Dynamic evaluation of liver fibrosis to assess hepatocellular carcinoma risk in patients with chronic hepatitis B receiving nucleoside analogs treatment.

Despite good hepatitis B virus (HBV) inhibition by nucleoside analogs (NAs), cases of hepatocellular carcinoma (HCC) still occur. This study proposed a non-invasive predictive model to assess HCC risk in patients with chronic hepatitis B (CHB) receiving NAs treatment. Data were obtained from a hospital-based retrospective cohort registered on the Platform of Medical Data Science Academy of Chongqing Medical University, from 2013 to 2019. A total of 501 patients under NAs treatment had their FIB-4 index updated semiannually by recalculation based on laboratory values. Patients were divided into three groups based on FIB-4 index values: < 1.45, 1.45-3.25, and ≥ 3.25. Subsequently, HCC incidence was reassessed every six months using Kaplan-Meier curves based on the updated FIB-4 index. The median follow-up time of CHB patients after receiving NAs treatment was 2.5 years. HCC incidences with FIB-4 index < 1.45, 1.45-3.25, and ≥ 3.25 were 1.18%, 1.32%, and 9.09%, respectively. Dynamic assessment showed that the percentage of patients with FIB-4 index < 1.45 significantly increased semiannually (P < 0.001), and of patients with FIB-4 index ≥ 3.25 significantly decreased (P < 0.001). HCC incidence was the highest among patients with FIB-4 index ≥ 3.25. The FIB-4 index effectively predicted HCC incidence, and its dynamic assessment could be used for regular surveillance to implement early intervention and reduce HCC risk.

The protective role of endothelial GLUT1 in ischemic stroke.

OBJECTIVE: To provide thorough insight on the protective role of endothelial glucose transporter 1 (GLUT1) in ischemic stroke. METHODS: We comprehensively review the role of endothelial GLUT1 in ischemic stroke by narrating the findings concerning biological characteristics of GLUT1 in brain in depth, summarizing the changes of endothelial GLUT1 expression and activity during ischemic stroke, discussing how GLUT1 achieves its neuroprotective effect via maintaining endothelial function, and identifying some outstanding blind spots in current studies. RESULTS: Endothelial GLUT1 maintains persistent high glucose and energy requirements of the brain by transporting glucose through the blood-brain barrier, which preserves endothelial function and is beneficial to stroke prognosis. CONCLUSION: This review underscores the potential involvement of GLUT1 trafficking, activity modulation, and degradation, and we look forward to more clinical and animal studies to illuminate these mechanisms.

Iron Deposition in Parkinson's Disease: A Mini-Review.

Iron deposition is crucial pathological changes observed in patients with Parkinson's disease (PD). Recently, scientists have actively explored therapeutic approaches targeting iron deposition in PD. However, several clinical studies have failed to yield consistent results. In this review, we provide an overview of iron deposition in PD, from both basic research and clinical perspectives. PD patients exhibit abnormalities in various iron metabolism-related proteins, leading to disruptions in iron distribution, transport, storage, and circulation, ultimately resulting in iron deposition. Excess iron can induce oxidative stress and iron-related cell death, and exacerbate mitochondrial dysfunction, contributing to the progression of PD pathology. Magnetic resonance imaging studies have indicated that the characteristics of iron deposition in the brains of PD patients vary. Iron deposition correlates with the clinical symptoms of PD, and patients with different disease courses and clinical presentations display distinct patterns of iron deposition. These iron deposition patterns may contribute to PD diagnosis. Iron deposition is a promising target for PD treatment. However, further research is required to elucidate the underlying mechanisms and their impacts on PD.

Mesenchymal stem cells alleviate sepsis-induced acute lung injury by blocking neutrophil extracellular traps formation and inhibiting ferroptosis in rats.

