Long-term impact of angiotensin receptor-neprilysin inhibitor based on short-term treatment response in heart failure.

AIMS: The long-term effect of angiotensin receptor-neprilysin inhibitor (ARNI) remains uncertain in patients who have experienced improvements in left ventricular (LV) systolic function or significant LV reverse remodelling following a certain period of treatment. It is also unclear how ARNI performs in patients who have not shown these improvements. This study aimed to assess the impact of prolonged ARNI use compared with angiotensin-converting enzyme inhibitors (ACEIs)/angiotensin receptor blockers (ARBs) in patients with and without significant treatment response after 1 year of heart failure (HF) treatment. METHODS AND RESULTS: The present study enrolled patients with HF with reduced ejection fraction (HFrEF) who were treated with either ARNI or ACEIs/ARBs within 1 year of undergoing index echocardiography. After 1 year of treatment, patients were reclassified into the following groups: (i) patients with HF with improved ejection fraction and persistent HFrEF and (ii) patients with and without LV reverse remodelling based on the follow-up echocardiography. The effect of ARNI versus that of ACEIs/ARBs in each group was assessed from the time of categorizing into new groups using the composite event of all-cause mortality and HF hospitalization. A total of 671 patients with HFrEF (age, 66.4 ± 14.1 years; males, 66.8%) were included, and 133 (19.8%) composite events of death and rehospitalization for HF were observed during the follow-up (median follow-up, 44 [interquartile range, 34-51] months). ARNI had a significantly lower event rate than ACEIs/ARBs in patients with HF with improved ejection fraction (7.0% vs. 30.4%, P = 0.020) and those with persistent HFrEF (17.6% vs. 49.7%, P < 0.001). Irrespective of whether patients exhibited LV reverse remodelling (15.8% vs. 31.1%, P = 0.001) or not (15.0% vs. 54.9%, P < 0.001), ARNIs were associated with a significantly lower event rate than ACEIs/ARBs. CONCLUSIONS: Regardless of significant treatment response measured by either LVEF or LV reverse remodelling after 1 year of treatment, the extended utilization of ARNI demonstrated a more favourable prognosis than that of ACEIs/ARBs in patients with HFrEF.

The Mechanism of Action and Clinical Efficacy of Low-Dose Long-Term Macrolide Therapy in Chronic Rhinosinusitis.

Various chronic inflammatory airway diseases can be treated with low-dose, long-term (LDLT) macrolide therapy. LDLT macrolides can be one of the therapeutic options for chronic rhinosinusitis (CRS) due to their immunomodulatory and anti-inflammatory actions. Currently, various immunomodulatory mechanisms of the LDLT macrolide treatment have been reported, as well as their antimicrobial properties. Several mechanisms have already been identified in CRS, including reduced cytokines such as interleukin (IL)-8, IL-6, IL-1ß, tumor necrosis factor-α, transforming growth factor-ß, inhibition of neutrophil recruitment, decreased mucus secretion, and increased mucociliary transport. Although some evidence of effectiveness for CRS has been published, the efficacy of this therapy has been inconsistent across clinical studies. LDLT macrolides are generally believed to act on the non-type 2 inflammatory endotype of CRS. However, the effectiveness of LDLT macrolide treatment in CRS is still controversial. Here, we reviewed the immunological mechanisms related to CRS in LDLT macrolide therapy and the treatment effects according to the clinical situation of CRS.

Obstructive Sleep Apnea and Its Influence on Intracranial Aneurysm.

