Application of ChatGPT for Orthopedic Surgeries and Patient Care.

Artificial intelligence (AI) has rapidly transformed various aspects of life, and the launch of the chatbot "ChatGPT" by OpenAI in November 2022 has garnered significant attention and user appreciation. ChatGPT utilizes natural language processing based on a "generative pre-trained transfer" (GPT) model, specifically the transformer architecture, to generate human-like responses to a wide range of questions and topics. Equipped with approximately 57 billion words and 175 billion parameters from online data, ChatGPT has potential applications in medicine and orthopedics. One of its key strengths is its personalized, easy-to-understand, and adaptive response, which allows it to learn continuously through user interaction. This article discusses how AI, especially ChatGPT, presents numerous opportunities in orthopedics, ranging from preoperative planning and surgical techniques to patient education and medical support. Although ChatGPT's user-friendly responses and adaptive capabilities are laudable, its limitations, including biased responses and ethical concerns, necessitate its cautious and responsible use. Surgeons and healthcare providers should leverage the strengths of the ChatGPT while recognizing its current limitations and verifying critical information through independent research and expert opinions. As AI technology continues to evolve, ChatGPT may become a valuable tool in orthopedic education and patient care, leading to improved outcomes and efficiency in healthcare delivery. The integration of AI into orthopedics offers substantial benefits but requires careful consideration and continuous improvement.

Microstructure-Based Modeling of Deformation and Damage Behavior of Extruded and Additively Manufactured 316L Stainless Steels.

In this study, we investigated the micromechanical deformation and damage behavior of commercially extruded and additively manufactured 316L stainless steels (AMed SS316L) by combining experimental examinations and crystal plasticity modeling. The AMed alloy was fabricated using the laser powder bed fusion (LPBF) technique with an orthogonal scanning strategy to control the directionality of the as-fabricated material. Optical microscopy and electron backscatter diffraction measurements revealed distinct grain morphologies and crystallographic textures in the two alloys. Uniaxial tensile test results suggested that the LPBFed alloy exhibited an increased yield strength, reduced elongation, and comparable ultimate tensile strength in comparison to those of the extruded alloy. A microstructure-based crystal plasticity model was developed to simulate the micromechanical deformation behavior of the alloys using representative volume elements based on realistic microstructures. A ductile fracture criterion based on the microscopically dissipated plastic energy on a slip system was adopted to predict the microscopic damage accumulation of the alloys during plastic deformation. The developed model could accurately predict the stress-strain behavior and evolution of the crystallographic textures in both the alloys. We reveal that the increased yield strength in the LPBFed alloy, compared to that in the extruded alloy, is attributed to the higher as-manufactured dislocation density and the cellular subgrain structure, resulting in a reduced elongation. The presence of annealing twins and favorable texture in the extruded alloy contributed to its excellent elongation, along with a higher hardening rate owing to twin-dislocation interactions during plastic deformation. Moreover, the grain morphology and defect state (e.g., dislocations and twins) in the initial state can significantly affect strain localization and damage accumulation in alloys.

The Effect of Denosumab on Rotator Cuff Repair in Women Aged 60 and over with Osteoporosis: A Prospective Observational Study.