Acute lung injury (ALI) is one of the most serious complications of sepsis, characterized by high morbidity and mortality rates. Ferroptosis has recently been reported to play an essential role in sepsis-induced ALI. Excessive neutrophil extracellular traps (NETs) formation induces exacerbated inflammation and is crucial to the development of ALI. In this study, we explored the effects of ferroptosis and NETs and observed the therapeutic function of mesenchymal stem cells (MSCs) on sepsis-induced ALI. First, we produced a cecal ligation and puncture (CLP) model of sepsis in rats. Ferrostain-1 and DNase-1 were used to inhibit ferroptosis and NETs formation separately, to confirm their effects on sepsis-induced ALI. Next, U0126 was applied to suppress the MEK/ERK signaling pathway, which is considered to be vital to NETs formation. Finally, the therapeutic effect of MSCs was observed on CLP models. The results demonstrated that both ferrostain-1 and DNase-1 application could improve sepsis-induced ALI. DNase-1 inhibited ferroptosis significantly in lung tissues, showing that ferroptosis could be regulated by NETs formation. With the inhibition of the MEK/ERK signaling pathway by U0126, NETs formation and ferroptosis in lung tissues were both reduced, and sepsis-induced ALI was improved. MSCs also had a similar protective effect against sepsis-induced ALI, not only inhibiting MEK/ERK signaling pathway-mediated NETs formation, but also alleviating ferroptosis in lung tissues. We concluded that MSCs could protect against sepsis-induced ALI by suppressing NETs formation and ferroptosis in lung tissues. In this study, we found that NETs formation and ferroptosis were both potential therapeutic targets for the treatment of sepsis-induced ALI, and provided new evidence supporting the clinical application of MSCs in sepsis-induced ALI treatment.

A New Porphyrin-based Covalent Organic Framework with High Iodine Capture Capacity and I-doping Enhanced Conductivity.

Covalent organic frameworks (COFs) are porous organic materials with well-defined and uniform structure. The material is an excellent candidate as a solid adsorbent for iodine adsorption. In the present study, we report the synthesis of COF with porphyrin moiety, TF-TA-COF, by solvothermal reaction, which was characterized by XRD, solid-state 13 C NMR, IR, TGA, and nitrogen adsorption-desorption analysis. TF-TA-COF showed a high specific surface area of 443 m2 g-1 , and exhibited good adsorption performance for iodine vapor, with an adsorption capacity of 2.74 g g-1 . XPS and Raman spectrum indicated that a hybrid of physisorption and chemisorption took place between host COF and iodine molecules. The electric properties of iodine-loaded TF-TA-COF were also studied. After doped with iodine, the conductivity of the material increased by more than 5 orders of magnitude. The photoconductivity of I2 -doped COF was also studied and TF-TA-COF showed doping-enhanced photocurrent generation.

LncRNA RP1-276N6.2 Expression and RP1-276N6.2 Gene Polymorphisms Contribute to the Risk of Coronary Artery Disease in Chinese Han Population.

Long noncoding RNAs (lncRNAs) have been implicated in coronary artery disease (CAD) processes. However, the relationship between the gene polymorphisms of lncRNA RP1-276N6.2 as a novel molecule and susceptibility to CAD remains unclear. In our case-control study, 949 CAD patients and 892 healthy controls were genotyped using the TaqMan genotyping assay. The quantitative real-time polymerase chain reaction and enzyme-linked immunosorbent assay were performed to examine the expression levels of RP1-276N6.2 and SLC22A3(OCT3). We observed that CAD patients had significantly lower RP1-276N6.2 levels than those healthy participants (p < 0.05). Compared to the wild-type genotype, the rs611950 T allele and the rs10499313 AG genotype and G allele significantly increased the premature CAD risk (p = 0.02, p = 0.002, and p = 0.01, respectively), while the rs505000 G allele reduced this risk (p = 0.01); moreover, the rs505000 CG genotype significantly enhanced the delayed CAD risk (p = 0.03), and the rs505000 G allele reduced the expression levels of RP1-276N6.2 and SLC22A3 (p < 0.05 and p < 0.05, respectively). In addition, RP1-276N6.2 positively regulated the mRNA and secreted protein levels of SLC22A3 (p < 0.05). In conclusion, the RP1-276N6.2 gene polymorphisms were closely associated with CAD risk. LncRNA RP1-276N6.2 may be a potential genetic target for CAD early diagnosis and treatment.

