ABSTRACT
INTRODUCTION: Oral frailty leads to poor nutritional status, which, in turn, leads to frailty. This cross-sectional study aimed to determine regional differences in the prevalence of oral frailty and to identify factors associated with oral frailty using 3-level multilevel models. METHODS: This study comprised 165,164 participants aged ≥65 y without long-term care requirements in the Japan Gerontological Evaluation Study. The dependent variable was oral frailty, which was calculated based on age, number of teeth, difficulty in eating tough foods, and choking. The individual-level independent variables included sociodemographics, present illness, social participation, frequency of meeting friends, and social capital. The local district-level independent variable was social capital (n = 1,008) derived from exploratory factor analyses. The municipality-level independent variable was population density (n = 62). Three-level multilevel Poisson regression analysis was performed to calculate the prevalence ratios (PRs). RESULTS: The prevalence of oral frailty in municipalities ranged from 39.9% to 77.6%. Regarding district-level factors, higher civic participation was significantly associated with a lower probability of oral frailty. At the municipality level, the PR of the rural-agricultural area was 1.17 (95% confidence interval, 1.11-1.23) (reference: metropolitan). CONCLUSION: These results highlight the usefulness of oral frailty prevention measures in encouraging social participation in rural areas. KNOWLEDGE TRANSFER STATEMENT: The results of the present study showed regional differences in oral frailty. In particular, rural-agricultural areas show higher prevalence rates of oral frailty than those in metropolitan cities. Promoting measures of social participation among older adults may help prevent oral frailty in rural areas.
ABSTRACT
Patients with end-stage renal disease are at a high risk for cardiovascular diseases. It is controversial whether end-stage renal disease patients with low cardiac function can safely accept kidney transplant. Here, we present a 42-year-old kidney transplant recipient with severe mitral regurgitation accompanied by low cardiac function. He wanted to undergo a pre-emptive kidney transplant from his uncle. We decided to perform living kidney transplant prior to cardiac surgery. Despite adequate ultrafiltration and hemodiafiltration before operation, the patient's ejection fraction still remained 35% 1 day before transplant. He showed complete recovery of cardiac function in only 2 days after pre-emptive kidney transplant, although his body weight did not change before and after the operation. Early removal of the uremic toxin or inflammatory cytokines may play a role in rapid improvement of the cardiac function. Increase of vasoactive substances by improvement of kidney function may lead to reduction of afterload and amelioration of cardiac microcirculation. This report also suggests that optimal timing for operation might be important.
Subject(s)
Kidney Failure, Chronic/complications , Kidney Failure, Chronic/surgery , Kidney Transplantation , Mitral Valve Insufficiency/complications , Adult , Humans , MaleABSTRACT
Ellis-van Creveld (EvC) syndrome is an autosomal-recessive skeletal dysplasia, characterized by short stature and postaxial polydactyly. A series of dental abnormalities, including hypomorphic enamel formation, has been reported in patients with EvC. Despite previous studies that attempted to uncover the mechanism leading to abnormal tooth development, little is known regarding how hypomorphic enamel is formed in patients with EvC. In the current study, using Evc2/ Limbin mutant mice we recently generated, we analyzed enamel formation in the mouse incisor. Consistent with symptoms in human patients, we observed that Evc2 mutant mice had smaller incisors with enamel hypoplasia. Histologic observations coupled with ameloblast marker analyses suggested that Evc2 mutant preameloblasts were capable of differentiating to secretory ameloblasts; this process, however, was apparently delayed, due to delayed odontoblast differentiation, mediated by a limited number of dental mesenchymal stem cells in Evc2 mutant mice. This concept was further supported by the observation that dental mesenchymal-specific deletion of Evc2 phenocopied the tooth abnormalities in Evc2 mutants. Overall, our findings suggest that mutations in Evc2 affect dental mesenchymal stem cell homeostasis, which further leads to hypomorphic enamel formation.
