Palliative arthroscopic debridement with continuous irrigation for infected total knee arthroplasty in high mortality risk patients.

PURPOSE: This study aimed to evaluate the infection control rate of palliative arthroscopic debridement, antibiotics, and implant retention (DAIR) for the high mortality risk or terminal cancer stage patients. METHODS: From March 2018 to August 2021, 21 patients met the following inclusion criteria: old age of more than 80, diagnosed as a terminal stage of cancer, high risk of mortality and morbidity representing as Charlson comorbidity index (CCI) ≥ 5, low daily activity with disabled extremity, and re-infection after two-stage revision. Each patient underwent arthroscopic DAIR and additional continuous irrigation for 48 hours. The need for subsequent re-arthroscopic DAIR or two-stage revision was determined by the post-operative trends of C-reactive protein (CRP) levels. Infection control was defined as continuing controlled status of infection based on clinical and laboratory results by one or two times of arthroscopic DAIR within initial two months. Treatment failure was defined as more than three times arthroscopic debridement, two-stage revision surgery, or expired due to uncontrolled infection. RESULTS: Arthroscopic DAIR controlled the infection in 19 (90.5%) of the 21 cases. The other knee underwent a total of three times of re-arthroscopic DAIR and the other one underwent two-stage revision. Although five patients expired during the follow-up period due to worsening medical problems or terminal cancer, there were no deaths from uncontrolled infection, sepsis, or surgery-related complications. CONCLUSIONS: Arthroscopic debridement with continuous irrigation for the infection TKA with high mortality risk or terminal cancer patients showed a 90.5% infection control rate. For high-risk patients, arthroscopic debridement with continuous irrigation can be an alternative treatment to improve the quality of life during survival.

Discovery of a High Affinity, Orally Bioavailable Macrocyclic FXIa Inhibitor with Antithrombotic Activity in Preclinical Species.

Oral factor XIa (FXIa) inhibitors may provide a promising new antithrombotic therapy with an improved benefit to bleeding risk profile over existing antithrombotic agents. Herein, we report application of a previously disclosed cyclic carbamate P1 linker which provided improved oral bioavailability in the imidazole-based 13-membered macrocycle to the 12-membered macrocycle. This resulted in identification of compound 4 with desired FXIa inhibitory potency and good oral bioavailability but high in vivo clearance. Further structure-activity relationship (SAR) studies of heterocyclic core modifications to replace the imidazole core as well as various linkers to the P1 group led to the discovery of compound 6f, a potent FXIa inhibitor with selectivity against most of the relevant serine proteases. Compound 6f also demonstrated excellent pharmacokinetics (PK) profile (high oral bioavailability and low clearance) in multiple preclinical species. Compound 6f achieved robust antithrombotic efficacy in a rabbit efficacy model at doses which preserved hemostasis.

Rhododendrin inhibits toll-like receptor-7-mediated psoriasis-like skin inflammation in mice.

Many active compounds present in Rhododendron brachycarpum have been used in traditional Oriental medicine for the treatment of various skin diseases. However, the precise mechanism of action of the compounds isolated from R. brachycarpum and their relevance as therapeutics for the treatment of psoriasis remain elusive. In this study, we report that rhododendrin isolated from R. brachycarpum strongly inhibits imiquimod (IMQ)-induced psoriasis-like skin inflammation in mice. We showed that topical treatment with rhododendrin reduces IMQ-induced skin hyperplasia, inflammatory mononuclear cell infiltration and the expression of pro-inflammatory mediators in mouse skin. In addition, we found that rhododendrin inhibits the activation of the TLR-7/NF-κB and mitogen-activated protein kinase pathways in both IMQ-induced psoriasis-like skin inflammation in mice and in normal human epidermal keratinocytes treated with IMQ. These results suggest that rhododendrin has an anti-inflammatory effect and can be used as a therapeutic to fight against psoriasis and other inflammatory skin diseases.

Antiobesity Effects of Salvia plebeia R. Br. Extract in High-Fat Diet-Induced Obese Mice.