Activation of mGlu2/3 receptors in the striatum alleviates L-DOPA-induced dyskinesia and inhibits abnormal postsynaptic molecular expression.

Group II metabotropic glutamate receptors (mGlu2/3 receptors) have been regarded as promising candidates for the treatment of L-DOPA-induced dyskinesia (LID); however, confirmation is still lacking. As the hub of the basal ganglia circuit, the striatum plays a critical role in action control. Supersensitive responsiveness of glutamatergic corticostriatal input may be the key mechanism for the development of LID. In this study, we first examined the potency of LY354740 (12 mg/kg, i.p.) in modulating glutamate and dopamine release in lesioned striatum of stable LID rats. Then, we injected LY354740 (20nmoL or 40nmoL in 4 µL of sterile 0.9 % saline) directly into the lesioned striatum to verify its ability to reduce or attenuate L-DOPA-induced abnormal involuntary movements. In experiment conducted in established LID rats, after continuous injection for 4 days, we found that LY354740 significantly reduced the expression of dyskinesia. In another experiment conducted in parkinsonism rat models, we found that LY354740 attenuated the development of LID with an inverted-U dose-response curve. The role of LY354740 in modulating striatal expressions of LID-related molecular changes was also assessed after these behavioral experiments. We found that LY354740 significantly inhibited abnormal expressions of p-Fyn/p-NMDA/p-ERK1/2/p-HistoneH3/ΔFosB, which is in line with its ability to alleviate abnormal involuntary movements in both LID expression and induction phase. Our study indicates that activation of striatal mGlu2/3 receptors can attenuate the development of dyskinesia in parkinsonism rats and provide some functional improvements in LID rats by inhibiting LID-related molecular changes.

Case report: Intensive statin and PCSK-9 inhibitor combo reduces plaque volume and stenosis in ischemic stroke patient.

Intracranial atherosclerotic ischemic stroke dramatically impacts the quality of life among the elderly. Statins therapy has been proven to be effective in plaque stabilization and alleviation in patients with intracranial atherosclerotic ischemic stroke. According to recent studies, these effects may be directly related to lipid levels rather than specific lipid-lowering drugs. Anti-proprotein convertase subtilisin/kexin type 9 (PCSK9) monoclonal antibodies (PCSK-9 inhibitor) are newer effective lipid-lowering drugs increasingly prescribed to patients at high cardiovascular risk to lower LDL cholesterol. Studies have provided evidence that PCSK9 inhibitor combined with statin therapy can lead to a decrease in the plaque volume measured by intravascular ultrasound in coronary heart disease patients. But the efficacy of combination of the two drugs in symptomatic intracranial artery stenosis has been unknown. Here we provide a case which was reported to suggest that a combination of Evolocumab and intensive statin therapy might reverse or alleviate symptomatic intracranial artery stenosis.

Dual-regulation by Cx32 in hepatocyte to trigger and worsen liver graft injury.

