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OBJECTIVES: Cold snare polypectomy (CSP)-dedicated snares (DSs) may have a higher resection ability than conventional snares. However, a model that can accurately and objectively evaluate and compare the resection ability of each snare has yet to be determined, and characteristics of snare parts that increase resection ability remain unknown. Therefore, we elucidated DSs' resection ability and all characteristics of the parts required for acquiring high resection ability. METHODS: An ex vivo model for evaluating resection ability was generated using human colons obtained from forensic autopsy specimens. The force required to resect a 15 mm wide human colonic mucosa (FRR) was measured using this model; if the FRR is small, the resection ability is high. Next, after measuring the stiffness of each snare part, the correlation between the stiffness and resection ability was analyzed. RESULTS: The force required to resect using SnareMaster Plus, Micro-Tech Cold Snare, Captivator Cold, Exacto Cold Snare, or Captivator II was 13.6 ± 1.0, 12.5 ± 1.2, 7.4 ± 1.2, 6.5 ± 1.0, and 28.7 ± 3.7 N, respectively. All DSs had significantly lower FRR than the conventional snare (Captivator II) and had higher resection ability (P < 0.001). A negative correlation was found between FRR and sheath or wire spindle stiffness, with correlation coefficients of 0.72 (P = 0.042) or 0.94 (P < 0.001), respectively. Moreover, 1 × 7 type wire rings had significantly higher friction coefficients than 1 × 3 type wire rings (P < 0.002). CONCLUSION: Sheath and wire spindle stiffness should be increased to increase resection ability; 1 × 7 type wire rings may be suitable for CSP-snare parts.
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INTRODUCTION: Intraoperative periprosthetic fracture, one of the most frequent complications of total hip arthroplasty, is a very important factor that affects rehabilitation, hospitalization time, and cost of treatment. Osteoporosis is common in total hip arthroplasty patients and likely contributes to the increasing incidence of periprosthetic fracture. Despite this awareness, preoperative and postoperative osteoporosis evaluations remain insufficient. The purpose of this study was to evaluate the relationships between the occurrence of intraoperative periprosthetic fractures and both bone mineral density (BMD) and osteoporosis-related biomarkers. MATERIALS AND METHODS: This single-center retrospective study included a total of consecutive 487 hip joints of patients with a mean age of 65.5 ± 11.8 years who underwent total hip arthroplasty between July 2017 and December 2020. Patients with low BMD defined as T-score < -1.0 versus those with normal BMD were matched by a 1:1 propensity score to balance for patient baseline characteristics, and outcome was analyzed by a modified Poisson regression model. Our primary outcome was the incidence of intraoperative periprosthetic fracture during surgery. We also investigated the effect modification of osteoporosis-related biomarkers, including tartrate-resistant acid phosphatase 5b (TRACP-5b), total procollagen type 1 amino-terminal propeptide (total P1-NP), intact parathyroid hormone (intact PTH), and homocysteine, on osteoporosis and outcomes. RESULTS: After matching, 250 patients were analyzed. The risk of fracture was significantly higher in patients with low BMD than in normal BMD patients (Incidence rate ratio 5.00 [95% CI 1.11-22.43], p = 0.036). We also observed significant effect of high serum homocysteine on the occurrence of intraoperative fractures (Incidence rate ratio 8.38 × 106 [95% C; 3.44 × 106-2.01 × 107], p < 0.01). CONCLUSION: Preoperative osteoporosis and high serum homocysteine levels were risk factors for intraoperative periprosthetic fractures. LEVEL OF EVIDENCE: III, A single-center retrospective study.
