A combined analysis of two prospective randomised studies exploring the impact of extended post-radiation temozolomide on survival outcomes in newly diagnosed glioblastoma.

PURPOSE: The optimal duration of post-radiation temozolomide in newly diagnosed glioblastoma remains unclear, with no published phase III randomised trials. Standard-of-care stipulates 6 months. However, in routine care, it is often extended to 12 months, despite lacking robust supporting data. METHODS: GEINO14-01 (Spain) and EX-TEM (Australia) studies enrolled glioblastoma patients without progression at the end of 6 months post-radiation temozolomide. Participants were randomised 1:1 to six additional months of temozolomide or observation. Primary endpoint was 6-month progression free survival from date of randomisation (6mPFS). Secondary endpoints included overall survival (OS) and toxicity. 204 patients were required to detect an improvement in 6mPFS from 50 to 60% (80% power). Neither study recruited sufficient patients. We performed a combined analysis of individual patient data. RESULTS: 205 patients were recruited: 159 in GEINO14-01 (2014-2018) and 46 in EX-TEM (2019-2022). Median follow-up was 20.0 and 14.5 months. Baseline characteristics were balanced. There was no significant improvement in 6mPFS (57.2% vs 64.0%, OR0.75, p = 0.4), nor across any subgroups, including MGMT methylated; PFS (HR0.92, p = 0.59, median 7.8 vs 9.7 months); or OS (HR1.03, p = 0.87, median 20.1 vs 19.4 months). During treatment extension, 64% experienced any grade adverse event, mainly fatigue and gastrointestinal (both 54%). Only a minority required treatment changes: 4.5% dose delay, 7.5% dose reduction, 1.5% temozolomide discontinuation. CONCLUSION: For glioblastoma patients, extending post-radiation temozolomide from 6 to 12 months is well tolerated but does not improve 6mPFS. We could not identify any subset that benefitted from extended treatment. Six months should remain standard-of-care.

Study of the optic nerve in patients with type 2 diabetic retinopathy by shear-wave elastography.

AIM: To investigate the clinical value of two-dimensional shear-wave elastography (2D-SWE) in detecting optic nerve elasticity and in-frame adipose tissue elasticity in patients with type 2 diabetic retinopathy (DR). MATERIALS AND METHODS: 2D-SWE was used to detect SWE values of the optic nerve and adipose tissue in adjacent optic nerve frames in 30 healthy participants, 30 patients with diabetic non-retinopathy (NDR), 35 patients with non-proliferative diabetic retinopathy (NPDR), and 30 patients with proliferative diabetic retinopathy (PDR). The correlation between SWE values and blood glucose, blood lipid, age, body mass index (BMI) was analysed. Receiver operating characteristic (ROC) curve analysis was performed for SWE values. RESULTS: The SWE values of the optic nerve and in-frame adipose tissue increased with the progression of DR, and analysis of variance was compared with groups: the SWE values of the optic nerve and in-frame adipose tissue in each group were significantly different (all p<0.001). The SWE values of the optic nerve and in-frame adipose tissue correlated positively with BMI, age, triglyceride, and fasting blood glucose, and correlated negatively with high-density lipoprotein. The SWE values of the optic nerve and in-frame adipose tissue had higher diagnostic efficacy. The combination of the two had higher diagnostic accuracy. CONCLUSION: The elastic modulus of optic nerve and in-frame adipose tissue can effectively predict and grade of DR, that is, 2D-SWE can be used as a non-invasive imaging diagnostic method for DR. The combined diagnostic efficacy of optic nerve SWE value and in-frame adipose tissue SWE value is significantly better than that of single use. This study found that increased BMI, age, triglyceride, and fasting blood glucose, and decreased high-density lipoprotein are risk factors for DR.

IL-37 alleviates intervertebral disc degeneration via the IL-1R8/NF-κB pathway.