Liver transplantation is the ultimate treatment option for end-stage liver failure. However, liver graft injury remains a challenge. This study aimed to investigate the role of connexin32 (Cx32) in liver graft injury and elucidate its mechanism of action. Through detecting liver graft samples from 6 patients, we observed that changes in the Cx32 level coincided with liver graft injury. Therefore, we established autologous orthotopic liver transplantation (AOLT) models using Cx32-knockout and wild-type mice and hypoxia/reoxygenation (H/R) and lipopolysaccharide (LPS) pretreatment models using alpha mouse liver 12 (AML12) cells, to explore Cx32 mechanisms in liver graft injury. Following in vivo and in vitro Cx32 knockout, oxidative stress and inflammatory response were inhibited through the regulation of PKC-α/NF-κB/NLRP3 and Nrf2/NOX4/ROS signaling pathways, thereby reducing Bak/Bax-related apoptosis and ameliorating liver graft injury. When the Cx32-based gap junction (GJ) was blocked with 2-aminoethoxydiphenyl borate (2-APB), ROS transfer was attenuated between neighboring cells, exacerbated oxidative stress and inflammatory response were prevented, and aggravation of liver graft injury was mitigated. These results highlight the dual regulation mechanism of Cx32 in liver graft injury. Through interaction with PKC-α, Cx32 regulated the NF-κB/NLRP3 and Nrf2/NOX4/ROS signaling pathways, thus directly triggering oxidative stress and inflammatory response. Simultaneously, mass-produced ROS were transferred to neighboring cells through Cx32 channels, for which oxidative stress and the inflammatory response were aggravated indirectly. Finally, Bak/Bax-related apoptosis was activated, thereby worsening liver graft injury. Our findings propose Cx32 as a dual mechanistic factor for oxidative stress and inflammatory signaling pathways in regulating cell apoptosis on liver graft injury, which suggests a promising therapeutic targets for liver graft injury.

Clinical characteristics and reaction to dopaminergic treatment of drug-naïve patients with Parkinson's disease in central China: A cross sectional study.

Background: The symptoms of early Parkinson's disease (PD) are complex and hidden. The aim of this study is to explore and summarize the characteristics of the symptoms of drug naïve patients with PD. Objectives: and Methods Drug-naïve patients with PD and age-matched healthy controls were recruited from the outpatient clinic of Wuhan Union Hospital. The motor and non-motor symptoms were evaluated for further analysis using Unified Parkinson's Disease Rating Scale (UPDRS) I, II, and III; Sniffin' Sticks Screening 12 test; Mini-Mental State Exam (MMSE); Montreal Cognitive Assessment (MoCA); Hamilton Anxiety Scale (HAMA); and Hamilton Depression Scale (HAMD) scores. The acute levodopa challenge test (ALCT) was adopted to assess the reaction to dopaminergic treatment. Results: We recruited 80 drug-naïve patients with PD and 40 age-matched healthy controls (HCs). Approximately 53.7% of the patients were females. The mean onset age was 59.96 ± 10.40 years. The mean UPDRS I, II, and III were 2.01 ± 1.90, 6.18 ± 3.68, and 26.13 ± 12.09, respectively. Compared with HCs, PD patients had lower scores in MMSE and MoCA; and higher scores in HAMA and HAMD (p < 0.05). In ALCT, 54 patients showed good responses to levodopa while 26 patients did not. The mean improvement rate of UPDRS III was 34.09% at 120 min. Conclusion: The motor symptoms of patients with early PD were mild but virous. They also suffered from different non-motor symptoms. In ALCT, about two thirds of patients (54/80) with early PD showed good response to levodopa. Among four aspects of motor symptoms, bradykinesia reacted best to ALCT, while axial symptoms were the worst.

Downregulation of connexin 43-based gap junctions underlies propofol-induced excessive relaxation in hypertensive vascular smooth muscle cells.

