Ferroptosis driven by radical oxidation of n-6 polyunsaturated fatty acids mediates acetaminophen-induced acute liver failure.

Acetaminophen (APAP) overdose is a common cause of drug-induced acute liver failure. Although hepatocyte cell death is considered to be the critical event in APAP-induced hepatotoxicity, the underlying mechanism remains unclear. Ferroptosis is a newly discovered type of cell death that is caused by a loss of cellular redox homeostasis. As glutathione (GSH) depletion triggers APAP-induced hepatotoxicity, we investigated the role of ferroptosis in a murine model of APAP-induced acute liver failure. APAP-induced hepatotoxicity (evaluated in terms of ALT, AST, and the histopathological score), lipid peroxidation (4-HNE and MDA), and upregulation of the ferroptosis maker PTGS2 mRNA were markedly prevented by the ferroptosis-specific inhibitor ferrostatin-1 (Fer-1). Fer-1 treatment also completely prevented mortality induced by high-dose APAP. Similarly, APAP-induced hepatotoxicity and lipid peroxidation were prevented by the iron chelator deferoxamine. Using mass spectrometry, we found that lipid peroxides derived from n-6 fatty acids, mainly arachidonic acid, were elevated by APAP, and that auto-oxidation is the predominant mechanism of APAP-derived lipid oxidation. APAP-induced hepatotoxicity was also prevented by genetic inhibition of acyl-CoA synthetase long-chain family member 4 or α-tocopherol supplementation. We found that ferroptosis is responsible for APAP-induced hepatocyte cell death. Our findings provide new insights into the mechanism of APAP-induced hepatotoxicity and suggest that ferroptosis is a potential therapeutic target for APAP-induced acute liver failure.

Combination Treatment With Sorafenib and Everolimus Regresses a Doxorubicin-resistant Osteosarcoma in a PDOX Mouse Model.

BACKGROUND/AIM: Osteosarcoma is a rare but recalcitrant type of bone cancer. To discover an effective therapy for osteosarcoma, we used a patient-derived orthotopic xenograft (PDOX) mouse model. A PDOX mouse model has been established for all major cancer types. Strong synergistic efficacy of sorafenib (SFN) and everolimus (EVL) has been demonstrated in several cancers. In the present study, we examined the efficacy of a SFN and EVL combination on a doxorubicin (DOX)-resistant osteosarcoma PDOX. MATERIALS AND METHODS: The osteosarcoma PDOX models were randomly divided into five treatment groups, each containing six mice: Control; DOX; SFN; EVL; and a combination of SFN and EVL. Mice were treated for 14 days. To observe the efficacy of these treatments, tumor size and body weight were measured, and histological sections were analyzed. RESULTS: Tumor growth regression was observed only in the mice treated with the combination of SFN-EVL. Histological analysis revealed necrosis with degenerative changes in tumors treated with a combination of SFN-EVL. CONCLUSION: A SFN-EVL combination could be a novel effective treatment option for osteosarcoma.

Calcium Phosphate Cement in the Surgical Management of Benign Bone Tumors.

BACKGROUND/AIM: This study assessed the mid- to long-term outcomes of calcium phosphate cement (CPC) implantation in benign bone tumor surgery. PATIENTS AND METHODS: Between 2000 and 2015, 130 patients underwent CPC implantation in benign bone tumor surgery. Radiographic findings and clinical outcomes were retrospectively evaluated. RESULTS: The mean follow-up period was 52 months. CPC filling immediately after surgery was sufficient, regardless of the amount of CPC used and the usage of adjuvant substances, which resulted in 92% of the patients' radiological results being classified as good or excellent. Significantly more patients had better CPC filling among patients with less hemorrhage and patients with tourniquet. The number of patients with good or excellent CPC filling had significantly increased by the final follow-up. CONCLUSION: CPC is a useful bone substitute for benign bone tumor surgery providing excellent osteoconductivity and long-lasting stability without internal fixation.