Subject(s)
Dental Enamel Hypoplasia/genetics , Incisor/abnormalities , Membrane Proteins/genetics , Tooth Abnormalities/genetics , Animals , Cell Differentiation , Disease Models, Animal , Ellis-Van Creveld Syndrome/genetics , Intercellular Signaling Peptides and Proteins , Mice , Mice, Knockout , Mutation , Real-Time Polymerase Chain Reaction , Signal TransductionABSTRACT
OBJECTIVE/BACKGROUND: Recently, the indications for thoracic endovascular aortic repair (TEVAR) have been expanding, and the applicability of TEVAR for acute type B aortic dissection (TBAD) is proposed with regard to the high mortality of open surgery for chronic TBAD. TEVAR in the acute phase may lead to remodeling of the false lumen (FL), but it is controversial whether it completely resolves the aortic expansion in the chronic phase. In this study, operative results and the relationship between FL status and the time before surgical intervention were retrospectively analyzed. METHODS: From January 2008 to September 2013, 234 patients underwent open surgery for chronic TBAD. Most patients were on left heart bypass. By considering Japanese aortic disease treatment guidelines and the smaller physique of Japanese patients, operative indications were aneurysm >50 mm in diameter or rapid aneurysm enlargement of >5 mm in a 6 month period. RESULTS: In 180 cases, the FL was patent. The mean interval between onset of TBAD and operation was 61 ± 54 months. There was no significant difference between patients in the patent FL group and those in the thrombosed FL group (p = .44). Mean ratio of FL diameter to maximum aortic diameter (FL/AD) was 0.64 ± 0.21. There was no correlation between FL and AD before the operation (r = .12). Descending thoracic aortic replacement (DTAR) was performed in 127 cases and thoracic ascending aortic replacement (TAAR) in 107 cases (Crawford type I, n = 9; Crawford type II, n = 65; Crawford type III and IV, n = 22, respectively; Safi type V, n = 11). The overall operative mortality was 6.8%: 3.9% (5/127) for DTAR and 10.3% (11/107) for TAAR. The three year survival was 86.7, and the freedom from re-intervention rate was 97.0%. CONCLUSION: Enlargement of uncomplicated TBAD in the chronic phase was poorly related to FL status and the results of open repair have improved. However, further prospective study is necessary.
Subject(s)
Aortic Aneurysm, Thoracic/surgery , Aortic Dissection/surgery , Blood Vessel Prosthesis Implantation , Aged , Aortic Dissection/diagnosis , Aortic Dissection/mortality , Aortic Dissection/physiopathology , Aortic Aneurysm, Thoracic/diagnosis , Aortic Aneurysm, Thoracic/mortality , Aortic Aneurysm, Thoracic/physiopathology , Blood Vessel Prosthesis Implantation/adverse effects , Blood Vessel Prosthesis Implantation/mortality , Chronic Disease , Disease-Free Survival , Female , Humans , Japan , Male , Middle Aged , Postoperative Complications/mortality , Postoperative Complications/surgery , Reoperation , Retrospective Studies , Risk Factors , Time Factors , Time-to-Treatment , Treatment Outcome , Vascular PatencyABSTRACT
The ubiquitin-proteasome system is central in the regulation of cellular proteins controlling cell cycle progression and apoptosis, drawing much interest for developing effective targeted cancer therapies. Herein, we developed a novel pH-responsive polymeric-micelle-based carrier system to effectively deliver the proteasome inhibitor MG132 into cancer cells. MG132 is covalently bound to the block copolymer composed of polyethylene glycol (PEG) and polyaspartate through an acid-labile hydrazone bond. This bond is stable at physiological condition, but hydrolytically degradable in acidic compartments in the cell, such as late-endosomes and lysosomes, and thus, it was used for controlled release of MG132 after EPR-mediated preferential accumulation of the micelles into the tumor. MG132-loaded micelles have monodispersed size distribution with an average diameter of 45nm, and critical micelle concentration is well below 10(-7)M. In vitro studies against several cancer cell lines confirmed that MG132-loaded micelles retained the cytotoxic effect, and this activity was indeed due to the inhibition of proteasome by released MG132 from the micelles. Real-time in vitro confocal-microscopy experiments clearly indicated that MG132-conjugated micelles disintegrated only inside the target cells. By intravital confocal micro-videography, we also confirmed the prolonged circulation of MG132 loaded micelles in the bloodstream, which lead to tumor specific accumulation of micelles, as confirmed by in vivo imaging 24h after injection. These micelles showed significantly lower in vivo toxicity than free MG132, while achieving remarkable antitumor effect against a subcutaneous HeLa-luc tumor model. Our findings create a paradigm for future development of polymeric-micelle-based carrier system for other peptide aldehyde type proteasome inhibitors to make them effective cohort of the existing cancer therapeutic regiments.