BACKGROUND: Postinduction hypotension caused by propofol remains a non-negligible problem for anesthesiologists, and is especially severe in chronic hypertensive patients with long-term vasoconstriction and decreased vascular elasticity. The functional change in gap junctions composed of Cx43 (Cx43-GJs) is reported as the biological basis of synchronized contraction or relaxation of blood vessels. Thus, we investigated the role of Cx43-GJs in propofol-induced dramatic blood pressure fluctuations in chronic hypertensive patients, and their internal mechanisms. METHODS: Human umbilical artery smooth muscle cells (HUASMCs) were pretreated with long-term angiotensin II (Ang II), with or without propofol, to simulate the contraction and relaxation of normal and hypertensive VSMCs during anesthesia induction. The levels of F-actin polymerization and MLC2 phosphorylation were used as indicators to observe the contraction and relaxation of HUASMCs. Different specific activators, inhibitors and siRNAs were used to explore the role of Cx43-GJs and Ca2+ as well as the RhoA/ LIMK2/cofilin and RhoA/MLCK signaling pathways in the contraction and relaxation of normal and hypertensive HUASMCs. RESULTS: Both F-actin polymerization and MLC2 phosphorylation were significantly enhanced in Ang II-pretreated HUASMCs, along with higher expression of Cx43 protein and stronger function of Cx43-GJs than in normal HUASMCs. However, with propofol administration, similar to Gap26 and Cx43-siRNA, the function of Cx43-GJs in Ang II-pretreated HUASMCs was inhibited compared with that in normal HUASMCs, accompanied by a larger decrease in intracellular Ca2+ and the RhoA/LIMK2/cofilin and RhoA/MLCK signaling pathways. Eventually F-actin polymerization and MLC2 phosphorylation were more dramatically decreased. However, these effects could be reversed by RA with enhanced Cx43-GJ function. CONCLUSION: Long-term exposure to Ang II significantly enhanced the expression of the Cx43 protein and function of Cx43-GJs in HUASMCs, resulting in the accumulation of intracellular Ca2+ and the activation of its downstream RhoA/LIMK2/cofilin and RhoA/MLCK signaling pathways, which maintained HUASMCs in a state of excessive-contraction. With inhibition of Cx43-GJs by propofol in Ang II-pretreated HUASMCs, intracellular Ca2+ and its downstream signaling pathways were dramatically inhibited, which ultimately excessively relaxed HUASMCs. This is the reason why the blood pressure fluctuation of patients with chronic hypertension was more severe after receiving propofol induction. Video Abstract.

Time-dependent alterations in the rat nigrostriatal system after intrastriatal injection of fibrils formed by α-Syn and tau fragments.

Introduction: Accurate demonstration of phosphorylated α-synuclein aggregation and propagation, progressive nigrostriatal degeneration and motor deficits will help further research on elucidating the mechanisms of Parkinson's Disease. α-synucleinN103 and tauN368, cleaved by activated asparagine endopeptidase in Parkinson's Disease, robustly interacted with each other and triggered endogenous α-synuclein accumulation in a strong manner. However, the detailed pathophysiological process caused by the complex remains to be established. Methods: In this study, rats were unilaterally inoculated with 15 or 30 µg of this complex or vehicle (phosphate buffered saline, PBS). Over a 6-month period post injection, we then investigated the abundance of pSyn inclusions, nigrostriatal degeneration, and changes in axonal transport proteins to identify the various dynamic pathological changes caused by pSyn aggregates in the nigrostriatal system. Results: As expected, rats displayed a dose-dependent increase in the amount of α-synuclein inclusions, and progressive dopaminergic neurodegeneration was observed throughout the study, reaching 30% at 6 months post injection. Impairments in anterograde axonal transport, followed by retrograde transport, were observed prior to neuron death, which was first discovered in the PFFs model. Discussion: The current results demonstrate the value of a novel rat model of Parkinson's disease characterized by widespread, "seed"-initiated endogenous α-Syn pathology, impaired axonal transport, and a neurodegenerative cascade in the nigrostriatal system. Notably, the present study is the first to examine alterations in axonal transport proteins in a PFF model, providing an appropriate foundation for future research regarding the mechanisms leading to subsequent neurodegeneration. As this model recapitulates some essential features of Parkinson's disease, it provides an important platform for further research on specific pathogenic mechanisms and pre-clinical evaluations of novel therapeutic strategies.

Function of connexin 43 and RhoA/LIMK2/Cofilin signaling pathway in transient changes of contraction and dilation of human umbilical arterial smooth muscle cells.