This study was designed to investigate the antiobesity effects of Salvia plebeia R. Br. ethanolic extracts (SPE) in mice fed high-fat diets (HFD). Male C57BL/6J mice were randomly assigned to four groups: normal diet (Chow), high-fat diet (HFD, 45% fat), HFD+SPE 200 (200 mg/kg b.w.), and HFD+SPE 400 (400 mg/kg b.w.). Extracts were administered orally every day for 8 weeks. Increases in body/fat weight and feed efficiency ratio were monitored in all mice. In addition, obesity resulting from feeding HFD to the mice was confirmed by the increase of glucose level, aspartate transaminase, alanine transaminase, triglyceride (TG), high-density lipoprotein cholesterol, very low-density lipoprotein-c, leptin, and adiponectin in blood. The SPE-treated mice gained less body and mesenteric/subcutaneous adipose tissues weights and had lower TG, very low-density lipoprotein cholesterol, leptin, and glucose level in serum, compared to the HFD group. Moreover, histopathological examinations revealed that the size of adipocytes in liver and adipose tissue was significantly decreased by SPE, compared to the HFD group. The expression of adipogenesis transcription factors (e.g., peroxisome proliferator activated receptor γ and CCAAT/enhancer binding protein α) and lipogenesis-related target genes (adipocyte fatty acid-binding protein 2, lipoprotein lipase, fatty acid synthase, and sterol regulatory element-binding transcription factor 1c) in HFD-induced obese mice was decreased by SPE treatment. These results suggest that SPE attenuates the fat accumulation in HFD-induced obese mice by suppressing the expressions of genes related to adipogenesis and lipogenesis activity. Therefore, SPE could be developed as a potential therapy for reduction of body weight and antiobesity intervention.

Artocarpus altilis (Parkinson) Fosberg Extracts and Geranyl Dihydrochalcone Inhibit STAT3 Activity in Prostate Cancer DU145 Cells.

Artocarpus altilis (Parkinson) Fosberg has traditionally been used in Indonesia for the treatment of liver cirrhosis, hypertension, and diabetes. In many other countries, it is used for the treatment of malaria, yellow fever, and dengue fever. It has been reported that A. altilis extracts have antiatherosclerotic and cytoprotective effects, but its molecular targets in tumor cells are not yet fully understood. The A. altilis extracts and the partially purified fraction have been shown to inhibit STAT3 activity and the phosphorylation of STAT3 in a dose-dependent manner. To identify the active components, a bioassay-guided isolation of the partially purified fraction resulted in the identification of a geranyl dihydrochalcone, CG901. Its chemical structure was established on the basis of spectroscopic evidence and comparison with published data. The partially purified fraction and the isolated a geranyl dihydrochalcone, CG901, down-regulated the expression of STAT3 target genes, induced apoptosis in DU145 prostate cancer cells via caspase-3 and PARP degradation, and inhibited tumor growth in human prostate tumor (DU145) xenograft initiation model. These results suggest that A. altilis could be a good natural source and that the isolated compound will be a potential lead molecule for developing novel therapeutics against STAT3-related diseases, including cancer and inflammation.

Rhododendrin ameliorates skin inflammation through inhibition of NF-κB, MAPK, and PI3K/Akt signaling.

A wide range of active compounds isolated from nature is used in clinical applications and as a source of lead compounds for drug development. Rhododendron brachycarpum has been used as an oriental herbal medicine for skin inflammatory diseases. In this study, we isolated rhododendrin from Rhododendron brachycarpum leaves and investigated its molecular mechanisms for anti-inflammatory effect. Rhododendrin showed intracellular reactive oxygen species scavenging activity and suppressed nuclear translocation of nuclear factor-κB (NF-κB) by inhibiting phosphorylation of NF-κB, inhibitor of NF-κB(IκBα), and IκBα kinase(IKKα/ß). Furthermore, rhododendrin inhibited mitogen-activated protein kinases (MAPKs), including ERK1/2, p38, and decreased c-Jun N-terminal kinase (JNK) and phosphoinositide 3-kinase (PI3K)/Akt signaling. As a result, rhododendrin reduced expression of pro-inflammatory mediators, such as cyclooxygenase-2 (COX-2), intracellular adhesion molecule-1 (ICAM-1), interleukin-1α (IL-1α), IL-1ß, IL-6, IL-8, tumor necrosis factor-α (TNF-α), interferon-γ (IFN-γ), chemokine (C-X-C) motif ligand 1 (CXCL1), and chemokine (C-C motif) ligand 17 (CCL17) in TNF-α/IFN-γ-stimulated keratinocytes. Notably, we demonstrated that topically applied rhododendrin alleviated skin inflammation in trinitrochlorobenzene (TNCB)-treated mouse ear skins. Collectively, these results indicate that rhododendrin is a biologically active compound that exhibits anti-inflammatory activity and is a promising candidate molecule to treat inflammatory skin diseases, such as psoriasis.