Obstructive sleep apnea syndrome (OSAS) is associated with cerebrovascular disease, which can lead to life-threatening outcomes. The purpose of the study was to investigate the relationship between OSAS and comorbid intracranial aneurysms. We retrospectively reviewed 564 patients who underwent a polysomnography and brain magnetic resonance angiography as part of their health checkup. We calculated the prevalence of an intracranial aneurysm and OSAS in patients and measured the size of the intracranial aneurysm if present. The mean patient age was 55.6 ± 8.5 years, and 82.3% of them were men. The prevalence of an intracranial aneurysm in patients with OSAS was 12.1%, which is significantly higher than patients with non-OSAS (5.9%, p = 0.031). Patients with OSAS had a much higher prevalence of intracranial aneurysms, after adjusting all possible confounding factors such as age, sex, smoking status, alcohol drinking, and body mass index (odds ratio: 2.32; 95% confidence interval: 1.07-5.04). Additionally, the OSAS group had noticeably larger aneurysms compared with those of the non-OSAS group (3.2 ± 2.0 mm vs. 2.0 ± 0.4 mm, p = 0.013). We found a significant association between OSAS and intracranial aneurysms. OSAS could be another risk factor for the development of intracranial aneurysms.

Impact of intravascular ultrasound and final kissing balloon dilatation on long-term clinical outcome in percutaneous revascularization with 1-stent strategy for left main coronary artery stenosis in drug-eluting stent era.

BACKGROUND: It remains uncertain whether intravascular ultrasound (IVUS) use and final kissing balloon (FKB) dilatation would be standard care of percutaneous coronary intervention (PCI) with a simple 1-stent technique in unprotected left main coronary artery (LMCA) stenosis. This study sought to investigate the impact of IVUS use and FKB dilatation on long-term major adverse cardiac events (MACEs) in PCI with a simple 1-stent technique for unprotected LMCA stenosis. METHODS: Between June 2006 and December 2012, 255 patients who underwent PCI with 1 drug-eluting stent for LMCA stenosis were analyzed. Mean follow-up duration was 1663 ± 946 days. Long-term MACEs were defined as death, nonfatal myocardial infarction (MI) and repeat revascularizations. RESULTS: During the follow-up, 72 (28.2%) MACEs occurred including 38 (14.9%) deaths, 21 (8.2%) nonfatal MIs and 13 (5.1%) revascularizations. The IVUS examination and FKB dilatation were done in 158 (62.0%) and 119 (46.7%), respectively. IVUS use (20.3 versus 41.2%; log-rank P < 0.001), not FKB dilatation (30.3 versus 26.5%; log-rank P = 0.614), significantly reduced MACEs. In multivariate analysis, IVUS use was a negative predictor of MACEs [hazards ratio 0.51; 95% confidence interval (CI) 0.29-0.88; P = 0.017], whereas FKB dilatation (hazard ratio 1.68; 95% CI, 1.01-2.80; P = 0.047) was a positive predictor of MACEs. In bifurcation LMCA stenosis, IVUS use (18.7 versus 48.0%; log-rank P < 0.001) significantly reduced MACEs. In nonbifurcation LMCA stenosis, FKB dilatation showed a trend of increased MACEs (P = 0.076). CONCLUSION: IVUS examination is helpful in reducing clinical events in PCI for LMCA bifurcation lesions, whereas mandatory FKB dilatation after the 1-stent technique might be harmful in nonbifurcation LMCA stenosis.

Potential Therapeutic Effect of Continuous Positive Airway Pressure on Laryngopharyngeal Reflux in Obstructive Sleep Apnea Patients.

To investigate the potential therapeutic effect of continuous positive airway pressure (CPAP) treatment on laryngopharyngeal reflux in obstructive sleep apnea (OSA) patients, we performed a retrospective analysis of data prospectively collected from patients who underwent CPAP therapy after being diagnosed with moderate to severe OSA between January 2019 and May 2020. Subjects were asked to complete the reflux symptom index (RSI) questionnaire before and after CPAP. Additionally, a laryngoscopic examination was performed to evaluate objective endoscopic findings and determine reflux finding score (RFS). A total of 46 patients were included in the analysis. Overall, significant decreases in mean RSI score (10.85 ± 6.40 vs. 8.80 ± 7.99, p < 0.001) and RFS (7.41 ± 3.32 vs. 4.65 ± 2.12, p < 0.001) were observed after CPAP treatment. Within subdomains of the RSI, throat clearing, postnasal drip, breathing difficulty, troublesome cough, and foreign body sensation were significantly improved by CPAP treatment. All subdomains of RFS, with the exception of posterior commissure hypertrophy and granuloma, showed significant differences after CPAP treatment. There were no differences between subgroups according to body mass index or severity of OSA. CPAP treatment in OSA potentially reduces laryngeal reflux symptoms and improves laryngeal examination findings.