OBJECTIVE: Intervertebral disc degeneration (IDD) has been reported to be a major cause of low back pain (LBP). Interleukin (IL)-37 is an anti-inflammatory cytokine of the interleukin-1 family, which exerts salutary physiological effects. In this study, we assessed the protective effect of IL-37 on IDD progression and its underlying mechanisms. METHODS: Immunofluorescence (IF) was conducted to measure IL-37 expression in nucleus pulposus tissues. CCK-8 assay and Edu staining were used to examine the vitality of IL-37-treated nucleus pulposus cells (NPCs). Western blot, qPCR, ELISA as well as immunohistochemistry were used to assess senescence associated secreted phenotype (SASP) factors expression; and NF-κB pathway was evaluated by western blot and IF; while IL-1R8 knock-down by siRNAs was performed to ascertain its significance in the senescence phenotype modulated by IL-37. The therapeutic effect of IL-37 on IDD were evaluated in puncture-induced rat model using X-ray, Hematoxylin-Eosin, Safranin O-Fast Green (SO), and alcian blue staining. RESULTS: We found IL-37 expression decreased in the IDD process. In vitro, IL-37 suppressed SASP factors level and senescence phenotype in IL-1ß treated NPCs. In vivo, IL-37 alleviated the IDD progression in the puncture-induced rat model. Mechanistic studies demonstrated that IL-37 inhibited IDD progression by downregulating NF-κB pathway activation in NPCs by activating IL-1R8. CONCLUSION: The present study suggests that IL-37 delays the IDD development through the IL-1R8/NF-κB pathway, which suggests IL-37 as a promising novel target for IDD therapy.

Effects of oleanolic acid on acute liver injury triggered by lipopolysaccharide in broiler chickens.

1. Infectious injury caused by lipopolysaccharide (LPS), a metabolite of gram-negative bacteria, can induce stress responses in animals and is a significant cause of morbidity and mortality in young birds. The purpose of this study was to investigate the effects of dietary supplementation with oleanolic acid (OA) on acute liver injury in broiler chickens challenged with LPS.2. In total, 120 broiler chickens were randomly divided into six groups and fed a basal diet containing 0, 50, 100, or 200 mg/kg OA or 100 mg/kg aureomycin. On d 15, broiler chickens were injected with either LPS or an equivalent volume of normal saline. Six hours after LPS injection, two broiler chicks were randomly selected for sampling in each replicate.3. The results indicated that dietary aureomycin was ineffective in alleviating LSP-associated liver injury, but protected broiler chickens from LPS-induced liver damage. This promoted a significant reduction in the levels of malondialdehyde and an increase in the levels of superoxide dismutase in liver. In addition, OA was found to cause significant reductions in the relative expression of IL-1ß, IL-6, and TNF-α in broiler liver tissues, whereas the relative expression of IL-10 was significantly increased.4. In conclusion, oleanolic acid can alleviate oxidative stress and injury in the livers of broiler chickens induced by lipopolysaccharide. Consequently, oleanolic acid has potential utility as a novel anti-inflammatory and antioxidant feed additive.

Acyl-CoA thioesterase 9 promotes tumour growth and metastasis through reprogramming of fatty acid metabolism in hepatocellular carcinoma.

Acyl-CoA thioesterase 9 (ACOT9) is a critical regulator of cellular utilization of fatty acids by catalysing the hydrolysis of acyl-CoA thioesters to non-esterified fatty acid and coenzyme A (CoA). Recently, ACOT9 was reported to participate in the pathogenesis of non-alcoholic liver disease (NAFLD), which arises from aberrant lipid metabolism and serves as a risk factor for hepatocellular carcinoma (HCC). However, the functions of ACOT9 in carcinogenesis and aberrant lipid metabolism in HCC remain unexplored. Here, we found that ACOT9 expression is significantly elevated in HCC at least partially due to the down-regulation of miR-449c-3p. Upregulation of ACOT9 is closely associated with poor prognosis for patients with HCC. Knockdown of ACOT9 expression in HCC cells significantly decreased cell proliferation, colony formation, migration and invasion, mainly through suppression of G1-to-S cell cycle transition and epithelial-to-mesenchymal transition (EMT). By contrast, forced ACOT9 expression promoted HCC growth and metastasis. In addition, we found that ACOT9 reprogrammed lipid metabolism in HCC cells by increasing de novo lipogenesis. Furthermore, we demonstrated that increased lipogenesis was involved in ACOT9-promoted HCC growth and metastasis. Altogether, we demonstrate that ACOT9 plays a critical oncogenic role in the promotion of tumour growth and metastasis by reprogramming lipid metabolism in HCC, indicating ACOT9 as a potential therapeutic target in treatment of HCC.

Surfactant Protein-A Protects against IL-13-Induced Inflammation in Asthma.

