In Vitro and In Vivo Evaluation of Synergistic Effects of Everolimus in Combination with Antifungal Agents on Exophiala dermatitidis.

To investigate the combined function of the novel oral mTOR inhibitor, everolimus, with antifungal agents and their potential mechanisms against Exophiala dermatitidis, the CLSI microliquid-based dilution method M38-A2, chequerboard technique, and disk diffusion testing were performed. The efficacy of everolimus was evaluated in combination with itraconazole, voriconazole, posaconazole, and amphotericin B against 16 clinically isolated strains of E. dermatitidis. The synergistic effect was determined by measuring the MIC and fractional inhibitory concentration index. Dihydrorhodamine 123 was used for the quantification of ROS levels. The differences in the expression of antifungal susceptibility-associated genes were analyzed following different types of treatment. Galleria mellonella was used as the in vivo model. While everolimus alone showed minimal antifungal effects, combinations with itraconazole, voriconazole, posaconazole, or amphotericin B resulted in synergy in 13/16 (81.25%), 2/16 (12.5%), 14/16 (87.75%), and 5/16 (31.25%) of isolates, respectively. The disk diffusion assay revealed that the combination of everolimus and antifungal drugs showed no significant increase in the inhibition zones compared with the single agent, but no antagonistic effects were observed. Combination of everolimus and antifungal agents resulted in increased ROS activity (everolimus + posaconazole versus posaconazole [P < 0.05], everolimus + amphotericin B versus amphotericin B [P < 0.002]). Simultaneously, compared to mono-treatment, the combination of everolimus + itraconazole suppressed the expression of MDR2 (P < 0.05) and the combination of everolimus + amphotericin B suppressed the expression of MDR3 (P < 0.05) and CDR1B (P < 0.02). In vivo, combinations of everolimus and antifungal agents improved survival rates, particularly the combination of everolimus + amphotericin B (P < 0.05). In summary, the in vivo and in vitro experiments performed in our study suggest that the combination of everolimus with azoles or amphotericin B can have synergistic effects against E. dermatitidis, potentially due to the induction of ROS activity and inhibition of efflux pumps, providing a promising new approach for the treatment of E. dermatitidis infections. IMPORTANCE Cancer patients with E. dermatitidis infection have high mortality if untreated. Clinically, the conventional treatment of E. dermatitidis is poor due to the long-term use of antifungal drugs. In this study, we have for the first time investigated the interaction and action mechanism of everolimus combined with itraconazole, voriconazole, posaconazole, and amphotericin B on E. dermatitidis in vitro and in vivo, which provided new ideas and direction for further exploring the mechanism of drug combination and clinical treatment of E. dermatitidis.

Prediction of Postoperative Pathologic Risk Factors in Cervical Cancer Patients Treated with Radical Hysterectomy by Machine Learning.

Pretherapeutic serological parameters play a predictive role in pathologic risk factors (PRF), which correlate with treatment and prognosis in cervical cancer (CC). However, the method of pre-operative prediction to PRF is limited and the clinical availability of machine learning methods remains unknown in CC. Overall, 1260 early-stage CC patients treated with radical hysterectomy (RH) were randomly split into training and test cohorts. Six machine learning classifiers, including Gradient Boosting Machine, Support Vector Machine with Gaussian kernel, Random Forest, Conditional Random Forest, Naive Bayes, and Elastic Net, were used to derive diagnostic information from nine clinical factors and 75 parameters readily available from pretreatment peripheral blood tests. The best results were obtained by RF in deep stromal infiltration prediction with an accuracy of 70.8% and AUC of 0.767. The highest accuracy and AUC for predicting lymphatic metastasis with Cforest were 64.3% and 0.620, respectively. The highest accuracy of prediction for lymphavascular space invasion with EN was 59.7% and the AUC was 0.628. Blood markers, including D-dimer and uric acid, were associated with PRF. Machine learning methods can provide critical diagnostic prediction on PRF in CC before surgical intervention. The use of predictive algorithms may facilitate individualized treatment options through diagnostic stratification.

In Vitro Interactions of Antifungal Agents and Everolimus Against Aspergillus Species.

