Targeting TNF/TNFR superfamilies in immune-mediated inflammatory diseases.

Dysregulated signaling from TNF and TNFR proteins is implicated in several immune-mediated inflammatory diseases (IMIDs). This review centers around seven IMIDs (rheumatoid arthritis, systemic lupus erythematosus, Crohn's disease, ulcerative colitis, psoriasis, atopic dermatitis, and asthma) with substantial unmet medical needs and sheds light on the signaling mechanisms, disease relevance, and evolving drug development activities for five TNF/TNFR signaling axes that garner substantial drug development interest in these focus conditions. The review also explores the current landscape of therapeutics, emphasizing the limitations of the approved biologics, and the opportunities presented by small-molecule inhibitors and combination antagonists of TNF/TNFR signaling.

Analgesic Effect of SKI306X on Chronic Postischemic Pain and Spinal Nerve Ligation-Induced Neuropathic Pain in Mice.

Neuropathic pain (NP) results from lesions or diseases affecting the peripheral or central somatosensory system. However, there are currently no drugs that are particularly effective in treating this condition. SKI306X is a blend of purified extracts of three oriental herbs (Clematis mandshurica, Trichosanthes kirilowii, and Prunella vulgaris) commonly used to treat osteoarthritis for their chondroprotective effects. Chronic postischemic pain (CPIP) and spinal nerve ligation (SNL) models were created by binding the upper left ankle of mice with an O-ring for 3 h and ligating the L5 spinal nerve, respectively. Mice with allodynia were injected intraperitoneally with 0.9% normal saline (NS group) or different doses (25, 50, or 100 mg/kg) of SKI306X (SKI groups). We assessed allodynia using von Frey filaments before injection and 30, 60, 90, 120, 180, and 240 min and 24 h after injection to confirm the antiallodynic effect of SKI306X. We also measured glial fibrillary acidic protein (GFAP) levels in the spinal cord and dorsal root ganglia to confirm the change of SKI306X administration. Both models exhibited significant mechanical allodynia. The intraperitoneal injection of SKI306X significantly increased the paw withdrawal threshold in a dose-dependent manner, as the paw withdrawal threshold was significantly increased after SKI306X administration compared with at baseline or after NS administration. GFAP levels in the SKI group decreased significantly (p < 0.05). Intraperitoneal administration of SKI306X dose-dependently attenuated mechanical allodynia and decreased GFAP levels, suggesting that GFAP is involved in the antiallodynic effect of SKI306X in mice with CPIP and SNL-induced NP.

Analysis of Magnetic Resonance Imaging Perfusion Parameters for the Identification of Spinal Metastatic Tumors with Rich Blood Supply.

PURPOSE: To determine the reliability of dynamic magnetic resonance imaging (MRI) perfusion parameters for the evaluation of blood supply to spinal metastatic tumors. METHODS: A total of 36 patients with spinal metastasis who underwent dynamic contrast-enhanced magnetic resonance spinal perfusion imaging at Tianjin Hospital from December 2018 to December 2020 were reviewed. Subsequently, the patients underwent corresponding preoperative examination using digital subtraction angiography of the spine at the hospital and were divided into 2 groups accordingly. Differences in dynamic MRI perfusion parameters between the 2 groups were analyzed. RESULTS: There were statistically significant differences between the 2 groups in the quantitative dynamic contrast-enhanced MRI perfusion parameters vascular permeability and plasma volume, as well as semi-quantitative peak enhancement and blood flow ratio parameters. CONCLUSIONS: Dynamic MRI perfusion may distinguish spinal metastatic lesions with rich blood supply from those with poor blood supply and may help clinicians identify patients that can benefit from invasive spinal angiography and preoperative embolization. This technique may also provide guidance on decision taking for surgery basing on dynamic MRI perfusion parameters.

Ultrasound-guided needle release of A1 pulley combined with corticosteroid injection is more effective than ultrasound-guided needle release alone in the treatment of trigger finger.