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Artroplastia de Quadril , Osteoporose , Fraturas Periprotéticas , Humanos , Pessoa de Meia-Idade , Idoso , Artroplastia de Quadril/efeitos adversos , Fraturas Periprotéticas/etiologia , Fraturas Periprotéticas/epidemiologia , Estudos Retrospectivos , Pontuação de Propensão , Osteoporose/complicações , Densidade Óssea , BiomarcadoresRESUMO
Evaluating the stability of highly pathogenic avian influenza viruses on human skin and measuring the effectiveness of disinfectants are crucial for preventing contact disease transmission. We constructed an evaluation model using autopsy skin samples and evaluated factors that affect the stability and disinfectant effectiveness for various subtypes. The survival time of the avian influenza A(H5N1) virus on plastic surfaces was ≈26 hours and on skin surfaces ≈4.5 hours, >2.5-fold longer than other subtypes. The effectiveness of a relatively low ethanol concentration (32%-36% wt/wt) against the H5N1 subtype was substantially reduced compared with other subtypes. Moreover, recombinant viruses with the neuraminidase gene of H5N1 survived longer on plastic and skin surfaces than other recombinant viruses and were resistant to ethanol. Our results imply that the H5N1 subtype poses a higher contact transmission risk because of its higher stability and ethanol resistance, which might depend on the neuraminidase protein.
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Virus da Influenza A Subtipo H5N1 , Vírus da Influenza A , Influenza Aviária , Influenza Humana , Animais , Etanol/farmacologia , Humanos , Virus da Influenza A Subtipo H5N1/genética , Neuraminidase/genéticaRESUMO
We report the synthesis and optoelectronic properties of high phase-purity (>94 mol %) bulk polycrystals of KCoO2-type layered nitrides AETMN2 (AE = Sr, Ba; and TM = Ti, Zr, Hf), which are expected to exhibit unique electron transport properties originating from their natural two-dimensional (2D) electronic structure, but high-purity intrinsic samples have yet been reported. The bulks were synthesized using a solid-state reaction between AENH and TMN precursors with NaN3 to achieve high N chemical potential during the reaction. The AETMN2 bulks are n-type semiconductors with optical band gaps of 1.63 eV for SrTiN2, 1.97 eV for BaZrN2, and 2.17 eV for BaHfN2. SrTiN2 and BaZrN2 bulks show degenerated electron conduction due to the natural high-density electron doping and paramagnetic behavior in all of the temperature ranges examined, while such unintentional carrier generation is largely suppressed in BaHfN2, which exhibits nondegenerated electron conduction. The BaHfN2 sample also exhibits weak ferromagnetic behavior at temperatures lower than 35 K. Density functional theory calculations suggest that the high-density electron carriers in SrTiN2 come from oxygen impurity substitution at the N site (ON) acting as a shallow donor even if the high-N chemical potential synthesis conditions are employed. On the other hand, the formation energy of ON becomes larger in BaHfN2 because of the stronger TM-N chemical bonds. Present results demonstrate that the easiness of impurity incorporation is designed by density functional calculations to produce a more intrinsic semiconductor in wider chemical conditions, opening a way to cultivating novel functional materials that are sensitive to atmospheric impurities and defects.
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INTRODUCTION: The assessment of the risk of virus transmission through papers, such as postcards, is important. However, the stability of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and influenza A virus (IAV) on different types of papers is currently unknown. Investigation of the survival time of these viruses on different types of papers will provide insights into their risk of long-distance transport by postal items. METHODS: We evaluated the stability of SARS-CoV-2 and IAV, mixed with a culture medium, on the surface of postcards with various coatings, including plain paper (PP), inkjet paper (IP), and inkjet photo paper (IPP). The surface structure of each paper was microscopically assessed. RESULTS: The surface structures of PP, IP, and IPP varied greatly depending on the presence or absence, and type, of coat layer, regardless of the base material. IP and IPP surfaces were less conducive to virus survival than PP surfaces, because of the difference in surface shapes. The survival times of SARS-CoV-2 on each paper were approximately 59.8 (PP), 6.5 (IP), and 9.8 h (IPP), and significantly longer than those of IAV (10.3, 1.8, and 3.3 h, respectively). CONCLUSIONS: The risk of SARS-CoV-2 transmission via paper, such as postcards, is significantly higher than that of IAV transmission. While PP, IP, and IPP have the same base material, their surface structures differ, which affects viral stability. The IP and IPP surfaces are less suitable for virus survival. This study provides novel insights into the risks of viral transmission via paper.
