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In original publication of the article, some of the co-author's names were not included. The correct author group is published in this article.
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Autoantibodies against cardiac proteins play an important role in the development of dilated cardiomyopathy (DCM). The efficacy and safety of apheresis such as immunoadsorption (IA) or plasma exchange (PE) to remove such antibodies have been reported in adult DCM patients. However, apheresis for pediatric DCM has not been performed because of technical difficulty due to relatively low blood volume and instability of hemodynamics. As we have experiences of preforming apheresis on hemodynamically unstable children, we have preformed ten courses of PE on seven child DCM patients including both patients in chronic and acute phase to assess the safety and efficacy to PE. Under general anesthesia, the patients were administered PE three times during 3 days as 1 course. Simultaneously, continuous hemodiafiltration (CHDF) was performed in series with the PE circuit to stabilize hemodynamic status and to minimize the adverse effects of PE. The changes in LVEF, CTR, mBP, the dosage of furosemide and NYHA were assessed before and after the procedure of PE. There were no severe adverse effects such as systemic bleeding or refractory hypotension due to apheresis. Echocardiography showed that mean baseline LVEF was 24.3 ± 7.8%. Mean LVEF significantly increased 1 week after PE to 30.5 ± 12.5%. CTR significantly decreased after PE. Mean BP significantly increased 1 month after PE (54.5 ± 10.7 to 60.7 ± 9.8 mmHg). NYHA improved after PE significantly (NYHA; 3.4 ± 1.1 to 2.5 ± 1.1). PE is safe and effective in improving both cardiac function and daily activities.
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Atividades Cotidianas , Cardiomiopatia Dilatada/terapia , Hemodinâmica/fisiologia , Troca Plasmática/métodos , Adolescente , Cardiomiopatia Dilatada/fisiopatologia , Criança , Pré-Escolar , Feminino , Humanos , Lactente , Masculino , Resultado do Tratamento , Adulto JovemRESUMO
Healthy bowel function is an important factor when judging the advisability of early enteral nutrition in critically ill patients, but long-term observation and objective evaluation of gastrointestinal motility are difficult. In the study, real-time continuous measurement of gastrointestinal motility was performed in patients with severe sepsis using a developed bowel sound analysis system, and the correlation between bowel sounds and changes over time in blood concentrations of interleukin (IL)-6, which is associated with sepsis severity, was evaluated. The subjects were five adult patients in the acute phase of severe sepsis on a mechanical ventilator, with IL-6 blood concentrations ≥100 pg/mL, who had consented to participate in the study. Gastrointestinal motility was measured for a total of 62,399 min: 31,544 min in 3 subjects in the no-steroids group and 30,855 min in 2 subjects in the steroid treatment group. In the no-steroids group, the bowel sound counts were negatively correlated with IL-6 blood concentration, suggesting that gastrointestinal motility was suppressed as IL-6 blood concentration increased. However, in the steroid treatment group, gastrointestinal motility showed no correlation with IL-6 blood concentration (r = -0.25, p = 0.27). The IL-6 blood concentration appears to have decreased with steroid treatment irrespective of changes in the state of sepsis, whereas bowel sound counts with the monitoring system reflected the changes in the state of sepsis, resulting in no correlation. This monitoring system provides a useful method of continuously, quantitatively, and non-invasively evaluating gastrointestinal motility in patients with severe sepsis. Gastrointestinal motility might be useful as a parameter reflecting disease severity, particularly in patients treated with steroids.
