However, the exact role of bexarotene in SAH has not been reported. Therefore, the present study was to determine whether bexarotene administration attenuate EBI after SAH in mice and to explore the underlying mechanism. Methods SAH was induced in C57BL/6 mice by endovascular perforation. Bexarotene was administrated intraperitoneally. Neurological score, cell death, microglia activation, and pro-inflammatory cytokines were detected at 24 h after SAH. The expression of PPARγ was measured by Western blot. Results Results showed that bexarotene significantly improved neurological score after SAH. In addition, the number of cell death and activated microglia were significantly reduced by bexarotene administration. Compared with vehicle-treated mice, bexarotene-treated mice showed reduced pro-inflammatory cytokines after SAH. The expression of PPARγ was significantly increased with bexarotene treatment compared with vehicle-treated controls. Discussion The present study demonstrats that bexarotene administration protects against EBI after SAH, inhibiting cell death, attenuating microglia activation, and alleviating neuroinflammation. The underlying mechanism may partially involve the activation of PPARγ.

Genetic diagnosis of two dopa-responsive dystonia families by exome sequencing.

Dopa-responsive dystonia, a rare disorder typically presenting in early childhood with lower limb dystonia and gait abnormality, responds well to levodopa. However, it is often misdiagnosed with the wide spectrum of phenotypes. By exome sequencing, we make a rapid genetic diagnosis for two atypical dopa-responsive dystonia pedigrees. One pedigree, presented with prominent parkinsonism, was misdiagnosed as Parkinson's disease until a known mutation in GCH1 (GTP cyclohydrolase 1) gene (NM_000161.2: c.631_632delAT, p.Met211ValfsX38) was found. The other pedigree was detected with a new compound heterozygous mutation in TH (tyrosine hydroxylase) gene [(NM_000360.3: c.911C>T, p.Ala304Val) and (NM_000360.3: c.1358G>A, p.Arg453His)], whose proband, a pregnant woman, required a rapid and less-biased genetic diagnosis. In conclusion, we demonstrated that exome sequencing could provide a precise and rapid genetic testing in the diagnosis of Mendelian diseases, especially for diseases with wide phenotypes.

VPS35 gene variants are not associated with Parkinson's disease in the mainland Chinese population.

VPS35 gene mutation has recently been reported in autosomal-dominant, late-onset Parkinson disease (PD). There are no reports regarding the association between VPS35 and Parkinson's disease (PD) in the Chinese population. We conducted a comprehensive genetic analysis of VPS35 gene in a cohort of twenty seven probands belonging to families with autosomal-dominant, late-onset PD, followed up with screening of specific variants in a separate group of 1011 sporadic PD patients and 1016 healthy controls. Our analysis revealed two exonic variants and three intronic variants across the entire VPS35 gene. There was no statistical difference in genotype or allele frequencies of rs3743928 and IVS14-24 t > c variants in VPS35 gene between sporadic PD group and healthy control group. None of the 1011 sporadic PD patients and 1016 controls carried the VPS35 gene c.1858G > A (p.Asp620Asn) mutation. Our data indicated that the VPS35 variants are not associated with PD in the mainland Chinese population.

Mutation analysis of LRRK2, SCNA, UCHL1, HtrA2 and GIGYF2 genes in Chinese patients with autosomal dorminant Parkinson's disease.

Autosomal dorminant Parkinson's disease (ADPD) has been associated with mutations in the SCNA, LRRK2, UCHL1, HtrA2 and GIGYF2 genes. We studied the prevalence of variants in all five genes in 12 Chinese unrelated families with ADPD and 4 families with both essential tremor (ET) and Parkinson's disease (PD) phenotypes using direct sequencing analysis. We found 27 variants in the LRRK2 gene, eight in GIGYF2 gene, three in the SCNA and UCHL1 gene respectively, in which five variants were novel. However, no pathogenic mutations in the five genes were found in these families. Our result indicated that SCNA, LRRK2, UCHL1, HtrA2 and GIGYF2 genes' mutations might not be a main reason for Chinese ADPD.

Analysis of PLA2G6 gene mutation in sporadic early-onset parkinsonism patients from Chinese population.

Recent studies have shown that PLA2G6 is a causative gene for PARK14-linked autosomal recessive early-onset complicated dystonia-parkinsonism, early-onset parkinsonism with frontotemporal dementia and autosomal recessive early-onset Parkinsonism without added complicated clinical features. In order to investigate the characteristics of PLA2G6 gene mutations in Chinese sporadic early-onset parkinsonism (EOP) patients, we performed polymerase chain reaction and DNA direct sequencing on a cohort of sporadic EOP patients from Chinese population. In this study, we found a novel heterozygous varient (p.G679V). Bioinformatics demonstrates that p.G679V exhibits highly conserved residues across species, which hints it might be a pathogenic mutation. Our result indicated that PLA2G6 mutations might not be a main cause of Chinese sporadic EOP.