Multiple cellular activities, including protein and lipid synthesis, ribosome biogenesis, and metabolic processes, are regulated by the target of rapamycin (TOR) pathway. Recent research suggests that the TOR might play an important role in various physiological functions of pathogenic fungi, such as nutrient sensing, stress response, and cell cycle progression. Given their robust immunosuppressant and antitumor activities, TOR inhibitors are widely used in clinical settings. In the present study, a microdilution checkerboard-based approach was employed to assess the interactions between the oral mammalian target of rapamycin (mTOR) inhibitor everolimus (EVL) and antifungal agents in the treatment of Aspergillus species derived from 35 clinical isolates in vitro. The results revealed that EVL exhibited promising inhibitory synergy with itraconazole (ITC), posaconazole (POS), and amphotericin B (AMB) for 85.7%, 74.2%, and 71.4%, respectively. In contrast, EVL exhibited minimal synergistic inhibitory activity (14.3%) when applied in combination with voriconazole (VRC). Antagonistic interactions were not observed. In vivo experiments conducted in Galleria mellonella revealed that EVL in combination with antifungal agents improved the larva survival rates in the ITC, VRC, POS, and AMB groups by 18.3%, 13.3%, 26.7%, and 13.3%, respectively. These data suggest that the combination treatment with antifungal agents and antifungal agents holds promise as a means of alleviating clinical aspergillosis.

Pharmacological activities and molecular mechanisms of Pulsatilla saponins.

Saponins are found in a variety of higher plants and display a wide range of pharmacological activities, including expectorant, anti-inflammatory, vasoprotective and antimicrobial properties. Pulsatilla chinensis (P. chinensis, Bai Tou Weng, ) has been used medically in China for thousands of years for the treatment of diseases caused by bacteria, and it is rich in triterpenoid saponins. In recent decades, anemoside B4 (Pulchinenoside C) is well studied since it has been used as a quality control marker for P. chinensis. At the same time, more and more other active compounds were found in the genus of Pulsatilla. In this review, we summarize the pharmacological activities of Pulsatilla saponins (PS) and discuss the cellular or molecular mechanisms that mediate their multiple activities, such as inducing cancer cell apoptosis, inhibiting tumor angiogenesis, and protecting organs via anti-inflammatory and antioxidant measures. We aim to provide comprehensive analysis and summary of research progress and future prospects in this field to facilitate further study and drug discovery of PS.

Glytabastan B, a coumestan isolated from Glycine tabacina, alleviated synovial inflammation, osteoclastogenesis and collagen-induced arthritis through inhibiting MAPK and PI3K/AKT pathways.

The roots of Glycine tabacina are used to treat rheumatoid arthritis (RA) and joint infection in folk medicine. Glytabastan B (GlyB), a newly reported coumestan isolated from this species, was found to significantly attenuate IL-1ß-induced inflammation in SW982 human synovial cells at 3 and 6 µM, as evidenced by the decreased levels of pro-inflammatory mediators and matrix metalloproteinases (MMPs). GlyB also suppressed RANKL-induced osteoclastogenesis, decreased the expression of osteoclastogenic markers (NFATc1, CTSK, MMP-9) and osteoclast-mediated bone resorption. Further, GlyB administration (12.5 and 25 mg/kg) significantly inhibited inflammation, osteoclast formation and disease progression in collagen-induced arthritis (CIA) mice. Integration of network pharmacology, quantitative phosphoproteomic and experimental pharmacology results revealed that these beneficial actions were closely associated with the blockade of GlyB on the activation of MAPK, PI3K/AKT and their downstream signals including NF-κB and GSK3ß/NFATc1. Drug affinity responsive target stability (DARTS) assay, cellular thermal shift (CETSA) assay and molecular docking analysis confirmed that there were direct interactions between GlyB and its target proteins ERK2, JNK1 and class Ⅰ PI3K catalytic subunit p110 (α, ß, δ and γ), which significantly contributed to the inhibition of activation of MAPK and PI3K/AKT pathways. In conclusion, these results strongly suggest GlyB is a promising multiple-target candidate for the development of agents for the prevention and treatment of RA.

In vitro synergistic effect of minocycline combined with antifungals against Cryptococcus neoformans.

