Metastatic choroid plexus papilloma presenting as a sellar mass: A case report and literature review.

Background: Choroid plexus papillomas (CPPs) are rare neoplasms arising from choroid plexus epithelium representing <1% of all intracranial tumors. Symptoms vary based on location and regional mass effect; however, hydrocephalus is common due to cerebrospinal fluid flow obstruction and/or overproduction. Distant site metastasis or de novo formation in extraventricular sites is rare. Case Description: A 57-year-old female with a history of a 4th ventricular CPP status post resection in 2004 and 2018 with subsequent gamma knife therapy in 2019 presented with increased thirst and urination. Since her initial surgery, she has experienced significant gait imbalance, diplopia, dysphagia, and right-sided hemiparesis and hemisensory loss. Magnetic resonance imaging revealed a new 1.5 × 1.8 cm suprasellar lesion. She underwent a left supraorbital craniotomy for tumor resection, with pathology revealing metastatic World Health Organization grade II CPP. Conclusion: Extraventricular manifestation of CPP is rare. De novo or metastatic involvement of the sella has seldom been reported. Treatment should target gross total surgical resection. Adjuvant chemotherapy and radiation may be useful in higher-grade lesions.

Machine learning for clinical outcome prediction in cerebrovascular and endovascular neurosurgery: systematic review and meta-analysis.

BACKGROUND: Machine learning (ML) may be superior to traditional methods for clinical outcome prediction. We sought to systematically review the literature on ML for clinical outcome prediction in cerebrovascular and endovascular neurosurgery. METHODS: A comprehensive literature search was performed, and original studies of patients undergoing cerebrovascular surgeries or endovascular procedures that developed a supervised ML model to predict a postoperative outcome or complication were included. RESULTS: A total of 60 studies predicting 71 outcomes were included. Most cohorts were derived from single institutions (66.7%). The studies included stroke (32), subarachnoid hemorrhage ((SAH) 16), unruptured aneurysm (7), arteriovenous malformation (4), and cavernous malformation (1). Random forest was the best performing model in 12 studies (20%) followed by XGBoost (13.3%). Among 42 studies in which the ML model was compared with a standard statistical model, ML was superior in 33 (78.6%). Of 10 studies in which the ML model was compared with a non-ML clinical prediction model, ML was superior in nine (90%). External validation was performed in 10 studies (16.7%). In studies predicting functional outcome after mechanical thrombectomy the pooled area under the receiver operator characteristics curve (AUROC) of the test set performances was 0.84 (95% CI 0.79 to 0.88). For studies predicting outcomes after SAH, the pooled AUROCs for functional outcomes and delayed cerebral ischemia were 0.89 (95% CI 0.76 to 0.95) and 0.90 (95% CI 0.66 to 0.98), respectively. CONCLUSION: ML performs favorably for clinical outcome prediction in cerebrovascular and endovascular neurosurgery. However, multicenter studies with external validation are needed to ensure the generalizability of these findings.

Redefining hyperviscosity in acute leukemia: Potential implications for red cell transfusions in the microvasculature.

Hyperleukocytosis is an emergency of acute leukemia leading to blood hyperviscosity, potentially resulting in life-threatening microvascular obstruction, or leukostasis. Due to the high number of red cells in the circulation, hematocrit/hemoglobin levels (Hct/Hgb) are major drivers of blood viscosity, but how Hct/Hgb mediates hyperviscosity in acute leukemia remains unknown. In vivo hemorheological studies are difficult to conduct and interpret due to issues related to visualizing and manipulating the microvasculature. To that end, a multi-vessel microfluidic device recapitulating the size-scale and geometry of the microvasculature was designed to investigate how Hct/Hgb interacts with acute leukemia to induce "in vitro" leukostasis. Using patient samples and cell lines, the degree of leukostasis was different among leukemia immunophenotypes with respect to white blood cell (WBC) count and Hct/Hgb. Among lymphoid immunophenotypes, severe anemia is protective against in vitro leukostasis and Hct/Hgb thresholds became apparent above which in vitro leukostasis significantly increased, to a greater extent with B-cell acute lymphoblastic leukemia (ALL) versus T-cell ALL. In vitro leukostasis in acute myeloid leukemia was primarily driven by WBC with little interaction with Hct/Hgb. This sets the stage for prospective clinical studies assessing how red cell transfusion may affect leukostasis risk in immunophenotypically different acute leukemia patients.