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Motilidade Gastrointestinal/fisiologia , Monitorização Fisiológica/métodos , Sepse/fisiopatologia , Adulto , Idoso , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Projetos Piloto , Estudos ProspectivosRESUMO
INTRODUCTION: Although hemodialysis is lifesaving in patients with kidney failure extensive interdialytic weight gain (IDWG) between dialyses worsens the prognosis. We recently showed a strong correlation between IDWG and predialytic values of cardiac markers. The aim of the present study was to evaluate if the cardiac markers N-terminal pro-B-type natriuretic peptide (proBNP) and troponin T were influenced by IDWG and speed of fluid removal (ultrafiltration-rate). METHODS: Twenty hemodialysis patients performed in total 60 hemodialysis (three each). Predialytic values of proBNP and troponin T and changes from predialysis to 180 min hemodialysis (180-0 min) were compared with the IDWG calculated in percent of body weight. The ultrafiltration-rate was adjusted (UF-rateadj ) to IDWG: (100 × weight gain between dialysis [kg])/(estimated body dry weight [kg] × length of hemodialysis session [hours]). RESULTS: UF-rateadj correlated (Spearman) with (1) predialytic values of IDWG (r = 0.983, p < 0.001), proBNP (r = 0.443, p < 0.001), and troponin T (r = 0.296, p = 0.025); and (2) differences in proBNP180-0min (r = 0.572, p < 0.001) and troponin T180-0min (r = 0.400, p = 0.002). UF-ratesadj above a breakpoint of 0.60 caused more release of proBNP180-0min (p = 0.027). Remaining variables in multiple regression analysis with ProBNP180-0min as dependent factor were predialytic proBNP (p < 0.001) and the ultrafiltration-rate (p < 0.001). CONCLUSION: Higher UF-rateadj during dialysis was correlated to increased levels of cardiac markers. Data support a UF-rateadj lower than 0.6 to limit such increase. Further studies may confirm if limited fluid intake and a lower UF-rateadj should be recommended to prevent cardiac injury during dialysis.
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Falência Renal Crônica , Diálise Renal , Humanos , Troponina T , Ultrafiltração , Falência Renal Crônica/terapia , Aumento de PesoRESUMO
Introduction: Enfortumab vedotin (EV) is an antibody-drug conjugate combining a monoclonal antibody targeting nectin-4 with a highly potent microtubule disrupting agent. EV is expected to be a candidate for the third-line treatment for urothelial carcinoma previously treated with platinum-based chemotherapy and PD-1/PD-L1 inhibitors. Very few cases of patients experienced hyperglycemia of unknown cause. Case Presentation: We describe a 72-year-old Asian man with mild obesity, type 2 diabetes, hyperlipidemia, hypertension, and chemo-resistant metastatic urothelial carcinoma. He developed hyperglycemia and febrile neutropenia after 3 doses of EV. He had hyperglycemia of 489 mg/dL and was started on continuous intravenous insulin infusion (CVII). The patient's intravenous insulin requirements peaked at 316 units per day. He also developed febrile neutropenia and consequent sepsis caused acute kidney injury. Continuous hemodialysis filtration (CHDF) together with antibiotics were started to treat the septic condition. The blood glucose level gradually decreased after CHDF treatment and CHDF was continued for 14 days. The timing of liberation from CHDF correlated with the elimination half-life of EV of 3.4 days. CVII was treated for 26 days and the patient was finally released from the intensive care unit. Conclusion: This case indicates that the uncontrollable hyperglycemia induced by EV during metastatic urothelial carcinoma treatment is effectively managed with CVII and CHDF until the elimination of the adverse effect of EV.
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BACKGROUND: Patients with severe acute kidney injury (AKI) who require continuous venovenous hemodiafiltration (CVVHDF) in intensive care unit (ICU) are at high mortality risk. Little is known about clinical biomarkers for risk prediction, optimal initiation, and optimal discontinuation of CVVHDF. METHODS: This prospective observational study was conducted in seven university-affiliated ICUs. For urinary neutrophil gelatinase-associated lipocalin (NGAL) and plasma IL-6 measurements, samples were collected at initiation, 24 h, 48 h after, and CVVHDF discontinuation in adult patients with severe AKI. The outcomes were deaths during CVVHDF and CVVHDF dependence. RESULTS: A total number of 133 patients were included. Twenty-eight patients died without CVVHDF discontinuation (CVVHDF nonsurvivors). Urinary NGAL and plasma IL-6 at the CVVHDF initiation were significantly higher in CVVHDF nonsurvivors than in survivors. Among 105 CVVHDF survivors, 70 patients were free from renal replacement therapy (RRT) or death in the next 7 days after discontinuation (success group), whereas 35 patients died or needed RRT again (failure group). Urinary NGAL at CVVHDF discontinuation was significantly lower in the success group (93.8 ng/ml vs. 999 ng/ml, p < 0.01), whereas no significant difference was observed in plasma IL-6 between the groups. Temporal elevations of urinary NGAL levels during the first 48 h since CVVHDF initiation were observed in CVVHDF nonsurvivors and those who failed in CVVHDF discontinuation. CONCLUSIONS: Urinary NGAL at CVVHDF initiation and discontinuation was associated with mortality and RRT dependence, respectively. The serial changes of urinary NGAL might also help predict the prognosis of patients with AKI on CVVHDF.