BACKGROUND: Cryptococcus neoformans infections occur in immunocompromised patients, especially those with HIV infection, chemoradiotherapy after cancer, and organ transplantation. Infection can cause pneumonia and meningoencephalitis in severe cases with a high mortality rate if not treated. Although fluconazole and amphotericin B are the first-line treatments for cryptococcosis, the rate of fluconazole resistance has increased significantly due to long-term use. Minocycline is a derivative of tetracycline that exerts its antibacterial effect through inhibition of bacterial protein synthesis. It is also able to pass the blood-brain barrier to act on the central nervous system. The present study investigates the effects of minocycline in combination with antifungals in treating C. neoformans. OBJECTIVE: To determine in vitro interactions of minocycline combined with itraconazole, voriconazole, posaconazole, fluconazole and amphotericin B against C. neoformans. METHODS: The minimum inhibitory concentrations (MIC) of the antifungals were determined by the CLSI Clinical and Laboratory Standards Institute M27-A3 microdilution method. The in vitro synergistic effects of minocycline combined with itraconazole, voriconazole, posaconazole, fluconazole, and amphotericin B on C. neoformans were detected by the broth microdilution checkerboard technique and disk diffusion testing. RESULTS AND CONCLUSION: The working concentration ranges were 0.125-4 µg/mL for itraconazole, 0.03-0.125 µg/ml for voriconazole, 0.03-1 µg/ml for posaconazole, 0.25-16 µg/ml for fluconazole, and 0.125-2 µg/ml for amphotericin B. The synergistic rates of minocycline combinations against C. neoformans were 55% with itraconazole, 10% with voriconazole, 85% with posaconazole, 20% with fluconazole, and 70% with amphotericin B. The effective MIC value of minocycline in the synergistic combination decreased to 2-32 µg/ml, while the MIC of itraconazole decreased to 0.03-0.125 µg/ml, voriconazole 0.03-0.125 µg/ml, posaconazole 0.03-0.125 µg/ml, 0.125-4 µg/ml fluconazole, and 0.06-0.50 µg/ml amphotericin B. The disk diffusion assay showed that the plates containing minocycline and antifungal drugs produced inhibition zones with diameters larger than the single drug plates. Minocycline showed no antagonistic effect in the combinations. In conclusion, the combination of minocycline and azoles or amphotericin B has synergistic effects against C. neoformans in vitro.

Low-Dose Berberine Attenuates the Anti-Breast Cancer Activity of Chemotherapeutic Agents via Induction of Autophagy and Antioxidation.

Berberine (BBR), a major active component of Rhizoma coptidis, is one of the most promising agents for breast cancer adjuvant therapy. It is well accepted that BBR could exhibit remarkable anticancer efficacy with few side effects, and when treated with chemotherapeutic agents in combination, BBR could enhance the chemosensitivity of cancer cells. Our previous study reported that low-dose BBR (LDB) induced hormetic effect and attenuated the anticancer activity of chemotherapeutic agents. However, the underlying mechanisms are still unclear. In this study, we confirmed that LDB could promote cancer cell proliferation and antagonize the anti-breast cancer activities of chemotherapeutic agents. And the mechanisms were proved to be induction of autophagy and antioxidation by LDB. Our results showed that LDB could mildly induce reactive oxygen species, raise the level of autophagy by promoting the phosphorylation of adenosine monophosphate-activated protein kinase, and promote antioxidant enzymes expression through activating nuclear factor erythroid 2-related factor 2 in breast cancer cells. These findings revealed a potential negative impact of BBR on its adjuvant anti-breast cancer therapy, providing guidance for a safe and effective use of naturally originated medicines in the clinic.

Isolation and Identification of Antiarthritic Constituents from Glycine tabacina and Network Pharmacology-Based Prediction of Their Protective Mechanisms against Rheumatoid Arthritis.

Glycine tabacina (Labill.) Benth is an edible medicinal herb for rheumatoid arthritis (RA) treatment in folk medicine. Current phytochemical research on this dried herb led to the isolation of eight new coumestans, named glytabastan A-H (1-8), and twenty-three known compounds 9-31. Their structures were elucidated using spectroscopic methods. The antiarthritic activities of all isolates were evaluated, and the results showed that coumestans 1-6 and 8-10 could inhibit arthritic inflammation in vitro, while coumestans 1, 2, 9, and 10 significantly blocked the osteoclastogenesis induced by receptor activator of nuclear factor (NF) κB ligand (RANKL). Moreover, network pharmacological analysis revealed that the anti-RA effect of G. tabacina involved multitargets, multipathways such as PI3K/Akt and MAPK signaling pathways, and various biological processes such as inflammatory response and cytokine-mediated signaling pathways. These results suggested that this species and its novel coumestans could serve as potential antiarthritic agents for functional food or medicinal use.

Dolichosin A, a coumestan isolated from Glycine tabacina, inhibits IL-1ß-induced inflammation in SW982 human synovial cells and suppresses RANKL-induced osteoclastogenesis: From network pharmacology to experimental pharmacology.