Limited clinical value of periablative changes of serum markers in the prediction of biochemical remission in patients with papillary thyroid cancer.

PURPOSE: Remnant thyroid ablation and 1-year stimulated thyroglobulin (sTg) measurement are recommended for those who have undergone total thyroidectomy for differentiated thyroid cancer. The serum Tg kinetics in such patients are still unclear. This study was designed to evaluate whether the periablative change in serum markers can predict biochemical remission in papillary thyroid cancer (PTC) patients. METHODS: We reviewed the medical records of 185 patients who were given high-dose radioactive iodine ablation therapy from January 2006 to December 2008. Serum Tg, TSH, and anti-Tg antibody (TgAb) were measured on the day and the following 10th day of radioactive iodine administration. We defined preablative sTg as Tg-1, postablative Tg measured on the 10th day of ablation as Tg-2, and the 1-year sTg as Tg-3. ΔTg means Tg2-Tg1. The same definition was applied to TgAb. RESULTS: A biochemical remission defined as Tg-3 < 2 ng/ml was achieved in 144 patients. Among the patients who achieved biochemical remission, PTC recurred in six during a median follow-up of 54 months. Tg-1 < 3.3 ng/ml (p < 0.0001) predicted biochemical remission. Neither the ΔTg nor ΔTgAb was useful for predicting biochemical remission. On the evaluation of recurrence after biochemical remission, Tg-1 > 5.32 (p < 0.0001) and Tg-3 > 2.9 (p = 0.01) were proven to be statistically significant cutoff values for predicting recurrence. The ΔTg and ΔTgAb were not able to predict recurrence. CONCLUSION: For the prediction of biochemical remission or recurrence after biochemical remission, preablative sTg was demonstrated to be a statistically significant serum marker. However, short-term changes in biochemical markers including Tg and TgAb around the day of ablation could not provide useful clinical information about biochemical remission or disease recurrence. In conclusion, 1-year sTg measurement cannot be omitted with short-term change.

Immunohistochemical study identifying prognostic biomolecular markers in nasopharyngeal carcinoma treated by radiotherapy.

BACKGROUND: We evaluated the predictive significance of 14 reported markers using immunohistochemical study in nasopharyngeal carcinoma. METHODS: Immunohistochemical stainings were done in 38 patients for Met, cyclooxygenase-2 (COX-2), nm23-H1, epidermal growth factor receptor (EGFR), p63, early growth response factor 1 (Egr1), chromosome segregation 1-like (CSE1L), cathepsin-D (aspartyl protease), C-erbB2, p53, signal transducers and activators of transcription (STAT3/STAT5), CD138 (Syndecan-1), and LIN28 with the usual methods. RESULTS: The median follow-up time was 30 months (11-83 months). High Met and CD138 expression were statistically significant negative prognostic factors on survival. The expression of Egr1 had a positive prognostic effect on survival. The combined score of these 3 markers, Met plus CD138 minus Egr1, was a strong prognostic factor. The median survival curve was distinctly separated in accord with this combined score. No prognostic value was revealed in COX-2, nm23-H1, EGFR, p63, CSE1L, cathepsin-D, C-erbB2, p53, STAT3, STAT5, and LIN28. CONCLUSIONS: The combined score of these markers could be used to stratify biomolecular risk groups.