Efficacy of botulinum toxin A combined with extracorporeal shockwave therapy in post-stroke spasticity: a systematic review.

Objectives: In recent years, there has been an increase in the number of randomized clinical trials of BTX-A combined with ESWT for the treatment of post-stroke spasticity. This has made it possible to observe the benefits of combination therapy in clinical practice. Therefore, this paper reviews the effectiveness of BTX-A in combination with ESWT for the treatment of post-stroke spasticity. Methods: By October 2023, a systematic review was conducted in the databases PubMed, Cochrane, Embase, Medline, Web of Science, China National Knowledge Infrastructure, Wan Fang Database, China Biology Medicine disc and China Science and Technology Journal Database were systematically searched. We included randomized controlled trials that reported outcome metrics such as MAS, FMA, and MBI score. Studies were excluded if MAS was not reported. The quality of the included studies was assessed by the Cochrane Collaboration's tool for assessing risk of bias, and the AMSTAR quality rating scale was selected for self-assessment. Results: A total of 70 articles were included in the initial search, and six were ultimately included. The results of the included studies showed that the combination therapy was effective in reducing MAS scores and improving FMA and MBI scores in patients with spasticity compared to the control group. Combination therapy has also been shown to improve joint mobility and reduce pain in spastic limbs. Conclusion: Cumulative evidence from clinical randomized controlled trial studies suggests that the combination therapy is effective in reducing lower limb spasticity and improving mobility after stroke. However, more clinical trials are still needed to corroborate the evidence regarding the efficacy of BTX-A combined with shockwave therapy. Systematic Review Registration: The system review can be searched in the PROSPERO database (CRD42023476654).

[Feasibility study of arterial pressure measurement by snuff pot artery puncture].

OBJECTIVE: To explore the feasibility of snuff pot arterial pressure measurement for patients undergoing routine elective surgery during anesthesia. METHODS: A prospective randomized controlled trial was conducted. Patients undergoing elective surgery admitted to the Handan Hospital of Traditional Chinese Medicine from June 1, 2020 to June 1, 2022 were enrolled. Patients who needed arterial pressure measurement for hemodynamic monitoring were randomly divided into routine radial artery puncture group and snuff pot artery puncture group with their informed consent. The patients in the routine radial artery puncture group were placed a catheter at the styloid process of the patient's radius to measure pressure. In the snuff pot artery puncture group, the snuff pot artery, that was, the radial fossa on the back of the hand (snuff box), was selected to conduct the snuff pot artery puncture and tube placement for pressure measurement. The indwelling time of arterial puncture catheter, arterial blood pressure, and complications of puncture catheterization of patients in the two groups were observed. Multivariate Logistic regression analysis was used to screen the relevant factors that affect the outcome of arterial catheterization. RESULTS: Finally, a total of 252 patients were enrolled, of which 130 patients received routine radial artery puncture and 122 patients received snuff pot artery puncture. There was no statistically significant difference in general information such as gender, age, body mass index (BMI), and surgical type of patients between the two groups. There was no significant difference in the indwelling time of artery puncture catheter between the routine radial artery puncture group and the snuff pot artery puncture group (minutes: 3.4±0.3 vs. 3.6±0.3, P > 0.05). The systolic blood pressure (SBP) and the diastolic blood pressure (DBP) measured in the snuff pot artery puncture group were significantly higher than those in the conventional radial artery puncture group [SBP (mmHg, 1 mmHg ≈ 0.133 kPa): 162.3±14.3 vs. 156.6±12.5, DBP (mmHg): 85.3±12.6 vs. 82.9±11.3, both P < 0.05]. There was no statistically significant difference in the incidence of complications such as arterial spasm, arterial occlusion, and pseudoaneurysm formation between the two groups. However, the incidence of hematoma formation in the snuff pot artery puncture group was significantly lower than that in the conventional radial artery puncture group (2.5% vs. 4.6%, P < 0.05). Based on the difficulty of arterial puncture, multivariate Logistic regression analysis showed that gender [odds ratio (OR) = 0.643, 95% confidence interval (95%CI) was 0.525-0.967], age (OR = 2.481, 95%CI was 1.442-4.268) and BMI (OR = 0.786, 95%CI was 0.570-0.825) were related factors that affect the outcome of arterial catheterization during anesthesia in patients undergoing elective surgery (all P < 0.05). CONCLUSIONS: Catheterization through the snuff pot artery can be a new and feasible alternative to conventional arterial pressure measurement.