Disrupted sleep-wake regulation in the MCI-Park mouse model of Parkinson's disease.

Disrupted sleep has a profound adverse impact on lives of Parkinson's disease (PD) patients and their caregivers. Sleep disturbances are exceedingly common in PD, with substantial heterogeneity in type, timing, and severity. Among the most common sleep-related symptoms reported by PD patients are insomnia, excessive daytime sleepiness, and sleep fragmentation, characterized by interruptions and decreased continuity of sleep. Alterations in brain wave activity, as measured on the electroencephalogram (EEG), also occur in PD, with changes in the pattern and relative contributions of different frequency bands of the EEG spectrum to overall EEG activity in different vigilance states consistently observed. The mechanisms underlying these PD-associated sleep-wake abnormalities are poorly understood, and they are ineffectively treated by conventional PD therapies. To help fill this gap in knowledge, a new progressive model of PD - the MCI-Park mouse - was studied. Near the transition to the parkinsonian state, these mice exhibited significantly altered sleep-wake regulation, including increased wakefulness, decreased non-rapid eye movement (NREM) sleep, increased sleep fragmentation, reduced rapid eye movement (REM) sleep, and altered EEG activity patterns. These sleep-wake abnormalities resemble those identified in PD patients. Thus, this model may help elucidate the circuit mechanisms underlying sleep disruption in PD and identify targets for novel therapeutic approaches.

Pseudogout mimicking cervical spine osteomyelitis and ventral epidural abscess: A case report and literature review.

Background: Calcium pyrophosphate deposition disease (CPPD), also known as "pseudogout," is a crystal deposition arthropathy involving the synovial and periarticular tissues. Pseudogout rarely presents in the axial spine. Here, we present the case of an 80-year-old female patient admitted after a mechanical fall, initially misdiagnosed on computed tomography (CT)/magnetic resonance studies with cervical osteodiscitis/ventral epidural abscess that proved to be pseudogout. Case Description: An 80-year-old female was admitted after a mechanical fall. The initial cervical CT scan showed multilevel degenerative changes with an acute C6 anterior wedge compression fracture, focal kyphosis, C5-6 disc space collapse, and endplate destruction. The magnetic resonance imaging showed marked contrast enhancement of the C5-6 vertebral bodies and disc space. An interventional radiology-guided biopsy of the C5-6 vertebral bodies and disc space was consistent with calcium pyrophosphate deposits, was diagnostic for pseudogout, and was negative for infection. She was managed conservatively with a rigid collar and seven days of oral prednisone. Conclusion: CPPD involvement in the axial spine is rare. Prompt pathologic diagnosis should be pursued to rule out an infectious process.

The Influence of Body Mass Index on Outcomes in Patients Undergoing Mechanical Thrombectomy for Anterior Circulation Large Vessel Occlusion: Institutional Experience and Meta-analysis.

BACKGROUND: An obesity paradox, whereby patients with higher body mass index (BMI) experience improved outcomes, has been described for ischemic stroke. It is unclear whether this applies to patients undergoing mechanical thrombectomy (MT) for large vessel occlusion (LVO). METHODS: Mechanical thrombectomies for anterior circulation LVO between 2015 and 2021 at a single institution were reviewed. Multivariable logistic regressions were used to determine the association between BMI and favorable functional outcome (90-day modified Rankin Scale 0-2), intracranial hemorrhage, and malignant middle cerebral infarction. A systematic review was performed to identify studies reporting the effect of BMI on outcomes among patients receiving MT for LVO. The data from the systematic review were combined with the institutional data by using a random effects model. RESULTS: The institutional cohort comprised 390 patients with a median BMI of 27 kg/m2. Most patients were obese [36.7% (BMI ≥ 30 kg/m2)], followed by overweight [30.5% (BMI ≥ 25 and < 30 kg/m2)], normal [27.9% (BMI ≥ 18.5 and < 25 kg/m2)], and underweight [4.9% (BMI < 18.5 kg/m2)]. As a continuous variable, BMI was not associated with any of the outcomes. When analyzing BMI ordinally, obesity was associated with lower odds of favorable 90-day modified Rankin Scale (odds ratio 0.42, 95% confidence interval 0.20-0.86). The systematic review identified three eligible studies comprising 1,348 patients for a total of 1,738 patients. In the random effects model, there was no association between obesity and favorable outcome (odds ratio 0.89, 95% confidence interval 0.63-1.24). CONCLUSIONS: Obesity is not associated with favorable outcomes in patients undergoing MT for LVO.