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BACKGROUND: Bisphosphonates are frequently used for osteoporosis. Medication-related osteonecrosis of the jaw, a complication of bone-modifying agents, including bisphosphonates or angiogenic inhibitors, can be challenging to treat in elderly patients with numerous preexisting conditions. Achieving good treatment outcomes is especially difficult in patients with pathological fractures accompanied with extraoral fistulae. CASE PRESENTATION: We report an unusual case of prominent bone regeneration following palliative surgical treatment in a 72-year-old Japanese female patient undergoing hemodialysis. She previously had severe osteoporosis due to renal osteodystrophy and was receiving antiresorptive intravenous bisphosphonate. Computed tomography revealed a discontinuous left lower mandibular margin with a pathologic fracture and extensive, morphologically irregular sequestrum formation (80 × 35 × 20 mm). The patient was diagnosed with stage III medication-related osteonecrosis of the jaw and pathologic mandibular fracture. Immediately before the surgery, the anticoagulant used for dialysis was changed from heparin to nafamostat mesylate to reduce the risk of intraoperative bleeding. Sequestrectomy was performed under general anesthesia. Postoperative infection was not observed, the intraoral and submandibular fistula disappeared, and, surprisingly, prominent spontaneous bone regeneration was observed postoperatively at 6 months. Despite the severe systemic condition of the patient, the conservative surgical approach with sequestrectomy has yielded desirable results for more than 6 years since the surgery. CONCLUSIONS: This rare report of spontaneous bone regeneration in a patient of advanced age and poor general condition is the oldest case of mandibular regeneration ever reported.
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Osteonecrose da Arcada Osseodentária Associada a Difosfonatos , Conservadores da Densidade Óssea , Fraturas Espontâneas , Osteonecrose , Idoso , Osteonecrose da Arcada Osseodentária Associada a Difosfonatos/diagnóstico por imagem , Osteonecrose da Arcada Osseodentária Associada a Difosfonatos/cirurgia , Conservadores da Densidade Óssea/efeitos adversos , Regeneração Óssea , Difosfonatos/efeitos adversos , Feminino , Fraturas Espontâneas/induzido quimicamente , Fraturas Espontâneas/diagnóstico por imagem , Humanos , Mandíbula/diagnóstico por imagem , Mandíbula/cirurgia , Osteonecrose/induzido quimicamente , Osteonecrose/diagnóstico por imagem , Diálise RenalRESUMO
AIMS: To investigate if a single low-flux HD induces a rise in cardiac biomarkers and if a change in clinical approach may limit such mechanism. MATERIAL AND METHODS: A total of 20 chronic HD patients each underwent three different study-dialyses. Dialyzers (low-flux polysulfone, 1.8 sqm) had been stored either dry or wet (Wet) and the blood level in the venous chamber kept low or high. Laboratory results were measured at baseline, 30 and 180 min, adjusted for the effect of fluid shift. Ultrasound measured microemboli signals (MES) within the return line. RESULTS: Hemodialysis raised cardiac biomarkers (p < 0.001): Pentraxin 3 (PTX) at 30 min (by 22%) and at 180 min PTX (53%), Pro-BNP (15%), and TnT (5%), similarly for all three HD modes. Baseline values of Pro-BNP correlated with TnT (rho = 0.38, p = 0.004) and PTX (rho = 0.52, p < 0.001). The changes from pre- to 180 min of HD (delta-) were related to baseline values (Pro-BNP: rho = 0.91, p < 0.001; TnT: rho = 0.41, p = 0.001; PTX: rho = 0.29, p = 0.027). Delta Pro-BNP (rho = 0.67, p < 0.001) and TnT (rho = 0.38, p = 0.004) correlated with inter-dialytic-weight-gain (IDWG). Biomarkers behaved similarly between the HD modes. The least negative impact was with an IDWG ⩽ 2.5%. Multiple regression analyses of the Wet-High mode does not exclude a relation between increased exposure of MES and factors such as release of Pro-BNP. CONCLUSION: Hemodialysis, independent of type of dialyzer storage, was associated with raised cardiac biomarkers, more profoundly in patients with higher pre-dialysis values and IDWG. A limitation in IDWG to <2.5% and prolonged ultrafiltration time may limit cardiac strain during HD, especially in patients with cardiovascular risk.