Phage-based peptides for pancreatic cancer diagnosis and treatment: alternative approach.

Pancreatic cancer is a devastating disease with a high mortality rate and a lack of effective therapies. The challenges associated with early detection and the highly aggressive nature of pancreatic cancer have limited treatment options, underscoring the urgent need for better disease-modifying therapies. Peptide-based biotherapeutics have become an attractive area of research due to their favorable properties such as high selectivity and affinity, chemical modifiability, good tissue permeability, and easy metabolism and excretion. Phage display, a powerful technique for identifying peptides with high affinity and specificity for their target molecules, has emerged as a key tool in the discovery of peptide-based drugs. Phage display technology involves the use of bacteriophages to express peptide libraries, which are then screened against a target of interest to identify peptides with desired properties. This approach has shown great promise in cancer diagnosis and treatment, with potential applications in targeting cancer cells and developing new therapies. In this comprehensive review, we provide an overview of the basic biology of phage vectors, the principles of phage library construction, and various methods for binding affinity assessment. We then describe the applications of phage display in pancreatic cancer therapy, targeted drug delivery, and early detection. Despite its promising potential, there are still challenges to be addressed, such as optimizing the selection process and improving the pharmacokinetic properties of phage-based drugs. Nevertheless, phage display represents a promising approach for the development of novel targeted therapies in pancreatic cancer and other tumors.

Nucleophilic Allylation of Acylsilanes in Water: An Effective Alternative to Functionalized Tertiary α-Silylalcohols.

A nucleophilic allylation of acylsilanes in water was developed, generating versatile functionalized tertiary α-silyl alcohols in high yields. With the assistance of hydrogen bonding, a reaction model of less reactive acylsilane was achieved. Unlike the conventional strategy, transition metals and an additional Lewis acid catalyst were not required, and rate acceleration was observed in water.

Drug-eluting bead transarterial chemoembolization could improve the hepatic hemodynamics of patients with unresectable hepatocellular carcinoma: a retrospective cohort study.

Background: Transarterial chemoembolization (TACE) is widely used for patients with unresectable hepatocellular carcinoma (HCC); however, previous studies have demonstrated that conventional TACE (cTACE) might affect hepatic hemodynamics, which both associate with liver cirrhosis and survival. Drug-eluting bead TACE (DEB-TACE) improves treatment efficacy and safety, but its effects on the hepatic hemodynamics of HCC patients with cirrhosis remain unknown. Methods: This retrospective cohort study included unresectable HCC patients treated with DEB-TACE from April 2018 to September 2020, who had limited tumor burden and liver function. The hepatic hemodynamics was measured by hepatic venous pressure gradient (HVPG) using occlusion balloon catheter before and after treatment. Baseline characteristics of demography, laboratory (tumoral and liver-function) and hepatic hemodynamics were compared between patients with and without clinically significant portal hypertension (CSPH). Laboratory examination and imaging assessments were performed 4-6 weeks; overall survival (OS) was defined as the time from DEB-TACE initiation until death or last follow-up. Results: Twenty-four eligible consecutive HCC patients were included, with a median age of 58.0 years and 54.2% in Child-Pugh A class. During a median follow-up of 9.8 months, median OS for the whole cohort of patients reached 10.0 months. Kaplan-Meier survival curves and Cox regression analyses demonstrated that age >60 years, ascites, Eastern Cooperative Oncology Group (ECOG) score of 1, Child-Pugh B class, Model for End-Stage Liver Disease (MELD) score >10, and albumin (ALB) <35 g/L were prognostic factors for decreased OS (P<0.05). Importantly, hepatic hemodynamics were significantly improved in patients after treatment with DEB-TACE (7.5 vs. 5.3 mmHg of HVPG, P<0.001), especially for those with CSPH (13.6 vs. 10.2 mmHg of HVPG, P=0.014). Conclusions: DEB-TACE can improve hepatic hemodynamics in HCC patients, especially those with CSPH. Combing these findings with its effects on tumor, DEB-TACE might be more suitable for HCC patients with cirrhosis.