Clinical outcomes of bulky parotid gland cancers: need for self-examination and screening program for early diagnosis of parotid tumors.

BACKGROUND: Early detection and diagnosis of parotid gland cancer (PGC) are essential to improve clinical outcomes, because Tumor-Node-Metastasis stage at diagnosis is a very strong indicator of prognosis in PGC. Nevertheless, some patients still present with large parotid mass, maybe due to the unawareness or ignorance of their disease. In this study, we aimed to present the clinical outcomes of bulky PGC (defined by a 4 cm cutoff point for T3-4 versus T1-2 tumors), to emphasize the necessity of a self-examination tool for parotid gland tumor. METHODS: We retrospectively reviewed 60 consecutive cases with bulky (equal to and greater than 4 cm in the longest diameter, determined radiologically) malignant tumors arising from the parotid gland from 1995 to 2016. The clinical and pathological factors were analyzed to identify risk factors for poor outcomes using Cox proportional hazard models. In addition, we designed a self-examination tool for parotid gland tumors, similar to breast self-examination for breast cancer detection. RESULTS: Patients with bulky parotid cancer showed 48.9% 5-year and 24.5% 10-year overall survival rates and a 47.9% risk of high-grade malignancy. The common pathological diagnoses were carcinoma ex pleomorphic adenoma (18.3%), adenocarcinoma (16.7%), mucoepidermoid carcinoma (16.7%), salivary duct carcinoma (16.7%), and adenoid cystic carcinoma (11.7%). Survival analyses revealed that tumor size (hazard ratio, HR = 1.262 upon increase of 1 cm, 95% confidence interval, 95%CI 1.059-1.502), lymph node metastasis (HR = 2.999, 95%CI 1.048-8.583), and high tumor grade (HR = 4.148, 95%CI 1.215-14.154) were independent prognostic factors in multivariable analysis. Functional preservation of the facial nerve was possible only in less than half of patients. CONCLUSION: In bulky PGC, lymph node metastasis at diagnosis and high tumor grade indicated poor survival outcomes, and functional outcomes of the facial nerve were suboptimal. Thus, a public effort seems to be necessary to decrease these patients with bulky PGC, and to increase patients' self-awareness of their disease. As a way of early detection, we proposed a parotid self-examination tool to detect parotid gland tumors at an early stage, which is similar to breast self-examination.

Incidence of postoperative facial weakness in parotid tumor surgery: a tumor subsite analysis of 794 parotidectomies.

BACKGROUND: The reported incidence of facial weakness immediately after parotid tumor surgery ranges from 14 to 65%. The purpose of this study was to evaluate the incidence of postoperative facial weakness related to parotidectomy with use of preoperative computed tomography (CT), intraoperative facial nerve monitoring, and surgical magnification. Also, we sought to elucidate additional information about risk factors for postoperative facial weakness in parotid tumor surgery, particularly focusing on the tumor subsites. METHODS: We retrospectively reviewed 794 cases with parotidectomy for benign and malignant tumors arising from the parotid gland (2009-2016). Patients with pretreatment facial palsy were excluded from the analyses. Tumor subsites were stratified based on their anatomical relations to the facial nerve as superficial, deep, or both. Multivariable logistic regression analyses were conducted to identify risk factors for postoperative facial weakness. RESULTS: The overall incidences of temporary and permanent (more than 6 months) facial weakness were 9.2 and 5.2% in our series utilizing preoperative CT, intraoperative facial nerve monitoring, and surgical magnification. Multivariable analysis revealed that old age, malignancy, and recurrent tumors (revision surgery) were common independent risk factors for both temporary and permanent postoperative facial weakness. In addition, tumor subsite (tumors involving superficial and deep lobe) was associated with postoperative facial weakness, but not tumor size. Extent of surgery was strongly correlated with tumor pathology (malignant tumors) and tumor subsite (tumors involving deep lobe). CONCLUSION: Aside from risk factors for facial weakness in parotid tumor surgery such as old age, malignant, or recurrent tumors, the location of tumors was found to be related to postoperative facial weakness. This study result may provide background data in a future prospective study and up-to-date information for patient counseling.

