Augmented interferon regulatory factor 7 axis in whole tumor cell vaccines prevents tumor recurrence by inducing interferon gamma-secreting B cells.

Among cancer immunotherapy, which has received great attention in recent years, cancer vaccines can potentially prevent recurrent tumors by using the exquisite power and specificity of the immune system. Specifically, whole tumor cell vaccines (WTCVs) based on surgically resected tumors have been considered to elicit robust anti-tumor immune responses by exposing various tumor-associated antigens to host immunity. However, most tumors have little immunogenicity because of immunoediting by continuous interactions with host immunity; thus, preparing WTCVs based on patient-derived non-modified tumors cannot prevent tumor onset. Hence, the immunogenicity of tumor cells must be improved for effective WTCVs. In this study, we indicate the importance of the interferon regulatory factor 7 (Irf7) axis, including Irf7 and its downstream factors, within tumor cells in regulating immunogenicity. Indeed, WTCVs that augmented the Irf7 axis have exerted remarkable recurrence-preventive effects when vaccinated after tumor inactivation by radiation. Most notably, vaccination with murine colon cancer cells that enhanced the Irf7 axis prevented the development of challenged tumors in all mice and resulted in a 100% survival rate during the observation period. Furthermore, the mechanism leading to vaccine effectiveness was mediated by interferon-gamma-producing B cells. This study provides novel insights into how to enhance tumor immunogenicity and use WTCVs as recurrence prophylaxis.

Medical Accidents Related to Ferromagnetic Objects Brought into the MRI Room: Analysis of the National Multicenter Database by Orthopedic Surgeons.

Introduction: Magnetic resonance imaging (MRI) is widely used in orthopedics, but orthopedic surgeons, including spine surgeons, do not have detailed knowledge of MRI-related accidents. We, as orthopedic surgeons, investigated the details of medical accidents related to ferromagnetic objects brought into the MRI room using a national multicenter database. Methods: We conducted an exploratory analysis of accidents involving MRI ferromagnets based on the Japanese database of adverse medical occurrences. From a total of 104,659 accident reports over nine years, 172 involving the presence of ferromagnetic objects in the MRI room were extracted and analyzed. Results: The accident reports frequently involved children and the elderly. Nurses filed the highest number of reports (44.8%) by occupation, which was more than twice as many as physicians (19.8%). The most common ferromagnetic devices brought into the MRI rooms were pacemakers (n = 22). There were also large magnetic objects such as oxygen cylinders (n = 12) and IV stands (n = 7). In the field of orthopedics, ankle weights (n = 4), pedometers (n = 3), and artificial limbs (n = 2) were brought in. "Failure to check" was the most common cause of accidents (69%). Actual harm to patients occurred in 9% of cases, with no fatalities. Conclusions: Manuals and checklists should be developed and continuous education provided to prevent accidents involving magnetic objects brought into the MR scanner room. As orthopedic surgeons, including spine surgeons, we should be cautious with emergency, geriatric, and pediatric patients because their information and medical history may not be accurate. We should not overlook equipment commonly found in orthopedic practice such as ankle weights and pedometers.

Pharmacological inhibition of the lipid phosphatase PTEN ameliorates heart damage and adipose tissue inflammation in stressed rats with metabolic syndrome.

Phosphatidylinositol 3-kinase (PI3K) signaling promotes the differentiation and proliferation of regulatory B (Breg) cells, and the lipid phosphatase phosphatase and tensin homolog deleted on chromosome 10 (PTEN) antagonizes the PI3K-Akt signaling pathway. We previously demonstrated that cardiac Akt activity is increased and that restraint stress exacerbates hypertension and both heart and adipose tissue (AT) inflammation in DS/obese rats, an animal model of metabolic syndrome (MetS). We here examined the effects of restraint stress and pharmacological inhibition of PTEN on heart and AT pathology in such rats. Nine-week-old animals were treated with the PTEN inhibitor bisperoxovanadium-pic [bpV(pic)] or vehicle in the absence or presence of restraint stress for 4 weeks. BpV(pic) treatment had no effect on body weight or fat mass but attenuated hypertension in DS/obese rats subjected to restraint stress. BpV(pic) ameliorated left ventricular (LV) inflammation, fibrosis, and diastolic dysfunction as well as AT inflammation in the stressed rats. Restraint stress reduced myocardial capillary density, and this effect was prevented by bpV(pic). In addition, bpV(pic) increased the proportions of Breg and B-1 cells as well as reduced those of CD8+ T and B-2 cells in AT of stressed rats. Our results indicate that inhibition of PTEN by bpV(pic) alleviated heart and AT inflammation in stressed rats with MetS. These positive effects of bpV(pic) are likely due, at least in part, to a reduction in blood pressure, an increase in myocardial capillary formation, and an altered distribution of immune cells in fat tissue that result from the activation of PI3K-Akt signaling.