The lung surfactant proteins are recognized as critical not only for their role in lowering lung surface tension but also in innate host defense. Reports have shown that some asthmatic patients have decreased levels of one member of this protein family in particular, surfactant protein-A (SP-A). Our studies set out to determine the contribution of SP-A to the response of a key effector cytokine in asthma, IL-13. Our studies employ both animal models sufficient and deficient in SP-A challenged with IL-13 and primary epithelial cells from participants with asthma that are exogenously treated with SP-A in the context of IL-13 challenge. The inflammatory response and mucin production were assessed in both model systems. As compared with WT mice, we show that the activity of IL-13 is dramatically augmented in SP-A-/- mice, which have significantly increased neutrophil and eosinophil recruitment, mucin production and asthma-associated cytokines in the bronchoalveolar lavage fluid. In parallel, we show asthma-associated factors are attenuated in human cells from asthma subjects when exogenous SP-A is added during IL-13 challenge. Although many of these phenotypes have previously been associated with STAT6 signaling, SP-A inhibited IL-13-induced STAT3 phosphorylation in mice and in human epithelial cells while having little effect on STAT6 phosphorylation. In addition, when either STAT3 or IL-6 were inhibited in mice, the phenotypes observed in SP-A-/- mice were significantly attenuated. These studies suggest a novel mechanism for SP-A in asthma as a modulator of IL-13-induced inflammation via mediating downstream IL-6/STAT3 signaling.

AWZ1066S, a highly specific anti-Wolbachia drug candidate for a short-course treatment of filariasis.

Onchocerciasis and lymphatic filariasis are two neglected tropical diseases that together affect ∼157 million people and inflict severe disability. Both diseases are caused by parasitic filarial nematodes with elimination efforts constrained by the lack of a safe drug that can kill the adult filaria (macrofilaricide). Previous proof-of-concept human trials have demonstrated that depleting >90% of the essential nematode endosymbiont bacterium, Wolbachia, using antibiotics, can lead to permanent sterilization of adult female parasites and a safe macrofilaricidal outcome. AWZ1066S is a highly specific anti-Wolbachia candidate selected through a lead optimization program focused on balancing efficacy, safety and drug metabolism/pharmacokinetic (DMPK) features of a thienopyrimidine/quinazoline scaffold derived from phenotypic screening. AWZ1066S shows superior efficacy to existing anti-Wolbachia therapies in validated preclinical models of infection and has DMPK characteristics that are compatible with a short therapeutic regimen of 7 days or less. This candidate molecule is well-positioned for onward development and has the potential to make a significant impact on communities affected by filariasis.

[Research progress on the characteristics of immune tolerant phase and antiviral therapy in children with chronic hepatitis B].

Whether or not children with chronic hepatitis B (CHB) in the immune-tolerant phase need to be treated is one of the hot clinical issues that have not yet been clarified. Thus, in order to make clinical antiviral treatment decisions in children with an immune tolerant phase, a comprehensive understanding of the natural history of HBV infection, as well as its relationship with disease progression and whether prompt treatment can alter the natural history and prognosis, is very important. To that end, this article reviews the research progress of clinical antiviral therapy in the immune-tolerant phase for children with chronic hepatitis B over the last decade, while also discussing the treatment's safety, effectiveness, and related immunological mechanisms, so as to clarify the next key step in research orientation, provide direct evidence-based medical evidence for hepatologists to better diagnose and treat, and ultimately improve the clinical cure rate.

Dose prediction for repurposing nitazoxanide in SARS-CoV-2 treatment or chemoprophylaxis.

BACKGROUND: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has been declared a global pandemic and urgent treatment and prevention strategies are needed. Nitazoxanide, an anthelmintic drug, has been shown to exhibit in vitro activity against SARS-CoV-2. The present study used physiologically based pharmacokinetic (PBPK) modelling to inform optimal doses of nitazoxanide capable of maintaining plasma and lung tizoxanide exposures above the reported SARS-CoV-2 EC90 . METHODS: A whole-body PBPK model was validated against available pharmacokinetic data for healthy individuals receiving single and multiple doses between 500 and 4000 mg with and without food. The validated model was used to predict doses expected to maintain tizoxanide plasma and lung concentrations above the EC90 in >90% of the simulated population. PopDes was used to estimate an optimal sparse sampling strategy for future clinical trials. RESULTS: The PBPK model was successfully validated against the reported human pharmacokinetics. The model predicted optimal doses of 1200 mg QID, 1600 mg TID and 2900 mg BID in the fasted state and 700 mg QID, 900 mg TID and 1400 mg BID when given with food. For BID regimens an optimal sparse sampling strategy of 0.25, 1, 3 and 12 hours post dose was estimated. CONCLUSION: The PBPK model predicted tizoxanide concentrations within doses of nitazoxanide already given to humans previously. The reported dosing strategies provide a rational basis for design of clinical trials with nitazoxanide for the treatment or prevention of SARS-CoV-2 infection. A concordant higher dose of nitazoxanide is now planned for investigation in the seamless phase I/IIa AGILE trial.