BACKGROUND: In previous studies, denosumab, a RANKL human monoclonal antibody used in osteoporosis treatment, has shown efficacy in tendon healing after rotator cuff repair. This prospective study investigated the effects of denosumab on tendon healing, re-tear rates, and clinical outcomes post rotator cuff repair in women with osteoporosis. METHOD: This was a prospective, observational study, employing propensity score matching for the control group. From March 2018 to March 2023, female patients over the age of 60 with normal bone density undergoing arthroscopic rotator cuff repair were selected as controls through propensity score matching (PSM) and compared with female patients of the same age group with osteoporosis who were receiving denosumab treatment. The control group was matched using 1-to-2 propensity score matching. Radiological examinations and functional outcomes were assessed preoperatively and at 6 months postoperatively. RESULTS: In the final analysis, the study comprised 34 patients in the denosumab treatment group (Group 1) and 68 patients in the control group (Group 2). The functional scores showed significant improvement at 6 months post-surgery in both groups. No significant difference in the functional scores was observed among the groups. The re-tear rate, defined according to Sugaya's classification (types IV and V) as re-tear, was slightly higher in Group 1 at 16.7% (6 of 34) compared to Group 2 at 11.7% (8 of 68), but the difference was not statistically significant (p = 0.469). The re-tear patterns, classified according to Rhee's classification, also showed no significant difference among the groups (Group 1: 2/4 of 6; Group 2: 4/4 of 8; p = 0.571). The occurrence of type I re-tear exhibited no significant difference between the two groups (5.9% vs. 5.9%; p = 1.000). CONCLUSIONS: The administration of denosumab following arthroscopic rotator cuff repair in women aged 60 and over with osteoporosis resulted in a re-tear rate that was similar to that observed in patients without osteoporosis. This result suggests that denosumab administration might be beneficial for rotator cuff healing, particularly in the context of osteoporosis, a known risk factor for increased retear rates. Therefore, comprehensive osteoporosis screening and treatment should be considered in conjunction with rotator cuff repair surgery in middle-aged women.

Reinforcement Techniques in Arthroscopic Repair of Large-to-Massive Rotator Cuff Tears: A Comparative Study of Superior Capsule Reconstruction and Patch Graft Augmentation.

Background: Large-to-massive rotator cuff tears (LMRCTs) present challenges in achieving successful repair due to factors such as muscle atrophy and tendon retraction. Arthroscopic rotator cuff repair (ARCR) with reinforcement techniques like superior capsule reconstruction (SCR) or patch graft augmentation (PGA) has emerged as a less invasive option to improve shoulder joint stability and prevent retear. This study aimed to compare the clinical and radiological outcomes of SCR and PGA as reinforcement techniques for the arthroscopic repair of LMRCTs. Methods: A single-center retrospective study was conducted on patients undergoing LMRCT repair between January 2019 and December 2021. Patients were divided into two groups: those receiving SCR (Group 1) and those receiving PGA (Group 2). Various clinical parameters including range of motion, functional scores, and radiological assessments were evaluated preoperatively and six months postoperatively. Results: Both SCR and PGA techniques demonstrated significant improvements in the range of motion and clinical scores postoperatively. However, Group 2 showed higher postoperative SST and UCLA scores compared to Group 1. Radiologically, there was a slightly higher retear rate in Group 2, although this was not statistically significant. Group 2 also had a shorter mean duration of surgery compared to Group 1. Conclusions: In the arthroscopic repair of LMRCTs, both SCR and PGA techniques exhibit favorable clinical and radiological outcomes. Despite the simplicity of PGA compared to SCR, it offers comparable results with a shorter surgical duration, making it a feasible reinforcement option for surgeons.

Opicapone to Treat Early Wearing-off in Parkinson's Disease Patients: The Korean ADOPTION Trial.

BACKGROUND: Increasing levodopa (L-dopa)/dopa decarboxylase inhibitor (DDCI) daily dose or adding a catechol-O-methyltransferase (COMT) inhibitor to levodopa/DDCI therapy are strategies used to manage wearing-off symptoms in Parkinson's disease (PD) patients. OBJECTIVES: To evaluate the COMT inhibitor opicapone versus an additional dose of levodopa to treat early wearing-off in PD patients. METHODS: ADOPTION was a randomized, parallel-group, open-label, Phase 4 study conducted in Korea. At baseline, eligible patients were randomized (1:1) to opicapone 50 mg (n = 87) or L-dopa 100 mg (n = 81) (added to current L-dopa/DDCI therapy) for 4 weeks. The main efficacy endpoint was change from baseline to end of study in absolute off time. Other endpoints included changes in on time, in Movement Disorder Society-Unified Parkinson's Disease Rating Scale and 8-item PD Questionnaire scores, and the Clinical and Patient Global Impression of Improvement/Change. RESULTS: The adjusted mean in absolute off time was significantly greater for opicapone 50 mg than for L-dopa 100 mg (-62.1 vs. -16.7 minutes; P = 0.0015). Opicapone-treated patients also reported a greater reduction in the percentage of off time (P = 0.0015), a greater increase in absolute on time (P = 0.0338) and a greater increase in the percentage of on time (P = 0.0015). There were no significant differences in other secondary endpoints. The L-dopa equivalent daily dose was significantly higher in the opicapone group (750.9 vs. 690.0 mg; P = 0.0247), when a 0.5 conversion factor is applied. CONCLUSIONS: Opicapone 50 mg was more effective than an additional 100 mg L-dopa dose at decreasing off time in patients with PD and early wearing-off.