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COVID-19 , Vírus da Influenza A , Orthomyxoviridae , Humanos , SARS-CoV-2RESUMO
BACKGROUND: Whether different body positions during surgery affect postoperative stem alignment in total hip arthroplasty (THA) remains unclear. The purpose of this study was to clarify differences in tapered wedge stem alignment between supine and lateral positions in THA under the modified Watson-Jones anterolateral approach. METHODS: We reviewed 242 consecutive, primary cementless THAs performed with ceramic-on-cross-linked polyethylene via the modified Watson-Jones approach in either supine or lateral positions between 2009 and 2015 (supine group: 113 cases; lateral group: 129 cases). No specific reasons to select supine or lateral positions for the surgery were given during the study period. Computed tomography was performed pre- and postoperatively to measure preoperative femoral anteversion and postoperative stem anteversion, respectively. Stem alignment in coronal and sagittal planes was also evaluated. RESULTS: Mean difference in stem anteversion and femoral anteversion was 8.6 ± 9.4 in the supine position and 13.0 ± 11.4 in the lateral position (p = 0.0013). Although no significant difference was seen between groups for stem alignment in the coronal plane, flexed implantation was more likely in the supine group (46/113, 40.7%) than in the lateral group (20/129, 15.5%). A significant correlation was found between femoral anteversion and stem anteversion in both the supine and lateral groups (r = 0.68, p < 0.0001 and r = 0.52, p < 0.0001, respectively). CONCLUSION: Although stem anteversion was more strongly correlated with femoral anteversion in the supine position than in the lateral position, neutral position in the sagittal plane was more likely to be found with the lateral position than with the supine position. Surgeons can achieve ideal stem positioning by considering these results in the modified Watson-Jones approach in both the supine and lateral positions.
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Artroplastia de Quadril , Prótese de Quadril , Artroplastia de Quadril/métodos , Fêmur/diagnóstico por imagem , Fêmur/cirurgia , Humanos , Período Pós-Operatório , Amplitude de Movimento ArticularRESUMO
BACKGROUND: The stability of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) on human skin remains unknown, considering the hazards of viral exposure to humans. We generated a model that allows the safe reproduction of clinical studies on the application of pathogens to human skin and elucidated the stability of SARS-CoV-2 on human skin. METHODS: We evaluated the stability of SARS-CoV-2 and influenza A virus (IAV), mixed with culture medium or upper respiratory mucus, on human skin surfaces and the dermal disinfection effectiveness of 80% (weight/weight) ethanol against SARS-CoV-2 and IAV. RESULTS: SARS-CoV-2 and IAV were inactivated more rapidly on skin surfaces than on other surfaces (stainless steel/glass/plastic); the survival time was significantly longer for SARS-CoV-2 than for IAV (9.04 hours [95% confidence interval, 7.96- 10.2 hours] vs 1.82 hours [1.65-2.00 hours]). IAV on other surfaces was inactivated faster in mucus versus medium conditions, while SARS-CoV-2 showed similar stability in the mucus and medium; the survival time was significantly longer for SARS-CoV-2 than for IAV (11.09 hours [10.22-12.00 hours] vs 1.69 hours [1.57-1.81 hours]). Moreover, both SARS-CoV-2 and IAV in the mucus/medium on human skin were completely inactivated within 15 seconds by ethanol treatment. CONCLUSIONS: The 9-hour survival of SARS-CoV-2 on human skin may increase the risk of contact transmission in comparison with IAV, thus accelerating the pandemic. Proper hand hygiene is important to prevent the spread of SARS-CoV-2 infections.