Effects of the difference between lumbar lordosis in the supine and standing positions on the clinical outcomes of decompression surgery for lumbar spinal stenosis.

OBJECTIVE: The authors sought to evaluate the relationship between the difference in lumbar lordosis (DiLL) in the preoperative supine and standing positions and spinal sagittal alignment in patients with lumbar spinal stenosis (LSS) and to determine whether this difference affects the clinical outcome of laminectomy. METHODS: Sixty patients who underwent single-level unilateral laminectomy for bilateral decompression of LSS were evaluated. Spinopelvic parameters in the supine and standing positions were measured preoperatively and at 3 months and 2 years postoperatively. DiLL between the supine and standing positions was determined as follows: DiLL = supine LL - standing LL. On the basis of this determination patients were then categorized into DiLL(+) and DiLL(-) groups. The relationship between DiLL and preoperative spinopelvic parameters was evaluated using Pearson's correlation coefficient. In addition, clinical outcomes such as visual analog scale (VAS) and Oswestry Disability Index (ODI) scores between the two groups were measured, and their relationship to DiLL was evaluated using two-group comparison and multivariate analysis. RESULTS: There were 31 patients in the DiLL(+) group and 29 in the DiLL(-) group. DiLL was not associated with supine LL but was strongly correlated with standing LL and pelvic incidence (PI) - LL (PI - LL). In the preoperative spinopelvic alignment, LL and SS in the standing position were significantly smaller in the DiLL(+) group than in the DiLL(-) group, and PI - LL was significantly higher in the DiLL(+) group than in the DiLL(-) group. There was no difference in the clinical outcomes 3 months postoperatively, but low-back pain, especially in the sitting position, was significantly higher in the DiLL(+) group 2 years postoperatively. DiLL was associated with low-back pain in the sitting position, which was likely to persist in the DiLL(+) group postoperatively. CONCLUSIONS: We evaluated the relationship between DiLL and spinal sagittal alignment and the influence of DiLL on postoperative outcomes in patients with LSS. DiLL was strongly correlated with PI - LL, and in the DiLL(+) group, postoperative low-back pain relapsed. DiLL can be useful as a new spinal alignment evaluation method that supports the conventional spinal sagittal alignment evaluation.

Rapidly destructive coxopathy due to dialysis amyloidosis: a case report.

Rapidly destructive coxopathy (RDC) is a disease that is sometimes seen in geriatric patients. A total hip arthroplasty (THA) is mostly chosen to treat the RDC, but few cases are known that received THAs due to RDC associated with dialysis amyloidosis. We report a case of RDC due to dialysis amyloidosis with special references to its pathophysiology. The case involved a 61-year-old male who had been on dialysis for seven years due to diabetic nephropathy. At his first visit, the radiographs showed collapse and flattening of the femoral head, which progressed within a month. Magnetic resonance imaging for the hip disclosed bone marrow edoema of the acetabulum and sclerosis of the subchondral bone of the femoral head. Biochemical analyses for the blood revealed high inflammatory reactions with elevated C-reactive protein and white blood cell count, but the joint fluid cultures were negative for general bacteria, tubercle bacillus, and nontuberculous mycobacteria. As he did not have gastrointestinal disorders or inflammatory arthritis other than the left hip and no disease that caused elevated inflammatory reactions was observed, we diagnosed the patient with RDC due to dialysis amyloidosis, and a THA was performed. Pathological findings for the synovium collected during surgery showed infiltration of the inflammatory mononuclear cells and vascular hyperplasia. The synovial tissues were extensively stained with an antibody to ß2-microglobulin. Many tartrate-resistant acid phosphatase-positive multinucleated cells were also observed in the synovium. One year after surgery, his left hip pain disappeared and he returned to work.

Alleviation of salt-induced exacerbation of cardiac, renal, and visceral fat pathology in rats with metabolic syndrome by surgical removal of subcutaneous fat.