BACKGROUND: The purpose of the present study was to evaluate the clinical effectiveness of ultrasonography-guided needle release of A1 pulley combined with corticosteroid injection by comparing it with ultrasound-guided needle release of the A1 pulley alone. METHODS: A total of 49 patients (55 fingers, thumb) with trigger fingers were included in this retrospective study. Twenty-seven fingers were treated with ultrasound-guided needle release of the A1 pulley alone (monotherapy group), and 28 fingers were treated with needle release of the A1 pulley combined with corticosteroid injection (combination group). Visual analog scale (VAS), Froimson scale, postoperative recurrence rate, and thickness of A1 pulley at baseline, Week-2, Week-12, and Month-6 were recorded. RESULTS: Higher clinical cure rates were observed in the combination group at Week-2 after treatment among patients with the Froimson scale Grade III and IV (p < 0.05). Among Froimson scale Grade IV patients, the combination group had a significantly thinner thickness of A1 pulley and better articular pain relief at Week-2 (all p < 0.05). No significant differences were found in the clinical cure rate, the thickness of the A1 pulley, articular pain relief, and recurrence rate between the two groups at Week-12 and Month-6 (all p > 0.05). CONCLUSIONS: Ultrasonography-guided needle release of A1 pulley plus corticosteroid injection was superior to ultrasonography-guided A1 pulley needle release alone during early-stage treatment of severe patients with trigger fingers. Moreover, ultrasonography-guided A1 pulley needle release combined with corticosteroid injection narrows the thickness of the A1 pulley. It is necessary to carry out preoperative evaluation and individualized treatment for patients of various severities.

Remifentanil pretreatment attenuates brain nerve injury in response to cardiopulmonary bypass by blocking AKT/NRF2 signal pathway.

OBJECTIVE: This study aimed to explore the effect and mechanism of remifentanil on cardiopulmonary bypass (CPB)-induced cerebral nerve injury. METHODS: After pretreating with remifentanil, or dexmedetomidine (DEX), SD rats were subjected to the CPB for 2 h. The data of body temperature, blood gas and mean arterial pressure (MAP) and hematocrit (HCT) were recorded at different time points. The cerebral tissue water content of rats was determined and immunohistochemical (IHC) and H&E assays on the hippocampal CA1 region of rats was performed. The levels of interleukin (IL)-6, IL-10, soluble protein-100ß (S100ß) and neuron-specific enolase (NSE) were analyzed by ELISA, and those of the indexes for oxidative stress (malondialdehyde (MDA) and superoxide dismutase (SOD)) were detected by the commercial kits. Morris water maze was used to evaluate the learning and memory abilities. Western blot/qRT-PCR were used to detect the protein/mRNA expressions in hippocampus. RESULTS: CPB increased the levels/expressions of IL-6, IL-10, S100ß, NSE, MDA, cleaved caspase-3, Bax and decreased those of Bcl-2, SOD, p-AKT, HO-1, in serum and parietal cortex tissue, with increased brain water content, lesions in the hippocampal CA1 area, swimming distance, brain nerve injury and decreased escape latency, retention time on platform and times of crossing the platform of rats. The preconditioning of remifentanil or DEX partially attenuated CPB-induced injury and -decreased expressions on p-AKT and HO-1, while further promoting CPB-induced expression of nuclear Nrf2 expression and inhibiting that of cytoplasm Nrf2. CONCLUSION: This paper demonstrates that remifentanil preconditioning could partially attenuate CPB-induced brain nerve injury of rats.

Effect of Pregabalin Combined with Duloxetine and Tramadol on Allodynia in Chronic Postischemic Pain and Spinal Nerve Ligation Mouse Models.

Although there are various drugs for Neuropathic pain (NP), the effects of single drugs are often not very satisfactory. The analgesic effects of different combinations of pregabalin, duloxetine, and tramadol or the combination of all three are still unclear. Mixtures of two or three drugs at low and high concentrations (7.5, 10, 15, and 20 mg/kg pregabalin; 7.5, 10, 15, and 30 mg/kg duloxetine; 5 and 10 mg/kg tramadol) were administered to chronic postischemic pain (CPIP) and spinal nerve ligation (SNL) model mice. The effects of these combinations of drugs on mechanical allodynia were investigated. The expression of the glial fibrillary acidic protein (GFAP) in the spinal cord and dorsal root ganglia (DRGs) was measured. The combination of pregabalin, duloxetine, and tramadol significantly alleviated mechanical hyperalgesia in mice with CPIP and SNL. After the administration of this drug combination, the expression of GFAP in the spinal cord and DRGs was lower in the CPIP and SNL model mice than in control mice. This result suggests that the combination of these three drugs may be advantageous for the treatment of NP because it can reduce side effects by preventing the overuse of a single drug class and exert increased analgesic effects via synergism.