Rare Sighting of Posterior Communicating Artery Infundibulum With Posterior Cerebral Artery Origin.

Infundibula are funnel-shaped lesions that develop at the intersections of major intracranial arteries. These lesions are prone to being misdiagnosed as intracranial aneurysms. The most common arterial infundibula have been noted in the posterior communicating artery (PCoA) branch of the internal carotid artery (ICA). Digitally subtracted angiography performed included catheter angiography of the vertebral artery and ipsilateral carotid to evaluate the suspected lesion. Right vertebral angiography demonstrated an infundibulum seen at the right PCoA/posterior cerebral artery (PCA) junction, with noted posterior-to-anterior circulation dominance of the Circle of Willis collateral flow. We report a case of posterior communicating artery infundibulum arising from the posterior cerebral artery origin in a 38-year-old man.

Controlling Microparticle Morphology in Melt-Jet Printing of Active Pharmaceutical Ingredients through Surface Phenomena.

Achieving homogeneity and reproducibility in the size, shape, and morphology of active pharmaceutical ingredient (API) particles is crucial for their successful manufacturing and performance. Herein, we describe a new method for API particle engineering using melt-jet printing technology as an alternative to the current solvent-based particle engineering methods. Paracetamol, a widely used API, was melted and jetted as droplets onto various surfaces to solidify and form microparticles. The influence of different surfaces (glass, aluminum, polytetrafluoroethylene, and polyethylene) on particle shape was investigated, revealing a correlation between substrate properties (heat conduction, surface energy, and roughness) and particle sphericity. Higher thermal conductivity, surface roughness, and decreased surface energy contributed to larger contact angles and increased sphericity, reaching a near-perfect micro-spherical shape on an aluminum substrate. The integrity and polymorphic form of the printed particles were confirmed through differential scanning calorimetry and X-ray diffraction. Additionally, high-performance liquid chromatography analysis revealed minimal degradation products. The applicability of the printing process to other APIs was demonstrated by printing carbamazepine and indomethacin on aluminum surfaces, resulting in spherical microparticles. This study emphasizes the potential of melt-jet printing as a promising approach for the precise engineering of pharmaceutical particles, enabling effective control over their physiochemical properties.

Development of constitutively synergistic nanoformulations to enhance chemosensitivity in T-cell leukemia.

Advances in multiagent chemotherapy have led to recent improvements in survival for patients with acute lymphoblastic leukemia (ALL); however, a significant fraction do not respond to frontline chemotherapy or later relapse with recurrent disease, after which long-term survival rates remain low. To develop new, effective treatment options for these patients, we conducted a series of high-throughput combination drug screens to identify chemotherapies that synergize in a lineage-specific manner with MRX-2843, a small molecule dual MERTK and FLT3 kinase inhibitor currently in clinical testing for treatment of relapsed/refractory leukemias and solid tumors. Using experimental and computational approaches, we found that MRX-2843 synergized strongly-and in a ratio-dependent manner-with vincristine to inhibit both B-ALL and T-ALL cell line expansion. Based on these findings, we developed multiagent lipid nanoparticle formulations of these drugs that not only delivered defined drug ratios intracellularly in T-ALL, but also improved anti-leukemia activity following drug encapsulation. Synergistic and additive interactions were recapitulated in primary T-ALL patient samples treated with MRX-2843 and vincristine nanoparticle formulations, suggesting their clinical relevance. Moreover, the nanoparticle formulations reduced disease burden and prolonged survival in an orthotopic murine xenograft model of early thymic precursor T-ALL (ETP-ALL), with both agents contributing to therapeutic activity in a dose-dependent manner. In contrast, nanoparticles containing MRX-2843 alone were ineffective in this model. Thus, MRX-2843 increased the sensitivity of ETP-ALL cells to vincristine in vivo. In this context, the additive particles, containing a higher dose of MRX-2843, provided more effective disease control than the synergistic particles. In contrast, particles containing an even higher, antagonistic ratio of MRX-2843 and vincristine were less effective. Thus, both the drug dose and the ratio-dependent interaction between MRX-2843 and vincristine significantly impacted therapeutic activity in vivo. Together, these findings present a systematic approach to high-throughput combination drug screening and multiagent drug delivery that maximizes the therapeutic potential of combined MRX-2843 and vincristine in T-ALL and describe a novel translational agent that could be used to enhance therapeutic responses to vincristine in patients with T-ALL. This broadly generalizable approach could also be applied to develop other constitutively synergistic combination products for the treatment of cancer and other diseases.