EEG-Based Brain Functional Network Analysis for Differential Identification of Dementia-Related Disorders and Their Onset.

Diagnosing and treating dementia, including mild cognitive impairment (MCI), is challenging due to diverse disease types and overlapping symptoms. Early MCI detection is vital as it can precede dementia, yet distinguishing it from later stage dementia is intricate due to subtle symptoms. The primary objective of this study is to adopt a complex network perspective to unravel the underlying pathophysiological mechanisms of dementia-related disorders. Leveraging the extensive availability of electroencephalogram (EEG) data, our study focuses on the meticulous identification and analysis of EEG-based brain functional network (BFNs) associated with dementia-related disorders. To achieve this, we employ the Phase Lag Index (PLI) as a connectivity measure, offering a comprehensive view of neural interactions. To enhance the analytical rigor, we introduce a data-driven threshold selection technique. This innovative approach allows us to compare the topological structures of the formulated BFNs using complex network measures quantitatively and statistically. Furthermore, we harness the power of these BFNs by utilizing them as pre-defined graph inputs for a Graph Convolution Network (GCN-net) based approach. The results demonstrate that graph theory metrics, such as the rich-club coefficient, transitivity, and assortativity coefficients, effectively distinguish between MCI, Alzheimer's disease (AD) and vascular dementia (VD). Furthermore, GCN-net achieves high accuracy (95.07% delta, 80.62% theta) and F1-scores (0.92 delta, 0.67 theta), highlighting the effectiveness of EEG-based BFNs in the analysis of dementia-related disorders.

Subsequent correlated changes in complement component 3 and amyloid beta oligomers in the blood of patients with Alzheimer's disease.

INTRODUCTION: Alzheimer's disease (AD) involves the complement cascade, with complement component 3 (C3) playing a key role. However, the relationship between C3 and amyloid beta (Aß) in blood is limited. METHODS: Plasma C3 and Aß oligomerization tendency (AßOt) were measured in 35 AD patients and 62 healthy controls. Correlations with cerebrospinal fluid (CSF) biomarkers, cognitive impairment, and amyloid positron emission tomography (PET) were analyzed. Differences between biomarkers were compared in groups classified by concordances of biomarkers. RESULTS: Plasma C3 and AßOt were elevated in AD patients and in CSF or amyloid PET-positive groups. Weak positive correlation was found between C3 and AßOt, while both had strong negative correlations with CSF Aß42 and cognitive performance. Abnormalities were observed for AßOt and CSF Aß42 followed by C3 changes. DISCUSSION: Increased plasma C3 in AD are associated with amyloid pathology, possibly reflecting a defense response for Aß clearance. Further studies on Aß-binding proteins will enhance understanding of Aß mechanisms in blood.

Fracture Severity and Triangular Fibrocartilage Complex Injury in Distal Radius Fractures with or without Osteoporosis.