ETHNOPHARMACOLOGICAL RELEVANCE: Glycine tabacina (Labill.) Benth has been used as a traditional Chinese herbal medicine for the treatment of rheumatoid arthritis (RA) and joint infection. It is also one of the sources of the renowned native herbal medicine 'I-Tiao-Gung' in Taiwan. AIM OF THE STUDY: This study aimed to investigate anti-arthritic effects and underlying mechanisms of dolichosin A (DoA), a coumestan compound isolated from G. tabacina, by the integration of network pharmacology and experimental pharmacology. MATERIALS AND METHODS: Putative therapeutic targets and potential pharmacological mechanisms of DoA for RA treatment were predicted by network pharmacology approach. The regulated network of DoA acting on RA was constructed using Cytoscape 3.7.1. Anti-arthritic effects of DoA and predicted mechanisms were further validated using IL-1ß-induced SW982 human synovial cell model and RANKL-induced osteoclastogenesis model. RESULTS: A regulatory network of DoA-targets-pathways-RA was successfully constructed using network pharmacology approach. In this network, 65 candidate targets of DoA related to its therapeutic effect on RA were identified and the functional enrichment analysis revealed that these candidate targets were significantly involved in 12 central signaling pathways such as PI3K/AKT pathway, MAPK pathway and osteoclast differentiation. Furthermore, we found that DoA could significantly inhibit IL-1ß-induced inflammation in SW982 human synovial cells, as evidenced by the decreased levels of pro-inflammatory mediators (TNF-α, IL-6 and COX-2) and MMP-3. DoA also suppressed RANKL-induced osteoclastogenesis in vitro, as evidenced by decreased number of TRAP-positive multinucleated osteoclasts and reduced TRAP activity. Further experimental mechanism evidence confirmed the predicted results of network pharmacology that the blockade of PI3K/AKT and MAPK pathways activation was closely associated with these regulated processes of DoA. CONCLUSIONS: Our results demonstrated that DoA exhibited strong anti-arthritic activity through suppressing PI3K/AKT and MAPK pathways activation in activated synovial cells and osteoclasts, suggesting its potential as a hopeful candidate for the development of novel agents for the prevention and treatment of RA.

Comparison of anti-inflammatory effects of berberine, and its natural oxidative and reduced derivatives from Rhizoma Coptidis in vitro and in vivo.

BACKGROUND: Berberine (BBR) is the most abundant and major active constituent of Rhizoma Coptidis (RC), which has been widely used to treat inflammatory diseases in traditional oriental medicine. Despite BBR has been found to exhibit pronounced anti-inflammatory effect, the anti-inflammatory activities of its natural derivatives were sparsely dissected out. PURPOSE: To comparatively investigate the anti-inflammatory potential of BBR, and its natural oxoderivative (oxyberberine, OBB) and reduced derivative (dihydroberberine, DHBB) in vitro and in vivo, and delineate the possible underlying mechanism. METHODS: LC-MS/MS was used to identify the natural derivatives of BBR in RC. The potential anti-inflammatory properties of BBR and its natural derivatives were comparatively evaluated in vitro by lipopolysaccharide (LPS)-induced RAW264.7 macrophages cells, and in vivo via three typical acute inflammation murine models. Some important inflammation-related molecules were analyzed by ELISA, qRT-PCR and Western blotting. RESULTS: LC-MS/MS led to the identification of BBR, OBB and DHBB in RC ethyl acetate extract. The in vitro assay indicated that BBR, OBB and DHBB (1.25, 2.5 and 5 µM) pretreatment significantly decreased the levels of pro-inflammatory cytokines tumor necrosis factor-α (TNF-α), interleukin-1ß (IL-1ß), interleukin-6 (IL-6), prostaglandinE2 (PGE2) and nitricoxide (NO), and inhibited the mRNA expressions of cyclooxygenase-2 (COX-2) and inducible nitricoxide synthase (iNOS) in a dose-dependent manner, with relative efficiency of OBB > BBR > DHBB. Furthermore, OBB, BBR and DHBB remarkably inhibited the phosphorylation of nuclear factor-κB (NF-κB) p65 and inhibitory kappa Bα (IκBα). In vivo, BBR (20 mg/kg) and OBB (5, 10, and 20 mg/kg) pretreatment significantly ameliorated the xylene-induced ear edema, carrageenan-stimulated paw edema, and acetic acid-elicited vascular permeability in mice in a dose-dependent manner, with OBB exhibiting superior anti-inflammatory effect at the same dose (20 mg/kg). Histopathological analysis indicated that OBB and BBR could markedly attenuate the inflammatory deterioration and decrease the cellular infiltration in paw tissues. Additionally, the carrageenan-induced increases in TNF-α, IL-6, IL-1ß, PGE2 and NO productions, and COX-2 and iNOS mRNA expressions were effectually and concentration-dependently suppressed by OBB and BBR pretreatment. CONCLUSION: The anti-inflammatory activity of BBR and its natural derivatives was in the order of OBB > BBR > DHBB. OBB was for the first time found to be endowed with pronounced anti-inflammatory property, which was probably associated with suppressing the activation of NF-κB signaling pathway, and the subsequent gene expressions and productions of pro-inflammatory mediators. The results might contribute to illuminating the pharmacodynamic underpinnings of RC and provide evidence for developing OBB as a safe and promising natural lead compound in inflammation treatment.

Protective effect of coptisine free base on indomethacin-induced gastric ulcers in rats: Characterization of potential molecular mechanisms.

