Risk factors for failure of eradicating infection in a single arthroscopic surgical procedure for septic arthritis of the adult native shoulder with a focus on the volume of irrigation.

BACKGROUND: Septic arthritis of a native joint is relatively rare but is still a challenging and important orthopedic emergency. Most previous reports have focused on the clinical outcomes rather than the risk factors for failure in arthroscopic surgery. METHODS: We retrospectively reviewed the records of patients with septic monoarthritis of the shoulder who underwent arthroscopic irrigation and débridement between January 2007 and January 2019. All patients were divided into 2 groups according to recurrence after a single arthroscopic surgical procedure: eradicated group or recurred group. To identify risk factors affecting the recurrence of septic arthritis of the shoulder after arthroscopic surgery, the following parameters were considered: age; sex; involved side; presentation of rotator cuff tear; volume of irrigation; bacterial organism involved; preoperative erythrocyte sedimentation rate, C-reactive protein level, and white blood cell count in blood and joint fluid; diabetes mellitus; and hypertension. We compared the eradicated and recurred groups regarding the presence of potential risk factors. RESULTS: The study included 97 patients with a mean age of 61 years. Septic arthritis of the shoulder was eradicated completely with a single arthroscopic surgical procedure in 85 patients. However, a second arthroscopic surgical procedure was necessary in 12 patients (12.4%) because of infection recurrence. No significant differences were found between groups except in the volume of irrigation (P < .001). CONCLUSIONS: Most patients with septic arthritis (87.6%) of native shoulders were effectively treated with a single arthroscopic irrigation and débridement. The amount of irrigation may be the most important factor for preventing the need for additional surgical management.

Design, synthesis, docking and biological evaluation of 4-phenyl-thiazole derivatives as autotaxin (ATX) inhibitors.

The autotaxin-lysophophatidic acid (ATX-LPA) signaling pathway is involved in several human diseases such as cancer, autoimmune diseases, inflammatory diseases neurodegenerative diseases and fibrotic diseases. Herein, a series of 4-phenyl-thiazole based compounds was designed and synthesized. Compounds were evaluated for their ATX inhibitory activity using FS-3 and human plasma assays. In the FS-3 assay, compounds 20 and 21 significantly inhibited the ATX at low nanomolar level (IC50=2.99 and 2.19nM, respectively). Inhibitory activity of 21 was found to be slightly better than PF-8380 (IC50=2.80nM), which is one of the most potent ATX inhibitors reported till date. Furthermore, 21 displayed higher potency (IC50=14.99nM) than the first clinical ATX inhibitor, GLPG1690 (IC50=242.00nM) in the human plasma assay. Molecular docking studies were carried out to explore the binding pattern of newly synthesized compounds within active site of ATX. Docking studies suggested the putative binding mode of the novel compounds. Good ATX inhibitory activity of 21 was attributed to the hydrogen bonding interactions with Asn230, Trp275 and active site water molecules; electrostatic interaction with catalytic zinc ion and hydrophobic interactions with amino acids of the hydrophobic pocket.

Total ischemic time and age as predictors of PCI failure in STEMIs: A systematic review.

BACKGROUND: When feasible, primary percutaneous coronary intervention (PCI) is the definitive intervention for ST-elevation myocardial infarction (STEMI). However, cardiac tissue reperfusion is not always achievable after opening the infarct-related artery. Studies have investigated associating factors and scoring for the "no-reflow" phenomenon. This paper aims to systematically establish the predictive values of total ischemic time and patient age as factors of coronary no-reflow in patients undergoing primary PCI. METHODS: A systematic search was performed using EBSCOhost, including CINAHL Complete, Academic Search Premier, MEDLINE with Full Text, Cochrane Central Register of Controlled Trials, and Cochrane Database of Systematic Reviews. Search results were compiled utilizing Zotero reference manager and exported to Covidence.org for screening, selection, and data extraction by two independent reviewers. The Newcastle-Ottawa Quality Assessment Scale for Cohort Studies was used to evaluate the eight selected studies. RESULTS: The initial search resulted in 367 articles, with eight meeting the inclusion criteria with a total of 7060 participants. Our systematic review demonstrated that for patients older than 60 years, the odds of the no-reflow phenomenon increased 1.53- 2.53 times. Additionally, patients with increased total ischemic time had 1.147- 4.655 times the odds of no-reflow incidence. CONCLUSIONS: Patients older than 60 years with a total ischemic time >4-6 h are at higher risk of PCI failure due to the no-reflow phenomenon. Therefore, new guidelines and more research to prevent and treat this physiologic occurrence are essential to improve coronary reperfusion after primary PCI.