Microbial detoxification of 3,5-xylenol via a novel process with sequential methyl oxidation by Rhodococcus sp. CHJ602.

The compound 3,5-xylenol is an essential precursor used in pesticides and industrial intermediate in the disinfectants and preservatives industry. Its widespread application makes it an important source of pollution. Microbial bioremediation is more environmentally friendly than the physicochemical treatment process for removing alkylphenols from a polluted environment. However, the 3,5-xylenol-degrading bacteria is unavailable, and its degradation mechanism remains unclear. Here, a 3,5-xylenol-metabolizing bacterial strain, designated Rhodococcus sp. CHJ602, was isolated using 3,5-xylenol as the sole source of carbon and energy from a wastewater treatment factory. Results showed that strain CHJ602 maintained a high 3,5-xylenol-degrading performance under the conditions of 30.15 °C and pH 7.37. The pathway involved in 3,5-xylenol degradation by strain CHJ602 must be induced by 3,5-xylenol. Based on the identification of intermediate metabolites and enzyme activities, this bacterium could oxidize 3,5-xylenol by a novel metabolic pathway. One methyl oxidation converted 3,5-xylenol to 3-hydroxymethyl-5-methylphenol, 3-hydroxy-5-methyl benzaldehyde, and 3-hydroxy-5-methylbenzoate. After that, another methyl oxidation is converted to 5-hydroxyisophthalicate, which is metabolized by the protocatechuate pathway. It is catalyzed by a series of enzymes in strain CHJ602. In addition, toxicity bioassay result indicates that 3,5-xylenol is toxic to zebrafish and Rhodococcus sp. CHJ602 could eliminate 3,5-xylenol in water to protect zebrafish from its toxicity. The results provide insights into the bioremediation of wastewater contaminated 3,5-xylenol.

Meteorin-like protein overexpression ameliorates fulminant hepatitis in mice by inhibiting chemokine-dependent immune cell infiltration.

Myokines, which are recently identified cytokines secreted by skeletal muscle in response to stimulation, are crucial for the maintenance of liver function. Fulminant hepatitis (FH) is a life-threatening pathological condition with severe hepatic dysfunction. In this study, we investigated the role of meteorin-like (METRNL), a new myokine, in the pathogenesis of FH. We compared serum samples and liver tissues from FH patients and healthy controls and found that hepatic and serum METRNL levels were significantly increased in FH patients, and serum METRNL levels were related to disease severity in FH patients. We then established a concanavalin A-induced FH model in METRNL-overexpressing and control mice. We found that hepatic METRNL levels in FH mice were significantly increased, and METRNL in the liver was mainly derived from macrophages. In the cultured mouse macrophage line (RAW264.7 cells) and mouse primary peritoneal macrophages (PMs), METRNL overexpression significantly inhibited the release of the proinflammatory cytokines TNF and IL-1ß. In METRNL-overexpressing mice, concanavalin A-induced liver injury was significantly ameliorated. Moreover, METRNL overexpression significantly reduced chemokine-dependent inflammatory cell infiltration into the liver. METRNL overexpression also suppressed liver CD4+ T cell differentiation into Th 1 cells and inhibited the secretion of Th 1 cytokines. Taken together, these data suggest that METRNL overexpression effectively ameliorates FH. Therefore, METRNL may serve as a potential biomarker and therapeutic target for FH.

Effect of Iron Deposition on Native T1 Mapping and Blood Oxygen Level Dependent for the Assessment of Liver Fibrosis in Rabbits With Carbon Tetrachloride Intoxication.