Modified bolster dressing with continuous suction improves skin graft survival for an oral cavity wound.

BACKGROUND: Skin engraftment of intraoral defects is known to be inconsistent due to mobility of the oral structure, uneven wounds, and accumulation of saliva under the skin graft. To improve the success rate of oral skin graft, we proposed a novel and simple dressing technique for intraoral skin graft to control saliva accumulation, in comparison with the conventional bolster dressing. METHODS: We retrospectively reviewed 31 patients reconstructed with skin graft in their intraoral defect. The patients were divided into two groups; conventional bolster group (n = 21) and modified bolster group (n = 10). In the modified bolster group, a polyvinyl alcohol sponge was designed to fit the skin graft and a suction drain was inserted with tagging suture to apply continuous suction. We analyzed the success rate, the size of the skin grafts and clinical variables of each method. RESULTS: The overall success rate of oral skin graft was not different between the two groups (90.0 and 90.5%). However, partial necrosis in the engrafted skin was observed frequently in the control group (57.1% versus 20.0%). The relative engrafted area was significantly higher in the modified bolster group (55.0 ± 11.6% versus 23.0 ± 18.7%, p = 0.015). The duration of bolster dressing and the time to start an oral diet were shorter in the modified bolster group. CONCLUSIONS: Our modified method could be easily applied for removing saliva accumulation under a skin graft and for enhancing skin engraftment of an oral cavity wound.

Discovery of novel 4-aryl-thieno[1,4]diazepin-2-one derivatives targeting multiple protein kinases as anticancer agents.

A series of 4-aryl-thieno[1,4]diazepin-2-one were synthesized and evaluated for their antiproliferative activities against the A375P melanoma and U937 hematopoietic cell lines. Several compounds showed very potent antiproliferative activities toward both cell lines and the activities were better than that of sorafenib, the reference standard. Derivatives were made as amide (8a-8i, 9a-9m) and urea (10a-10d, 11a-11d) with diverse hydrophobic moieties. One of the most potent inhibitor 10d, 1-(4-((4-ethylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)-3-(4-(2-oxo-2,3-dihydro-1H-thieno [3,4-b][1,4]diazepin-4-yl)phenyl)urea was found to be very potent inhibitor of multi-protein kinases including FMS kinase (IC50 = 3.73 nM) and is a promising candidate for further development in therapeutics for cancer.

Prognostic factors for recurrence of locally advanced differentiated thyroid cancer.

Background and Objectives To present treatment outcomes and prognostic factors for surgical management of locally advanced differentiated thyroid cancer (DTC). METHODS: Retrospective review of 70 patients in a single, tertiary referral institution was done. Clinical pathology characteristics were analyzed to investigate prognosticators, based on primary endpoints; locoregional recurrence alone (LRR), total recurrence (LRR or distant metastasis (DM)), and recurrence-free survival. RESULTS: Recurrent laryngeal nerve (n = 31) and trachea (n = 30) were most commonly invaded organs by tumor. At the mean follow-up of 81.7 months, LRR occurred in 15 patients and/or DM was detected in 15 patients (10 developed LRR and DM). By multivariate analysis, R1 resection (positive margin) and pN1b stage increased risk of LRR with a fold of 3.16 [95%CI 1.08-9.24, P = 0.03] and 5.92 [1.61-21.7, P = 0.007], respectively. Also, they increased risk of total recurrence with a fold of 3.04 [95%CI 1.26-7.31, P = 0.01] and 3.42 [95%CI 1.16-10.0, P = 0.02], respectively. Patients with pN1b stage showed better LRR-free survival than pN0/N1a stage (P = 0.03). Conclusions Along with careful preoperative evaluation of the extent of primary and neck disease, obtaining negative resection margin and aggressive neck management is critical to improve oncologic outcomes of locally advanced DTC.