Subject(s)
Antineoplastic Agents/administration & dosage , Delayed-Action Preparations/chemistry , Leupeptins/administration & dosage , Micelles , Proteasome Inhibitors/administration & dosage , Animals , Antineoplastic Agents/pharmacokinetics , Antineoplastic Agents/therapeutic use , Cell Line, Tumor , Female , Humans , Hydrogen-Ion Concentration , Leupeptins/pharmacokinetics , Leupeptins/therapeutic use , Mice, Inbred BALB C , Neoplasms/drug therapy , Neoplasms/pathology , Polymers/chemistry , Proteasome Inhibitors/pharmacokinetics , Proteasome Inhibitors/therapeutic useABSTRACT
OBJECTIVES: We simultaneously assessed ultrasonography (US) and magnetic resonance imaging (MRI) in comparison with histopathological changes in the knee joints of long-lasting arthritis patients. METHODS: We studied 15 patients with rheumatoid arthritis and 5 patients with osteoarthritis, who underwent total knee arthroplasty. On the day before surgery, the joints were examined by US and contrast-enhanced MRI. In US, synovitis was graded with 0-3 grey scale (GSUS) and power Doppler (PDUS). In MRI, synovitis was graded according to OMERACT-RAMRIS (grade 0-3). Synovial tissue samples were obtained during arthroplasty and evaluated on the basis of inflammatory cell infiltrates (grade 0-3), synovial lining layer thickness (grade 0-3) and vascularity (grade 0-3). RESULTS: Positive findings of PDUS and contrast-enhanced MRI were 45% and 85% of 20 operated joints, respectively. GSUS, PDUS and MRI synovitis were well correlated with overall histopathological grades of synovitis (Spearman correlation coefficients 0.48, 0.84 and 0.48, p<0.05, p<0.01 and p<0.05, respectively). Moreover, positive PDUS findings were closely associated with all pathological comportments of synovitis including inflammatory cell infiltrates, synovial lining layer thickness and vascularity. CONCLUSIONS: The present study revealed that positive PDUS findings more faithfully illustrated active synovitis than MRI, whereas contrast-enhanced MRI was more sensitive in detecting synovitis in patients with long-lasting arthritis. It is important to understand distinct features of the both modalities for clinical assessment of chronic joint diseases.
Subject(s)
Arthroplasty, Replacement, Knee , Knee Joint/surgery , Magnetic Resonance Imaging/methods , Synovitis/diagnosis , Ultrasonography, Doppler/methods , Adult , Aged , Aged, 80 and over , Arthritis, Rheumatoid/diagnostic imaging , Arthritis, Rheumatoid/pathology , Arthritis, Rheumatoid/surgery , Female , Humans , Knee Joint/diagnostic imaging , Knee Joint/pathology , Male , Middle Aged , Osteoarthritis/diagnostic imaging , Osteoarthritis/pathology , Osteoarthritis/surgery , Synovitis/diagnostic imaging , Synovitis/pathology , Synovitis/surgeryABSTRACT
PURPOSE: The correction angle after high tibial osteotomy (HTO) depends on an accurate preoperative planning and an accurate intraoperative technique. We hypothesized that the use of a navigation system in opening wedge HTO would improve the intraoperative target angles in the coronal and sagittal planes. METHODS: Postoperative femoro-tibial angle (FTA) and tibial posterior slope (TPS) in 28 knees with navigated opening wedge HTO were compared to those in 31 knees with the conventional method. Intraoperative correction angle was determined by the predicted medial opening width in the conventional group, and by the change of hip-knee-ankle angle in the navigated group. We defined lateral unstable knee as the knees with lateral cortex breakage or lateral tibial plateau fracture. RESULTS: Mean postoperative FTA was higher in the conventional group than in the navigated group (P < 0.037). In the conventional group, 4 lateral unstable knees were corrected to 174.6°. In the navigated group, 5 lateral unstable knees were corrected to 170.3° and no knees showed FTA > 173°. Mean change in TPS was greater in the conventional group than in the navigated group (P = 0.001). CONCLUSION: The navigation system in opening wedge HTO might reduce undercorrection in the knees with lateral cortex breakage or lateral tibial plateau fracture, and provide the better intraoperative FTA and TPS. LEVEL OF EVIDENCE: III.