RATIONALE AND OBJECTIVES: This study aimed to explore the effect of iron deposition on native T1 mapping and blood oxygen level-dependent (BOLD) imaging in detecting liver fibrosis (LF) in a rabbit model. MATERIALS AND METHODS: An LF group (n = 100) was established by subcutaneously injecting 50% carbon tetrachloride (CCl4) oil solution, and 20 normal rabbits composed a control group. Native T1 mapping and BOLD were performed, and the T1native and R2* quantitative parameters were analyzed by receiver operating characteristic (ROC) and multiple logistic regression analyses, with histopathological results and liver iron content (LIC) serving as reference standards. RESULTS: In total, 18, 17, 16, 18, and 15 rabbits were histopathologically diagnosed with LF stages F0, F1, F2, F3, and F4, respectively. T1native (r = 0.47), R2* (r = 0.75) and LIC (r = 0.61) increased with LF stage progression (p < 0.001). Compared to T1native values, R2* performed better in diagnosing the LF stage, especially for distinguishing F1-F2 from F3-F4 (AUC = 0.66 vs. 0.91, p = 0.01). Combined with the LIC, both T1native and R2* showed improved diagnostic value in comparison to the individual imaging techniques, particularly for diagnosing F0 vs. F1-F2 and F0 vs. F1-F4, with AUC values of 0.90 vs. 0.70 (p = 0.01) and 0.93 vs. 0.77 (p = 0.01) for T1native + LIC vs. LIC, respectively. CONCLUSION: BOLD imaging performed better than native T1 mapping in predicting and diagnosing LF stage progression. The decrease in diagnostic accuracy caused by the deposition of liver iron is a potential pitfall in the assessment of LF with BOLD imaging and native T1 mapping.

[Big Data Management and Application: Specialty Construction Overview and Exploration of Personnel Training System in Medical Schools].

Focusing on the undergraduate specialty construction of big data management and application in medical colleges and universities in the context of New Medical Education, we first analyzed, in this paper, the demand for trained personnel of this specialization and the status of program construction at the national and regional levels. Then, taking Anhui Medical University as an example, a key medical university in Anhui Province, we introduced the preparations made by medical colleges and universities to set up big data management and application specialty. Finally, from the perspectives of the objectives of personnel training, curriculum system, and practical teaching system, we presented in detail the exploratory efforts made by Anhui Medical University to construct a training system for personnel specializing in big data management and application. In this paper, we reported mainly the work done on the exploration of the personnel training curriculum system, covering general education, professional education, and extracurricular activities, highlighting the interdisciplinary characteristics of a personnel training curricular system that integrates medicine, engineering, and management. We also reported on a practice teaching system that combined in-class practical teaching and extracurricular activities, and that incorporated tiered contents of increasing challenge--basic practice level, cognitive practice level, comprehensive practice level, and innovative practice level. This study is expected to provide useful references for the training of personnel specializing in medical big data in the context of New Medical Education.

Hydrogel-based co-delivery of CIK cells and oncolytic adenovirus armed with IL12 and IL15 for cancer immunotherapy.

Intratumoral injection of various effector cells combined with oncolytic adenovirus expressing antitumor cytokines exert an effective antitumor immune effect by oncolysis and altering the tumor microenvironment. However, this combination therapy had certain limitations. When used in high concentrations, effector cells and oncolytic viruses can spread rapidly to surrounding non-target tissues. And because both therapies used in combination are immunogenic and exhibit shorter biological activity, multiple injections were required to attain an adequate therapeutic index. To overcome these drawbacks, we encapsulated gelatin-based hydrogel capable of co-deliver oncolytic adenovirus armed with IL12 and IL15 (CRAd-IL12-IL15) and CIK cells for enhancing and prolonging the antitumor effects of both therapies after a single intratumoral injection. The injectable and biodegradable hydrogel reduced the dispersion of high-dose oncolytic adenovirus and CIK cells from the injection site to the liver and other non-target tissues. In this study, a novel oncolytic adenoviral vector CRAd-IL12-IL15 was constructed to verify the cytokine expression and oncolytic ability, which can upregulate the expression levels of Bcl-2, Cish and Gzmb in tumor cells. The CRAd-IL12-IL15 + CIKs/gelatin treatment maintained sustained release of CRAd-IL12-IL15 and active CIK cells over a longer period of time, attenuating the antiviral immune response against adenovirus. In conclusion, the results suggested that hydrogel-mediated co-delivery of CRAd-IL12-IL15 and CIK cells might be a an approach to overcome limitations. Both treatments could be effectively retained in tumor tissue and sustained to induce potent anti-tumor immune responses with a single administration.

Whole-liver histogram analysis of blood oxygen level-dependent functional magnetic resonance imaging in evaluating hepatic fibrosis.