The purpose of this study was to investigate the fracture morphology of distal radius fractures (DRFs) with the status of triangular fibrocartilage complex (TFCC) foveal insertion in patients with or without osteoporosis and to identify the relationship between osteoporosis and foveal tear. Seventy-five patients who underwent surgery for DRF from January 2021 to September 2023 were included. All patients were evaluated by standard radiography and dual-energy X-ray absorptiometry and underwent a 3.0 T magnetic-resonance imaging examination of the involved wrist to identify TFCC foveal tear. Patients were allocated into two groups according to the presence of osteoporosis: patients with osteoporosis (group I) and those without osteoporosis (group II). Group I showed a significantly larger displacement of fractures compared to group II (radial inclination; 13.7 ± 5.4 vs. 17.9 ± 4.2; p < 0.001, dorsal angulation; 22.2 ± 12.1 vs. 16.5 ± 9.4; p = 0.024, ulnar variance; 4.15 ± 2.1 vs. 2.2 ± 1.9; p < 0.001). Dorsal angulation and ulnar variance were found to be independent prognostic factors for TFCC foveal tear in logistic regression analysis. Displacement of fractures was related to osteoporosis, and dorsal angulation and ulnar variance were independent prognostic factors for TFCC foveal tear. However, osteoporosis was not identified as a factor associated with TFCC foveal tears.

Identification and characterization of novel ERBB4 variant associated with sporadic amyotrophic lateral sclerosis (ALS).

Amyotrophic Lateral Sclerosis (ALS) is the most common type of motor neuron disease characterized by progressive motor neuron degeneration in brain and spinal cord. Most cases are sporadic in ALS and 5-10% of cases are familiar. >50 genes are known to be associated with ALS and one of them is ERBB4. In this paper, we report the case of a 53-year-old ALS patient with progressive muscle weakness and fasciculation, but he had no cognitive decline. We performed the next generation sequencing (NGS) and in silico analysis, it predicted a highly pathogenic variant, c.2116 A > G, p.Asn706Asp (N706D) in the ERBB4 gene. The amino acid residue is highly conserved among species. ERBB4 is a member of the ERBB family of receptor tyrosine kinases. ERBB4 has multiple tyrosine phosphorylation sites, including an autophosphorylation site at tyrosine 1284 residue. Autophosphorylation of ERBB4 promotes biological activity and it associated with NRG-1/ERBB4 pathway. It is already known that tyrosine 128 phosphorylation of ERBB4 is decreased in patients who have ALS-associated ERBB4 mutations. We generated ERBB4 N706D construct using site-directed mutagenesis and checked the phosphorylation level of ERBB4 N706D in NSC-34 cells. We found that the phosphorylation of ERBB4 N706D was decreased compared to ERBB4 wild-type, indicating a loss of function mutation in ERBB4. We report a novel variant in ERBB4 gene leading to ALS through dysfunction of ERBB4.

Pan-cancer analysis reveals multifaceted roles of retrotransposon-fusion RNAs.

Transposon-derived transcripts are abundant in RNA sequences, yet their landscape and function, especially for fusion transcripts derived from unannotated or somatically acquired transposons, remains underexplored. Here, we developed a new bioinformatic tool to detect transposon-fusion transcripts in RNA-sequencing data and performed a pan-cancer analysis of 10,257 cancer samples across 34 cancer types as well as 3,088 normal tissue samples. We identified 52,277 cancer-specific fusions with ~30 events per cancer and hotspot loci within transposons vulnerable to fusion formation. Exonization of intronic transposons was the most prevalent genic fusions, while somatic L1 insertions constituted a small fraction of cancer-specific fusions. Source L1s and HERVs, but not Alus showed decreased DNA methylation in cancer upon fusion formation. Overall cancer-specific L1 fusions were enriched in tumor suppressors while Alu fusions were enriched in oncogenes, including recurrent Alu fusions in EZH2 predictive of patient survival. We also demonstrated that transposon-derived peptides triggered CD8+ T-cell activation to the extent comparable to EBV viruses. Our findings reveal distinct epigenetic and tumorigenic mechanisms underlying transposon fusions across different families and highlight transposons as novel therapeutic targets and the source of potent neoantigens.

Optic neuritis associated with seronegative autoimmune encephalitis: a case report.