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Falência Renal Crônica , Biomarcadores , Humanos , Diálise Renal/efeitos adversos , Aumento de PesoRESUMO
The 2019 novel coronavirus, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has caused a global outbreak of infection. In general, children with coronavirus disease-2019 have been reported to show milder respiratory symptoms than adult patients. Here, we have described a case of a SARS-CoV-2-infected infant who presented to our hospital with a severe episode of an apparent life-threatening event (ALTE). An 8-month-old, otherwise healthy female infant presented to our hospital because of a sudden cardiopulmonary arrest. Approximately 1 h before this episode, the patient showed no symptoms, except a worse humor than usual. On arrival at our hospital, the patient had severe acidosis, but there were no clear signs of inflammatory response. Chest computed tomography showed weak consolidations in the upper right lung and atelectasis in the lower left lung. No signs of congenital heart disease or cardiomyopathy were observed on echocardiography, and no significant arrhythmia was observed during the clinical course. However, SARS-CoV-2 RNA was detected by real-time reverse transcription polymerase chain reaction in tracheal aspirate and urine samples. Although the assessment of further similar cases is indispensable, this case suggests that SARS-CoV-2 infection may be an underlying factor in the pathophysiology of ALTE.
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Evento Inexplicável Breve Resolvido/etiologia , COVID-19/etiologia , Evento Inexplicável Breve Resolvido/diagnóstico por imagem , COVID-19/diagnóstico , Teste de Ácido Nucleico para COVID-19 , Eletrocardiografia , Feminino , Parada Cardíaca/etiologia , Testes Hematológicos , Humanos , Lactente , Tomografia Computadorizada por Raios XRESUMO
Coagulation factor XI (FXI) has emerged as a promising target for the development of safer anticoagulation drugs that limit the risk of severe and life-threatening bleeding. Herein, we report the first cyclic peptide-based FXI inhibitor that selectively and potently inhibits activated FXI (FXIa) in human and animal blood. The cyclic peptide inhibitor (Ki = 2.8 ± 0.5 nM) achieved anticoagulation effects that are comparable to that of the gold standard heparin applied at a therapeutic dose (0.3-0.7 IU/mL in plasma) but with a substantially broader estimated therapeutic range. We extended the plasma half-life of the peptide via PEGylation and demonstrated effective FXIa inhibition over extended periods in vivo. We validated the anticoagulant effects of the PEGylated inhibitor in an ex vivo hemodialysis model with human blood. Our work shows that FXI can be selectively targeted with peptides and provides a promising candidate for the development of a safe anticoagulation therapy.
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Anticoagulantes/química , Fator XIa/antagonistas & inibidores , Peptídeos Cíclicos/química , Sequência de Aminoácidos , Animais , Anticoagulantes/metabolismo , Anticoagulantes/farmacologia , Coagulação Sanguínea/efeitos dos fármacos , Fator XIa/metabolismo , Meia-Vida , Humanos , Isomerismo , Modelos Biológicos , Tempo de Tromboplastina Parcial , Biblioteca de Peptídeos , Peptídeos Cíclicos/metabolismo , Peptídeos Cíclicos/farmacologia , Polietilenoglicóis/química , Coelhos , Diálise RenalRESUMO
Alcohol based hand rubs have been used for hand hygiene in health-care settings. Compared with hand scrubbing, using suitable alcohol based hand rub provides several advantages like usability in a ward with no tap, requiring less time and mildly-irritating. Alcohol provides immediate activity, but poor virucidal activity against certain viruses including norovirus. It is important to develop further improved alcohol based hand rubs which have characteristics of sufficient effectiveness, skin-safe and extended spectrum to non-enveloped viruses for infection control. In the study, in vitro microbicidal evaluations and in vivo efficacy evaluation study were investigated to clarify the characteristics of a novel hand antiseptic MR06B7 composed of additives with synergetic activities. MR06B7 showed bactericidal activity of more than 5 Log(10) reduction within 15 sec against 20 challenged strains. MR06B7 also demonstrated potent fungicidal activities at exposure time of 30 sec (more than 4 Log(10) reduction). Against all test viruses including non-enveloped viruses (adenovirus, feline calicivirus, murine norovirus and poliovirus), MR06B7 had excellent virucidal activity to reduce the titer of viability to the limit of detection within 30 sec exposure (more than 4 Log(10) reduction), whereas 83%(v/v) ethanol indicated the inadequate effectiveness. On the clinical study conducted in accordance with standard method for Healthcare Personnel Handwash of American Society for Testing and Materials, MR06B7 showed excellent immediate antimicrobial activity. The result surpassed the critical indices set forth in the FDA's Tentative Final Monograph. These findings suggest MR06B7 which satisfies most requirements of efficacy qualifications including potent virucidal activity against non-enveloped viruses may contribute to accomplish advanced infection control in clinical practice.