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COVID-19 , Higiene das Mãos , Vírus da Influenza A , Orthomyxoviridae , Humanos , SARS-CoV-2RESUMO
BACKGROUND AIMS: Platelet concentrates (PCs) are pooled to prepare human platelet lysate (HPL) supplements of growth media to expand primary human cells for transplantation; this increases the risk of contamination by known, emerging, and unknown viruses. This possibility should be of concern because viral contamination of cell cultures is difficult to detect and may have detrimental consequences for recipients of cell therapies. Viral reduction treatments of chemically defined growth media have been proposed, but they are not applicable when media contain protein supplements currently needed to expand primary cell cultures. Recently, we successfully developed a Planova 35NPlanova 20N nanofiltration sequence of growth media supplemented with two types of HPL. The nanofiltered medium was found to be suitable for mesenchymal Stromal cell (MSC) expansion. METHODS: Herein, we report viral clearance achieved by this nanofiltration process used for assessing a new experimental model using non-infectious minute virus of mice-mock virus particle (MVM-MVP) and its quantification by an immunoqPCR. Then, high doses of MVM-MVP (1012 MVPs/mL) were spiked to obtain a final concentration of 1010 MVPs/mL in Planova 35N-nanofiltered growth medium supplemented with both types of HPLs [serum converted platelet lysate SCPL) and intercept human platelet lysate (I-HPL)] at 10% (v/v) and then filtering through Planova 20N. RESULTS: No substantial interference of growth medium matrices by the immune-qPCR assay was first verified. Log reduction values (LRVs) were ≥ 5.43 and ≥ 5.36 respectively, SCPL and I-HPL media. MVM-MVPs were also undetectable by dynamic light scattering and transmission electron microscopy. CONCLUSIONS: The nanofiltration of growth media supplemented with 10% HPL provides robust removal of small nonenveloped viruses, and is an option to improve the safety of therapeutic cells expanded using HPL supplements.
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Células-Tronco Mesenquimais , Vírus Miúdo do Camundongo , Animais , Técnicas de Cultura de Células , Meios de Cultura , Humanos , Camundongos , VírionRESUMO
Lasting disinfection effects, that is, the residual disinfection effects (RDEs), of skin-coated disinfectants have rarely been considered for infection control owing to the challenges involved in the accurate evaluation of RDEs. In this study, we constructed a new skin evaluation model and determined the RDEs of existing disinfectants against viruses. Our results showed that ethanol and isopropanol had no RDE, whereas povidone-iodine, chlorhexidine gluconate, and benzalkonium chloride (BAC) exhibited RDEs, with 10% povidone-iodine and 0.2% BAC showing particularly strong RDEs. The RDE of 0.2% BAC was strong enough to reduce the median survival times of severe acute respiratory syndrome coronavirus-2, human coronavirus-OC43, and influenza virus from 670 to 5.2, 1300 to 12, and 120 to 4.2 min, respectively. Additionally, this strong RDE was maintained even 4 h after coating the skin. Clinical data also showed that the strong RDE of 0.2% BAC was maintained for more than 2 h. Thus, applying disinfectants with strong RDEs on the skin correlates with a reduction in virus survival time and appears to create a skin surface environment that is not conducive to virus survival. A prolonged reduction in virus survival decreases the contact transmission risk, thereby enabling stronger infection control.
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COVID-19 , Desinfetantes , Desinfecção , Humanos , Povidona-Iodo , SARS-CoV-2RESUMO
A 52-year-old woman presented to a clinic in late August with exacerbated fatigue and dyspnea on exertion for several months. Then, she was referred and admitted to our hospital in late September. Her chest CT showed bilateral diffuse centrilobular micronodules. In her detailed clinical history, she had kept budgerigars indoors for 15 years. These findings suggested she had a bird-related hypersensitivity pneumonitis (BRHP). By a site environmental investigation, 40 budgerigars were kept in a single breeding room and there were large amounts of droppings on the floor. Serum specific antibody for bird antigens and an environmental provocation test were positive. Bronchoalveolar lavage fluid showed lymphocytosis and a low CD4/CD8 ratio. Trans-bronchial lung biopsy showed lymphocytic infiltration of the alveolar wall and interlobular septa. After antigen avoidance as hospitalization, her symptoms and abnormal shadow improved. From these results, the patient was diagnosed as an acute BRHP.BRHP often presents a chronic onset. This case was diagnosed as an acute type despite the 15-years of budgerigars breeding. Increased exposure of antigens due to lack of cleaning after several days' antigen avoidance was suspected with one of the causes of acute onset.