Subject(s)
Osteoarthritis, Knee/surgery , Osteotomy/methods , Tibia/surgery , Female , Humans , Knee Joint/anatomy & histology , Male , Middle Aged , Monitoring, Intraoperative/methods , Surgery, Computer-AssistedABSTRACT
Recently we have reported that biglycan (BGN) promotes osteoblast differentiation and that this function is due in part to its ability to positively modulate bone morphogenetic protein (BMP) functions. In this study we investigated the role of glycosaminoglycans (GAGs) of BGN in this function using in vitro and in vivo models. C2C12 myogenic cells were treated or untreated with BMP-2 alone or in combination with glycanated, partially glycanated or de-glycanated BGN, and the effects on BMP signaling and function were assessed by Smad1/5/8 phosphorylation and alkaline phosphatase (ALP) activity. Furthermore, the effect of de-glycanation of BGN on BMP-2 induced osteogenesis was investigated employing a rat mandible defect model. The defects were filled with collagen scaffolds loaded with glycanated or de-glycanated BGN alone or in combination with a sub-optimal dose of BMP-2 (subBMP). In in vitro experiments, BMP signaling and function were the greatest when BMP-2 was combined with de-glycanated BGN among the groups tested. In the rat mandible experiments, µCT analyses revealed that the newly formed bone was significantly increased only when subBMP was combined with de-glycanated BGN. The data indicate that the GAG component of BGN functions as a suppressor for the BGN-assisted BMP function.
Subject(s)
Biglycan/physiology , Bone Morphogenetic Protein 2/physiology , Glycosaminoglycans/physiology , Osteogenesis/physiology , Animals , Biglycan/chemistry , Biglycan/genetics , Bone Morphogenetic Protein 2/pharmacology , Glycosaminoglycans/pharmacology , Male , Osteogenesis/drug effects , Rats , Rats, Sprague-Dawley , Recombinant Proteins/chemistry , Recombinant Proteins/genetics , Signal TransductionABSTRACT
OBJECTIVE: Differential diagnosis of cementifying fibroma, ossifying fibroma and fibrous dysplasia by histological evaluation is often difficult. The aim of this study was to examine the immunoreactivities for keratan sulfate (KS) and chondroitin-4-sulfate (C4S) glycosaminoglycans of the histological samples obtained from mandibles of patients with these diseases. MATERIALS AND METHODS: The samples were collected from three patients with cementifying fibroma, two with ossifying fibroma and three with fibrous dysplasia and were subjected to immunohistochemical analyses. RESULTS: The results demonstrated that a significant immunoreactivity for KS was found in lacunae housing cells in the cementum-particles of cementifying fibromas, while both ossifying fibromas and fibrous dysplasias showed no significant immunoreactivity for KS. For C4S, while the former showed little immunoreactivity, the latter two cases exhibited intensive immunostaining in the pre- and poorly mineralized matrices. CONCLUSIONS: These results suggest that cementifying fibromas could be distinguished from these fibro-osseous tumors by using immunohistochemical analysis for KS and C4S.