The Novel Tetra-Specific Drug C-192, Conjugated Using UniStac, Alleviates Non-Alcoholic Steatohepatitis in an MCD Diet-Induced Mouse Model.

Non-alcoholic steatohepatitis (NASH) is a complex disease resulting from chronic liver injury associated with obesity, type 2 diabetes, and inflammation. Recently, the importance of developing multi-target drugs as a strategy to address complex diseases such as NASH has been growing; however, their manufacturing processes remain time- and cost-intensive and inefficient. To overcome these limitations, we developed UniStac, a novel enzyme-mediated conjugation platform for multi-specific drug development. UniStac demonstrated high conjugation yields, optimal thermal stabilities, and robust biological activities. We designed a tetra-specific compound, C-192, targeting glucagon-like peptide 1 (GLP-1), glucagon (GCG), fibroblast growth factor 21 (FGF21), and interleukin-1 receptor antagonist (IL-1RA) simultaneously for the treatment of NASH using UniStac. The biological activity and treatment efficacy of C-192 were confirmed both in vitro and in vivo using a methionine-choline-deficient (MCD) diet-induced mouse model. C-192 exhibited profound therapeutic efficacies compared to conventional drugs, including liraglutide and dulaglutide. C-192 significantly improved alanine transaminase levels, triglyceride accumulation, and the non-alcoholic fatty liver disease activity score. In this study, we demonstrated the feasibility of UniStac in creating multi-specific drugs and confirmed the therapeutic potential of C-192, a drug that integrates multiple mechanisms into a single molecule for the treatment of NASH.

Repeated Dry Sauna Therapy Improves Quality of Life in Obese Korean People.

BACKGROUND: Dry sauna treatments improve the quality of life for chronic pain, congestive heart failure, and type 2 diabetes patients. This study aimed to determine whether dry sauna therapy improved the quality of life of obese people. METHODS: A total of 38 consecutive participants aged over 20 years with a body mass index of ≥25 kg/m2 were recruited for the study. The participants were treated with a 90°C dry sauna for 15 minutes, twice daily for 4 consecutive days. To assess the quality of life, all participants completed the 5 level EQ-5D questionnaires and the EQ-Visual Analog Scale. Study parameters were measured on the same day prior to commencing the sauna sessions in a fasted state and 2 days after the last sauna session. RESULTS: The average age was 62.3±9.5 years; 84.2% of the participants were female. The mean body mass index was 28.5±2.4 kg/m2. Dry sauna significantly improved the mean 5 level EQ-5D index scores from 0.83±0.12 to 0.89±0.11 and increased the mean EQ-Visual Analog Scale from 79.0±15.2 to 91.1±9.7. However, there were no significant changes in body mass index, blood pressure, heart rate, or body composition before and after the 8-session sauna therapy. CONCLUSION: Dry sauna improved the health-related quality of life of obese patients without adverse events. Further clinical studies in larger study populations are needed to verify these findings and provide concrete evidence for obesity treatment.

Arthroscopic Treatment for Femoroacetabular Impingement with Extraspinal Diffuse Idiopathic Skeletal Hyperostosis.