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Alveolite Alérgica Extrínseca , Pulmão do Criador de Aves , Alveolite Alérgica Extrínseca/diagnóstico , Antígenos , Pulmão do Criador de Aves/diagnóstico , Dispneia , Feminino , Humanos , Pessoa de Meia-Idade , Tomografia Computadorizada por Raios XRESUMO
BACKGROUND AIMS: Human platelet lysate can replace fetal bovine serum (FBS) for xeno-free ex vivo expansion of mesenchymal stromal cells (MSCs), but pooling of platelet concentrates (PCs) increases risks of pathogen transmission. We evaluated the feasibility of performing nanofiltration of platelet lysates and determined the impact on expansion of bone marrow-derived MSCs. METHODS: Platelet lysates were prepared by freeze-thawing of pathogen-reduced (Intercept) PCs suspended in 65% storage solution (SPP+) and 35% plasma, and by serum-conversion of PCs suspended in 100% plasma. Lysates were added to the MSC growth media at 10% (v/v), filtered and subjected to cascade nanofiltration on 35- and 19-nm Planova filters. Media supplemented with 10% starting platelet lysates or FBS were used as the controls. Impacts of nanofiltration on the growth media composition, removal of platelet extracellular vesicles (PEVs) and MSC expansion were evaluated. RESULTS: Nanofiltration did not detrimentally affect contents of total protein and growth factors or the biochemical composition. The clearance factor of PEVs was >3 log values. Expansion, proliferation, membrane markers, differentiation potential and immunosuppressive properties of cells in nanofiltered media were consistently better than those expanded in FBS-supplemented media. Compared with FBS, chondrogenesis and osteogenesis genes were expressed more in nanofiltered media, and there were fewer senescent cells over six passages. CONCLUSIONS: Nanofiltration of growth media supplemented with two types of platelet lysates, including one prepared from pathogen-reduced PCs, is technically feasible. These data support the possibility of developing pathogen-reduced xeno-free growth media for clinical-grade propagation of human cells.
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Plaquetas/citologia , Técnicas de Cultura de Células/métodos , Filtração , Células-Tronco Mesenquimais/citologia , Nanotecnologia , Adipogenia/efeitos dos fármacos , Biomarcadores/metabolismo , Diferenciação Celular/efeitos dos fármacos , Linhagem da Célula/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Células Cultivadas , Senescência Celular/efeitos dos fármacos , Meios de Cultura/farmacologia , Vesículas Extracelulares/metabolismo , Perfilação da Expressão Gênica , Humanos , Imunofenotipagem , Terapia de Imunossupressão , Peptídeos e Proteínas de Sinalização Intercelular/metabolismo , Peptídeos e Proteínas de Sinalização Intercelular/farmacologia , Células-Tronco Mesenquimais/efeitos dos fármacos , Osteogênese/efeitos dos fármacos , Tamanho da Partícula , Soro/químicaRESUMO
Recessive skeletal dysplasia, characterized by joint- and/or hip bone-enlargement, was mapped within the critical region for a major quantitative trait locus (QTL) influencing carcass weight; previously named CW-3 in Japanese Black cattle. The risk allele was on the same chromosome as the Q allele that increases carcass weight. Phenotypic characterization revealed that the risk allele causes disproportional tall stature and bone size that increases carcass weight in heterozygous individuals but causes disproportionately narrow chest width in homozygotes. A non-synonymous variant of FGD3 was identified as a positional candidate quantitative trait nucleotide (QTN) and the corresponding mutant protein showed reduced activity as a guanine nucleotide exchange factor for Cdc42. FGD3 is expressed in the growth plate cartilage of femurs from bovine and mouse. Thus, loss of FDG3 activity may lead to subsequent loss of Cdc42 function. This would be consistent with the columnar disorganization of proliferating chondrocytes in chondrocyte-specific inactivated Cdc42 mutant mice. This is the first report showing association of FGD3 with skeletal dysplasia.