Subject(s)
Cementoma/chemistry , Chondroitin Sulfates/analysis , Fibroma, Ossifying/chemistry , Fibrous Dysplasia of Bone/metabolism , Keratan Sulfate/analysis , Mandibular Neoplasms/chemistry , Odontogenic Tumors/chemistry , Adolescent , Adult , Dental Cementum/chemistry , Diagnosis, Differential , Female , Humans , Immunohistochemistry , MaleABSTRACT
To compare the properties of wear debris between ceramic-on-ceramic and ceramic-on-polyethylene total hip prostheses, particles were isolated and characterized from tissue biopsies obtained at revision arthroplasty or autopsy from two similar uncemented modular hip systems. Group A hips (11 patients; mean, 31 months in vivo) had titanium shells with alumina inserts, alumina femoral heads, and titanium alloy stems. Group B hips (seven patients; mean, 42 months) were the same as Group A but with polyethylene acetabular inserts. Particles were characterized using an electrical resistance particle analyzer, scanning electron microscope, and energy dispersive xray spectroscope. Most of the particles in Group A were ceramic, whereas most of the particles in Group B were polyethylene. Metal particles from the femoral stem and the acetabular shell also were present. If one Group A hip with impingement is excluded, the rate of particle production is significantly lower in the ceramic-on-ceramic group than in the ceramic-on-polyethylene group. With the number of samples available, no significant difference in average size could be detected among the different types of particles or among the groups.
Subject(s)
Ceramics , Foreign Bodies/etiology , Hip Prosthesis , Polyethylene , Prosthesis Failure , Humans , Middle Aged , Particle SizeABSTRACT
A proliferating trichilemmal tumor is relatively uncommon. It is composed of multiple cysts consisting of squamous epithelium with trichilemmal keratinization without granular layer interposition. This lesion usually occurs in the scalp of elderly women. We describe a 67-year-old woman with a malignant proliferating trichilemmal tumor in the skin over the breast. We first misdiagnosed the disease as a primary squamous cell carcinoma of the breast with a metastatic lymph node in the axilla because of the disease site and our unfamiliarity with the disease. The patient underwent radical mastectomy with axillary dissection. Eight months postoperatively, a tumor appeared in her right axilla and progressively enlarged. We subsequently excised the tumor. She is healthy as of 8 months postoperatively. To the best of our knowledge, only one case of a proliferating trichilemmal tumor occurring in the skin over the breast has been reported.
Subject(s)
Breast Neoplasms/pathology , Hair Diseases/pathology , Hair Follicle/pathology , Skin Neoplasms/pathology , Aged , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Axilla , Breast Neoplasms/diagnosis , Breast Neoplasms/drug therapy , Breast Neoplasms/surgery , Carcinoma, Squamous Cell/diagnosis , Combined Modality Therapy , Cyclophosphamide/administration & dosage , Diagnostic Errors , Doxorubicin/administration & dosage , Fadrozole/administration & dosage , Female , Fluorouracil/administration & dosage , Hair Diseases/diagnosis , Hair Diseases/drug therapy , Hair Diseases/surgery , Humans , Lymphatic Metastasis , Mastectomy, Radical , Mitomycin/administration & dosage , Neoplasm Recurrence, Local/drug therapy , Neoplasm Recurrence, Local/surgery , Skin Neoplasms/diagnosis , Skin Neoplasms/drug therapy , Skin Neoplasms/surgeryABSTRACT
We compared wear particles from two different designs of total hip arthroplasty with polycrystalline alumina-ceramic bearings of different production periods (group 1, before ISO 6474: group 2, according to ISO 6474). The neocapsules and interfacial connective tissue membranes were retrieved after mean implantation times of 131 months and 38 months, respectively. Specimen blocks were freed from embedding media, either methylmethacrylate or paraffin and digested in concentrated nitric acid. Particles were then counted and their sizes and composition determined by SEM and energy-dispersive x-ray analysis (EDXA). The mean numbers and sizes of most alumina wear particles did not differ for both production periods, but the larger sizes of particle in group 1 point to more severe surface destruction. The increased metal wear in group 2 was apparently due to alumina-induced abrasion of the stems. In this study the concentrations of particles in the periprosthetic tissues were 2 to 22 times lower than those observed previously with polyethylene and alumina/polyethylene wear couples.