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Álcoois/farmacologia , Anti-Infecciosos Locais/farmacologia , Bactérias/efeitos dos fármacos , Fungos/efeitos dos fármacos , Desinfecção das Mãos , Mãos/microbiologia , Vírus/efeitos dos fármacos , Animais , Gatos , Células Cultivadas , Chlorocebus aethiops , Farmacorresistência Bacteriana , Farmacorresistência Fúngica , Farmacorresistência Viral , Patos , Humanos , Camundongos , Fatores de TempoRESUMO
Novel coronavirus (SARS-Coronavirus-2:SARS-CoV-2) which emerged in Wuhan, China, has spread to multiple countries rapidly. We report the first case of meningitis associated with SARS-CoV-2 who was brought in by ambulance due to a convulsion accompanied by unconsciousness. He had never been to any foreign countries. He felt generalized fatigue and fever (day 1). He saw doctors nearby twice (day 2 and 5) and was prescribed Laninamivir and antipyretic agents, His family visited his home and found that he was unconsciousness and lying on the floor in his vomit. He was immediately transported to this hospital by ambulance (day 9). Under emergency transport, he had transient generalized seizures that lasted about a minute. He had obvious neck stiffness. The specific SARS-CoV-2 RNA was not detected in the nasopharyngeal swab but was detected in a CSF. Anti- HSV 1 and varicella-zoster IgM antibodies were not detected in serum samples. A brain MRI showed hyperintensity along the wall of right lateral ventricle and hyperintense signal changes in the right mesial temporal lobe and hippocampus, suggesting the possibility of SARS-CoV-2 meningitis. This case warns the physicians of patients who have CNS symptoms.
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Betacoronavirus , Infecções por Coronavirus/complicações , Encefalite/virologia , Meningite Viral/virologia , Pneumonia Viral/complicações , COVID-19 , China , Encefalite/diagnóstico por imagem , Fadiga , Febre , Humanos , Imageamento por Ressonância Magnética , Masculino , Meningite Viral/diagnóstico por imagem , Pandemias , SARS-CoV-2 , Adulto JovemRESUMO
The aim of this study was to investigate whether PMMA-CHDF in the treatment of a patient with septic acute renal failure (septic ARF) is clinically relevant. Thirteen patients were treated with PMMA-CHDF. Thirteen patients were treated with PAN-CHDF. The urinary output significantly increased in PMMA-CHDF group following 24h of the treatment (p<0.05), whereas those did not improve in PAN-CHDF group. The 28-day survival was 84.6% in PMMA-CHDF group and 38.5% in PAN-CHDF group, respectively (p<0.05). We can assume that the cytokine modulation with PMMA-CHDF in the treatment of patients with septic ARF is clinically relevant.
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Resinas Acrílicas , Acrilonitrila/análogos & derivados , Injúria Renal Aguda/terapia , Hemodiafiltração , Polimetil Metacrilato , Sepse/terapia , Injúria Renal Aguda/complicações , Injúria Renal Aguda/mortalidade , Idoso , Intervalo Livre de Doença , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Sepse/complicações , Sepse/mortalidade , Taxa de SobrevidaRESUMO
We report a rare case of polycystic ovary syndrome (PCOS) complicated with acromegaly due to a growth hormone (GH)-producing pituitary adenoma. Complete removal of the pituitary adenoma successfully reduced circulating levels of GH and insulin-like growth factor (IGF)-1, which, in turn, resulted in the amelioration of gonadal dysfunction, hyperandrogenism, lutenizing hormone hypersecretion, and severe insulin resistance. This clinical complication suggests that activation of systemic GH-IGF-1 axis is potentially involved in the development of PCOS.