The value of interventional radiology in clinical trial teams: experience from the BATTLE lung cancer trials.

AIM: To report on the multidisciplinary approach, focusing specifically on the role of the interventional radiologist (IR), used to support the Biomarker-integrated Approaches of Targeted Therapy for Lung Cancer Elimination (BATTLE) and BATTLE-2 trials. MATERIALS AND METHODS: Patients who underwent percutaneous image-guided biopsy for the BATTLE and BATTLE-2 trials were reviewed. A radiology-based, three-point, lesion-scoring system was developed and used by two IRs. Lesions were given a score of 3 (most likely to yield sufficient material for biomarker analysis) if they met the following criteria: size >2 cm, solid mass, demonstrated imaging evidence of viability, and were technically easy to sample. Lesions not meeting all four criteria were scored 2 with the missing criteria noted as negative factors. Lesions considered to have risks that outweighed potential benefits receive a score of 1 and were not biopsied. Univariate and multivariate analyses were performed to evaluate the score's ability to predict successful yield for biomarker adequacy. RESULTS: A total of 555 biopsies were performed. The overall yield for analysis of the required biomarkers was 86.1% (478/555), and 84% (268/319) and 88.9% (210/236) for BATTLE and BATTLE-2, respectively (p=0.09). Lesions receiving a score of 3 were adequate for biomarker analysis in 89% of cases. Lesions receiving a score of 2 with more than two negative factors were adequate for molecular analysis in 69.2% (IR1, p=0.03) and 74% (IR2, p=0.04) of cases. The two IRs scored 78.4% of the lesions the same indicating moderate agreement (kappa=0.55; 95% confidence interval [CI]: 0.48, 0.61). CONCLUSIONS: IRs add value to clinical trial teams by optimising lesions selected for biopsy and biomarker analysis.

A Novel Surgical Approach for Type 2 Mirizzi Syndrome: Based on a Decade of Clinical Experience at a Teaching Hospital.

Background. The Mirizzi syndrome (MS) is a rare complication of cholecystolithiasis that is often accompanied by severe inflammation and fibrosis around Calot's triangle. It is difficult to treat Type 2 MS surgically, and the treatment for this condition has not yet been standardized. The data on operative management are limited. The study aimed to review our institutional clinical experience regarding surgery and provide recommendations for treating Type 2 MS. Methods: We conducted a retrospective study on 6 patients with MS who were surgically treated at our institution between January 2010 and December 2019. The classification of MS by McSherry CK, Ferstenberg H, Virshup M. The Mirizzi syndrome: Suggested classification and surgical therapy. Surg Gastroenterol. 1982;1:219-225 was used. Mucosal approach was used to treat Type 2 MS. The parameters for comparison included patient demographics, operative procedures, operation time, blood loss, length of hospital stay, complications, and follow-up. Results: There were 23 patients with MS among 10 386 cholecystectomies in our area. Six patients with Type 2 MS had successful surgery, and the mucosal approach was used. The average operative time was 253.3 ± 32.5 minutes. The average blood loss was 70.0 ± 14.1 mL. The mean postoperative hospital stay was 9.5 ± 3.9 days. There was no postoperative mortality. The most frequent postoperative complications were bile leakage (16.7%), and postoperative intra-abdominal collection (16.7%). The mean postoperative follow-up was 10 months, and all patients are asymptomatic. The mucosal approach may decrease the risk of bile duct injury, biliary tract infection, and blood loss more than other surgical approaches. Conclusion: This study demonstrates that the mucosal approach is an effective surgical procedure for Type 2 MS.

Osteoporosis care after distal radius fracture reduces subsequent hip or spine fractures: a 4-year longitudinal study.