Pediatric sialolithiasis is not related to oral or oropharyngeal infection: A population-based case control study using the Korean National Health Insurance Database.

OBJECTIVES: Poor oral hygiene is one of the risk factors for sialolithiasis particularly in adults; however the etiology of sialolithiasis in pediatric patients remains largely unknown. The purpose of this study is to identify the association between sialolithiasis and the oral/oropharyngeal infections in the pediatric population, as surrogate indicators for oral hygiene and retrograde infections to the affected salivary gland. METHODS: This was a population based case-control study using the Korean National Health Insurance Database. We identified 10,095 pediatric patients, diagnosed with sialolithiasis, as cases (study period 2011-2015) and 50,475 age/gender/residence matched subjects without sialolithiasis, but with unrelated diseases (e.g., simple trauma in extremities) were set as controls. Logistic regression analyses were conducted to evaluate the association of sialolithiasis with oral or oropharyngeal infections. RESULTS: The morbidity rate of sialadenitis was much higher in the cases than the controls (32.92% vs 0.72%, p < 0.0001). By contrast, the prevalence of oral or oropharyngeal infections (stomatitis, gingivitis, periodontitis, and pharyngo-tonsillitis) was significantly lower in pediatric sialolithiasis patients in all age (0-18) groups. The adjusted odds ratios of the multivariate analyses also confirmed significantly less prevalence of the oral and oropharyngeal infections in pediatric sialolithiasis patients. CONCLUSION: Oral or oropharyngeal infections were inversely associated with pediatric sialolithiasis, suggesting that pediatric sialolithiasis may result from the intrinsic factors of the salivary gland itself, not from oral or oropharyngeal infections.

Efficacy comparison of Korean ginseng and American ginseng on body temperature and metabolic parameters.

Ginseng has beneficial effects in cancer, diabetes and aging. There are two main varieties of ginseng: Panax ginseng (Korean ginseng) and Panax quinquefolius (American ginseng). There are anecdotal reports that American ginseng helps reduce body temperature, whereas Korean ginseng improves blood circulation and increases body temperature; however, their respective effects on body temperature and metabolic parameters have not been studied. We investigated body temperature and metabolic parameters in mice using a metabolic cage. After administering ginseng extracts acutely (single dose of 1000 mg/kg) or chronically (200 mg/kg/day for four weeks), core body temperature, food intake, oxygen consumption and activity were measured, as well as serum levels of pyrogen-related factors and mRNA expression of metabolic genes. Acute treatment with American ginseng reduced body temperature compared with PBS-treated mice during the night; however, there was no significant effect of ginseng treatment on body temperature after four weeks of treatment. VO 2, VCO 2, food intake, activity and energy expenditure were unchanged after both acute and chronic ginseng treatment compared with PBS treatment. In acutely treated mice, serum thyroxin levels were reduced by red and American ginseng, and the serum prostaglandin E2 level was reduced by American ginseng. In chronically treated mice, red and white ginseng reduced thyroxin levels. We conclude that Korean ginseng does not stimulate metabolism in mice, whereas a high dose of American ginseng may reduce night-time body temperature and pyrogen-related factors.

Sodium meta-arsenite ameliorates hyperglycemia in obese diabetic db/db mice by inhibition of hepatic gluconeogenesis.