Optic neuritis is an inflammatory demyelinating disorder that primarily affects the optic nerve and is often associated with multiple sclerosis. While it is rare for optic neuritis to be accompanied by autoimmune encephalitis, it can occur in some cases. A 65-year-old woman with bipolar disorder presented with a progressively altered mentality. Magnetic resonance imaging of the brain showed no definite abnormal findings. Electroencephalography revealed nonconvulsive status epilepticus. Cerebrospinal fluid study and autoimmune and paraneoplastic encephalitis antibodies were negative. The patient was diagnosed with seronegative autoimmune encephalitis and treated with methylprednisolone, intravenous immunoglobulin, and rituximab. Her condition gradually improved except for persistent blindness on the left side. This case highlights the importance of considering autoimmune encephalitis even in the absence of identifiable pathogenic antibodies when clinical manifestations and response to immunotherapy support such a diagnosis.

Computational Analysis of miR-140 and miR-135 as Potential Targets to Develop Combinatorial Therapeutics for Degenerative Tendinopathy.

Background: Degenerative tendinopathy, a condition causing movement restriction due to high pain, highly impacts productivity and quality of life. The healing process is a complex phenomenon and involves a series of intra-cellular and inter-cellular processes. Proliferation and differentiation of the tenocyte is a major and essential process to heal degenerative tendinopathy. The recent development in microRNA (miRNA)-mediated reprogramming of the cellular function through specific pathways opened door for the development of new regenerative therapeutics. Based on information about gene expression and regulation of tendon injury and healing, we attempted to evaluate the combinatorial effect of selected miRNAs for better healing of degenerative tendinopathy. Methods: The present study was designed to evaluate the combinatorial effect of two miRNAs (has-miR-140 and has-miR-135) in the healing process of the tendon. Publicly available information/data were retrieved from appropriate platforms such as PubMed. Only molecular data, directly associated with tendinopathies, including genes/proteins and miRNAs, were used in this study. The miRNAs involved in tendinopathy were analyzed by a Bioinformatics tools (e.g., TargetScan, miRDB, and the RNA22v2). Interactive involvement of the miRNAs with key proteins involved in tendinopathy was predicted by the Insilco approach. Results: Based on information available in the public domain, tendon healing-associated miRNAs were predicted to explore their therapeutic potentials. Based on computation analysis, focusing on the potential regulatory effect on tendon healing, the miR-135 and miR-140 were selected for this study. These miRNAs were found as key players in tendon healing through Rho-associated coiled-coil containing protein kinase 1 (ROCK1), IGF-1/PI3K/Akt, PIN, and Wnt signaling pathways. It was also predicted that these miRNAs may reprogram the cells to induce proliferation and differentiation activity. Many miRNAs are likely to regulate genes important for the tendinopathy healing process, and the result of this study allows an approach for miRNA-mediated regeneration of the tenocyte for tendon healing. Based on computational analysis, the role of these miRNAs in different pathways was established, and the results provided insights into the combinatorial approach of miRNA-mediated cell reprogramming. Conclusions: In this study, the association between miRNAs and the disease was evaluated to correlate the tendinopathy genes and the relevant role of different miRNAs in their regulation. Through this study, it was established that the synergistic effect of more than one miRNA on directed reprogramming of the cell could be helpful in the regeneration of damaged tissue. It is anticipated that this study will be helpful for the design of miRNA cocktails for the orchestration of cellular reprogramming events.

Mesenchymal Stem Cell Transplantation Ameliorates Ara-C-Induced Motor Deficits in a Mouse Model of Cerebellar Ataxia.