AIMS: The aim of this study was to comparatively investigate the potential gastroprotective effect and underlying mechanisms of coptisine free base (CFB, 8-hydroxy-7, 8-dihydrocoptisine), berberine and lansoprazole against indomethacin-induced gastric ulcer in rats. MATERIALS AND METHODS: CFB (10, 20 and 40mg/kg), berberine (20mg/kg) and lansoprazole (30mg/kg) were orally administrated to rats prior to indometacin ingestion, and gastric lesions were evaluated macroscopically and histologically, and further analyzed by ELISA, qRT-PCR and Western blot. KEY FINDINGS: CFB exerted comparable or superior gastroprotective effect to berberine in protecting against indomethacin-induced gastric injury. CFB pretreatment significantly enhanced the levels of superoxide dismutase (SOD) and glutathione (GSH), and markedly decreased the malonaldehyde (MDA) content. CFB administration effectively suppressed the levels of myeloperoxidase (MPO), interleukin-1ß (IL-1ß), tumor necrosis factor-α (TNF-α) and angiotensin II (Ang II). Besides, CFB substantially up-regulated the mRNA expressions of cyclooxygenase-1 (COX-1) and cyclooxygenase-2 (COX-2), and promoted gastric mucosal prostaglandin E2 level (PGE2). Furthermore, CFB pretreatment remarkably increased the translocation of nuclear factor erythroid 2-related factor 2 (Nrf2) from cytosol into the nucleus, and the expression of heme oxygenase-1 (HO-1), while significantly decreased the expression of mitogen activated protein Kinase Kinase 6 (MKK6) and translocation of p38 mitogen-activated protein kinase (p38 MAPK). SIGNIFICANCE: This was the first investigation reporting the anti-ulcer effect of protoberberine alkaloid free base on in vivo rodent model. The gastroprotective mechanism of CFB might involve favorable regulation of antioxidant and anti-inflammatory status mediated, at least partially, by the Nrf2 signaling pathway and p38 MAPK translocation.

Anti-inflammatory activity of coptisine free base in mice through inhibition of NF-κB and MAPK signaling pathways.

Coptisine is one of the main constituents of Coptis chinensis which has been widely used for the remedy of inflammatory disorders. Although the biological activities of coptisine have been well known, the pharmacological properties of its free base have seldomly been elucidated thus far. The aim of this study was to investigate the potential anti-inflammatory properties of coptisine free base (CFB, 8-hydroxy-7,8-dihydrocoptisine) on three animal models, namely xylene-induced ear edema, acetic acid-induced vascular permeability and carrageenan-induced paw edema. The results exhibited that CFB exerted a dose-dependent suppression on ear edema induced by xylene, significantly mitigated the aggravation of vascular permeability caused by acetic acid and paw edema induced by carrageenan. Additionally, CFB significantly suppressed the productions of interleukin-1ß (IL-1ß), interleukin-6 (IL-6), prostaglandinE2 (PGE2) and tumor necrosis factor (TNF-α) in the drug-treated groups as compared with the vehicle group after treatment with carrageenan. Signaling events of nuclear factor-κB (NF-κB) translocation, such as p-IKKα, p-IKKß, p-IκBα and p65 (nucleus) were significantly inactivated, while inhibitor of nuclear factor κBα (IκBα) and p65 (cytosolic) were markedly up-regulated by CFB. Furthermore, CFB also significantly suppressed the mitogen-activated protein kinase (MAPK) pathway by blocking the phosphorylation of p-p38 (phospho-p38 mitogen-activated protein kinases) and p-JNK (phospho-c-jun N-terminal kinase) but not p-ERK (phospho-extracellular signal-regulated kinase). Hence, CFB efficiently prevented inflammation, at least partially, via inhibition of NF-κB and MAPK pathways. These findings provided a pioneering pharmacological basis for the anti-inflammatory effect of CFB and suggested CFB might be a potential candidate for the therapy of inflammatory disorders.

Epiberberine, a natural protoberberine alkaloid, inhibits urease of Helicobacter pylori and jack bean: Susceptibility and mechanism.