Survival outcomes and prognostic factors of patients with salvage surgery for hypopharyngeal carcinoma after radiotherapy / 中华耳鼻咽喉头颈外科杂志

Objective: To investigate the survival outcomes and prognostic factors of patients with salvage surgery for hypopharyngeal carcinoma after radiotherapy. Methods: A retrospective analysis was performed, including 26 patients treated in Ningbo Medical Center Lihuili Hospital between January 2010 and December 2015. All patients were males, aged 48-83 years, of whom 8 cases were local residual after radiotherapy alone, 8 cases were local recurrence after postoperative radiotherapy, 2 cases were residual of cervical lymph nodes after radiotherapy alone, 2 cases were recurrence of cervical lymph nodes after radiotherapy alone, 2 cases were recurrence of cervical lymph nodes after postoperative radiotherapy and 4 cases were recurrence of tracheal stoma. The salvage operations included: local resection, local resection with neck dissection, simple neck dissection, tumor resection of tracheostomy, and additional repair according to the defect. Chi square test was used for recurrence and metastasis analysis, Kaplan-Meier method for survival analysis, Log-rank test for univariate analysis, and Cox regression model for multivariate analysis. Results: The complication rate of salvage surgery was 23.1% (6/26). The recurrence rate was 65.4% (17/26) and the distant metastasis rate was 42.3% (11/26) in the 5-year follow-up after salvage surgery. Patient's age and tumor invasion extent were correlated with recurrence. Initial treatment, tumor persistence or recurrence after radiotherapy, recurrence location and tumor invasion extent were correlated with distant metastasis (all P<0.05). Overall, 3 year and 5 year survival rates were 42.3% and 23.1% respectively. Age, recurrence location, surgical margin and tumor invasion extent were related to prognosis (χ²=6.56, 10.68, 9.32, and 7.90 respectively, all P<0.05). Multivariate analysis showed that surgical margin and tumor invasion extent were independent risk factors for prognosis (OR (95%CI) = 3.19 (1.03-9.84), 14.37 (2.46-84.08), both P<0.05). Conclusion: Salvage surgery is the first choice for patients with recurrence after radiotherapy for hypopharyngeal carcinoma. Safe surgical margin should be ensured, especially in tumors invading muscle, bone tissue or lymph node capsule.

Antitumor Necrosis Factor-like Ligand 1A Therapy Targets Tissue Inflammation and Fibrosis Pathways and Reduces Gut Pathobionts in Ulcerative Colitis.

BACKGROUND: The first-in-class treatment PF-06480605 targets the tumor necrosis factor-like ligand 1A (TL1A) molecule in humans. Results from the phase 2a TUSCANY trial highlighted the safety and efficacy of PF-06480605 in ulcerative colitis. Preclinical and in vitro models have identified a role for TL1A in both innate and adaptive immune responses, but the mechanisms underlying the efficacy of anti-TL1A treatment in inflammatory bowel disease (IBD) are not known. METHODS: Here, we provide analysis of tissue transcriptomic, peripheral blood proteomic, and fecal metagenomic data from the recently completed phase 2a TUSCANY trial and demonstrate endoscopic improvement post-treatment with PF-06480605 in participants with ulcerative colitis. RESULTS: Our results revealed robust TL1A target engagement in colonic tissue and a distinct colonic transcriptional response reflecting a reduction in inflammatory T helper 17 cell, macrophage, and fibrosis pathways in patients with endoscopic improvement. Proteomic analysis of peripheral blood revealed a corresponding decrease in inflammatory T-cell cytokines. Finally, microbiome analysis showed significant changes in IBD-associated pathobionts, Streptococcus salivarius, S. parasanguinis, and Haemophilus parainfluenzae post-therapy. CONCLUSIONS: The ability of PF-06480605 to engage and inhibit colonic TL1A, targeting inflammatory T cell and fibrosis pathways, provides the first-in-human mechanistic data to guide anti-TL1A therapy for the treatment of IBD.

Cell type-specific genetic regulation of gene expression across human tissues.