OBJECTIVES: Evidence suggests that visceral adipose tissue (VAT) and subcutaneous adipose tissue (SAT) should be considered as distinct types of white fat. Although VAT plays a key role in metabolic syndrome (MetS), the role of subcutaneous adipose tissue (SAT) has been unclear. DahlS.Z-Leprfa/Leprfa (DS/obese) rats, an animal model of MetS, develop adipocyte hypertrophy and inflammation to similar extents in SAT and VAT. We have now investigated the effects of salt loading and SAT removal on cardiac, renal, and VAT pathology in DS/obese rats. METHODS: DS/obese rats were subjected to surgical removal of inguinal SAT or sham surgery at 8 weeks of age. They were provided with a 0.3% NaCl solution as drinking water or water alone for 4 weeks from 9 weeks of age. RESULTS: Salt loading exacerbated hypertension, insulin resistance, as well as left ventricular (LV) hypertrophy, inflammation, fibrosis, and diastolic dysfunction in DS/obese rats. It also reduced both SAT and VAT mass but aggravated inflammation only in VAT. Although SAT removal did not affect LV hypertrophy in salt-loaded DS/obese rats, it attenuated hypertension, insulin resistance, and LV injury as well as restored fat mass and alleviated inflammation and the downregulation of adiponectin gene expression in VAT. In addition, whereas salt loading worsened renal injury as well as upregulated the expression of renin-angiotensin-aldosterone system-related genes in the kidney, these effects were suppressed by removal of SAT. CONCLUSIONS: SAT removal attenuated salt-induced exacerbation of MetS and LV and renal pathology in DS/obese rats. These beneficial effects of SAT removal are likely attributable, at least in part, to inhibition of both VAT and systemic inflammation.

Anti-inflammatory effects of heat-killed Lactobacillus plantarum L-137 on cardiac and adipose tissue in rats with metabolic syndrome.

The effects of heat-killed Lactobacillus plantarum L-137 (HK L-137) on chronic inflammation associated with metabolic disorders have remained unknown. We examined the effects of HK L-137 on cardiac and adipose tissue pathophysiology in DahlS.Z-Lepr fa /Lepr fa (DS/obese) rats as a model of metabolic syndrome. DS/obese rats were treated orally with HK L-137 (2 or 75 mg kg-1 day-1) from 9 to 13 weeks of age. HK L-137 attenuated left ventricular (LV) inflammation and fibrosis as well as adipocyte hypertrophy, inflammation, and up-regulation of sterol regulatory element-binding protein-1c (SREBP-1c) gene expression in visceral and subcutaneous adipose tissue, without affecting body weight gain or hypertension. The low dose of HK L-137 also ameliorated LV diastolic dysfunction, the increase in subcutaneous fat mass, and insulin resistance as well as attenuated the down-regulation of Akt phosphorylation in visceral and subcutaneous adipose tissue, and the elevation of the circulating interleukin-6 concentration. Furthermore, the proportion of regulatory T (Treg) cells among CD4+ T cells in the spleen was increased by HK L-137. These results suggest that the anti-inflammatory effects of HK L-137 on the heart and adipose tissue are related, at least partly, to suppression of systemic inflammation associated with an increase in splenic Treg cell.

Functional validation and expression analysis of myotubes converted from skin fibroblasts using a simple direct reprogramming strategy.

Previously, we reported that MyoD, a master gene for myogenic cells, could efficiently convert primary skin fibroblasts into myoblasts and myotubes, thereby effecting direct reprogramming. In this study, we further demonstrated that MyoD-expressing primary fibroblasts displayed rapid movement in culture, with a movement velocity that was significantly faster, almost four times, than mouse primary myoblasts. MyoD-transduced cells obtained the characteristics of Ca2 + release and electrically-stimulated contraction, which was comparable to C2C12 myotubes, suggesting that the essential features of muscle were observed in the transduced cells. Furthermore, the ability to fuse to the host myoblasts means that gene transfer from MyoD-transduced cells to host muscle cells could be obtained by cell fusion. In comparison with the iPS method (indirect reprogramming), our transduction method has a low risk for tumorigenesis and carcinogenesis because the starting cells are fibroblasts and the transduced cells are myoblasts, both normal and mortal cells. Accordingly, MyoD transduction of human skin fibroblasts using the adenoviral vector is a simple, inexpensive and promising candidate as a new cell transplantation therapy for patients with muscular disorders.

Blunt cardiac injury due to trauma associated with snowboarding: a case report.