This study investigated the therapeutic effects of transplanting human mesenchymal stem cells (hMSCs) into wild-type mice that were intraperitoneally administered cytosine arabinoside (Ara-C) to develop cerebellar ataxia (CA) during the first three postnatal days. hMSCs were intrathecally injected into 10-week-old mice once or thrice at 4-week intervals. Compared to the nontreated mice, the hMSC-treated mice showed improved motor and balance coordination, as measured using the rotarod, open-field, and ataxic scoring assessments, and increased protein levels in Purkinje and cerebellar granule cells, as measured using calbindin and NeuN protein markers. Multiple hMSC injections preserved Ara-C-induced cerebellar neuronal loss and improved cerebellar weight. Furthermore, the hMSC implantation significantly elevated the levels of neurotrophic factors, including brain-derived and glial cell line-derived neurotrophic factors, and suppressed TNF-α-, IL-1ß-, and iNOS-mediated proinflammatory responses. Collectively, our results demonstrate that hMSCs exhibit therapeutic potential for Ara-C-induced CA by protecting neurons through the stimulation of neurotrophic factors and inhibition of cerebellar inflammatory responses, which can improve motor behavior and alleviate ataxia-related neuropathology. In summary, this study suggests that hMSC administration, particularly multiple treatments, can effectively treat ataxia-related symptoms with cerebellar toxicity.

Glycan-Controlled Human PD-1 Variants Displaying Broad-Spectrum High Binding to PD-1 Ligands Potentiate T Cell.

Although therapeutic immunoglobulin G (IgG) antibodies that regulate the activity of immune checkpoints bring innovation to the field of immuno-oncology, they are still limited in their efficiency to infiltrate the tumor microenvironment due to their large molecular size (150 kDa) and the necessity of additional engineering works to ablate effector functions for antibodies targeting immune cells. To address these issues, the human PD-1 (hPD-1) ectodomain, a small protein moiety of 14-17 kDa, has been considered as a therapeutic agent. Here, we used bacterial display-based high-throughput directed evolution to successfully isolate glycan-controlled (aglycosylated or only single-N-linked glycosylated) human PD-1 variants exhibiting over 1000-fold increased hPD-L1 binding affinity compared to that of wild-type hPD-1. The resulting hPD-1 variants, aglycosylated JYQ12 and JYQ12-2 with a single-N-linked glycan chain, showed exceptionally high binding affinity to hPD-L1 and very high affinity to both hPD-L2 and mPD-L1. Moreover, the JYQ12-2 efficiently potentiated the proliferation of human T cells. hPD-1 variants with significantly improved binding affinities for hPD-1 ligands could be used as effective therapeutics or diagnostics that can be differentiated from large-sized IgG antibody-based molecules.

Distinct cerebral cortical perfusion patterns in idiopathic normal-pressure hydrocephalus.

The aims of the study are to evaluate idiopathic normal-pressure hydrocephalus (INPH)-related cerebral blood flow (CBF) abnormalities and to investigate their relation to cortical thickness in INPH patients. We investigated cortical CBF utilizing surface-based early-phase 18 F-florbetaben (E-FBB) PET analysis in two groups: INPH patients and healthy controls. All 39 INPH patients and 20 healthy controls were imaged with MRI, including three-dimensional volumetric images, for automated surface-based cortical thickness analysis across the entire brain. A subgroup with 37 participants (22 INPH patients and 15 healthy controls) that also underwent 18 F-fluorodeoxyglucose (FDG) PET imaging was further analyzed. Compared with age- and gender-matched healthy controls, INPH patients showed statistically significant hyperperfusion in the high convexity of the frontal and parietal cortical regions. Importantly, within the INPH group, increased perfusion correlated with cortical thickening in these regions. Additionally, significant hypoperfusion mainly in the ventrolateral frontal cortex, supramarginal gyrus, and temporal cortical regions was observed in the INPH group relative to the control group. However, this hypoperfusion was not associated with cortical thinning. A subgroup analysis of participants that also underwent FDG PET imaging showed that increased (or decreased) cerebral perfusion was associated with increased (or decreased) glucose metabolism in INPH. A distinctive regional relationship between cerebral cortical perfusion and cortical thickness was shown in INPH patients. Our findings suggest distinct pathophysiologic mechanisms of hyperperfusion and hypoperfusion in INPH patients.

Comparison of Extracorporeal Shock Wave Therapy and Ultrasound-Guided Shoulder Injection Therapy in Patients with Supraspinatus Tendinitis.