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Acromegalia/complicações , Adenoma/cirurgia , Adenoma Hipofisário Secretor de Hormônio do Crescimento/cirurgia , Hormônio do Crescimento/sangue , Síndrome do Ovário Policístico/complicações , Acromegalia/sangue , Acromegalia/cirurgia , Adenoma/sangue , Adenoma/metabolismo , Adulto , Regulação para Baixo/fisiologia , Feminino , Hormônio do Crescimento/metabolismo , Adenoma Hipofisário Secretor de Hormônio do Crescimento/sangue , Adenoma Hipofisário Secretor de Hormônio do Crescimento/metabolismo , Humanos , Síndrome do Ovário Policístico/sangue , Síndrome do Ovário Policístico/etiologia , Síndrome do Ovário Policístico/cirurgia , Resultado do TratamentoRESUMO
Interleukin (IL)-6 and IL-8 were measured in 101 serum samples collected from eight intensive-care unit patients using a polystyrene-based stick enzyme-linked immunosorbent assay (STICKELISA) system. This system consisted of an immobilized-antibody ELISA stick and a noncontact spectrophotometer. Cytokine concentration was detected by two ways: first, rapidly and semi-quantitatively by naked-eye observation of the color change and second, quantitatively using the spectrophotometer for accurate concentration determination. The spectrophotometric assay enabled the quantitation of as little as 100 pg/mL cytokine and took only 45 min to complete. There was a good agreement between the STICKELISA observations and data obtained using a plate ELISA system. The agreement between STICKELISA naked-eye observation and plate ELISA determination was 94 and 85% for IL-6 and IL-8, respectively. The correlation coefficients between the STICKELISA spectrophotometric determination and plate ELISA determination were 0.88 and 0.91 for IL-6 and IL-8, respectively, in a 0.1-5 ng/mL cytokine concentration range. These results demonstrate that the STICKELISA system is a simple, rapid, and quantitative method for bedside cytokine measurement in critical-care settings.
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Ensaio de Imunoadsorção Enzimática/instrumentação , Ensaio de Imunoadsorção Enzimática/métodos , Interleucina-6/sangue , Interleucina-8/sangue , Idoso , Idoso de 80 Anos ou mais , Cuidados Críticos , Feminino , Humanos , Unidades de Terapia Intensiva , Modelos Lineares , Masculino , Pessoa de Meia-Idade , Reprodutibilidade dos Testes , Sensibilidade e Especificidade , EspectrofotometriaRESUMO
In Kawasaki disease (KD), the effect of plasma exchange (PE) on immune cells has not been fully elucidated. Therefore, we examined the changes in the number of CD14+ CD16+ activated monocytes, regulatory T (Treg ), and T-helper type 17 (Th17) cells in KD patients treated with PE. The percentage of total monocytes and subclasses of lymphocytes, including CD4+ and CD8+ T cells, and CD19+ B cells, showed no significant difference before and after PE. However, the percentage of CD14+ CD16+ monocytes in total leukocytes decreased significantly after PE (1.1% ± 1.5% vs. 2.1% ± 2.3%, P < 0.05). Furthermore, while the percentage of Th17 cells in CD4+ T cells did not change, the percentage of Treg cells in CD4+ T cells increased significantly after PE (11.1% ± 5.1% vs. 8.0% ± 4.4%, P < 0.05). Therefore, PE downregulates activated monocytes and upregulates Treg cells toward normal levels and thus attenuates inflammation in KD.