Subject(s)
Aluminum Oxide/adverse effects , Arthroplasty, Replacement, Hip/instrumentation , Ceramics/adverse effects , Connective Tissue/pathology , Hip Prosthesis/adverse effects , Prosthesis Failure , Adult , Aged , Biopsy , Electron Probe Microanalysis , Equipment Failure Analysis , Hip Prosthesis/supply & distribution , Humans , Microscopy, Electron, Scanning , Middle Aged , Particle Size , Prosthesis Design , Time FactorsABSTRACT
PURPOSE: This study was performed to clarify the sonographic features of acute colonic diverticulitis to enable its differentiation from appendicitis. METHODS: Of 119 patients who were referred to our hospitals for lower abdominal pain between June 1997 and December 1998 and underwent sonography, 12 patients had a definitive diagnosis of acute colonic diverticulitis and 4 patients a tentative diagnosis. Seventy-eight patients were diagnosed as having acute appendicitis, confirmed by appendectomy. In the 16 patients with diagnoses of diverticulitis, the sonographic and clinical features of acute colonic diverticulitis were studied. RESULTS: Among the 12 patients with definitive diagnoses of acute colonic diverticulitis, sonographic findings included localized thickening of the colonic wall (100%) and a hemispheric mass (the "dome sign") protruding at the thickened colonic wall (100%) and consisting of a hypoechoic wall (100%) and a central echogenic area (66%). The presence of diverticula was confirmed by barium-enema x-ray study in all 12 patients. The 4 patients with tentative diagnoses of acute colonic diverticulitis all had colonic wall thickening but no dome sign. Colonoscopy revealed colitis in 3 of these patients. All 16 patients recovered with conservative treatment, without laparotomy. CONCLUSIONS: Sonography was useful for differentiating acute colonic diverticulitis from appendicitis. The sonographic finding of the dome sign seems to be specific for acute colonic diverticulitis.
Subject(s)
Appendicitis/diagnostic imaging , Diverticulitis, Colonic/diagnostic imaging , Abdominal Pain/etiology , Acute Disease , Adult , Aged , Aged, 80 and over , Diagnosis, Differential , Female , Humans , Male , Middle Aged , UltrasonographyABSTRACT
Apoptosis signal-regulating kinase 1 (ASK1) is a member of the MAPKKK family in the JNK and p38 mitogen-activated protein kinase cascades and critically involved in stress- and cytokine-induced apoptosis. The transcription factor nuclear factor-kappaB (NF-kappaB) is a pivotal regulator of immune and inflammatory responses and exerts anti-apoptotic roles in various cells. Here we show that ASK1 directly interacts with transforming growth factor-beta-activated kinase 1 (TAK1), another MAPKKK that has been identified as a signaling intermediate in the interleukin 1 (IL-1)-induced NF-kappaB pathway as well as the transforming growth factor-beta superfamily-induced JNK/p38 pathway. Overexpression of ASK1 inhibits IL-1-, TRAF6-, or TAK1-induced, but not NF-kappaB-inducing kinase-induced, NF-kappaB activation. ASK1 dissociates TAK1 but not NF-kappaB-inducing kinase from TRAF6. Moreover, IL-1-induced complex formation of endogenous TAK1 and TRAF6 was blocked by ASK1 overexpression. It thus appears that the inhibition of NF-kappaB by ASK1 may result at least in part from the disruption of the TRAF6.TAK1 complex formation in the IL-1 signaling pathway. These results provide a new insight in the mode of action of MAPKKK family members; two distinct MAPKKKs in the same MAP kinase cascades directly interact and exert opposite effects in another signaling pathway, NF-kappaB.