We evaluated whether active osteoporosis care in patients experiencing their first distal radius fracture (DRF) reduces subsequent hip or spine fractures by comparing two cohorts. The incidence of subsequent fractures was significantly lower in the active care cohort than the other cohort in 4-year follow-up. PURPOSE: Studies show that osteoporosis care in patients with osteoporotic fracture reduces subsequent fractures, but the impact of such active care in patients with distal radius fracture (DRF) has not been well studied. We evaluated how much osteoporosis care in patients experiencing their first DRF can reduce subsequent hip or spine fractures at 4-year follow-up. METHODS: Active osteoporosis care by orthopedic surgeons for patients with DRF started from September 2009 at our institution, thus we had a unique opportunity to compare the two cohorts: pre-involvement (PreI) group (DRF before September 2009) and post-involvement (PostI) group (DRF from September 2009). We compared the two cohorts for subsequent hip or spine fracture incidence in the 4 years following DRF. RESULTS: Overall, 1057 patients with a DRF (85% women; mean age, 70 years) were studied, of whom 205 patients were in PreI group and 852 in PostI group. Subsequent fractures occurred in 27 patients (2.6%), with a mean interval of 29 months after DRF. The incidence was significantly lower in the PostI group than in the PreI group (1.9% vs. 5.4%, p = 0.004), especially in hip fractures (0.4% vs. 2.9%, p = 0.002). The relative risk reduction was 65% for all subsequent fractures and 86% for hip fractures. CONCLUSION: This study demonstrates that active osteoporosis care in patients with DRF significantly reduces subsequent fracture incidence even for the 4-year follow-up period. These findings add an evidence for the current proactive osteoporosis care programs such as fracture liaison services. LEVEL OF EVIDENCE: Therapeutic level III.

[Relationship between inorganic elements in rhizosphere soil and rhizome radial striations in Ligusticum chuanxiong].

The study is aimed to reveal the fluctuation of the inorganic elements in the rhizosphere soil of Ligusticum chuanxiong during their whole growth period, and explore the relationship between that fluctuation and the formation of radial striations character in the rhizomes. During the cultivation period of L. chuanxiong, the rhizosphere soil samples were taken regularly, and the content of 26 inorganic elements were determined by X-ray fluorescence spectrometry(XRF). Then the difference between the radial striations and un-radial striations rhizomes were analyzed for their fluctuation of the inorganic elements. The results showed that there were different "key period" and "key elements" in the rhizosphere elements content of L. chuanxiong rhizome with radial and un-radial striations, and different element coordination and antagonistic relationship. The key fluctuation period of rhizosphere elements in un-radial striations group were in 0-60 and 60-150 days, of which 22 elements such as Na, Mg, Al were the key elements in 0-60 days, and 5 elements such as Sr, Hf, Pb, Co, Ce were the key elements in 60-150 days. The key fluctuation period of rhizosphere elements in radial striations group were in 0-60 and 210-270 days, of which four elements such as Na, Co, Ce, As are the key change elements in 0-60 days, and 18 elements such as Mg, Al, Si are the key change elements in 210-270 days. At the same time, the study showed that the fluctuation of inorganic elements in rhizosphere soil coincided with the growth and development process of L. chuanxiong and the key period of the formation of "radial striations rhizome". The key stage which the rapid growth of lateral buds of rhizome affected the formation of radial striations is 60-150 days after planting, while the increase of Sr and Co elements is likely to be an important reason for the expansion of lateral buds of rhizome and the failure to form typical "radial striations rhizome" in un-radial striations group.

Increased risk of osteoporotic vertebral fracture in rheumatoid arthritis patients with new-onset cardiovascular diseases: a retrospective nationwide cohort study in Taiwan.