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Doenças do Desenvolvimento Ósseo/veterinária , Doenças dos Bovinos/genética , Fatores de Troca do Nucleotídeo Guanina/genética , Sequência de Aminoácidos , Animais , Estatura/genética , Peso Corporal/genética , Doenças do Desenvolvimento Ósseo/genética , Bovinos , Análise Mutacional de DNA , Feminino , Expressão Gênica , Estudos de Associação Genética , Predisposição Genética para Doença , Lâmina de Crescimento/metabolismo , Fatores de Troca do Nucleotídeo Guanina/metabolismo , Haplótipos , Homozigoto , Humanos , Masculino , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Dados de Sequência Molecular , Mutação de Sentido Incorreto , Linhagem , Proteínas Tirosina Fosfatases/genética , Locos de Características Quantitativas , RiscoRESUMO
Chromobacterium violaceum is sensitive to temperature and the infection is usually confined to tropical or subtropical regions. Since Japan has a warm climate, C. violaceum has been scarcely isolated from clinical specimens. With global warming, however, the geographical distribution of C. violaceum infection is likely to change. We report two cases of C. violaceum nosocomial pneumonia that occurred at an intensive care center in Japan. C. violaceum was first detected from a patient in the same center as a pathogenic organism of pneumonia. Later, the organism was isolated from sputum and a ventilator circuit tube of another patient in the center. The two patients were admitted to the center in nearby beds for several days. All of the pathogens were confirmed to be C. violaceum by the nucleic acid sequence of the 16S rRNA gene and were proven to be genetically identical organisms by pulsed field gel electrophoresis. Both patients were managed with well-humidified and heated oxygen using a venturi mask and ventilator to promote excretion of sputum. It was thought that the medical respiratory care devices that provide a humid and warm environment, an optimal condition for proliferation of C. violaceum, can contribute to C. violaceum infection in a hospital environment.
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Chromobacterium/isolamento & purificação , Infecção Hospitalar/microbiologia , Infecções por Bactérias Gram-Negativas/microbiologia , Pneumonia Bacteriana/microbiologia , Idoso , Idoso de 80 Anos ou mais , Antibacterianos/uso terapêutico , Chromobacterium/efeitos dos fármacos , Chromobacterium/genética , Infecção Hospitalar/tratamento farmacológico , Infecções por Bactérias Gram-Negativas/tratamento farmacológico , Humanos , Masculino , Meropeném , Pneumonia Bacteriana/tratamento farmacológico , Escarro/microbiologia , Tienamicinas/uso terapêuticoAssuntos
Antialérgicos/uso terapêutico , Anticorpos Monoclonais Humanizados/uso terapêutico , Aspergilose Broncopulmonar Alérgica/tratamento farmacológico , Aspergillus fumigatus/fisiologia , Alérgenos/imunologia , Antígenos de Fungos/imunologia , Amarelo de Eosina-(YS)/análogos & derivados , Feminino , Humanos , Imunoglobulina E/metabolismo , Pessoa de Meia-Idade , Tapsigargina/análogos & derivados , Fatores de TempoRESUMO
Rapid joint destruction caused by rapidly destructive coxarthrosis (RDC) can increase surgical complexity and intraoperative blood loss. This single-center retrospective study investigates osteoporosis-related biomarkers for early RDC diagnosis and explores new treatment targets. We included 398 hip joints from patients who underwent total hip arthroplasty, examining medical records for preoperative patient demographics, bone mineral density of the hip and lumbar spine from dual-energy X-ray absorptiometry scans, and osteoporosis-related biomarkers including TRACP-5b, total P1NP, intact parathyroid hormone, and homocysteine. We compared RDC and osteoarthritis (OA) patients, and univariate analysis showed that RDC patients were older (p < 0.001) and had lower serum levels of albumin (p < 0.001) and higher serum levels of TRACP-5b, total P1NP (p < 0.001), and homocysteine (p = 0.006). Multivariable analysis showed that the ratio of serum TRACP-5b to total P1NP had a more significant difference in RDC patients than in OA patients (p = 0.04). Serum TRACP-5b levels were negatively correlated with the time between RDC onset and blood collection, and Japanese Orthopedic Association pain score. Receiver operating characteristic curve analysis revealed that the ratio of serum TRACP-5b to total P1NP had the highest area under the curve value. This study is the first to demonstrate that the ratio of serum TRACP-5b to total P1NP-increased bone resorption that outpaces increased bone formation-is significantly elevated in patients with RDC and that TRACP-5b is higher in the early stages of RDC. Inhibiting serum levels of TRACP-5b, activated osteoclasts, during early RDC may suppress disease progression.