Preoperative evaluation of the efficacy of radio-hyperthermo-chemotherapy for soft tissue sarcoma in a case series.

PURPOSE: Radio-hyperthermo-chemo (RHC) therapy, which combines radiotherapy, hyperthermia, and chemotherapy, for malignant soft tissue tumors has been introduced with the aim of decreasing the possibility of local recurrence after surgery. To avoid unnecessary neoadjuvant therapy and to plan the appropriate surgical treatment, surveillance of RHC therapeutic efficacy during treatment is necessary. In this study, we determined the optimal response criteria to evaluate the efficacy of RHC by comparing preoperative images before and after RHC with pathological evaluation of necrosis in the resected tumor. PATIENTS AND METHODS: From 2004 to 2014, 20 patients were enrolled into this study. Needle biopsy revealed 6 cases of myxoid liposarcoma, 6 cases of undifferentiated pleomorphic sarcoma, 4 cases of myxofibrosarcoma, and 4 cases of synovial sarcoma. Based on the Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 or modified RECIST, we calculated the responses to RHC therapy by comparing pre- and post-RHC therapy images. In addition, resected specimens underwent pathological analysis to evaluate response based on tumor necrosis. The correlation between assessment based on preoperative images and resected tumors were evaluated by the Spearman's rank-order correlation coefficient. RESULT: From the surgical specimens, pathological assessment of necrosis in resected tumor were assessed as less than 50% (2 cases), 50-90% (9 cases), 90-99% (6 cases), and total necrosis (3 cases). Use of the RECIST 1.1 underestimated good responders as stable disease (SD) or progressive disease (PD) in 5 out of 15 cases; on the other hand, use of the modified RECIST did not underestimate the pathological assessment of necrosis. The correlations between responses based on preoperative images and those based on histological assessments were 0.23 (RECIST 1.1) and 0.76 (modified RECIST). CONCLUSION: Because pathological responses can be underestimated using the RECIST 1.1, the modified RECIST, which take into consideration tumor viability, as assessed by contrast MRI, should also be considered when evaluating the efficacy of RHC.

Clinical outcomes of radio-hyperthermo-chemotherapy for soft tissue sarcoma compared to a soft tissue sarcoma registry in Japan: a retrospective matched-pair cohort study.

Regional hyperthermia is considered to enhance the antitumor effects of chemotherapy and radiotherapy. In this study, we confirmed the efficacy of concomitant radiotherapy, hyperthermia, and chemotherapy (RHC) for neoadjuvant treatment of malignant soft tissue sarcoma (STS). From 1994 to 2013, we performed RHC in 150 patients. This study was limited to 60 patients using the following exclusion criteria: salvage for recurrence or unplanned excision, trunk location, metastasis at initiation, non-STS, and no definitive surgery. As a control group, we collected data from 11,031 patients in the Bone and Soft Tissue Tumor Registry in Japan (BSTT). We performed multivariate logistic regression analysis, and propensity scores were created for comparisons between groups. The primary outcome of this study was to compare oncologic outcomes (5-year local control rate [LC] and overall survival rate [OS]). In the RHC group, two local recurrences (3.3%) occurred, and no patients underwent amputation. Margins of definitive surgery were not identical between groups [wide margins (60.0% vs. 85.3%), marginal margins (28.3% vs. 10.5%), and intralesional margins (7.4% vs. 4.2%), RHC and BSTT groups, respectively, P < 0.001]. After adjustment, the difference in OS was not significant between groups (HR = 1.26, P = 0.532); however, a statistically significant difference in LC was observed (HR = 4.82, P = 0.037). RHC resulted in a high LC at 5 years compared to the BSTT group, and amputation was averted in the RHC group, despite the wider margins in the BSTT group. This indicates that less invasive surgery might be achieved with effective neoadjuvant therapy.