INTRODUCTION: Both cardiovascular diseases (CVD) and osteoporosis are common comorbidities in rheumatoid arthritis (RA) patients. Although accumulating evidence indicates a link between CVD and osteoporotic fracture, whether CVD contributes to osteoporotic fracture risk in RA has yet to be explored. We examined the incidence rate and risk factors of osteoporotic vertebral fracture in RA patients with new-onset CVD (RA-CVD) and evaluated the effects of medications on such fracture risk. METHODS: A retrospective study was conducted using a nationwide database from 2000 to 2010: 1267 RA-CVD and 1267 non-CVD patients were enrolled from 30,507 patients with newly diagnosed RA. The main outcome was the development of osteoporotic vertebral fracture. After being adjusted for age, gender, and comorbidities, the Cox proportional hazard model was used to identify independent factors contributing to osteoporotic vertebral fracture. RESULTS: The adjusted hazard ratio (aHR) of developing osteoporotic vertebral fracture was 1.47-fold greater in RA-CVD group than in non-CVD group (95% confidence interval 1.19-1.81, p < 0.001). Both the age above 40 years and female gender were significant risk factors for developing osteoporotic vertebral fracture in RA-CVD patients. Using patients not taking medication as a reference group, the aHR of osteoporotic vertebral fracture was significantly lower in those receiving statins (0.50), low-dose corticosteroids (0.57), or hydroxychloroquine (0.12). CONCLUSIONS: The risk of osteoporotic vertebral fracture was significantly increased in RA-CVD patients, particularly women above 40 years of age, and could be reduced by statin therapy. However, the protective effect of low-dose corticosteroids or hydroxychloroquine on osteoporotic vertebral fracture risk needs further validation.

Expression and characterization of the cyp19a gene and its responses to estradiol/letrozole exposure in Chinese soft-shelled turtle (Pelodiscus sinensis).

Cytochrome P450 aromatase (CYP19) catalyzes the conversion of androgens to estrogens and is critical in sex differentiation. CYP19 exists as the ovarian type and brain type. Herein, we cloned the full-length ovarian cyp19a gene from the Chinese soft-shelled turtle, Pelodiscus sinensis (pscyp19a). We determined the distribution of pscyp19a in adult tissue and evaluated its expression during embryonic development, following treatment with 17ß-estradiol (E2) or letrozole (LE). The pscyp19a complementary DNA is 2,285 bp in length and comprises a 1,512 bp open reading frame that encodes a protein of 503 AA. The nucleotide sequence and amino acid of pscyp19a shared significant identity with other vertebrate sequences. Expression of pscyp19a was high in the ovary (p < 0.01), and exhibited modest expression in the female brain and intestine. Expression of pscyp19a displayed significant differences between sexes during early embryo development stages; expression increased gradually during embryonic development in females, but the opposite trend was observed in males. Female embryos treated with different concentrations of E2 and LE displayed altered pscyp19a expression compared with untreated individuals, and E2 clearly induced pscyp19a expression. These results indicate that pscyp19a gene plays important roles in early developmental stages in Chinese soft-shelled turtle, and may assist future studies on sex differentiation and sex control in this and similar species.

[Clinical features of long segmental myelopathy caused by nitrous oxide].

OBJECTIVE: To analyze the clinical and imaging characteristics of the neurological damage caused by nitrous oxide (N2O). METHODS: In the study, 10 patients in the Department of Neurology of China-Japan Friendship Hospital from October 2015 to February 2018 were retrospectively analyzed for the demographic data, the history of inhaled N2O, clinical features, blood examination, electrophysiological examination, spinal magnetic resonance imaging and therapeutic efficacy profiles. RESULTS: The male-to-female ratio was 4:6 and it presented with an age-of-onset 17-26 years [the average age: (20.80±3.12) years]. The time from inhaled N2O to onset was 1 month to 1 year [the average time: (6.95±4.19) months]. Paralysis in all the patients and numbness in 9 patients were the main clinical features, while positive Lhermitte's sign in 3 patients, urinary and defecation disturbance in 4 patients were also found. Blood examination indicated anemia in 2 patients, giant cell anemia in 1 case and small cell hypochromic anemia in 1 case. 3 cases had been treated with vitamin B12 in an external hospital, and the other 7 cases had abnormal increase in homocysteine levels. Electrophysiological examinations showed sensory and motor nerve involvement in 9 patients, and motor nerve involvement in 1 patient. The severity of lower extremity lesion was significantly heavier than that of upper extremity. Spinal magnetic resonance imagings showed that long segmental lesions were present in the cervical spinal cord of all the patients, 3 cases with long segmental lesions of the thoracic cord and 2 cases with spinal cord swelling. In 6 cases, the horizontal axis had an "inverted V-type" T2 high signal, 1 case was classified as "crescent", and 3 cases were "eight-shaped". The symptoms in these 10 cases were alleviated in varying degrees after stopping the inhalation of nitrous oxide, actively supplementing high doses of vitamin B12 and doing early rehabilitation exercises. CONCLUSION: Myelopathy with nitrous oxide presents as paralysis and numbness in limb extremities. In imaging, cervical spinal cord damage is common, accompanied by thoracic spinal cord damage. The horizontal axis is more common in the "inverted V-type". Treatment with high doses of vitamin B12 is effective.