iCLOTS: open-source, artificial intelligence-enabled software for analyses of blood cells in microfluidic and microscopy-based assays.

While microscopy-based cellular assays, including microfluidics, have significantly advanced over the last several decades, there has not been concurrent development of widely-accessible techniques to analyze time-dependent microscopy data incorporating phenomena such as fluid flow and dynamic cell adhesion. As such, experimentalists typically rely on error-prone and time-consuming manual analysis, resulting in lost resolution and missed opportunities for innovative metrics. We present a user-adaptable toolkit packaged into the open-source, standalone Interactive Cellular assay Labeled Observation and Tracking Software (iCLOTS). We benchmark cell adhesion, single-cell tracking, velocity profile, and multiscale microfluidic-centric applications with blood samples, the prototypical biofluid specimen. Moreover, machine learning algorithms characterize previously imperceptible data groupings from numerical outputs. Free to download/use, iCLOTS addresses a need for a field stymied by a lack of analytical tools for innovative, physiologically-relevant assays of any design, democratizing use of well-validated algorithms for all end-user biomedical researchers who would benefit from advanced computational methods.

Illustrative resection of mixed intra- and extramedullary thoracic spinal cord capillary hemangioma.

Background: Capillary hemangiomas are typically superficial benign tumors of the cutaneous and mucosal tissues of the face and neck in pediatric patients. In adults, they typically occur in middle-aged males who present with pain, myelopathy, radiculopathy, paresthesias, and bowel/bladder dysfunction. The optimal treatment for intramedullary spinal cord capillary hemangiomas is gross total/en bloc resection. Methods: Here, we present a 63-year-old male with increasing right greater than left lower extremity numbness/ weakness, attributed to a T8-9 mixed intra- and extramedullary capillary hemangioma. Results: One year following complete lesion resection, the patient used an assistive device to ambulate and continued to improve neurologically. Conclusion: We presented a 63-year-old male whose paraparesis was attributed to a T8-9 mixed intra- and extramedullary capillary hemangioma who did well following total en bloc lesion resection. In addition to this case study/technical note, we provide a 2-D intraoperative video detailing the resection technique.

Comparison of Retroauricular and Reverse Question Mark Incisions for Decompressive Hemicraniectomy.

BACKGROUND: The retroauricular (RA) incision has several theoretical benefits compared with the reverse question mark (RQM) incision for decompressive hemicraniectomy (DHC), but limited data comparing the 2 exist. METHODS: Consecutive patients who underwent DHC between 2016 and 2022 and survived ≥30 days at a single institution were included. The primary outcome was wound complication within 30 days (30dWC) requiring reoperation. Secondary outcomes included 90-day wound complication (90dWC), craniectomy size in anterior-posterior (AP) and superior-inferior dimensions, distance from the inferior craniectomy margin to the middle cranial fossa (MCF), estimated blood loss (EBL), and operative duration. Multivariate analyses were performed for each outcome. RESULTS: A total of 110 patients (RA group: 27, RQM group: 83) were included. The incidence of 30dWC was 1.2% and 0 in the RQM and RA groups, respectively. The incidence of 90dWC was 2.4% and 3.7% in the RQM and RA groups, respectively. There was no difference in mean AP size (RQM: 15 cm, RA: 14.4 cm; P = 0.18), superior-inferior size (RQM: 11.8 cm, RA: 11.9 cm; P = 0.92), and distance from MCF (RQM: 15.4 mm, RA: 18 mm; P = 0.18). Mean EBL (RQM: 418 mL, RA: 314 mL; P = 0.36) and operative duration (RQM: 103 min, RA: 89 min; P = 0.14) were similar. There was no difference in cranioplasty wound complications, EBL, or operative duration. CONCLUSIONS: Wound complications are comparable between the RQM and RA incisions. The RA incision does not compromise craniectomy size or temporal bone removal.