BACKGROUND: Post-induction hypotension, a common complication after propofol-based induction regimen, is a life-threatening challenge for anesthesiologists especially when unexpected pre-induction hypertension characterized by angiotensin release and increased vascular tone was presented by the same patient. Gap junctions (GJs) composed of connexin 43 (Cx43) have been considered a key factor in regulating vascular contraction and dilation. We aimed to explore the role of Cx43-GJs during peri-induction blood pressure fluctuation and elucidate the underlying mechanisms. METHODS: Human umbilical arterial smooth muscle cells (HUASMCs) were pretreated by short-term Angiotensin Ⅱ (Ang Ⅱ) with or without subsequent propofol treatment to simulate transient contraction and dilation of vascular smooth muscle cells during anesthesia induction. F-actin polymerization, a classic indicator of HUASMCs constriction, was determined by F-actin staining assay. Both the function and expression of Cx43-GJs during transient contraction and dilation of HUASMCs, and their potential regulation of downstream Ca2+/RhoA/LIMK2/Cofilin signaling pathway were explored via different targeting inhibitors and siRNAs. RESULTS: Ang Ⅱ pretreatment significantly induced F-actin polymerization that indicate cell contraction, accompanied by enhanced GJs function on HUASMCs. With the inhibition of Cx43 GJs by the specific inhibitor, Gap26, and Cx43-siRNA, Ang Ⅱ-induced F-actin polymerization was reversed accompanied with the decrease of intracellular Ca2+ mobility and the RhoA/LIMK2/Cofilin signaling pathway activity. We also noticed that propofol application could inhibit GJs function, the same as Gap26. Simultaneously, intracellular Ca2+ mobility and RhoA/LIMK2/Cofilin signaling pathway activity on HUASMCs were both downregulated, finally resulting in downstream reduction of F-actin polymerization. CONCLUSION: The function of Cx43-GJs lies in the center of Ang Ⅱ-induced contraction of HUASMCs, which potentially regulates intracellular Ca2+ mobility as well as RhoA/LIMK2/Cofilin signaling pathway activity. Propofol can reverse this effect induced by Ang Ⅱ through suppressing the function of Cx43-GJs.

Dual Effects: Intrastriatal Injection of α-syn N103/tau N368 Preformed Fibrils Promotes Endogenous α-synuclein Aggregates in the Proximal Colon.

BACKGROUND: Pathological changes in the brain can affect the gastrointestinal tract, whereas there is less evidence regarding the brain-gut axis. OBJECTIVE: To identify whether cerebral endogenous phosphorylated α-synuclein induces gastrointestinal dysfunction via the brain-gut axis, mediated by the vagus nerve. METHODS: α-syn N103/tau N368 preformed fibrils were injected into the dorsal lateral striatum of rodents, and the cerebral and colonic synucleinopathies and changes in the enteric nervous system were analyzed. Moreover, subdiaphragmatic vagotomy was conducted to confirm the role of the vagus nerve in brain-gut propagation. RESULTS: An anterograde propagation of phosphorylated α-synuclein from the brain to the proximal colon mainly via the vagus nerve was observed at one month. The accumulation of phosphorylated α-synuclein was detected in the proximal colon over time, accompanied by infiltration of macrophages and eosinophils in the mucosa and submucosa. Upon injection with lower doses of preformed fibrils, the accumulation of phosphorylated α-synuclein and dopaminergic neuron loss was reduced to levels consistent with control at six months, while the expression levels of GFAP, Iba-1, and IL-6 increased. Under high preformed fibrils dose conditions, fecal traits and gastrointestinal motility were significantly reduced at six months, and aggregations of phosphorylated α-synuclein and an increasing level of IL-1ß appeared. CONCLUSION: Induced endogenous α-synuclein can quickly propagate into the proximal colon mainly via the vagus nerve. Injections of low doses of preformed fibrils can elicit recovery of the enteric nervous system and degradation of α-synuclein aggregates whereas high doses cause accumulation of pathological α-synuclein, enteric inflammation, and prominent gastrointestinal dysfunction.

The convoluted process of diagnosing pulmonary mycosis caused by Exophiala dermatitidis: a case report.