The Genotype-Tissue Expression (GTEx) project has identified expression and splicing quantitative trait loci in cis (QTLs) for the majority of genes across a wide range of human tissues. However, the functional characterization of these QTLs has been limited by the heterogeneous cellular composition of GTEx tissue samples. We mapped interactions between computational estimates of cell type abundance and genotype to identify cell type-interaction QTLs for seven cell types and show that cell type-interaction expression QTLs (eQTLs) provide finer resolution to tissue specificity than bulk tissue cis-eQTLs. Analyses of genetic associations with 87 complex traits show a contribution from cell type-interaction QTLs and enables the discovery of hundreds of previously unidentified colocalized loci that are masked in bulk tissue.

Comparison of the clinical effectiveness of ultrasound-guided corticosteroid injection with and without needle release of the A1 pulley in treating trigger finger.

OBJECTIVE: To compare the clinical effectiveness of ultrasound-guided corticosteroid injection with and without needle release of the A1 pulley in treating trigger finger. METHODS: A total of 60 patients with trigger finger were enrolled in this retrospective study. Among them, 30 patients were treated with ultrasound-guided needle release of the A1 pulley with corticosteroid injection (group A) and 30 patients were treated with single ultrasound-guided corticosteroids injection (group B). The following parameters were evaluated including clinical parameters (pain degree, function of joint, finger tendon function, postoperative satisfaction), and ultrasound parameter (thickness of A1 pulley). RESULTS: The postoperative visual analogue scale (VAS) and Quinnell scores in two groups were significantly lower than that before operation (p < 0.05). The postoperative Quinnell score of group A was significantly lower than that in group B (p < 0.05). The TAM results showed that the postoperative overall excellent and good rate of group A was significantly higher than that in group B (p < 0.05). The postoperative survey showed that more than 80% patients reported satisfaction in the two groups. The ultrasound imaging results showed that the postoperative thickness of A1 pulley in two groups were thinner than that before operation (p < 0.05). There were no adverse effects and complications in the two groups. CONCLUSIONS: Both approaches had treatment benefit in trigger finger. Ultrasound-guided needle release of the A1 pulley with corticosteroid injection had better treatment benefits than single ultrasound-guided corticosteroids injection in improving finger tendon function and joint function.

3'Pool-seq: an optimized cost-efficient and scalable method of whole-transcriptome gene expression profiling.

BACKGROUND: The advent of Next Generation Sequencing has allowed transcriptomes to be profiled with unprecedented accuracy, but the high costs of full-length mRNA sequencing have posed a limit on the accessibility and scalability of the technology. To address this, we developed 3'Pool-seq: a simple, cost-effective, and scalable RNA-seq method that focuses sequencing to the 3'-end of mRNA. We drew from aspects of SMART-seq, Drop-seq, and TruSeq to implement an easy workflow, and optimized parameters such as input RNA concentrations, tagmentation conditions, and read depth specifically for bulk-RNA. RESULTS: Thorough optimization resulted in a protocol that takes less than 12 h to perform, does not require custom sequencing primers or instrumentation, and cuts over 90% of the costs associated with TruSeq, while still achieving accurate gene expression quantification (Pearson's correlation coefficient with ERCC theoretical concentration r = 0.96) and differential gene detection (ROC analysis of 3'Pool-seq compared to TruSeq AUC = 0.921). The 3'Pool-seq dual indexing scheme was further adapted for a 96-well plate format, and ERCC spike-ins were used to correct for potential row or column pooling effects. Transcriptional profiling of troglitazone and pioglitazone treatments at multiple doses and time points in HepG2 cells was then used to show how 3'Pool-seq could distinguish the two molecules based on their molecular signatures. CONCLUSIONS: 3'Pool-seq can accurately detect gene expression at a level that is on par with TruSeq, at one tenth of the total cost. Furthermore, its unprecedented TruSeq/Nextera hybrid indexing scheme and streamlined workflow can be applied in several different formats, including 96-well plates, which allows users to thoroughly evaluate biological systems under several conditions and timepoints. Care must be taken regarding experimental design and plate layout such that potential pooling effects can be accounted for and corrected. Lastly, further studies using multiple sets of ERCC spike-ins may be used to simulate differential gene expression in a system with known ground-state values.

Dexmedetomidine Exerts Brain-Protective Effects Under Cardiopulmonary Bypass Through Inhibiting the Janus Kinase 2/Signal Transducers and Activators of Transcription 3 Pathway.