Lithium chloride promotes neural functional recovery after local cerebral ischaemia injury in rats through Wnt signalling pathway activation.

BACKGROUND: Lithium chloride (LiCl) has a significant neuroprotective effect in cerebral ischaemia. However, to date, there is a paucity of evidence on the role of LiCl in neural restoration after brain ischaemia and the signalling pathways involved remain unclear. MATERIALS AND METHODS: Therefore, to address this gap, the middle cerebral artery occlusion (MCAO) rat model was used to simulate human ischaemia stroke. Male Sprague-Dawley rats were given MCAO for 90 min followed by reperfusion, and Dickkopf-1 (DKK1, 5.0 µg/kg) was administered half an hour before MCAO. Rats were then treated with hypodermic injection of LiCl (2.0 mmol/kg) twice a day for 1 week. After treatment, cognitive impairment was assessed by the Morris water maze test. Neurological deficit score, 2,3,5-triphenyl tetrazolium chloride staining, brain water content, and histopathology were used to evaluate brain damage. Enzyme-linked immunosorbent assay was used to measure oxidative stress damage and inflammatory cytokines. Apoptosis of the hippocampal neurons was tested by western blot. The key factors of Wnt signalling pathway in the ischaemic penumbra were detected by immunofluorescence staining and quantitative real-time polymerase chain reaction. RESULTS: Current experimental results showed that LiCl treatment significantly improved the impaired spatial learning and memory ability, suppressed oxidative stress, inflammatory reaction, and neuron apoptosis accompanied by attenuating neuronal damage, which subsequently decreased the brain oedema, infarct volume and neurological deficit. Furthermore, the treatment of LiCl activated Wnt signalling pathway. Interestingly, the aforementioned effects of LiCl treatment were markedly reversed by administration of DKK1, an inhibitor of Wnt signalling pathway. CONCLUSIONS: These results indicate that LiCl exhibits neuroprotective effects in focal cerebral ischaemia by Wnt signalling pathway activation, and it might have latent clinical application for the prevention and treatment of ischaemic stroke.

Pregnancy Outcomes in Women With Moderate-to-Severe Psoriasis From the Psoriasis Longitudinal Assessment and Registry (PSOLAR).

Importance: Prospective data are limited on pregnancy outcomes among women with psoriasis who may be receiving biologic or conventional systemic therapy. Objective: To report pregnancy outcomes observed in the Psoriasis Longitudinal Assessment and Registry (PSOLAR). Design, Setting, and Participants: This cohort study used data from PSOLAR, a multicenter, disease-based, observational registry evaluating long-term safety and clinical outcomes for patients receiving or eligible to receive treatment for psoriasis with biologics and/or conventional systemic therapies. Of 12 090 enrollees, 5456 were women (45.1%), and 2224 women were of childbearing age (18-45 years). Participants had a total of 12 929 patient-years of follow-up (median, 7.2 [range, 3.3-8.0] years per patient). Data were collected from June 20, 2007, to August 23, 2019, and analyzed from April 23 to June 23, 2020. Exposures: Exposure to biologics within the prenatal period (≤1 year before birth or ≤6 months before spontaneous abortion) or at any other time. Main Outcomes and Measures: Descriptive summaries of pregnancies and pregnancy-related outcomes were self-reported in PSOLAR, including births, stillbirths, spontaneous abortions, and elective terminations. Live birth characteristics collected in PSOLAR include whether a birth was full-term (≥37 weeks) or premature (<37 weeks) and whether neonatal adverse events or congenital anomalies occurred. Results: A total of 298 pregnancies occurred among 220 women (mean [SD] age, 27.8 [5.2] years), and the general fertility rate was 18.9 per 1000 women aged 18 to 45 years. Of the 298 pregnancies, 244 (81.9%) resulted in birth, 41 (13.8%) ended in spontaneous abortion, and 13 (4.4%) were electively terminated. Gestational age was available for 243 births; 221 infants (90.9%) were full-term, and 22 (9.1%) were born prematurely. Birth outcomes included 231 healthy newborns, 10 infants with a neonatal problem, 2 infants with a congenital anomaly, and 1 stillbirth. Of the 298 pregnancies, 252 were associated with biologic exposure before or during pregnancy. Pregnancy outcomes for women exposed to biologics were similar to those for women exposed to nonbiologics. Among women who became pregnant, mean (SD) age at the time of pregnancy outcome was 30.9 (4.8) years; at enrollment into the registry, 74 of 219 (33.8%) had obesity, and 121 of 220 (55.0%) were past or current smokers. Conclusions and Relevance: The findings of this cohort study suggest that pregnancy outcomes in PSOLAR have remained consistent with previous reports. Overall and live birth outcomes were similar to those for the general population.