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Monócitos/imunologia , Síndrome de Linfonodos Mucocutâneos , Troca Plasmática/métodos , Linfócitos T Reguladores/imunologia , Células Th17/imunologia , Antígenos de Diferenciação de Linfócitos T/análise , Pré-Escolar , Feminino , Humanos , Japão , Subpopulações de Linfócitos , Masculino , Síndrome de Linfonodos Mucocutâneos/diagnóstico , Síndrome de Linfonodos Mucocutâneos/imunologia , Síndrome de Linfonodos Mucocutâneos/terapia , Resultado do TratamentoRESUMO
Circulating aldosterone concentrations occasionally increase after initial suppression with angiotensin II (Ang II) converting enzyme inhibitors or Ang II type 1 receptor blockers (ARBs), a phenomenon referred to as aldosterone breakthrough. However, the underlying mechanism causing the aldosterone breakthrough remains unknown. Here we investigated whether aldosterone breakthrough occurs in human adrenocortical H295R cells in vitro. We recently reported that bone morphogenetic protein (BMP)-6, which is expressed in adrenocortical cells, enhances Ang II- but not potassium-induced aldosterone production in human adrenocortical cells. Accordingly, we examined the roles of BMP-6 in aldosterone breakthrough induced by long-term treatment with ARB. Ang II stimulated aldosterone production by adrenocortical cells. This Ang II stimulation was blocked by an ARB, candesartan. Interestingly, the candesartan effects on Ang II-induced aldosterone synthesis and CYP11B2 expression were attenuated in a course of candesartan treatment for 15 d. The impairment of candesartan effects on Ang II-induced aldosterone production was also observed in Ang II- or candesartan-pretreated cells. Levels of Ang II type 1 receptor mRNA were not changed by chronic candesartan treatment. However, BMP-6 enhancement of Ang II-induced ERK1/2 signaling was resistant to candesartan. The BMP-6-induced Smad1, -5, and -8 phosphorylation, and BRE-Luc activity was augmented in the presence of Ang II and candesartan in the chronic phase. Chronic Ang II exposure decreased cellular expression levels of BMP-6 and its receptors activin receptor-like kinase-2 and activin type II receptor mRNAs. Cotreatment with candesartan reversed the inhibitory effects of Ang II on the expression levels of these mRNAs. The breakthrough phenomenon was attenuated by neutralization of endogenous BMP-6 and activin receptor-like kinase-2. Collectively, these data suggest that changes in BMP-6 availability and response may be involved in the occurrence of cellular escape from aldosterone suppression under chronic treatment with ARB.
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Córtex Suprarrenal/fisiologia , Aldosterona/metabolismo , Proteínas Morfogenéticas Ósseas/fisiologia , Receptor Tipo 1 de Angiotensina/fisiologia , Córtex Suprarrenal/citologia , Córtex Suprarrenal/efeitos dos fármacos , Bloqueadores do Receptor Tipo 1 de Angiotensina II/farmacologia , Benzimidazóis/farmacologia , Compostos de Bifenilo , Proteína Morfogenética Óssea 6 , Linhagem Celular , Genes Reporter , Humanos , Imuno-Histoquímica , Cinética , Receptor Tipo 1 de Angiotensina/efeitos dos fármacos , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Tetrazóis/farmacologia , TransfecçãoRESUMO
A 73-year-old Japanese woman was referred for examination of right flank pain and progressive hypertension. Abdominal CT incidentally detected a right adrenal mass 8 cm in size. The tumor exhibited isodensity by CT and contained high-intense lesion by T2-weighted MRI. Scintigraphy with (131) I-metaiodobenzylguanidine and (131) I-adosterol showed no abnormal uptake by whole body scan. Positron emission tomography scan with (18) F-2-fluoro-D-deoxyglucose demonstrated an exclusive uptake in the right adrenal mass. Adrenocortical hormone levels and catecholamine secretion were within normal range; however, the level of serum neuron-specific enolase (NSE) was found to be markedly high. After controlling systemic blood pressure with an alpha1-blocker, the right adrenal tumor was surgically removed, along with the right kidney and inferior vena cava which adhered to it. The tumor was pathologically proven to be leiomyosarcoma, which was immunohistochemically positive with alpha-smooth muscle actin and negative with CD57, S-100 and c-kit proteins. Notably, NSE protein was massively expressed in the resected tumor. After surgery blood pressure was controlled with regular medication and serum NSE levels have since normalized. The possibility of leiomyosarcoma should be kept in mind in adrenal incidentalomas with rapid growth and atypical radiological images. Our findings suggest that circulating NSE levels may be clinically useful for early detection of recurrence.