In our previous study, Rhizoma Coptidis extract was found to exert more potent inhibitory effect than its major component berberine towards urease from Helicobacter pylori (HPU) and jack bean (JBU). In continuation of our work, the present study was designed to further comparatively investigate the urease inhibitory activities of five major protoberberine alkaloids in Rhizoma Coptidis, namely berberine, palmatine, coptisine, epiberberine, jateorhizine to identify the bioactive constituent, and illuminate the potential mechanism of action. Results indicated that the five protoberberine alkaloids acted as concentration-dependent inactivators of urease with IC50 values ranging between 3.0 and 5087µM for HPU and 2.3->10,000µM for JBU, respectively. Notably, epiberberine (EB) was found to be the most potent inhibitor against both ureases with IC50 values of 3.0±0.01µM for HPU and 2.3±0.01µM for JBU, which was more effective than the standard urease inhibitor, acetohydroxamic acid (83±0.01µM for HPU and 22±0.01µM for JBU, respectively). Further kinetic analysis revealed that the type of EB inhibition against HPU was slow-binding and uncompetitive, with Ki of 10.6±0.01µM, while slow-binding and competitive against JBU with Ki of 4.6±0.01µM. Addition of thiol reagents, such as l-cysteine, glutathione and dithiothreitol, significantly abolished the inhibition, while Ni2+ competitive inhibitors, boric acid and sodium fluoride, synergetically inhibited urease with EB, indicating the obligatory role of the active site sulfhydryl group for the inhibition. In addition, binding of EB with the urease proved to be reversible, as about 65% and 90% enzymatic activity of HPU and JBU, respectively, could be restored by dithiothreitol application. These findings highlighted the potential role of Rhizoma Coptidis protoberberine alkaloids, especially EB, as a lead urease inhibitor in the treatment of diseases associated with ureolytic bacteria. Thus, EB had good potential for further development into a promising therapeutic approach for the treatment of urease-related diseases.

Xanthomatosis in bilateral hands mimicking rheumatoid arthritis: A case report.

RATIONALE: Xanthomatosis often accompanies familial hypercholesterolemia. This disease usually occurs in tendons, most commonly located in the Achilles tendon; occasionally it can also be seen in other systems. Although there are previous reports for bilateral hand extensor tendon involvement, to our knowledge there is no report in English literature regarding bilateral hands with small joint synovium presenting as rheumatoid arthritis. Therefore, the case that is presented in this report is unique. PATIENT CONCERNS: An 18-year-old woman was admitted to our department because she presented with morning stiffness, joint deformation, and swelling in both hands. Computed tomography of the right hand showed soft tissue swelling on multiple small joints, including metacarpophalangeal and proximal interphalangeal joints, but without obvious bone destruction. There was soft tissue swelling around the small joints, which were hypointensities on T1-weighted and hyperintensities on T2-weighted images, not uniformly enhanced appearances on magnetic resonance imaging. DIAGNOSES: Biopsy from the 3rd metacarpophalangeal joint capsule of the left hand confirmed xanthoma. INTERVENTIONS: She was treated with statin drugs to reduce blood fat. OUTCOMES: After 3 months of follow-up, no recurrence or complications were detected regarding a full range of motion remaining of the affected joints. LESSONS: The young patient with symptoms of small joint synovium involved in both hands and the performance of magnetic resonance imaging similar to rheumatoid arthritis may be suffering from xanthomatosis.

Atypical, multilevel and noncontiguous tuberculous spondylitis that affected the vertebrae of thoracic, lumbar and sacrum: a case report.

AIM: Tuberculous spondylitis (TS, also called Spinal tuberculosis, Pott's spine or Pott's disease) is a common extrapulmonary manifestation of tuberculosis (TB), but multilevel, noncontiguous TS cases are rare. METHODS: Physical examination, CT, MRI imaging, percutaneous biopsy and other lab tests were used to confirm the diagnosis. RESULT: we report a rare case of atypical, multilevel and noncontiguous TS in a 50-year-old woman. We found four noncontiguous osteolytic lesions in her spine that affected the Intervertebral joints of T10/11, L1/2, L3/4 and L5/S1. Patient was then treated conservatively with anti-TB drugs and was followed-up for about 1 year. The treatment turned out to be successful. CONCLUSION: The conservative anti-TB treatment was enough at least for this particular patient.

Imaging assessment of profound sensorineural deafness with inner ear anatomical abnormalities.

OBJECTIVE: To explore the value of a combined computed tomography (CT) and magnetic resonance imaging (MRI) in evaluating profound sensorineural deafness patients before cochlear implant (CI) surgery. METHODS: A retrospective analysis of 1012 cases of profound sensorineural deafness that received CI was performed. RESULTS: A total of 96 cases were diagnosed with inner ear abnormalities including large vestibular aqueduct syndrome (LVAS, n = 61), Michel deformity (n = 3), cochlear incomplete partition I (n = 2), cochlear incomplete partition II (n = 6), cochlear hypoplasia with vestibular malformation (n = 3), cochlear ossification (n = 3), bilateral internal auditory canal obstruction (n = 5) and internal auditory canal stenosis (n = 2). CONCLUSION: High resolution CT (HRCT) can display bony structures while MRI can image the membranous labyrinth in preoperative evaluation for cochlear implantation. The combination of these two modalities provides reliable anatomical information regarding the bony and membranous labyrinths, as well as the auditory nerve.