Brain injury is a major complication resulted from cardiopulmonary bypass (CPB). Dexmedetomidine (DEX) has potential brain-protective effects; however, the mechanism is unclear. The aim of this study is to investigate the effect of DEX on brain injury in CPB rats and its mechanism. The levels of interleukin-6 (IL-6), interleukin-10 (IL-10), S100ß, and neuron-specific enolase (NSE) were measured by enzyme-linked immunosorbent assay. The hippocampus CA1 region in rats was observed by hematoxylin-eosin staining. Western blot and quantitative real-time polymerase chain reaction were performed to detect related proteins and mRNA expressions in the hippocampus tissues. We found that after CPB, the neuron cells in hippocampus CA1 region of rats were randomly arranged, and that the levels of IL-6, IL-10, S100ß, NSE, Cleaved Caspase-3, and Bax were upregulated, while Bal-2 level was downregulated. However, after DEX treatment, the neuron cells arranged in an orderly manner, and the levels of IL-6, IL-10, S100ß, NSE, Cleaved Caspase-3, and Bax were downregulated, but Bal-2 level was upregulated. DEX suppressed Janus kinase 2 (JAK2)/signal transducers and activators of transcription 3 (STAT3) pathway activated by CPB, ameliorated CPB-induced brain injury in rats by reducing inflammatory response, and inhibited neuronal apoptosis. The brain-protective effect of DEX may be related to the inhibition of the activation of JAK2/STAT3 pathway.

Feasibility and Reliability of an Ultrasound Examination to Diagnose Piriformis Syndrome.

OBJECTIVE: We explored the diagnostic performance of ultrasound examinations in the diagnosis of piriformis syndrome (PS). METHODS: In our single-center retrospective study, 52 patients with a diagnosis of PS and 50 healthy volunteers were enrolled to undergo ultrasound examination of the piriformis and sciatic nerve. The thicknesses of the piriformis and the diameter of the sciatic nerve were measured to compare the differences between the patients with PS and healthy volunteers. The diagnostic performance of ultrasound examinations was assessed by constructing a receiver operating characteristic curve and calculating the area under the curve. RESULTS: In patients with PS, the piriformis and sciatic nerve were enlarged on the abnormal side compared with the asymptomatic side, accompanied by a decreased echo intensity and an unclear perineurium. In addition, the piriformis thickness and sciatic nerve diameter of those with PS were significantly greater than were those of the healthy volunteers. The diagnostic performance of ultrasonography was significant. The area under the receiver operating characteristic curve for piriformis thickness and sciatic nerve diameter to discriminate between the abnormal and asymptomatic sides was 0.778 and 0.871, respectively. CONCLUSION: Ultrasound examinations can assist in the clinical diagnosis of PS and have the potential to be an alternative method for the diagnosis of PS for most musculoskeletal clinicians.

Genetic and Real-World Clinical Data, Combined with Empirical Validation, Nominate Jak-Stat Signaling as a Target for Alzheimer's Disease Therapeutic Development.

As genome-wide association studies (GWAS) have grown in size, the number of genetic variants that have been associated per disease has correspondingly increased. Despite this increase in the number of single-nucleotide polymorphisms (SNPs) identified per disease, their biological interpretation has in many cases remained elusive. To address this, we have combined GWAS results with orthogonal sources of evidence, namely the current knowledge of molecular pathways; real-world clinical data from six million patients; RNA expression across tissues from Alzheimer's disease (AD) patients, and purpose-built rodent models for experimental validation. In more detail, first we show that when examined at a pathway level, analysis of all GWAS studies groups AD in a cluster with disorders of immunity and inflammation. Using clinical data, we show that the degree of comorbidity of these diseases with AD correlates with the strength of their genetic association with molecular participants in the Janus kinases/signal transducer and activator of transcription (JAK-STAT) pathway. Using four independent RNA expression datasets we then find evidence for the altered regulation of JAK-STAT pathway genes in AD. Finally, we use both in vitro and in vivo rodent models to demonstrate that Aß induces gene expression of the key drivers of this pathway, providing experimental evidence to validate these data-driven observations. These results therefore nominate JAK-STAT anomalies as a prominent aetiopathological event in AD and hence a potential target for therapeutic development, and moreover demonstrate a de novo multi-modal approach to derive information from rapidly increasing genomic datasets.

Human MxB Inhibits the Replication of Hepatitis C Virus.