Increased demand for NAD+ relative to ATP drives aerobic glycolysis.

Aerobic glycolysis, or preferential fermentation of glucose-derived pyruvate to lactate despite available oxygen, is associated with proliferation across many organisms and conditions. To better understand that association, we examined the metabolic consequence of activating the pyruvate dehydrogenase complex (PDH) to increase pyruvate oxidation at the expense of fermentation. We find that increasing PDH activity impairs cell proliferation by reducing the NAD+/NADH ratio. This change in NAD+/NADH is caused by increased mitochondrial membrane potential that impairs mitochondrial electron transport and NAD+ regeneration. Uncoupling respiration from ATP synthesis or increasing ATP hydrolysis restores NAD+/NADH homeostasis and proliferation even when glucose oxidation is increased. These data suggest that when demand for NAD+ to support oxidation reactions exceeds the rate of ATP turnover in cells, NAD+ regeneration by mitochondrial respiration becomes constrained, promoting fermentation, despite available oxygen. This argues that cells engage in aerobic glycolysis when the demand for NAD+ is in excess of the demand for ATP.

[Situation analysis of off-label drug use in China].

To introduce current literature reporting situations of the off-label drug use(OLDU) by analyzing relevant literatures published in China, this study comprehensively focused on literatures about OLDU in China in seven Chinese and English databases, then extracted and analyzed the data by different literature types. A total of 667 papers were analyzed. The number of literatures about OLDU data analyzed in hospitals was 325, and the number of clinical studies relating to OLDU was 329, in which case series and case reports were the majority(69.91%). In addition, there were 13 expert consensuses of OLDU and another 56 studies about drug use based on the real-world data characteristics and influencing factors. The number of OLDU data studies has increased year by year. Based on the existing studies, there were more western medicine reports than traditional Chinese medicines, and OLDU types were mainly for over-dosage use. The literatures from OLDU data in hospital were mostly limited to one or several tertiary hospitals in a certain area, and the OLDU types were not uniform. Clinical studies were mainly clinical control trials and case series/reports, but with contradictory reporting results. There were fewer OLDU consensus, and the recommended classification was not uniform. The characteristics and analysis of influencing factors of drug using data in real-world focused on traditional Chinese medicine injections, and the results were not the same. In the future, we shall pay more attention to and strengthen reporting and analysis of OLDU, define study objectives, and unify the content and reporting standards, so as to promote the integrated utilization of OLDU data and reflect real situations in our country.

Full-Spectrum Cannabis Extract Microdepots Support Controlled Release of Multiple Phytocannabinoids for Extended Therapeutic Effect.

The therapeutic effect of the Cannabis plant largely depends on the presence and specific ratio of a spectrum of phytocannabinoids. Although prescription of medicinal Cannabis for various conditions constantly grows, its consumption is mostly limited to oral or respiratory pathways, impeding its duration of action, bioavailability, and efficacy. Herein, a long-acting formulation in the form of melt-printed polymeric microdepots for full-spectrum cannabidiol (CBD)-rich extract administration is described. When injected subcutaneously in mice, the microdepots facilitate sustained release of the encapsulated extract over a two-week period. The prolonged delivery results in elevated serum levels of multiple, major and minor, phytocannabinoids for over 14 days, compared to Cannabis extract injection. A direct analysis of the microdepots retrieved from the injection site gives rise to an empirical model for the release kinetics of the phytocannabinoids as a function of their physical traits. As a proof of concept, we compare the long-term efficacy of a single administration of the microdepots to a single administration of Cannabis extract in a pentylenetetrazol-induced convulsion model. One week following administration, the microdepots reduce the incidence of tonic-clonic seizures by 40%, increase the survival rate by 50%, and the latency to first tonic-clonic seizures by 170%. These results suggest that a long-term full-spectrum Cannabis delivery system may provide new form of Cannabis administration and treatments.