[Effect of renal sympathetic denervation on left ventricular hypertrophy and inflammatory factors in spontaneously hypertensive rats].

OBJECTIVE: To investigate the effect of renal sympathetic denervation on left ventricular hypertrophy and inflammatory factors in spontaneously hypertensive rats. METHODS: Thirty six spontaneously hypertensive rats (SHR) were divided into 3 groups with 12 animals in each group: SHR control group,operation group and sham operation group. Bilateral renal sympathectomy or sham operation were performed in operation and sham groups,respectively; another 12 WKY rats served as normal controls. The blood pressure and body weight were examined weekly. The animals were sacrificed at w1 and w6, rat hearts were collected and left ventricular mass index (LVMI) was calculated. The expression of TLR4,TNF-α and IL-6 in heart tissue were detected by immunohistochemistry and Western blot. RESULTS: The systolic blood pressure [(201.67 ± 11.09) mmHg compared with (140.0 ± 10.86)mmHg,P<0.05],diastolic blood pressure [(144.50 ± 10.48)mmHg compared with (78.50 ± 7.32)mmHg,P<0.05], LVMI (2.44 ± 0.05 compared with 1.93 ± 0.05,P<0.05),the expression of TLR4 (0.298 ± 0.004 compared with 0.126 ± 0.004, P<0.05), NF-κB (0.249 ± 0.006 compared with 0.195 ± 0.005, P<0.05),TNF-α(0.323 ± 0.004 compared with 0.146 ± 0.004,P <0.05), IL-6 (0.283 ± 0.005 compared with 0.207 ± 0.006, P<0.05) in SHR control group were significantly higher than those in WKY group. Compared to sham operation group,the systolic blood pressure (157.30 ± 9.35 compared with 197.30 ± 11.5, P<0.05),diastolic blood pressure (112.50 ± 6.25 compared with 146.80 ± 7.6, P<0.05),LVMI (2.32 ± 0.04 compared with 2.57 ± 0.09, P<0.05, TLR4 (0.198 ± 0.006 compared with 0.317 ± 0.008, P<0.05), NF-κB (0.208 ± 0.006 compared with 0.332 ± 0.007, P<0.05), TNF-α(0.27 ± 0.009 compared with 0.375 ± 0.004,P<0.05), IL-6 (0.218 ± 0.004 compared with 0.376 ± 0.009, P<0.05) in operation group were all decreased at w1 after sympathectomy. Six weeks after the operation,there were no significant differences in systolic blood pressure (197.50 ± 12.13 compared with 208.83 ± 10.23,P>0.05) and diastolic blood pressure (150.33 ± 7.74 compared with 151.50 ± 8.22, P>0.05) between denervated and sham-operated SHRs; however,the LVMI (2.46 ± 0.07 compared with 2.81 ± 0.05,P<0.05) and the expression of TLR4(0.301 ± 0.009 compared with 0.567 ± 0.006, P<0.05), NF-κB (0.251 ± 0.004 compared with 0.476 ± 0.009,P<0.05),TNF-α(0.324 ± 0.005 compared with 0.535 ± 0.006, P<0.05,IL-6 (0.285 ± 0.009 compared with 0.549 ± 0.007, P<0.05) in operation group were still significantly lower than those in sham operation group. CONCLUSION: Renal sympathetic denervation can significantly delay the progression of LVH in SHR, which may associated with lowering blood pressure and decreasing expression of TLR4, NF-κB,TNF-α, IL-6 in myocardial tissue.

Impact of renal denervation on renalase expression in adult rats with spontaneous hypertension.

The aim of this study was to investigate the impact of renal denervation on the blood pressure, plasma renalase content and expression of renalase and tyrosine hydroxylase (TH) in the kidney of spontaneous hypertensive (SH) rats and to explore the mechanism of renal denervation involved in lowering blood pressure. SH rats (n=48) were randomly assigned to baseline, surgery (renal denervation), sham and control groups. WKY rats matched in age (n=12) served as the baseline control group. All rats were housed until they were 12 weeks old. The rats in the baseline group and the WKY group rats were sacrificed, and blood and kidney were collected for examination. In the renal denervation, sham and control groups, the blood pressure was continuously monitored. One and six weeks after renal denervation, 6 rats in each group were sacrificed, and blood and kidney were collected for examination. ELISA was employed to measure the plasma renalase, and western blot analysis was performed to detect the expression of TH and renalase in the kidney. Compared with the WKY rats, SH rats in the baseline group had significantly increased blood pressure and markedly elevated TH protein expression (P<0.05), but dramatically reduced plasma renalase content and protein expression of renalase in the kidney (P<0.05). One week after surgery, the mean arterial pressure and TH protein expression in the surgery group was lowered compared with the baseline group and dramatically reduced when compared with the sham and control groups (P<0.05). In the surgery group, renalase levels were markedly increased compared with the baseline, sham and control groups (P<0.05). Six weeks after renal denervation, the mean arterial pressure and TH levels in the surgery group were significantly increased while the renalase content and expression were markedly reduced compared with those at week 1, however, there were no marked differences among the surgery, sham and control groups (P>0.05). Moreover, no pronounced differences in the above variables were found between the sham and control groups at any timepoint (P>0.05). Renal denervation can lower blood pressure, which may be attributed to the suppression of sympathetic nerves, increase in plasma renalase content and renalase expression in the kidney.