BACKGROUND: To explore whole-liver histogram analysis (HA) with blood oxygen level-dependent functional magnetic resonance imaging (BOLD-fMRI) in evaluating and diagnosing hepatic fibrosis (HF) in a CCl4-induced rabbit model. METHODS: One hundred rabbits were classified as CCl4-induced HF groups (n=80) and control group (n=20), and were scheduled for BOLD-fMRI examination on a 3.0T scanner. Whole-liver HA metrics, including the mean, median, skewness, kurtosis, inhomogeneity, entropy, and nth percentiles, were extracted from the R2* map. Parameters were compared among the different HF stages using receivers operating characteristic analysis and Mann-Whitney U-test. RESULTS: In all, 17, 18, 19, 17, and 15 rabbits were pathologically diagnosed as F0, F1, F2, F3, and F4, respectively. HA parameters, including the median, inhomogeneity, entropy, and the 75th and 90th percentiles of the BOLD R2* map, demonstrated significant positive correlations with the fibrosis stage (r=0.226-0.718, P≤0.039). The 75th percentiles demonstrated higher diagnostic efficacy than the other HA parameters in fibrosis staging, with an AUC value of 0.86 for ≥ F1, 0.87 for ≥ F2, 0.87 for ≥ F3, and 0.86 for ≥ F4. CONCLUSIONS: BOLD-fMRI HA provides increased diagnostic performance in staging HF, especially for the 75th percentiles.

Increases in the seaward river flux of nutrients driven by human migration and land-use changes in the tide-influenced delta.

Most large megacities are located on areas adjacent to tide-influenced deltas. However, contribution of megacities to seaward nutrient fluxes in tide-influenced deltas are poorly quantified in regional and global levels. We analyzed nutrient concentrations and water current data for a large and tide-influenced delta, the Changjiang (Yangtze River) since 1980. Concentrations, species ratios and fluxes of nutrients in tide-influenced delta has been found to differ dramatically from those at upstream. Over the period 2004 to 2015, the seaward nutrient fluxes of dissolved inorganic nitrogen and dissolved silica increased by 5%-10%, but dissolved inorganic phosphorus increased by 15%-20%, in the tide-influenced delta of the Changjiang. Consequently, the DIP/DIN decreases by 11% and DIP/DSi increases by 14% at the river mouth relative to those farther upstream the tidal limit. The legacy and/or recycled contribution accounts for 10%-30% of this increased nutrient flux, hence additional sources are predominantly those involving anthropogenic land-use changes. These findings have implications not only for the Changjiang but also for other riverine systems with respect to management strategy. Nutrient dynamics in tide-influenced deltas near urban areas should receive increased research and policy attention. By not considering nutrient sources in tide-influenced deltas, knowledge of the seaward fluxes and species ratios of nutrients from land sources is incomplete and can be biased, to the point that assessments of their impacts on adjacent marine environments may be inaccurate and mitigation policies therefore ineffective.

Dynamic contrast-enhanced MRI with Gd-EOB-DTPA for the quantitative assessment of early-stage liver fibrosis induced by carbon tetrachloride in rabbits.

PURPOSE: To explore quantitative parameters obtained by dynamic contrast-enhanced magnetic resonance imaging (DCE MRI) with Gd-EOB-DTPA in discriminating early-stage liver fibrosis (LF) in a rabbit model. MATERIALS AND METHODS: LF was established in 60 rabbits by the injection of 50% CCl4 oil solution, whereas 30 rabbits served as the control group. All rabbits underwent pathological examination to determine the LF stage using the METAVIR classification system. DCE MRI was performed, and quantitative parameters, including Ktrans, Kep, Ve, Vp and Re were measured and evaluated among the different LF stages using spearman correlation coefficients and receiver operating characteristic curve. RESULTS: In all, 24, 25, and 22 rabbits had stage F0, stage F1, and stage F2 LF, respectively. Ktrans (r = 0.803) increased, and Kep (r = -0.495) and Re (r = -0.701) decreased with LF stage progression (P < 0.001), while no significant correlation was found for Ve or Vp. Ktrans and Re were significantly different between all LF stage pairs compared (F0 vs. F1, F0 vs. F2, F1 vs. F2, F0 vs. F1-F2, P < 0.05). With the exception of F0 vs. F1, Kep differed significantly between stages (P < 0.05). The AUC of Ktrans was higher than that of other quantitative parameters, with an AUC of 0.92, 0.99, 0.94 and 0.92 for staging F0 vs. F1, F0 vs. F2, F1 vs. F2, and F0 vs. F1-F2, respectively. CONCLUSION: Among quantitative parameters of Gd-EOB-DTPA DCE MRI, Ktrans was the best predictor for quantitatively differentiating early-stage LF.