[Advances in new type of biomolecular markers for liver fibrosis].

Liver fibrosis is a common pathological process of chronic liver disease, and the number of deaths from liver cirrhosis, liver failure and liver cancer is increasing year-by-year worldwide. Presently, the detection methods to evaluate hepatic fibrosis mainly include hepatic histological examination, imaging and serum markers, but all these have many limitations in clinical aspects. Recently, there have been more and more studies related to the development of non-coding RNA, exosomes and liver fibrosis that are considered as a new type of biomolecular markers with potential clinical application. Herein, we did a preliminary assessment in conjunction with relevant advances to provide a reference for the early diagnosis and treatment of liver fibrosis.

Endovascular shedding markers in patients with heart failure with reduced ejection fraction: Results from a single-center exploratory study.

BACKGROUND: Endothelial glycocalyx degradation has been associated with multiple pathophysiological processes in cardiovascular disease. AIMS: To explore the role of glycocalyx shedding markers in pathophysiology of HFrEF. METHODS: In 123 HFrEF patients, the concentration, prognostic value, and association of glycocalyx shedding markers with other disease processes were investigated. RESULTS: Median HA levels and syndecan-1 levels in HFrEF patients were, respectively, 29.4 (10.7;61.6) ng/mL and 48.5 (33.6;80.8) ng/mL. Overall, HA-levels were significantly higher in HFrEF patients compared to healthy subjects, but only 31% of HFrEF patients had HA-levels above the cutoff of normal. There was no significant difference among HFrEF patients and healthy subjects regarding syndecan-1 levels. HFrEF patients with elevated HA-levels had a significantly worse outcome (log rank = 0.01) which remained significant after correction for established risk factors (HR 2.53 (1.13-5.69); P = .024). There was no significant relation between levels of shedding markers and neurohumoral activation (PRA, serum aldosterone, NT-proBNP), myocardial injury (HS-trop), inflammation (CRP), or other baseline characteristics. CONCLUSIONS: The glycocalyx shedding marker HA is significantly elevated in a subgroup of HFrEF patients and an independent predictor for worse clinical outcome. Glycocalyx shedding might be an additional factor in the pathophysiology of HF which warrants further investigation.

[The mechanism of nicotine on human bronchial smooth muscle cell contraction].

Objective: To investigate the molecular mechanism of contractility dysfunction of human bronchial smooth muscle cells induced by nicotine. Methods: Primary human bronchial smooth muscle cells were cultured in vitro. The cells were divided into a control group and a nicotine group which was treated with 10(-5) mol/L nicotine for 48 h and transfected with or without α7nAChR-siRNA (The siNC group, siNC + nicotine group and siα7nAChR + nicotine group). The effects of nicotine on the cell contractile function were examined by collagen gel shrinkage assay. The expressions of α7nAChR and TRPC6 protein in nicotine-treated human bronchial smooth muscle cells were detected by Western blotting. The change of intracellular calcium concentration by nicotine was detected by calcium ion imaging system.Data were analyzed by t test or single factor analysis of variance. Results: The area of collagen gel in the nicotine group (24±8)% was significantly lower than that in the control group (59±14)% (t=3.78, P<0.05). Compared with the control group, the expression of α7nAChR protein in nicotine-induced group (173±16)% was significantly higher than that of controls 100±0)%, t=-6.848, P<0.05. Compared with the siNC group [(72±10)%, (0.79±0.07), (0.41±0.04) and (0.17±0.02) respectively], the collagen gel area of siNC + nicotine group was significantly reduced by (37±10)%. However, the basal calcium level (1.04±0.02), store operated calcium entry level (SOCE, 0.68±0.03) and receptor operated calcium entry level (ROCE, 0.36±0.02) were remarkably elevated in the nicotine treated group (all P<0.05). Furthermore, compared with siNC + nicotine group, the area of collagen gel in siα7nAChR + nicotine group was significantly increased (62±10)%, and the basal calcium level (0.78±0.06), SOCE level (0.39±0.05) and ROCE level (0.15±0.02) were significantly reduced (all P<0.05). Conclusions: Nicotine can increase the expression of TRPC6 protein, SOCE and ROCE level, and increase the intracellular calcium concentration by upregulating the expression of α7nAChR protein, thereby promoting smooth muscle cell contraction.