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Reabsorção Óssea , Osteoartrite do Quadril , Osteólise , Osteoporose , Humanos , Fosfatase Ácida Resistente a Tartarato , Osteogênese , Estudos Retrospectivos , Biomarcadores , Homocisteína , Fosfatase ÁcidaRESUMO
Background: Post-cardiac arrest (CA) shock is associated with multiple organ failure, including acute kidney injury, and is the leading cause of early death among patient successfully resuscitated from CA. Arginine-vasopressin (AVP) may be an interesting therapeutic alternative or complement to noradrenaline (NAD) to both control shock and preserve regional, especially renal, organ perfusions. Methods: 18 swine (24-39 kg) were submitted to 14 min of ventricular fibrillation and cardio-pulmonary resuscitation. After return of spontaneous circulation (ROSC), animals randomly received either AVP, NAD or AVP-NAD combination for maintaining a targeted mean arterial pressure of 70 ± 5 mmHg for 6 h. Haemodynamic and biological parameters, including kidney function biomarkers and diuresis, were monitored throughout the follow-up. Results: Targeted mean arterial pressure was successfully obtained in the NAD (n = 6) and the AVP-NAD (n = 6) groups, but not in the AVP group (n = 6), where 4 animals died. As compared to NAD alone, renal blood flow (2.9 ± 1.15 vs 4.36 ± 0.64 mL//kg/min in NAD and AVP-NAD groups) and diuresis were higher in the AVP-NAD group. This was associated with a reduction of carotid blood flow and a more severe metabolic acidosis during the first 3 h of follow-up in the AVP-NAD group as compared to NAD group. Conclusion: Combination of AVP and NAD improved renal perfusion and diuresis but reduced carotid blood flow as compared to NAD alone in a porcine model of post-resuscitation syndrome. AVP alone failed to manage shock and led to mortality.
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BACKGROUND: A sepsis-like syndrome is known to occur after cardiac arrest, leading to cerebral infiltration by white blood cells (WBC). We hypothesized that pharmacological sequestration of WBC, and more specifically lymphocytes within lymphoid tissues, could reduce the cerebral infiltration by these inflammatory cells and subsequent acute brain injury in a porcine model of cardiac arrest. Lymphocyte sequestration was induced by the sphingosine-1 phosphate receptors agonist fingolimod. METHODS: In a first set of experiments, anesthetized pigs underwent a sham instrumentation with no cardiac arrest (n = 4). They received an administration of fingolimod (1 mg/kg, i.v.) in order to confirm its effect on WBC. In a second set of experiments, animals randomly received fingolimod or saline two hours prior to an episode of ventricular fibrillation (14 min) with subsequent resuscitation (n = 6 in each group). Neurological injury was assessed 24 h after resuscitation. RESULTS: In the first set of experiments, WBC and blood lymphocyte counts were significantly reduced by - 61 ± 10% and - 75 ± 6% two hours after fingolimod administration. In the second set of experiments, blood lymphocyte counts, but not WBC, were also significantly reduced after cardiac arrest in Fingolimod vs Control group. However, most cytokine blood levels were not different among groups, including Interleukin (IL)-1ra, IL-8 or IL-18 blood levels. A difference was only observed for IL-6, which decreased in Fingolimod vs Control (e.g., 5.6 ± 4.8 vs 59.4 ± 20.6 pg/ml at 2 h after cardiac arrest, respectively; p = 0.126). Neurofilament light chain (NFL) blood levels were not different among groups (57 ± 25 vs 84 ± 41 pg/ml in Fingolimod vs Control at 6 h after resuscitation, respectively). After awakening, 3 and 2 animals were prematurely euthanized for ethical reasons due to recurrent seizures in Fingolimod and Control groups, respectively. At Day 1, neurological dysfunction score was not different between groups (87 ± 7 vs 87 ± 5% in Fingolimod vs Control, respectively). Conversely, a decrease in the number of CD3 + cells was observed in the brain of surviving animals in Fingolimod vs Control group (3.10 ± 0.50 vs 7.53 ± 0.57 CD3 + cells/field, respectively; p = 0.0286). CONCLUSION: Fingolimod-induced WBC sequestration, and more specifically lymphocytes sequestration, did not improve clinical neurological dysfunction following cardiac arrest although it reduced cerebral infiltration by lymphocytes.