BACKGROUND: Patients with extraspinal diffuse idiopathic skeletal hyperostosis (DISH) involving the hip joint have symptoms like femoroacetabular impingement (FAI). To date, no reported study has determined the clinical outcomes of arthroscopic treatment in extraspinal DISH involving the hip joint. METHODS: A total of 421 hips with FAI that underwent arthroscopic treatment were reviewed retrospectively. We determined the extraspinal involvement of DISH with three-dimensional computed tomography (3D-CT) and simple radiography of the pelvis and hip joint. Clinical outcomes were evaluated at a minimum of 2 years postoperatively. The visual analog scale score (VAS), modified Harris hip score (MHHS), and hip outcome score-activity of daily living scale (HOS-ADL) were used, and hip range of motion (ROM) was evaluated pre- and postoperatively and at the time of the final follow-up. RESULTS: Among the 421 hips (372 patients) with FAI that underwent arthroscopic treatment, 17 hips (12 patients, 4.04%) had extraspinal DISH on the hip joints. The mean age of the patients was 51.5 years. The 3D-CT scans and simple radiographs showed extraspinal DISH on multiple points around the pelvis and hip joint. Nine of the 17 hips (seven of 12 patients) had spinal DISH. At the final follow-up, VAS, MHHS, and HOS-ADL improved significantly from 6.5, 65.3, and 66.6, respectively, to 1.2, 87.8, and 89.5, respectively, and hip flexion and internal rotation improved significantly from 97.7° and 7.9°, respectively, to 117.1° and 18.2°, respectively. CONCLUSIONS: This study has demonstrated that extraspinal DISH involving the hip joint could lead to FAI, and arthroscopic treatment could result in relief of symptoms, including pain and ROM limitation, in extraspinal DISH patients.

Discovery and optimization of ATX inhibitors via modeling, synthesis and biological evaluation.

Autotaxin (ATX) is a potential target for the treatment of various cancers. A new series of ATX inhibitors was rationally designed and synthesized based on our previous study. Biological evaluation and structure-activity relationship (SAR) of this series are discussed. Among fourteen synthesized derivatives, six compounds (2, 3, 4, 12, 13 and 14) exhibited enhanced ATX inhibitory activities with IC50 values in the low nanomolar range. Molecular interactions of all the synthesized compounds within the active site of ATX were studied through molecular docking studies. Herein, we describe our lead optimization efforts that resulted in the identification of a potent ATX inhibitor (compound 4 with IC50 = 1.23 nM, FS-3 and 2.18 nM, bis-pNPP). Furthermore, pharmacokinetic properties of this most promising compound are profiled.

Differential sensitivity of melanoma cell lines with differing B-Raf mutational status to the new oncogenic B-Raf kinase inhibitor UI-152.

Activating mutations in B-Raf kinase are common in malignant melanoma, an aggressive tumor of neuroectodermal origin. In the present study, the antiproliferative effect of the new oncogenic B-Raf targeting drug UI-152 on two types of melanoma cell lines with differing B-Raf mutational status was examined, and the underlying mechanisms were investigated. In cellular assays, UI-152 displayed high selectivity for tumor cells bearing B-Raf(V600E), showing more than 1000-fold higher inhibition of their proliferation than wild-type B-Raf-bearing cells. As expected, UI-152 completely abolished MEK-ERK phosphorylation in A375P cells harboring B-Raf(V600E). In SK-MEL-2 cells expressing B-Raf(WT), UI-152 caused the paradoxical activation of the MAPK pathway but to a much lesser extent than that observed of other oncogenic B-Raf inhibitors. These data suggest that UI-152 may be a more ideal B-Raf inhibitor capable of preserving potency against oncogenic B-Raf while minimizing the paradoxical activation of MAPK signaling. In addition, we showed that UI-152 treatment of A375P cells simultaneously induced cellular autophagy and apoptosis. However, autophagy inhibition with 3-methyladenine and inhibition of apoptosis by overexpression of the X-linked inhibitor of apoptosis failed to rescue melanoma cells from UI-152-induced cell death, implying that apoptosis and autophagy may cooperate in the induction of cell death in UI-152-treated cells. Collectively, our data suggest that UI-152 may be an effective B-Raf inhibitor and a potential therapeutic strategy for B-Raf(WT) and Ras mutant melanoma.

Src Family Kinase Inhibitor PP2 Induces LC3 Conversion in a Manner That is Uncoupled from Autophagy and Increases Apoptosis in Multidrug-Resistant Cells.