Efficacy of cardiopulmonary rehabilitation with adaptive servo-ventilation in patients undergoing off-pump coronary artery bypass grafting.

BACKGROUND: Postoperative complications after cardiac surgery increase mortality. This study aimed to evaluate the efficacy of cardiopulmonary rehabilitation with adaptive servo-ventilation (ASV) in patients undergoing off-pump coronary artery bypass grafting (OPCAB). METHODS AND RESULTS: A total of 66 patients undergoing OPCAB were enrolled and divided into 2 groups according to the use of ASV (ASV group, 30 patients; non-ASV group, 36 patients). During the perioperative period, all patients undertook cardiopulmonary rehabilitation. ASV was used from postoperative day (POD) 1 to POD5. Hemodynamics showed a different pattern in the 2 groups. Blood pressure (BP) on POD6 in the ASV group was significantly lower than that in the non-ASV group (systolic BP, 112.9±12.6 vs. 126.2±15.8 mmHg, P=0.0006; diastolic BP, 62.3±9.1 vs. 67.6±9.3 mmHg, P=0.0277). The incidence of postoperative atrial fibrillation (POAF) was lower in the ASV group than in the non-ASV group (10% vs. 33%, P=0.0377). The duration of oxygen inhalation in the ASV group was significantly shorter than that in the non-ASV group (5.1±2.2 vs. 7.6±6.0 days, P=0.0238). The duration of postoperative hospitalization was significantly shorter in the ASV group than in the non-ASV group (23.5±6.6 vs. 29.0±13.1 days, P=0.0392). CONCLUSIONS: Cardiopulmonary rehabilitation with ASV after OPCAB reduces both POAF occurrence and the duration of hospitalization.

Autoimmune thyroid diseases.

PURPOSE OF REVIEW: Interesting clinical and basic studies have been published in the field of autoimmune thyroiditis (represented by Graves' disease and Hashimoto's thyroiditis) since January 2005. The review is organized into four main areas: genetics, environment, adaptive immune system, and innate immune system. RECENT FINDINGS: The quest continues for the identification of susceptibility genes for autoimmune thyroiditis. In addition to the classical major histocompatibility complex class II genes and cytotoxic T cell antigen-4, new studies have appeared on CD40 the protein tyrosine phosphatase-22. Too much iodine increases the incidence of Hashimoto's thyroiditis, perhaps by augmenting the antigenicity of thyroglobulin. T regulatory cells, Toll-like receptors and presentation of lipid antigens by CD1 molecules are new areas of basic immunological investigation that have been applied to autoimmune thyroiditis. SUMMARY: Overall, the studies have greatly expanded our understanding of the pathogenesis of thyroiditis. They have opened new lines of investigations that will ultimately result in a better clinical practice.

Antinociceptive effect of linear polarized 0.6 to 1.6 microm irradiation of lumbar sympathetic ganglia in chronic constriction injury rats.

Linear polarized near-infrared light created with linear polarized near-infrared light therapy equipment (Super Lizer HA-550, Tokyo Iken Co, Ltd, Tokyo, Japan) has been used for the treatment of various painful disorders in Japan. Irradiation near the stellate ganglion with a Super Lizer (ISGL) is an especially notable therapeutic method used with stellate ganglion block (SGB) or substitutes for SGB. ISGL is a safe, simple, well-tolerated, and effective treatment. We examined the effects of irradiation with a Super Lizer applied to an area near the lumbar sympathetic ganglia on the ligated side in a chronic constriction injury (CCI) model, which is believed to be an animal model of complex regional pain syndrome (CRPS). Rats showing thermal hyperalgesia in a radiant heat test 1 wk postoperatively were used in Experiments 1 and 2: (1) Thermal hyperalgesia of irradiation group (n = 11) was less than that of the control or nonirradiation (n = 11) group at 1, 3, and 8 h after irradiation; however, the effect disappeared 12 h after irradiation. (2) Daily irradiation (n = 16) and 1 wk (n = 14) from 7 days after nerve ligation significantly shortened the interval from thermal hyperalgesia until recovery. Rats showing mechanical hyperalgesia in the von Frey hair test 1 wk postoperatively were used in Experiment 3: 1 wk irradiation beginning 7 days after nerve ligation (n = 9) did not promote the recovery from mechanical hyperalgesia. We speculate that repeated ISGL may be more effective than a single ISGL in alleviating pain in CRPS patients. We cannot explain the discrepancy between the results obtained in Experiments 2 and 3. We believe the results of this study are relevant to the effect of ISGL for patients with upper-limb CRPS: irradiation near the lumbar sympathetic ganglia of the rat is effective for thermal but not mechanical pain in CCI.