Membrane raft redox signalling contributes to endothelial dysfunction and vascular remodelling of thoracic aorta in angiotensin II-infused rats.

NEW FINDINGS: What is the central question of this study? Is the membrane raft redox signalling pathway involved in blood pressure increase, endothelial dysfunction and vascular remodelling in an angiotensin II-induced hypertensive animal model? What is the main finding and its importance? The membrane raft redox signalling pathway was involved in endothelial dysfunction and medial remodelling in angiotensin II-induced hypertension. ABSTRACT: The membrane raft (MR) redox pathway is characterized by NADPH oxidase activation via the clustering of its subunits through lysosome fusion and the activation of acid sphingomyelinase (ASMase). Our previous study shows that the MR redox signalling pathway is associated with angiontensin II (AngII)-induced production of reactive oxygen species (ROS) and endothelial dysfunction in rat mesenteric arteries. In the present study, we hypothesized that this signalling pathway is involved in blood pressure increase, endothelial dysfunction and vascular remodelling in an AngII-induced hypertensive animal model. Sixteen-week-old male Sprague-Dawley rats were subjected to AngII infusion for 2 weeks with or without treatment with the lysosome fusion inhibitor bafilomycin A1 and ASMase inhibitor amitriptyline. After treatments, aortas were harvested for further study. The results showed that the MR redox signalling pathway was activated as indicated by the increase of MR formation, ASMase activity and ROS production in aorta from AngII-infused rats compared with that from control rats. MR formation and ROS production were significantly inhibited in thoracic aorta from AngII-induced rats treated with bafilomycin A1 and amitriptyline. Both treatments significantly attenuated blood pressure increase, endothelial dysfunction and vascular remodelling including medial hypertrophy, and increased collagen and fibronectin deposition in thoracic aortas from AngII-infused rats. Finally, both treatments significantly prevented the increase of inflammatory factors including monocyte chemotactic protein 1, intercellular adhesion molecule 1 and tumour necrosis factor α in thoracic aorta from AngII-infused rats. In conclusion, the present study demonstrates that the MR redox signalling pathway was involved in endothelial dysfunction and medial remodelling in AngII-induced hypertension.

SGK1-FoxO1 Signaling Pathway Mediates Th17/Treg Imbalance and Target Organ Inflammation in Angiotensin II-Induced Hypertension.

It has been demonstrated that serum/glucocorticoid regulated kinase 1 (SGK1) and the downstream transcription factor forkhead box O1 (FoxO1) plays a critical role in the differentiation of T helper 17 cells/regulatory T cells (Th17/Treg). In the present study, we hypothesized that this SGK1-FoxO1 signaling pathway is involved in Th17/Treg imbalance and target organ damage in angiotensin II (AngII)-induced hypertensive mice. Results show that SGK1 inhibitor EMD638683 significantly reversed renal dysfunction and cardiac dysfunction in echocardiography as indicated by decreased blood urine nitrogen and serum creatinine in AngII-infused mice. Flow cytometric assay shows that there was significant Th17/Treg imbalance in spleen and in renal/cardiac infiltrating lymphocytes as indicated by the increased Th17 cells (CD4+-IL17A+ cells) and decreased Treg cells (CD4+-Foxp3+). Consistently, real-time PCR shows that Th17-related cytokines including IL-17A, IL-23, and tumor necrosis factor α (TNF-α) was increased and Treg-related cytokine IL-10 was decreased in renal and cardiac infiltrating lymphocytes in AngII-infused mice. Meanwhile, SGK1 protein level, as well as its phosphorylation and activity, was significantly increased in spleen in AngII-infused rats. Furthermore, it was found that splenic phosphorylated FoxO1 was significantly increased, whereas total FoxO1 in nuclear preparation was significantly decreased in AngII-infused mice, suggesting that increased FoxO1 phosphorylation initiate its translocation from cytoplasm to nucleus. Notably, all changes were significantly inhibited by the treatment of EMD638683. These results suggest that SGK1 was involved in Th17/Treg imbalance and target organ damage in AngII-induced hypertension.