BACKGROUND: Cardiac trauma is associated with a much higher mortality rate than injuries to other organ systems, even though cardiac trauma is identified in less than 10% of all trauma admissions. Here we report blunt trauma of the left atrium due to snowboarding trauma. CASE PRESENTATION: A 45-year-old Asian man collided with a tree while he was snowboarding and drinking. He lost consciousness temporarily. An air ambulance was requested and he was transported to an advanced critical care center. On arrival, a pericardial effusion was detected by a focused assessment with sonography for trauma. His presenting electrocardiogram revealed normal sinus rhythm and complete right bundle branch block. Laboratory findings included a white blood cell count of 13.5 × 103/µl, serum creatine kinase level of 459 IU/l, and creatine kinase-myocardial band level of 185 IU/l. Enhanced computed tomography showed a large pericardial effusion and bleeding from his left adrenal gland. There were no pelvic fractures. A diagnosis of cardiac tamponade due to blunt cardiac injury and left adrenal injury due to blunt trauma was made. Subsequently, emergency thoracic surgery and transcatheter arterial embolization of his left adrenal artery were performed simultaneously. A laceration of the left atrial appendage in the lateral wall of his left ventricle was detected intraoperatively and repaired. His postoperative course progressed favorably, although a pericardial effusion was still detected on chest computed tomography on hospital day 35. His electrocardiogram showed normal sinus rhythm and the complete right bundle branch block pattern changed to a narrow QRS wave pattern. He was discharged on hospital day 40. CONCLUSIONS: The present case report illustrates two points: (1) severe injuries resulted from snowboarding, and (2) complete right bundle branch block was caused by blunt cardiac injury. The present report showed blunt trauma of the left atrium with complete right bundle branch block as an electrocardiogram change due to snowboarding trauma. To detect cardiac trauma in snowboarding accidents, an examination of an electrocardiogram is required in all patients who might have a bruised chest.

Much caution does no harm! Organophosphate poisoning often causes pancreatitis.

Organophosphate poisoning (OP) results in various poisoning symptoms due to its strong inhibitory effect on cholinesterase. One of the occasional complications of OP is pancreatitis. A 62-year-old woman drank alcohol and went home at midnight. After she quarreled with her husband and drank 100 ml of malathion, a parasympathomimetic organophosphate that binds irreversibly to cholinesterase, she was transported to our hospital in an ambulance. On admission, activated charcoal, magnesium citrate, and pralidoxime methiodide (PAM) were used for decontamination after gastric lavage. Abdominal computed tomography detected edema of the small intestine and colon with doubtful bowel ischemia, and acute pancreatitis was suspected. Arterial blood gas analysis revealed severe lactic acidosis. The Ranson score was 6 and the APACHE II (Acute Physiology and Chronic Health Evaluation) score was 14. Based on these findings, severe acute pancreatitis was diagnosed. One day after admission, hemodiafiltration (HDF) was started for the treatment of acute pancreatitis. On the third hospital day, OP symptoms were exacerbated, with muscarinic manifestations including bradycardia and hypersalivation and decreased plasma cholinesterase activity. Atropine was given and the symptoms improved. The patient's general condition including hemodynamic status improved. Pancreatitis was attenuated by 5 days of HDF. Ultimately, it took 14 days for acute pancreatitis to improve, and the patient discharged on hospital day 32. Generally, acute pancreatitis associated with OP is mild. In fact, one previous report showed that the influence of organophosphates on the pancreas disappears in approximately 72 hours, and complicated acute pancreatitis often improves in 4-5 days. However, it was necessary to treat pancreatitis for more than 2 weeks in this case. Therefore, organophosphate-associated pancreatitis due to malathion is more severe. Although OP sometime causes severe necrotic pancreatitis or pancreatic pseudocysts, it was thought that the present patient had a good clinical course without these complications due to the appropriate intensive care including nafamostat, antibiotics, fluid resuscitation, and HDF. In conclusion, OP-associated pancreatitis requires careful assessment because it may be aggravated, as in this case.

Usefulness of serum cystatin C to determine the dose of vancomycin in critically ill patients.

OBJECTIVES: Serum creatinine (Scr) is not a reliable marker of renal function in critically ill patients because of an enhancement of protein catabolism, which makes it difficult to adjust the dosage of renally eliminated drugs such as antibiotics. This study aimed to investigate whether serum cystatin C (Scys-C) could be used as a reliable marker of renal function. METHODS: We investigated whether Scys-C was a reliable marker of renal function in 56 critically ill patients. Subsequently, the usefulness of Scys-C to determine the initial loading and the maintenance dose of vancomycin was examined in 18 patients. Crea- tinine clearance (Ccr) was assessed from Scr and creatinine in urine collected over 24 h (24-h Ccr). KEY FINDINGS: There was a good correlation between 24-h Ccr and 1/Scys-C (r(2) = 0.616), whereas less marked correlation was observed between 24-h Ccr and 1/Scr (r(2) = 0.221). On the other hand, vancomycin concentration was predicted from population pharmacokinetic parameters based on a two-compartment linear model. There were significant correlations between real trough concentrations of vancomycin and the values predicted from Scys-C using various equations (r(2) = 0.416-0.488), while less pronounced relationships were observed between real concentrations and the values predicted from Scr (r(2) = 0.134-0.187). CONCLUSIONS: These findings suggest that Scys-C is a reliable marker reflecting renal function in critically ill patients and is applicable to determine the initial loading dose as well as the maintenance dose of vancomycin.