Background: The present study compared the clinical effect of extracorporeal shock wave therapy (ESWT) with that of ultrasound (US)-guided shoulder steroid injection therapy in patients with supraspinatus tendinitis. We hypothesized that the two treatments would show comparable results. Methods: The inclusion criteria were age over 20 years and diagnosis of supraspinatus tendinitis using US. Ultimately, 26 patients were assigned using blocked randomization: 13 in the US-guided shoulder injection group and 13 in the ESWT group. Treatment outcomes were evaluated using the pain visual analog scale (pVAS), the American Shoulder and Elbow Society (ASES) score, and the Constant score at baseline and at 1 and 3 months after the procedure. Results: At 1 month after the intervention, pVAS, ASES, and constant score were significantly higher in the US-guided shoulder injection group than in the ESWT group, but not at 3 months after the intervention. Both groups showed clinically significant treatment effects at 3 months after the intervention compared to baseline. No significance was shown using equivalence testing. Conclusions: US-guided shoulder injection therapy was not superior to ESWT therapy. Considering the complications and rebound phenomenon of steroid injections, interventions using ESWT may be a good alternative to treat patients with supraspinatus tendinitis.

Soluble ANPEP Released From Human Astrocytes as a Positive Regulator of Microglial Activation and Neuroinflammation: Brain Renin-Angiotensin System in Astrocyte-Microglia Crosstalk.

Astrocytes are major supportive glia and immune modulators in the brain; they are highly secretory in nature and interact with other cell types via their secreted proteomes. To understand how astrocytes communicate during neuroinflammation, we profiled the secretome of human astrocytes following stimulation with proinflammatory factors. A total of 149 proteins were significantly upregulated in stimulated astrocytes, and a bioinformatics analysis of the astrocyte secretome revealed that the brain renin-angiotensin system (RAS) is an important mechanism of astrocyte communication. We observed that the levels of soluble form of aminopeptidase N (sANPEP), an RAS component that converts angiotensin (Ang) III to Ang IV in a neuroinflammatory milieu, significantly increased in the astrocyte secretome. To elucidate the role of sANPEP and Ang IV in neuroinflammation, we first evaluated the expression of Ang IV receptors in human glial cells because Ang IV mediates biological effects through its receptors. The expression of angiotensin type 1 receptor was considerably upregulated in activated human microglial cells but not in human astrocytes. Moreover, interleukin-1ß release from human microglial cells was synergistically increased by cotreatment with sANPEP and its substrate, Ang III, suggesting the proinflammatory action of Ang IV generated by sANPEP. In a mouse neuroinflammation model, brain microglial activation and proinflammatory cytokine expression levels were increased by intracerebroventricular injection of sANPEP and attenuated by an enzymatic inhibitor and neutralizing antibody against sANPEP. Collectively, our results indicate that astrocytic sANPEP-induced increase in Ang IV exacerbates neuroinflammation by interacting with microglial proinflammatory receptor angiotensin type 1 receptor, highlighting an important role of indirect crosstalk between astrocytes and microglia through the brain RAS in neuroinflammation.

Serum neurofilament light chain levels are correlated with the infarct volume in patients with acute ischemic stroke.

Neurofilament light chains (NfLs) are promising biomarkers of neuroaxonal damage in stroke patients. We investigated the correlations between NfL levels and infarct volume, initial stroke severity, and functional outcomes at discharge in patients with acute ischemic stroke. We prospectively included 15 patients with first-ever acute ischemic stroke and 8 age- and sex-matched healthy controls without other neurological disorders. Serum NfL levels were measured using the single-molecule array (Simoa) technique twice within 24 hours of admission (NfL1D) and on the seventh hospital day (NfL7D) in patients with stroke and once in healthy controls. We assessed the infarct volume on diffusion-weighted magnetic resonance imaging using the free software ITK-SNAP. Serum NfL1D levels in stroke patients were significantly higher (28.4 pg/mL; interquartile range [IQR], 43.0) than in healthy controls (14.5 pg/mL; IQR, 3.2; P = .005). Temporal pattern analyses demonstrated that NfL7D levels were increased (114.0 pg/mL; IQR, 109.6) compared to NfL1D levels in all stroke patients (P = .001). There was a strong correlation between NfL7D levels and infarct volume (R = 0.67, P = .007). The difference between NfL1D and NfL7D (NfLdiff levels) was strongly correlated with the infarct volume (R = 0.63; P = .013). However, there was no statistically significant correlation between NfL levels and the initial stroke severity or functional outcomes at discharge. NfL levels in the subacute stage of stroke and the NfL difference between admission and 7th day of hospital were correlated with infarct volume in patients with acute ischemic stroke.