Type I interferon (IFN) inhibits viruses by inducing the expression of antiviral proteins. The IFN-induced myxovirus resistance B (MxB) protein has been reported to inhibit a limited number of viruses, including HIV-1 and herpesviruses, but its antiviral coverage remains to be explored further. Here we show that MxB interferes with RNA replication of hepatitis C virus (HCV) and significantly inhibits viral replication in a cyclophilin A (CypA)-dependent manner. Our data further show that MxB interacts with the HCV protein NS5A, thereby impairing NS5A interaction with CypA and NS5A localization to the endoplasmic reticulum, two events essential for HCV RNA replication. Interestingly, we found that MxB significantly inhibits two additional CypA-dependent viruses of the Flaviviridae family, namely, Japanese encephalitis virus and dengue virus, suggesting a potential link between virus dependence on CypA and virus susceptibility to MxB inhibition. Collectively, these data have identified MxB as a key factor behind IFN-mediated suppression of HCV infection, and they suggest that other CypA-dependent viruses may also be subjected to MxB restriction.IMPORTANCE Viruses of the Flaviviridae family cause major illness and death around the world and thus pose a great threat to human health. Here we show that IFN-inducible MxB restricts several members of the Flaviviridae, including HCV, Japanese encephalitis virus, and dengue virus. This finding not only suggests an active role of MxB in combating these major pathogenic human viruses but also significantly expands the antiviral spectrum of MxB. Our study further strengthens the link between virus dependence on CypA and susceptibility to MxB restriction and also suggests that MxB may employ a common mechanism to inhibit different viruses. Elucidating the antiviral functions of MxB advances our understanding of IFN-mediated host antiviral defense and may open new avenues to the development of novel antiviral therapeutics.

Developmental and genetic regulation of the human cortex transcriptome illuminate schizophrenia pathogenesis.

Genome-wide association studies have identified 108 schizophrenia risk loci, but biological mechanisms for individual loci are largely unknown. Using developmental, genetic and illness-based RNA sequencing expression analysis in human brain, we characterized the human brain transcriptome around these loci and found enrichment for developmentally regulated genes with novel examples of shifting isoform usage across pre- and postnatal life. We found widespread expression quantitative trait loci (eQTLs), including many with transcript specificity and previously unannotated sequence that were independently replicated. We leveraged this general eQTL database to show that 48.1% of risk variants for schizophrenia associate with nearby expression. We lastly found 237 genes significantly differentially expressed between patients and controls, which replicated in an independent dataset, implicated synaptic processes, and were strongly regulated in early development. These findings together offer genetics- and diagnosis-related targets for better modeling of schizophrenia risk. This resource is publicly available at http://eqtl.brainseq.org/phase1 .

Using an atlas of gene regulation across 44 human tissues to inform complex disease- and trait-associated variation.

We apply integrative approaches to expression quantitative loci (eQTLs) from 44 tissues from the Genotype-Tissue Expression project and genome-wide association study data. About 60% of known trait-associated loci are in linkage disequilibrium with a cis-eQTL, over half of which were not found in previous large-scale whole blood studies. Applying polygenic analyses to metabolic, cardiovascular, anthropometric, autoimmune, and neurodegenerative traits, we find that eQTLs are significantly enriched for trait associations in relevant pathogenic tissues and explain a substantial proportion of the heritability (40-80%). For most traits, tissue-shared eQTLs underlie a greater proportion of trait associations, although tissue-specific eQTLs have a greater contribution to some traits, such as blood pressure. By integrating information from biological pathways with eQTL target genes and applying a gene-based approach, we validate previously implicated causal genes and pathways, and propose new variant and gene associations for several complex traits, which we replicate in the UK BioBank and BioVU.

Inhibition of 2-AG hydrolysis differentially regulates blood brain barrier permeability after injury.