Subject(s)
Interleukin-1/pharmacology , MAP Kinase Kinase Kinases/metabolism , NF-kappa B/metabolism , Receptors, Interleukin-1/physiology , Cell Line , Humans , Interleukin-1/physiology , JNK Mitogen-Activated Protein Kinases , Kinetics , MAP Kinase Kinase Kinase 5 , Mitogen-Activated Protein Kinases/metabolism , Proteins/metabolism , Receptors, Interleukin-1/genetics , Receptors, Interleukin-1 Type I , Recombinant Proteins/immunology , Signal Transduction/physiology , TNF Receptor-Associated Factor 6 , Transfection , p38 Mitogen-Activated Protein KinasesABSTRACT
Tumor necrosis factor (TNF) and interleukin-1 (IL-1) are pleiotropic cytokines that activate two transcription factors, Activator Protein-1 (AP-1) and Nuclear Factor-kappa B (NF-kappa B). Apoptosis signal-regulating kinase 1 (ASK 1) is a mitogen-activated protein (MAP) kinase kinase kinase (MAPKKK) that is activated by TNF and IL-1, and stimulates c-Jun N-terminal kinase (JNK also known as SAPK; stress-activated protein kinase) and p38 activation. Through genetic screening for ASK 1-binding proteins, Transforming Growth Factor beta (TGF-beta)-activated kinase (TAK 1), another MAPKKK family protein, was identified. Here we report that ASK 1 binds to TAK 1 and dissociates TAK 1 from TNF receptor-associated factor 6 (TRAF 6), and inhibits TAK 1- and TRAF 6-, but not NF-kappa B-inducing kinase (NIK)-induced NF-kappa B activation.
Subject(s)
MAP Kinase Kinase Kinases/physiology , Animals , Humans , Interleukin-1/physiology , MAP Kinase Kinase Kinase 5 , MAP Kinase Kinase Kinases/metabolism , MAP Kinase Signaling System/physiology , NF-kappa B/metabolism , NF-kappa B/physiology , Protein Binding , Tumor Necrosis Factor-alpha/physiologyABSTRACT
ASK1 activates JNK and p38 mitogen-activated protein kinases and constitutes a pivotal signaling pathway in cytokine- and stress-induced apoptosis. However, little is known about the mechanism of how ASK1 executes apoptosis. Here we investigated the roles of caspases and mitochondria in ASK1-induced apoptosis. We found that benzyloxycarbonyl-Val-Ala-Asp-fluoromethyl ketone (zVAD-fmk), a broad-spectrum caspase inhibitor, mostly inhibited ASK1-induced cell death, suggesting that caspases are required for ASK1-induced apoptosis. Overexpression of ASK1DeltaN, a constitutively active mutant of ASK1, induced cytochrome c release from mitochondria and activation of caspase-9 and caspase-3 but not of caspase-8-like proteases. Consistently, caspase-8-deficient (Casp8 (-/-)) cells were sensitive to ASK1-induced caspase-3 activation and apoptosis, suggesting that caspase-8 is dispensable for ASK1-induced apoptosis, whereas ASK1 failed to activate caspase-3 in caspase-9-dificient (Casp9 (-/-)) cells. Moreover, mitochondrial cytochrome c release, which was not inhibited by zVAD-fmk, preceded the onset of caspase-3 activation and cell death induced by ASK1. ASK1 thus appears to execute apoptosis mainly by the mitochondria-dependent caspase activation.
Subject(s)
Apoptosis , Caspases/metabolism , MAP Kinase Kinase Kinases/metabolism , Mitochondria/metabolism , Amino Acid Chloromethyl Ketones/pharmacology , Animals , Cell Death , Cells, Cultured , Enzyme Activation , Enzyme Inhibitors/pharmacology , JNK Mitogen-Activated Protein Kinases , MAP Kinase Kinase Kinase 5 , Mink , Mitogen-Activated Protein Kinases/metabolism , p38 Mitogen-Activated Protein KinasesABSTRACT
Recently, it was confirmed that embryos derived from diapausing eggs of the silkworm, Bombyx mori, begin their development and reach larval maturity on mulberry leaves, when the naked eggs are cultured in vitro. In this study, we found that the method of embryo culture is useful for determining the physiological regulation of diapause. We show that the development of embryos derived from diapausing eggs was strongly inhibited by the addition of either sorbitol or trehalose to the culture medium. Furthermore, this inhibitory effect disappeared when the embryos were cultured in a control medium which did not contain either sorbitol or trehalose, indicating that the inhibitory reactions caused by both substances are reversible. The minimal effective dose of either sorbitol or trehalose was approximately 0.2 M, a value similar to the in vivo concentration of sorbitol in diapausing eggs (0.2 M). Glycerol, mannitol or glucose were moderately effective for inhibition. Sorbitol present in diapausing silkworm eggs does not appear to serve as an antifreeze, but as an strong arresting factor of embryonic development. Furthermore, these results show that a decrease in sorbitol releases the embryos from diapause at the termination of diapause.