Sodium meta-arsenite (SA) is implicated in the regulation of hepatic gluconeogenesis-related genes in vitro; however, the effects in vivo have not been studied. We investigated whether SA has antidiabetic effects in a type 2 diabetic mouse model. Diabetic db/db mice were orally intubated with SA (10 mg kg(-1) body weight/day) for 8 weeks. We examined hemoglobin A1c (HbA1c), blood glucose levels, food intake, and body weight. We performed glucose, insulin, and pyruvate tolerance tests and analyzed glucose production and the expression of gluconeogenesis-related genes in hepatocytes. We analyzed energy metabolism using a comprehensive animal metabolic monitoring system. SA-treated diabetic db/db mice had reduced concentrations of HbA1c and blood glucose levels. Exogenous glucose was quickly cleared in glucose tolerance tests. The mRNA expressions of genes for gluconeogenesis-related enzymes, glucose 6-phosphatase (G6Pase), and phosphoenolpyruvate carboxykinase (PEPCK) were significantly reduced in the liver of SA-treated diabetic db/db mice. In primary hepatocytes, SA treatment decreased glucose production and the expression of G6Pase, PEPCK, and hepatocyte nuclear factor 4 alpha (HNF-4α) mRNA. Small heterodimer partner (SHP) mRNA expression was increased in hepatocytes dependent upon the SA concentration. The expression of Sirt1 mRNA and protein was reduced, and acetylated forkhead box protein O1 (FoxO1) was induced by SA treatment in hepatocytes. In addition, SA-treated diabetic db/db mice showed reduced energy expenditure. Oral intubation of SA ameliorates hyperglycemia in db/db mice by reducing hepatic gluconeogenesis through the decrease of Sirt1 expression and increase in acetylated FoxO1.

Enhanced delivery of T cells to tumor after chemotherapy using membrane-anchored, apoptosis-targeted peptide.

Chemotherapy-induced apoptosis of tumor cells enhances the antigen presentation and sensitizes tumor cells to T cell-mediated cytotoxicity. Here we harnessed the apoptosis of tumor cells as a homing signal for the delivery of T cells to tumor. Jurkat T cells were anchored with ApoPep-1, an apoptosis-targeted peptide ligand, using the biocompatible anchor for membrane (BAM), an oleyl acid derivative. The ApoPep-1-BAM conjugate was efficiently anchored to cell membrane, while little anchoring was obtained with ApoPep-1 alone. The retention period of the ApoPep-1-BAM conjugate on cell membrane was approximately 80 and 40 min in the absence and presence of serum, respectively. ApoPep-1 was resistant to degradation in serum until 2h. The apoptosis-targeted T cells that were anchored with the ApoPep-1-BAM preferentially bound to apoptotic tumor cells over living cells. When intravenously injected into tumor-bearing mice, the number of apoptosis-targeted T cells and in vivo fluorescence signals by the homing of the cells to doxorubicin-treated tumor were higher than those of untargeted T cells. Accumulation of apoptosis-targeted T cells at other organs such as liver was not detected. These results suggest that the chemotherapy-induced apoptosis and subsequent enhancement of T cell delivery to tumor by the membrane anchoring of the apoptosis-targeted peptide could be a novel strategy for cancer immunotherapy.

Treadmill exercise prevents aging-induced failure of memory through an increase in neurogenesis and suppression of apoptosis in rat hippocampus.

Aging leads to functional changes in the hippocampus, and consequently induces cognitive deficits, such as failure of memory. Neurogenesis in the hippocampal dentate gyrus continues throughout life, but steadily declines from early adulthood. Apoptosis occurs under various pathologic and physiologic conditions, and excessive apoptotic cell death can cause a number of functional disorders in humans. Apoptosis in the hippocampus also disturbs cognitive functions. In this study, we examined the effect of treadmill exercise on memory in relation to neurogensis and apoptosis in the hippocampal dentate gyrus of old-aged rats. The present results showed that loss of memory by aging was associated with a decrease in neurogenesis and an increase in apoptosis in the hippocampal dentate gyrus. Treadmill exercise improved short-term and spatial memories by enhancing neurogenesis and suppressing apoptosis in the hippocampal dentate gyrus of old-aged rats. In the present study, we showed that treadmill exercise is a very useful strategy for preventing failure of memory in the elderly.