Interleukin-4 Receptor Targeting Peptide Decorated Extracellular Vesicles as a Platform for In Vivo Drug Delivery to Thyroid Cancer.

Mesenchymal stem cell (MSC)-derived extracellular vesicles (EVs) have been demonstrated to deliver therapeutic drugs in preclinical studies. However, their use is limited, as they lack the ability to specifically deliver drugs to tumor tissues in vivo. In the present study, we propose the use of a targeting peptide, IL-4R-binding peptide (IL4RPep-1), to specifically deliver intravenously (i.v.) infused EVs to thyroid tumors. In vivo, a xenograft tumor model was treated with either the control peptide (NSSSVDK) or IL4RPep-1-Flamma; mice were fluorescently imaged (FLI) using an in vivo imaging system at 0-3 h post-treatment. EVs (labeled with DiD dye) were conjugated with IL4RPep-1 through a DOPE-NHS linker and administered to mice intravenously. FLI was performed 0-24 h post-injection, and the animals were sacrificed for further experiments. The morphology and size of EVs, the presence of EV markers such as CD63 and ALIX, and the absence of the markers GM130 and Cyto-C were confirmed. In vivo, FLI indicated an accumulation of i.v. injected IL4RPep-1-Flamma at the tumor site 90 min post-injection. No accumulation of NSSSVDK-Flamma was detected. In vivo, IL4RPep-1-EVs targeted the Cal-62 tumor 2 h post-injection. NSSSVDK-EVs were not even detected in the tumor 24 h post-injection. The quantification of FLI showed a significant accumulation of MSC-EVs in the tumor 2 h, 3 h, and 24 h post-injection. Furthermore, ex vivo imaging and an IF analysis confirmed the in vivo findings. Our results demonstrate the use of the IL4RPep-1 peptide as a targeting moiety of EVs for IL-4R-expressing anaplastic thyroid tumors.

Distinct volumetric features of cerebrospinal fluid distribution in idiopathic normal-pressure hydrocephalus and Alzheimer's disease.

OBJECTIVE: The aims of the study were to measure the cerebrospinal fluid (CSF) volumes in the lateral ventricle, high-convexity subarachnoid space, and Sylvian fissure region in patients with idiopathic normal-pressure hydrocephalus (INPH) and Alzheimer's disease (AD), and to evaluate differences in these volumes between INPH and AD groups and healthy controls. METHODS: Forty-nine INPH patients, 59 AD patients, and 26 healthy controls were imaged with automated three-dimensional volumetric MRI. RESULTS: INPH patients had larger lateral ventricles and CSF spaces of the Sylvian fissure region and smaller high-convexity subarachnoid spaces than other groups, and AD patients had larger lateral ventricles and CSF spaces of the Sylvian fissure region than the control group. The INPH group showed a negative correlation between lateral ventricle and high-convexity subarachnoid space volumes, while the AD group showed a positive correlation between lateral ventricle volume and volume for CSF spaces of the Sylvian fissure region. The ratio of lateral ventricle to high-convexity subarachnoid space volumes yielded an area under the curve of 0.990, differentiating INPH from AD. CONCLUSIONS: Associations between CSF volumes suggest that there might be different mechanisms between INPH and AD to explain their respective lateral ventricular dilations. The ratio of lateral ventricle to high-convexity subarachnoid space volumes distinguishes INPH from AD with good diagnostic sensitivity and specificity. We propose to refer to this ratio as the VOSS (ventricle over subarachnoid space) index.