Liver fibrosis and CD206+ macrophage accumulation are suppressed by anti-GM-CSF therapy.

BACKGROUND & AIMS: Chronic liver inflammation leads to fibrosis and cirrhosis and is associated with an accumulation of intrahepatic TNFα-secreting CD206+ macrophages, which may participate in maintaining chronic liver disease in a GM-CSF-dependent manner. We aimed to elucidate the exact role of GM-CSF in the development and progression of chronic liver disease. METHODS: Liver immunohistochemistry and serum quantification were performed in patients with viral and non-viral-related liver disease to compare CD206+ monocyte/macrophages, fibrosis and GM-CSF. This was followed by functional validations in vitro and in vivo in humanised mice. RESULTS: Using multiplex immunofluorescence and histo-cytometry, we show that highly fibrotic livers had a greater density of CD206+ macrophages that produced more TNFα and GM-CSF in the non-tumour liver regions of patients with hepatocellular carcinoma (n = 47), independent of aetiology. In addition, the absolute number of CD206+ macrophages strongly correlated with the absolute number of GM-CSF-producing macrophages. In non-HCC chronic HCV+ patients (n = 40), circulating GM-CSF levels were also increased in proportion to the degree of liver fibrosis and serum viral titres. We then demonstrated in vitro that monocytes converted to TNFα-producing CD206+ macrophage-like cells in response to bacterial products (lipopolysaccharide) in a GM-CSF-dependent manner, confirming the in vivo normalisation of serum GM-CSF concentration following oral antibiotic treatment observed in HBV-infected humanised mice. Finally, anti-GM-CSF neutralising antibody treatment reduced intrahepatic CD206+ macrophage accumulation and abolished liver fibrosis in HBV-infected humanised mice. CONCLUSIONS: While the direct involvement of CD206+ macrophages in liver fibrosis remains to be demonstrated, these findings show that GM-CSF may play a central role in liver fibrosis and could guide the development of anti-GM-CSF antibody-based therapy for the management of patients with chronic liver disease. LAY SUMMARY: Liver fibrosis is a major driver of liver disease progression. Herein, we have shown that granulocyte-macrophage colony-stimulating factor (GM-CSF) plays an important role in the development of liver fibrosis. Our findings support the use of anti-GM-CSF neutralising antibodies for the management of patients with chronic liver disease resulting from both viral and non-viral causes.

Effect of air pollution on hospital admissions for systemic lupus erythematosus in Bengbu, China: a time series study.

Recently, exposure to air pollutants has been associated with the development and progression of systemic lupus erythematosus (SLE). The current study aims to evaluate the effects of air pollutants on SLE hospital admissions in Bengbu, China. We performed distributed lag non-linear model combined with quasi-Poisson generalized linear regression to assess the impacts of air pollutants on SLE admissions from 2015 to 2017. Subgroup analyses by admission status (first admission or readmission) were also evaluated. A total of 546 hospital admissions during 2015-2017 were included. For single-day lag structures, the risk effects occurred from lag 2 to lag 9 for the 75th percentile particulate matter (PM)2.5, lag 3 to lag 9 for the 80th percentile PM2.5. For cumulative lag structures, the risk effects occurred from lag 0-5 to lag 0-14 for both 75th PM2.5 and 80th PM2.5, and no significant effect was observed for 90th PM2.5. In addition, the adverse effects on SLE first admissions occurred from lag 0 to lag 1 for NO2, lag 1 to lag 2 for SO2. The maximum effect of PM2.5 on SLE was 4.27 (95% confidence interval: 1.34-13.59) at lag 0-13 day, the minimum effect value was 1.12 (95% confidence interval: 1.03-1.23) at lag 9 day. These findings demonstrate that high PM2.5, NO2 and SO2 are associated with SLE hospital admissions. In addition, this study further revealed that exposure to high concentration of PM2.5 increased the risk of SLE relapse, while high levels of NO2 and SO2 increased the risk of SLE first admissions.