Endoscopy-assisted breast-conserving surgery for early breast cancer.

PURPOSE: Breast-conserving surgery is now accepted as one of the standard therapeutic options for stages I and II breast cancers. Although breast-conserving surgery can help retain a good breast shape, a long marked scar would be a disadvantage. Endoscopic surgery can be performed via a small and remote incision that becomes inconspicuous after surgery. To improve the cosmetic outcome, endoscopic breast-conserving surgery, which can be performed through minimal axillary and periareolar semicircular incisions, was undertaken. METHODS AND MATERIALS: From October 2002 to October 2004, 20 breast cancer patients whose tumor sizes were less than 3 cm and who were clinically node negative without invasion to the skin and pectoralis major muscle underwent endoscopic breast-conserving surgery. First, endoscopic dye-guided sentinel node biopsy was done through a low transverse axillary incision lateral to the pectoralis major muscle. The subpectoral pocket was gently created by Vein Harvest under the view of endoscopic monitor. We made the periareolar semicircular incision to create the skin flap and to resect the tumor-containing quadrant by using Visiport and PowerStar scissors. Frozen-section biopsies were done to rule out tumor invasion to the resection margin. Patient characteristics, tumor characteristics, operation time, and amount of bleedings were all evaluated. RESULTS: The mean age of patients was 45 (range: 25-64). The mean tumor size was 2.2 cm (range: 0.2-4.0 cm). The average operation time of the early 9 cases, except the 3 cases that underwent axillary-node dissection, was 178 minutes, and that of the later 8 cases was 130 minutes (P<0.001). The mean amount of operative bleeding was 184+/-130 ml. There were no major complications. CONCLUSION: Endoscopic breast-conserving surgery is a new technique that can minimize the long operation scar of classic breast-conserving surgery. In properly selected cases, our results showed the maximized cosmetic satisfaction of the breast cancer patients and a shortened operation time after the learning period, promising it could be an alternative to the classic breast-conserving surgery.

Essential roles of Toll-like receptor-4 signaling in arthritis induced by type II collagen antibody and LPS.

Although bacterial LPS has been used to boost the susceptibility to antibody-induced arthritis, the mechanism of the action of LPS remains to be clarified. We investigated whether signals triggered by Toll-like receptor (TLR)-4 mediate the effects of LPS in the context of anti-type II collagen-induced arthritis. The mice defective in the Tlr-4 gene (Tlr-4(lps-d)) were markedly less susceptible than wild type to arthritis, as manifested in arthritic index, incidence and synovitis. Levels of the pro-inflammatory mediators, tumor necrosis factor-alpha and cyclooxygenase-2, in their synovial tissue were also much lower. Serum C3 deposition through the alternative pathway and de novo synthesis of C3 were lower in the Tlr-4(lps-d) mice in the post-acute phase, pointing to an influence of TLR-4 signals on the turnover rate of complement cascades. T cells from the Tlr-4(lps-d) mice failed to proliferate in response to an auto-antigen, glucose-6-phosphate isomerase (GPI), unlike those from wild-type mice, and the serum level of GPI-specific IgG antibody was significantly lower than in the wild-type mice. Interestingly, type 2 responses, such as GPI-specific IgG1 and IL-4 production, were up-regulated in the Tlr-4(lps-d) mice. Taken together, our data suggest that the TLR-4 signaling pathway plays an essential role in the initiation and progression of auto-antibody/LPS-triggered arthritis by inducing pro-inflammatory mediators, C3 deposition, auto-antigen-specific adaptive immune responses and immune deviation between type 1 and type 2 responses.