Perivascular Adipose Tissue-Derived PDGF-D Contributes to Aortic Aneurysm Formation During Obesity.

Obesity increases the risk of vascular diseases, including aortic aneurysm (AA). Perivascular adipose tissue (PVAT) surrounding arteries are altered during obesity. However, the underlying mechanism of adipose tissue, especially PVAT, in the pathogenesis of AA is still unclear. Here we showed that angiotensin II (AngII) infusion increases the incidence of AA in leptin-deficient obese mice (ob/ob) and high-fat diet-induced obese mice with adventitial inflammation. Furthermore, transcriptome analysis revealed that platelet-derived growth factor-D (PDGF-D) was highly expressed in the PVAT of ob/ob mice. Therefore, we hypothesized that PDGF-D mediates adventitial inflammation, which provides a direct link between PVAT dysfunction and AA formation in AngII-infused obese mice. We found that PDGF-D promotes the proliferation, migration, and inflammatory factors expression in cultured adventitial fibroblasts. In addition, the inhibition of PDGF-D function significantly reduced the incidence of AA in AngII-infused obese mice. More importantly, adipocyte-specific PDGF-D transgenic mice are more susceptible to AA formation after AngII infusion accompanied by exaggerated adventitial inflammatory and fibrotic responses. Collectively, our findings reveal a notable role of PDGF-D in the AA formation during obesity, and modulation of this cytokine might be an exploitable treatment strategy for the condition.

In vitro antimicrobial susceptibility testing of human Brucella melitensis isolates from Ulanqab of Inner Mongolia, China.

BACKGROUND: Brucellosis is an endemic disease in the Inner Mongolia Autonomous Region of China and Ulanqab exhibits the highest prevalence of brucellosis in this region. Due to the complex nature of Brucellosis, a cure for this disease has proven to be elusive. Furthermore, the reduced susceptibility of Brucella spp. to antimicrobial agents has been reported as a potential cause of therapeutic failure. However, detailed in vitro antimicrobial susceptibility patterns pertaining to Brucella isolates from this region have not yet been published. The aim of this study was to evaluate the antibiotic susceptibility profile of Brucella melitensis clinical isolates from Ulanqab, Inner Mongolia, China. METHODS: A total of 85 B. melitesis isolates were obtained from humans in Ulanqab of Inner Mongolia, China; the antimicrobial susceptibility of 85 clinical isolates to nine antibiotics was assessed using the E-test method according to the CLSI (Clinical and Laboratory Standards Institute) guidelines. RESULTS: All of the tested isolates were susceptible to minocycline, sparfloxacin, doxycycline, tetracycline, ciprofloxacin, gentamicin and levofloxacin. Resistance to rifampin and cotrimoxazole was observed in 1.0% (1/85) and 7.0% (6/85) of the isolates, respectively. However, rpoB gene mutations were not observed in single isolates exhibiting resistance to rifampin. CONCLUSIONS: We observed that B. melitensis isolates are susceptible to the majority of the tested antibiotics. Furthermore, minocycline and sparfloxacin exhibited extremely high bactericidal effects in relation to the B. melitensis isolates. The sensitivity of commonly used drugs for the treatment of brucellosis should be regularly monitored. To the best of our knowledge, this is the first report of rifampin and cotrimoxazole resistant isolates of B. melitensis in China. In summary, based on the findings from this study, we suggest that antibiotic administration and use should be rationalized to prevent future drug resistance.

In vitro and in vivo evaluation of hypothermia on pharmacokinetics and pharmacodynamics of nimodipine in rabbits.