BACKGROUND: Acute neurological insults caused by infection, systemic inflammation, ischemia, or traumatic injury are often associated with breakdown of the blood-brain barrier (BBB) followed by infiltration of peripheral immune cells, cytotoxic proteins, and water. BBB breakdown and extravasation of these peripheral components into the brain parenchyma result in inflammation, oxidative stress, edema, excitotoxicity, and neurodegeneration. These downstream consequences of BBB dysfunction can drive pathophysiological processes and play a substantial role in the morbidity and mortality of acute and chronic neurological insults, and contribute to long-term sequelae. Preserving or rescuing BBB integrity and homeostasis therefore represents a translational research area of high therapeutic potential. METHODS: Induction of general and localized BBB disruption in mice was carried out using systemic administration of LPS and focal photothrombotic ischemic insult, respectively, in the presence and absence of the monoacylglycerol lipase (MAGL) inhibitor, CPD-4645. The effects of CPD-4645 treatment were assessed by gene expression analysis performed on neurovascular-enriched brain fractions, cytokine and inflammatory mediator measurement, and functional assessment of BBB permeability. The mechanism of action of CPD-4645 was studied pharmacologically using inverse agonists/antagonists of the cannabinoid receptors CB1 and CB2. RESULTS: Here, we demonstrate that the neurovasculature exhibits a unique transcriptional signature following inflammatory insults, and pharmacological inhibition of MAGL using a newly characterized inhibitor rescues the transcriptional profile of brain vasculature and restores its functional homeostasis. This pronounced effect of MAGL inhibition on blood-brain barrier permeability is evident following both systemic inflammatory and localized ischemic insults. Mechanistically, the protective effects of the MAGL inhibitor are partially mediated by cannabinoid receptor signaling in the ischemic brain insult. CONCLUSIONS: Our results support considering MAGL inhibitors as potential therapeutics for BBB dysfunction and cerebral edema associated with inflammatory brain insults.

Ultrasound-guided needle release of the transverse carpal ligament with and without corticosteroid injection for the treatment of carpal tunnel syndrome.

BACKGROUND: To compare the clinical effectiveness of ultrasound-guided needle release of the transverse carpal ligament (TCL) with and without corticosteroid injection in carpal tunnel syndrome (CTS). METHODS: From June 2016 to June 2017, 49 CTS patients (50 wrists) were included in this study. Twenty-five wrists were treated with ultrasound-guided needle release of the TCL plus corticosteroid injection (group A), and 25 wrists were treated with single ultrasound-guided needle release of the TCL (group B). The following parameters were assessed and compared including postprocedure results according to relief of symptoms, ultrasound parameters (cross-sectional area of the median nerve at the levels of pisiform, flattening ratio of median nerve at the levels of the hamate bone, and the thicknesses of TCL on the cross-section at the level of the hamate bone), and electrophysiological parameters (distal motor latency and sensory conduction velocity). RESULTS: Group A had higher overall excellent and good rate 3 months after the procedure than group B (84 vs 52%, P < 0.05). There were significant differences regarding the above ultrasonic and electrophysiological parameters between the baseline and postprocedure values in both groups (all P < 0.05). There were significant differences regarding the postprocedure values of above ultrasonic and electrophysiological parameters between the two groups (all P < 0.05). No complications such as infection or tendon rupture were noted. No procedures were converted to the open release. CONCLUSIONS: Both techniques are effective in treating CTS. Ultrasound-guided needle release of the TCL with corticosteroid injection had better treatment benefits than single ultrasound-guided needle release of the TCL in treating CTS.

A New Algorithm for Crossing Chronic Total Occlusions From the Asia Pacific Chronic Total Occlusion Club.

Although the hybrid chronic total occlusion (CTO) algorithm had many excellent recommendations, there has been infrequent adoption in the Asia Pacific region. The Asia Pacific CTO club propose an algorithm for case selection based on the Japan-CTO score and a new CTO algorithm, which is applicable globally. This algorithm allows for differing skill sets and equipment availability and contains practical teaching for CTO percutaneous coronary intervention. Similar to the hybrid algorithm there are 3 main questions that determine whether the primary approach is antegrade or retrograde: 1) is there proximal cap ambiguity; 2) is the distal vessel of poor quality; and 3) are there interventional collaterals present. In contrast to the hybrid algorithm occlusion length alone does not determine the choice of either a wire escalation strategy or a dissection re-entry strategy. Rather a combination of factors including ambiguity of the vessel course, severe calcification, tortuosity, length, and previous failure are used to determine this. The role of intravascular ultrasound-guided entry to overcome proximal cap ambiguity and the CrossBoss catheter in occlusive in-stent restenosis are highlighted in the algorithm. Both the parallel wire technique and dissection re-entry with the Stingray system have been included as options when the initial antegrade wire passage fails. Intravascular ultrasound-guided wiring along with limited subintimal tracking and re-entry are included as final options in the algorithm. Finally, the algorithm incorporates guidance on when to stop the procedure. It is hoped that this algorithm will serve as the basis for future CTO percutaneous coronary intervention proctoring and training.