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BACKGROUND: Brain injury is one of the most serious complications after cardiac arrest (CA). To prevent this phenomenon, rapid cooling with total liquid ventilation (TLV) has been proposed in small animal models of CA (rabbits and piglets). Here, we aimed to determine whether hypothermic TLV can also offer neuroprotection and mitigate cerebral inflammatory response in large animals. METHODS AND RESULTS: Anesthetized pigs were subjected to 14 minutes of ventricular fibrillation followed by cardiopulmonary resuscitation. After return of spontaneous circulation, animals were randomly subjected to normothermia (control group, n=8) or ultrafast cooling with TLV (TLV group, n=8). In the latter group, TLV was initiated within a window of 15 minutes after return of spontaneous circulation and allowed to reduce tympanic, esophageal, and bladder temperature to the 32 to 34 °C range within 30 minutes. After 45 minutes of TLV, gas ventilation was resumed, and hypothermia was maintained externally until 3 hours after CA, before rewarming using heat pads (0.5 °C-1 °C/h). After an additional period of progressive rewarming for 3 hours, animals were euthanized for brain withdrawal and histological analysis. At the end of the follow-up (ie, 6 hours after CA), histology showed reduced brain injury as witnessed by the reduced number of Fluroro-Jade C-positive cerebral degenerating neurons in TLV versus control. IL (interleukin)-1ra and IL-8 levels were also significantly reduced in the cerebrospinal fluid in TLV versus control along with cerebral infiltration by CD3+ cells. Conversely, circulating levels of cytokines were not different among groups, suggesting a discrepancy between local and systemic inflammatory levels. CONCLUSIONS: Ultrafast cooling with TLV mitigates neuroinflammation and attenuates acute brain lesions in the early phase following resuscitation in large animals subjected to CA.
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Modelos Animais de Doenças , Parada Cardíaca , Hipotermia Induzida , Ventilação Líquida , Animais , Hipotermia Induzida/métodos , Parada Cardíaca/terapia , Ventilação Líquida/métodos , Suínos , Fatores de Tempo , Reanimação Cardiopulmonar/métodos , Encéfalo/patologia , Encéfalo/metabolismo , Neuroproteção , Citocinas/metabolismo , Citocinas/sangue , Mediadores da Inflamação/metabolismo , Mediadores da Inflamação/sangueRESUMO
γ-Secretase is an intramembrane-cleaving protease related to the etiology of Alzheimer disease. γ-Secretase is a membrane protein complex composed of presenilin (PS) and three indispensable subunits: nicastrin, Aph-1, and Pen-2. PS functions as a protease subunit forming a hydrophilic catalytic pore structure within the lipid bilayer. However, it remains unclear how other subunits are involved in the pore formation. Here, we show that the hydrophilic pore adopted with an open conformation has already been formed by PS within the immature γ-secretase complex. The binding of the subunits induces the close proximity between transmembrane domains facing the catalytic pore. We propose a model in which the γ-secretase subunits restrict the arrangement of the transmembrane domains of PS during the formation of the functional structure of the catalytic pore.