A patient with MRSA infection to prosthesis of femoral head diagnosed non-invasively using bi-digital O-ring test: a clinical case report.

Prosthesis of femoral head is a common surgical procedure, but the diagnosis of infection associated with the prosthesis remains difficult. We diagnosed non-invasively methicillin resistant Staphylococcus aureus (MRSA) infection of prosthesis of femoral head with Bi-Digital O-Ring Test (BDORT). BDORT uses the resonance phenomenon between 2 identical substances, and electromagnetic field principle. The method can non-invasively detect viral & bacterial infection. Accuracy of the BDORT findings was confirmed through bacterial culture & sensitivity test to antibiotics. Patient was successfully treated with operation of evulsion of the prosthesis of femoral head and administration of antibiotics and Cilantro. The drug compatibility was tested with BDORT. BDORT was an effective technique for non-invasively detecting infection of prosthesis and selecting the most effective antibiotics.

Does a viral infection cause complex regional pain syndrome?

In 1990 Omura, Y. reported that Herpes Simplex Virus Type 1 as the major cause of chronic intractable pain and its effective treatment using mixture of EPA & DHA with Selective Drug Uptake Enhancement Method. Subsequently among the other causes of pain, he included Chlamydia Trachomatis, Borrelia Burgdorferi, Mycobacterium Tuberculosis, human Herpes Virus type 6, and Circulatory Disturbances. In order to test possible involvement of viral infection in Complex Regional Pain Syndrome (CRPS), a disease which usually occurs in the extremities, we did a study of 17 patients with CRPS. They were examined for Herpes Simplex Virus (HSV) and Varicella Zoster Virus (VZV) by measuring IgG and IgM antibody titers, and 14 of these patients were also examined for Cytomegalo-Virus (CMV). As a control group 100 healthy Japanese employees at SRL, Inc. were also studied. In CRPS group, HSV IgG was positive in 12 of the 17 patients with an average antibody titer of 90.0 EIA value. VZV IgG was positive in all 17 patients with an average antibody titer of 26.8 EIA value. CMV IgG was positive in all 14 patients with an average antibody titer of 66.6 UA/ml. In control group, HSV IgG was positive in 54 subjects with an average antibody titer of 42.3 EIA value. VZV IgG was positive in 97 subjects with an average antibody titer of 26.2 EIA value. CMV IgG was positive in 82 subjects. There were no significant differences of positive rate of IgG antibody for the three viruses between patient and control groups. Although the difference was not significant, the average antibody titers of HSV in CRPS group were more than twice of those in healthy group. Antibody titers were almost equal in both groups for VZV. Possibly, some people in the control group who had latent virus, were also asymptomatic. In 2000, Takasaki, I. et al. in a separate animal study, inoculated with HSV Type-I the shin of the mouse causing allodynia and hyperalgesia (which are some of the characteristic findings seen in CRPS in humans). Also, VZV, which causes shingles which is sometimes followed by Post-Herpetic Neuralgia (PHN), is in the same family of HSV. As PHN resembles CRPS in symptoms, it is possible that HSV contributes to CRPS. Therefore, virus infection theory is an attractive hypothesis that accounts for many enigmas of CRPS.