Recently, we reported that defective autophagy may contribute to the inhibition of the growth in response to PP2 (4-amino-5-(4-chlorophenyl)-7-(t-butyl)pyrazolo[3,4-d]pyrimidine), a selective SFK inhibitor, in multidrug-resistant v-Ha-ras-transformed NIH 3T3 cells (Ras-NIH 3T3/Mdr). In this study, we demonstrated that PP2 induces LC3 conversion via a mechanism that is uncoupled from autophagy and increases apoptosis in Ras-NIH 3T3/Mdr cells. PP2 preferentially induced autophagy in Ras-NIH 3T3 cells rather than in Ras-NIH 3T3/Mdr cells as determined by LC3-I to LC3-II conversion and GFP-LC3 fluorescence microscopy. Beclin 1 knockdown experiments showed that, regardless of drug resistance, PP2 induces autophagy via a Beclin 1-dependent mechanism. PP2 induced a conformational change in Beclin 1, resulting in the enhancement of the pro-autophagic activity of Beclin 1, in Ras-NIH 3T3 cells. Further, PI3K inhibition induced by wortmannin caused a significant increase in apoptosis in Ras-NIH 3T3 cells, as demonstrated by flow cytometric analysis of Annexin V staining, implying that autophagy inhibition through PI3K increases apoptosis in response to PP2 in Ras-NIH 3T3 cells. However, despite the fact that wortmannin abrogates PP2-induced GFP-LC3 punctae formation, some LC3 conversion remains in Ras-NIH 3T3/Mdr cells, suggesting that LC3 conversion may occur in an autophagy-independent manner. Taken together, these results suggest that PP2 induces LC3 conversion independent of PI3K, concomitant with the uncoupling of LC3 conversion from autophagy, in multidrug-resistant cells.

Occurrence and prognostic implications of micrometastases in lymph nodes from patients with submucosal gastric carcinoma.

BACKGROUND: The aims of this study were to assess the incidence of micrometastases of lymph nodes in patients with early gastric cancer invading the submucosal layer and to investigate the correlation between nodal micrometastases and malignancy potential to determine whether micrometastases of lymph nodes have prognostic significance, by use of an anticytokeratin immunohistochemical technique. METHODS: A total of 2272 lymph nodes taken from 88 patients (25.8 per case) were assessed by immunohistochemical technique by use of monoclonal anti-human cytokeratin 8 antibodies. Clinicopathologic parameters and prognosis were compared between patients with and without micrometastases. RESULTS: The incidence of nodal involvement by tumor cells in 88 patients with submucosal gastric cancer increased from 19.3% (17 patients) by hematoxylin-eosin (H&E) staining to 31.8% (28 patients) by cytokeratin immunostaining. The rate of positive node in this study increased from 1.0% (23 of 2272 nodes) by H&E staining to 2.5% (57 of 2272 nodes) by immunostaining (P = .0002). No correlation was observed between the incidence of lymph node micrometastases and various clinicopathologic parameters, including tumor site and size, histological differentiation, Lauren classification, gross tumor type, vascular and lymphatic invasion, and perineural invasion. There was no difference in disease-free survival, estimated by the Kaplan-Meier life-table method, between the micrometastasis-negative and -positive groups (95% and 92.9%, respectively). Multivariate analyses showed that tumor size and diffuse subtype by the Lauren classification were significant factors for survival time (P = .0042 and .014, respectively). CONCLUSIONS: Immunohistochemical staining with an anticytokeratin antibody seems to be of little prognostic value in patients with submucosal gastric carcinoma. Thus, this immunostaining technique does not offer a significant benefit of different strategies for additional therapy or follow-up over conventional pathologic staging with H&E staining.

Room-temperature ferromagnetism in (Zn1-xMnx)GeP2 semiconductors.

We report on the discovery of a room-temperature ferromagnetic semiconductor in chalcopyrite (Zn1-xMnx)GeP2 with Tc = 312 K. We have also observed that, at temperatures below 47 K, samples for x = 0.056 and 0.2 show a transition to the antiferromagnetic (AFM) state, so that ferromagnetism is well defined to be present between 47 and 312 K. The observation that the AFM phase is most stable at low temperatures is consistent with the predictions of full-potential linearized augmented plane wave total energy calculations and has consequences for other chalcopyrite materials.