ABSTRACT
A prospective and quantitative animal study was performed to evaluate the production of wear particles from a spinal fixation device, and to test the hypothesis that the concentration of wear debris particles adjacent to spinal fixation hardware is correlated with the stiffness of the spinal fusion construct and local bone formation at the fusion site. An established canine segmental spinal fusion model with three interfacet fusions was used in this study. Several bone substitute materials were grafted to the area of the interfacet fusion. Internal fixation was performed on both sides of the spinous processes at each site using a stainless steel plate system in 19 dogs. After 12 weeks, spinal segments were excised, then 3-dimensional computerized tomography was used to measure bone volume and bone area of the individual fusion sites. The stiffness of each segment was tested using a servohydraulic materials testing machine. Biopsies were obtained from the soft tissues immediately around the plate system, and wear particles were collected and characterized using an electrical resistance particle analyzer, light and scanning electron microscopy (SEM) with energy-dispersive X-ray spectroscopy (EDX). Biopsies from para-spinal tissue from adjacent, unoperated spinal levels served as negative controls. Histologically, 24 of 57 specimens (42.1%) showed only fibrous tissue with no recognizable macrophages, inflammation, or debris. Fourteen of 57 specimens (24.6%), however, contained many particles that were composed of Fe, Cr, and Ni, corresponding to elements found in the fixation hardware. Another 19 specimens showed only occasional particles. The mean concentration of particles from the tissue around the plate system was 2.8 x 10(9) per gram dry tissue weight, compared to 0.5 x 10(9) particles per gram for controls (p < 0.05). Statistical analyses showed significant inverse correlation between the log particle number and stiffness (r = -0.41, p < 0.01), bone volume (r = -0.28, p < 0.05), and bone area (r = -0.34, p < 0. 05) of the corresponding segments. The concentration of particles in the tissue showed a significant inverse correlation with stiffness, bone volume, and bone area of the fusion constructs.
Subject(s)
Biocompatible Materials , Bone Substitutes , Internal Fixators , Spinal Fractures , Animals , Dogs , Mechanics , Spinal FusionABSTRACT
In patients with inferior wall acute myocardial infarction (AMI), the site of the culprit lesion is an important determinant of outcome. Patients with right ventricular infarction have a poor prognosis, whereas those with occlusion of the left circumflex coronary artery (LCx) have a good prognosis. Therefore, we assessed whether standard 12-lead electrocardiograms obtained on admission could identify the site of coronary artery occlusion, (i.e., a site proximal to the origin of the right ventricular branch of the right coronary artery [RCA], a site distal to the origin of the right ventricular branch of the RCA, or a site in the LCx). The ratio of ST depression in lead V3 to ST elevation in lead III (V3/III ratio) was evaluated immediately before coronary angiography in 152 patients with a first inferior wall AMI confirmed by coronary angiography within 12 hours after the onset of symptoms. For occlusion of the proximal RCA, distal RCA, and LCx, V3/III ratio was 0.2+/-0.3, 0.8+/-0.5, and 2.5+/-2.5 (p = 0.0001), respectively. The V3/III ratio <0.5 identified proximal RCA occlusion, 0.5 Subject(s)
Coronary Disease/pathology
, Coronary Vessels/pathology
, Electrocardiography
, Myocardial Infarction/complications
, Adult
, Aged
, Aged, 80 and over
, Female
, Humans
, Male
, Middle Aged
, Myocardial Infarction/pathology
, Prognosis
, Retrospective Studies
, Sensitivity and Specificity