BACKGROUND: Etiological diagnosis is a key step in the treatment of patients with rare pulmonary mycosis, and the lack of understanding of this disease and lack of specific markers for the detection of rare species, such as Exophiala dermatitidis, add to the difficulty in diagnosing the condition. Therefore, improving the diagnostic strategies for this disease is very important. CASE PRESENTATION: A 52-year-old man presented with cough, sputum production and hemoptysis; chest computed tomography (CT) revealed multiple bilateral lesions. The pathogen was unable to be identified after three biopsies. Subsequently, we performed combined tissue metagenomic next-generation sequencing (mNGS). The results of mNGS and a good therapeutic response helped to identify the causative pathogen as Exophiala dermatitidis. Finally, the patient was diagnosed with Exophiala dermatitidis pneumonia. CONCLUSIONS: Combining molecular techniques, such as mNGS, with clinical microbiological tests will improve the rate of positivity in the diagnosis of rare fungal infections, and the importance of follow-up should be emphasized.

Vision-Based Finger Tapping Test in Patients With Parkinson's Disease via Spatial-Temporal 3D Hand Pose Estimation.

Finger tapping test is crucial for diagnosing Parkinson's Disease (PD), but manual visual evaluations can result in score discrepancy due to clinicians' subjectivity. Moreover, applying wearable sensors requires making physical contact and may hinder PD patient's raw movement patterns. Accordingly, a novel computer-vision approach is proposed using depth camera and spatial-temporal 3D hand pose estimation to capture and evaluate PD patients' 3D hand movement. Within this approach, a temporal encoding module is leveraged to extend A2J's deep learning framework to counter the pose jittering problem, and a pose refinement process is utilized to alleviate dependency on massive data. Additionally, the first vision-based 3D PD hand dataset of 112 hand samples from 48 PD patients and 11 control subjects is constructed, fully annotated by qualified physicians under clinical settings. Testing on this real-world data, this new model achieves 81.2% classification accuracy, even surpassing that of individual clinicians in comparison, fully demonstrating this proposition's effectiveness. The demo video can be accessed at https://github.com/ZhilinGuo/ST-A2J.

Altered Intra- and Inter-Network Connectivity in Drug-Naïve Patients With Early Parkinson's Disease.

The aim of our study was to investigate differences in whole brain connectivity at different levels between drug-naïve individuals with early Parkinson's disease (PD) and healthy controls (HCs). Resting-state functional magnetic resonance imaging data were collected from 47 patients with early-stage, drug-naïve PD and 50 HCs. Functional brain connectivity was analyzed at the integrity, network, and edge levels; UPDRS-III, MMSE, MOCA, HAMA, and HAMD scores, reflecting the symptoms of PD, were collected for further regression analysis. Compared with age-matched HCs, reduced functional connectivity were mainly observed in the visual (VSN), somatomotor (SMN), limbic (LBN), and deep gray matter networks (DGN) at integrity level [p < 0.05, false discovery rate (FDR) corrected]. Intra-network analysis indicated decreased functional connectivity in DGN, SMN, LBN, and ventral attention networks (VAN). Inter-network analysis indicated reduced functional connectivity in nine pairs of resting-state networks. At the edge level, the LBN was the center of abnormal functional connectivity (p < 0.05, FDR corrected). MOCA score was associated with the intra-network functional connectivity strength (FC) of the DGN, and inter-network FC of the DGN-VAN. HAMA and HAMD scores were associated with the FC of the SMN and DGN, and either the LBN or VAN, respectively. We demonstrated variations in whole brain connections of drug-naïve patients with early PD. Major changes involved the SMN, DGN, LBN, and VSN, which may be relevant to symptoms of early PD. Additionally, our results support PD as a disconnection syndrome.

Transcranial Magnetic Stimulation Alleviates Levodopa-Induced Dyskinesia in Parkinson's Disease and the Related Mechanisms: A Mini-Review.