Objective To investigate the effect of hypothermia on the pharmacokinetics and pharmacodynamics of nimodipine in rabbits using in vivo and in vitro methods. Methods Five healthy New Zealand rabbits received a single dose of nimodipine (0.5 mg/kg) intravenously under normothermic and hypothermic conditions. Doppler ultrasound was used to monitor cerebral blood flow, vascular resistance, and heart rate. In vitro evaluations of protein binding, hepatocyte uptake and intrinsic clearance of liver microsomes at different temperatures were also conducted. Results Plasma concentrations of nimodipine were significantly higher in hypothermia than in normothermia. Nimodipine improved cerebral blood flow under both conditions, but had a longer effective duration during the hypothermic period. Low temperature decreased the intrinsic clearance of liver microsomes, with no change in protein binding or hepatocyte uptake of nimodipine. Conclusion Nimodipine is eliminated at a slower rate during hypothermia than during normothermia, mainly due to the decreased activity of cytochrome P450 enzymes. This results in elevated system exposure with little enhancement in pharmacological effect.

Longitudinal assessment of rabbit renal fibrosis induced by unilateral ureteral obstruction using two-dimensional susceptibility weighted imaging.

BACKGROUND: Previous studies indicated that two-dimensional-susceptibility weighted imaging (2D-SWI) could serve as a useful biomarker for differentiating the grade of liver fibrosis. PURPOSE: To evaluate the feasibility of 2D-SWI in the dynamic quantification of renal fibrosis in a rabbit model. STUDY TYPE: Longitudinal study. ANIMAL MODEL: Twenty-Four New Zealand White Rabbits including control group (n = 4); and renal fibrosis group (n = 20), by means of a unilateral ureteral obstruction (UUO) model. FIELD STRENGTH/SEQUENCE: The 3.0 T SWI using a 2D gradient-echo sequence. ASSESSMENT: The relative SWI signal ratio(r) of cortical and medulla (r = SIrenal /SImuscle ) was longitudinally assessed before ligation and on weeks 2, 4, 6, and 8 following ligation. Sirius Red staining was used to assess the degree of fibrosis in five high-power fields. STATISTICAL TESTS: The repeated measures of analysis of variance and linear regression analysis. RESULTS: Both the cortical and medullary r values were significantly higher in the UUO kidneys at week 2 compared with the kidneys before ligation. Over the course of UUO progression, significant changes occurred in the cortical and medullary r values in vivo and fibrosis scores in vitro (all P values < 0.05). The r values gradually decreased, while the fibrosis scores gradually increased over 8 weeks following ligation. The linear regression analysis showed a strong and significant correlation between cortical and medullary r values and the pathologic fibrosis scores (R2 = 0.91, 0.81, respectively). DATA CONCLUSION: The SWI sequence could provide a quantitative evaluation of renal fibrosis during UUO progression. LEVEL OF EVIDENCE: 2 Technical Efficacy: Stage 1 J. Magn. Reson. Imaging 2018;47:1572-1577.

Characterization of the metallo-dependent amidohydrolases responsible for "auxiliary" leucinyl removal in the biosynthesis of 2,2'-bipyridine antibiotics.

2,2'-Bipyridine (2,2'-BiPy) is an attractive core structure present in a number of biologically active natural products, including the structurally related antibiotics caerulomycins (CAEs) and collismycins (COLs). Their biosynthetic pathways share a similar key 2,2'-BiPy-l-leucine intermediate, which is desulfurated or sulfurated at C5, arises from a polyketide synthase/nonribosomal peptide synthetase hybrid assembly line. Focusing on the common off-line modification steps, we here report that the removal of the "auxiliary" l-leucine residue relies on the metallo-dependent amidohydrolase activity of CaeD or ColD. This activity leads to the production of similar 2,2'-BiPy carboxylate products that then receive an oxime functionality that is characteristic for both CAEs and COLs. Unlike many metallo-dependent amidohydrolase superfamily proteins that have been previously reported, these proteins (particularly CaeD) exhibited a strong zinc ion-binding capacity that was proven by site-specific mutagenesis studies to be essential to proteolytic activity. The kinetics of the conversions that respectively involve CaeD and ColD were analyzed, showing the differences in the efficiency and substrate specificity of these two proteins. These findings would generate interest in the metallo-dependent amidohydrolase superfamily proteins that are involved in the biosynthesis of bioactive natural products.