Effect of renal denervation procedure on left ventricular hypertrophy of hypertensive rats and its mechanisms.

PURPOSE: To investigate the effect of renal denervation (RDN) on the blood pressure, left ventricular hypertrophy and myocardial expression of TLR4/NF-κB in spontaneously hypertensive rats (SHR). METHODS: A total of 36 SHR were randomly assigned into control group (D0), RDN group (D) and sham group (S). 12 WKY rats of same age served as controls (WKY group). Rats in the D0 and WKY groups were sacrificed, but rats in the D and S group were sacrificed at one week and six weeks after surgery. The heart was collected and the left ventricle weighted followed by calculation of left ventricular mass index (LVMI). RESULTS: In the D0 group, the blood pressure, LVMI and protein expression of TLR4, NF-κB, TNF-α and IL-6 in the myocardium were markedly higher than that in the WKY group (p<0.05). In the D1 and D2 group, the LVMI, NE and protein expression of TLR4, NF-κB, TNF-α and IL-6 in the myocardium were significantly reduced (p<0.05). CONCLUSION: Renal denervation can significantly delay the progression of left ventricular hypertrophy in spontaneously hypertensive rats, which may be attributed to the not only the suppression of sympathetic activity and attenuation of pressure load but the improvement of myocardial immuno-inflammation.

Effect of renal denervation procedure on left ventricular hypertrophy of hypertensive rats and its mechanisms / Efeito da denervação renal na hipertrofia do ventrículo esquerdo de ratos hipertensos e seu mecanismo

PURPOSE: To investigate the effect of renal denervation (RDN) on the blood pressure, left ventricular hypertrophy and myocardial expression of TLR4/NF-κB in spontaneously hypertensive rats (SHR). METHODS: A total of 36 SHR were randomly assigned into control group (D0), RDN group (D) and sham group (S). 12 WKY rats of same age served as controls (WKY group). Rats in the D0 and WKY groups were sacrificed, but rats in the D and S group were sacrificed at one week and six weeks after surgery. The heart was collected and the left ventricle weighted followed by calculation of left ventricular mass index (LVMI). RESULTS: In the D0 group, the blood pressure, LVMI and protein expression of TLR4, NF-κB, TNF-α and IL-6 in the myocardium were markedly higher than that in the WKY group (p<0.05). In the D1 and D2 group, the LVMI, NE and protein expression of TLR4, NF-κB, TNF-α and IL-6 in the myocardium were significantly reduced (p<0.05). CONCLUSION: Renal denervation can significantly delay the progression of left ventricular hypertrophy in spontaneously hypertensive rats, which may be attributed to the not only the suppression of sympathetic activity and attenuation of pressure load but the improvement of myocardial immuno-inflammation.

OBJETIVO: Investigar o efeito da denervação renal na pressão sanguínea, na hipertrofia do ventrículo esquerdo e a expressão miocárdica de TLR4/NF-kB em ratos espontaneamente hipertensos. MÉTODOS: Trinta e seis SHR ratos foram aleatoriamente distribuídos em grupo controle, grupo denervação renal (D) e grupo sham(S). 12 WKY ratos de mesma idade serviram de controle. Os ratos controles foram sacrificados, mas os ratos com denervação renal e sham foram sacrificados uma semana e seis semanas após a cirurgia. O coração foi retirado e o ventrículo esquerdo pesado seguido pelo cálculo da massa ventricular (LVMI). RESULTADOS: No grupo DO, a pressão sanguínea, LVMI e a expressão proteica de TLR4, NF-κB, TNF-α e IL-6, no miocárdio foram marcadamente maiores do que o grupo WKY (p<0,05). Nos grupos D1 e D2, o LVMI, NE e a expressão proteica de TLR4, NF-κB, TNF-α e IL-6 no miocárdio foi significantemente reduzido (p<0,05). CONCLUSÃO: A denervação renal pode significantemente retardar a progressão da hipertrofia ventricular esquerda em ratos espontaneamente hipertensos, o que pode ser atribuído não apenas pela supressão da atividade simpática e atenuação da pressão, mas pela melhora na imunoinflamação miocárdica.