After long-term use of levodopa, Parkinson's patients almost inevitably develop dyskinesia, a kind of drug side effect manifesting as uncontrollable choreic movements and dystonia, which could be crippling yet have limited therapeutic options. Transcranial magnetic stimulation is the most widely studied non-invasive neuromodulation technology to treat levodopa-induced dyskinesia. Many studies have shown that transcranial magnetic stimulation has beneficial effects on levodopa-induced dyskinesia and is patient-tolerable, barely with reported adverse effects. Changes in brain connectivity, neuroplasticity, neurotransmitter, neurorestoration, and blood flow modulation could play crucial roles in the efficacy of transcranial magnetic stimulation for levodopa-induced dyskinesia. The appearance of new modes and application for emerging targets are possible solutions for transcranial magnetic stimulation to achieve sustained efficacy. Since the sample size in all available studies is small, more randomized double-blind controlled studies are needed to elucidate the specific treatment mechanisms and optimize treatment parameters.

Histological Correlates of Neuroanatomical Changes in a Rat Model of Levodopa-Induced Dyskinesia Based on Voxel-Based Morphometry.

Long-term therapy with levodopa (L-DOPA) in patients with Parkinson's disease (PD) often triggers motor complications termed as L-DOPA-induced dyskinesia (LID). However, few studies have explored the pathogenesis of LID from the perspective of neuroanatomy. This study aimed to investigate macroscopic structural changes in a rat model of LID and the underlying histological mechanisms. First, we established the hemiparkinsonism rat model through stereotaxic injection of 6-hydroxydopamine (6-OHDA) into the right medial forebrain bundle, followed by administration of saline (PD) or L-DOPA to induce LID. Magnetic resonance imaging (MRI) and behavioral evaluations were performed at different time points. Histological analysis was conducted to assess the correlations between MRI signal changes and cellular contributors. Voxel-based morphometry (VBM) analysis revealed progressive bilateral volume reduction in the cortical and subcortical areas in PD rats compared with the sham rats. These changes were partially reversed by chronic L-DOPA administration; moreover, there was a significant volume increase mainly in the dorsolateral striatum, substantia nigra, and piriform cortex of the lesioned side compared with that of PD rats. At the striatal cellular level, glial fibrillary acidic protein-positive (GFAP+) astrocytes were significantly increased in the lesioned dorsolateral striatum of PD rats compared with the intact side and the sham group. Prolonged L-DOPA treatment further increased GFAP levels. Neither 6-OHDA damage nor L-DOPA treatment influenced the striatal expression of vascular endothelial growth factor (VEGF). Additionally, there was a considerable increase in synapse-associated proteins (SYP, PSD95, and SAP97) in the lesioned striatum of LID rats relative to the PD rats. Golgi-Cox staining analysis of the dendritic spine morphology revealed an increased density of dendritic spines after chronic L-DOPA treatment. Taken together, our findings suggest that striatal volume changes in LID rats involve astrocyte activation, enrichment of synaptic ultrastructure and signaling proteins in the ipsilateral striatum. Meanwhile, the data highlight the enormous potential of structural MRI, especially VBM analysis, in determining the morphological phenotype of rodent models of LID.

Development and Clinical Evaluation of a CRISPR-Based Diagnostic for Rapid Group B Streptococcus Screening.

Vertical transmission of group B Streptococcus (GBS) is among the leading causes of neonatal illness and death. Colonization with GBS usually is screened weeks before delivery during pregnancy, on the basis of which preventive measures, such as antibiotic prophylaxis, were taken. However, the accuracy of such an antenatal screening strategy has been questionable because of the intermittent nature of GBS carriage. We developed a simple-to-use, rapid, CRISPR-based assay for GBS detection. We conducted studies in a prospective cohort of 412 pregnant women and a retrospective validation cohort to evaluate its diagnostic performance. We demonstrated that CRISPR-GBS is highly sensitive and offered shorter turnaround times and lower instrument demands than PCR-based assays. This novel GBS test exhibited an overall improved diagnostic performance over culture and PCR-based assays and represents a novel diagnostic for potential rapid, point-of-care GBS screening.