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Neoplasias das Glândulas Suprarrenais/diagnóstico , Neoplasias das Glândulas Suprarrenais/metabolismo , Hipertensão/complicações , Leiomiossarcoma/diagnóstico , Leiomiossarcoma/metabolismo , Fosfopiruvato Hidratase/metabolismo , Actinas/metabolismo , Neoplasias das Glândulas Suprarrenais/complicações , Idoso , Antígenos CD57/metabolismo , Feminino , Humanos , Leiomiossarcoma/complicações , Tomografia por Emissão de Pósitrons , Proteínas Proto-Oncogênicas c-kit/metabolismo , Proteínas S100/metabolismo , Imagem Corporal TotalRESUMO
In the present study, we investigated the cellular mechanism by which oocytes and bone morphogenetic proteins (BMPs) govern FSH-induced steroidogenesis using rat primary granulosa cells. BMP-6 and BMP-7 both inhibited FSH- and forskolin (FSK)-induced progesterone synthesis and reduced cAMP synthesis independent of the presence or absence of oocytes. BMP-7 also increased FSH-induced estradiol production, and the response was further augmented in the presence of oocytes. In contrast, BMP-6 had no impact on estradiol synthesis regardless of the presence of oocytes. Because BMP-7 changed neither FSK- nor cAMP-induced estradiol production, the BMP-7 action was mediated through a FSH receptor signaling mechanism that was independent of cAMP-protein kinase A pathway. Treatment with FSH but not cAMP activated ERK1/2 phosphorylation in granulosa cells, which was further accelerated by oocytes. A specific ERK inhibitor, U0126, increased estradiol production and decreased FSH- and FSK-induced progesterone production and cAMP synthesis. This suggests that ERK activation is directly linked to inhibition of estradiol synthesis and amplification of cAMP. Moreover, FSH-induced ERK1/2 phosphorylation was inhibited by BMP-7 but not influenced by BMP-6. In contrast, BMP signaling including Smad1/5/8 phosphorylation and Id-1 transcription was up-regulated by FSH and oocytes in granulosa cells through inhibition of Smad6/7 expression. Collectively, oocytes enhance FSH-induced MAPK activation and BMP signaling in granulosa cells, which leads to differential regulation of steroidogenesis elicited by BMPs in the presence of FSH in developing follicles.
Assuntos
Proteínas Morfogenéticas Ósseas/metabolismo , Estrogênios/metabolismo , Hormônio Foliculoestimulante/metabolismo , Sistema de Sinalização das MAP Quinases/fisiologia , Oócitos/metabolismo , Fator de Crescimento Transformador beta/metabolismo , Animais , Proteína Morfogenética Óssea 6 , Proteína Morfogenética Óssea 7 , Proteínas Morfogenéticas Ósseas/farmacologia , Comunicação Celular/efeitos dos fármacos , Comunicação Celular/fisiologia , Células Cultivadas , Proteínas Quinases Dependentes de AMP Cíclico/metabolismo , Feminino , Hormônio Foliculoestimulante/farmacologia , Células da Granulosa/citologia , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Proteína Quinase 1 Ativada por Mitógeno/metabolismo , Proteína Quinase 3 Ativada por Mitógeno/metabolismo , Oócitos/citologia , Oócitos/efeitos dos fármacos , Ratos , Ratos Sprague-Dawley , Fator de Crescimento Transformador beta/farmacologiaRESUMO
AIM: To clarify the relationship between self-esteem of stroke survivors at home and their living conditions. METHODS: Study participants were stroke survivors who lived at home and commuted to one of two medical facilities in the Tohoku region of Japan. Stroke survivors were recruited for the present study when they came to the hospital for a routine visit. The researcher or research assistant explained the study objective and methods to the stroke survivor, and the questionnaire survey was conducted. Survey contents included the Japanese version of the Rosenberg Self-Esteem Scale (RSE) and questions designed to assess living conditions. A total of 65 participants with complete RSE data were included in the analysis. RESULTS: The mean (standard deviation) age of participants was 70.9 years (± 11.1), with a mean RSE score of 32.12 (± 8.32). Only a minor decrease in participant self-esteem was observed, even after having experienced a stroke. Factors associated with self-esteem, including "independent bathing" (standardized partial regression coefficient, ß = 0.405, P < 0.001), "being needed by family members" (ß = 0.389, P < 0.001), "independent grooming" (ß = 0.292, P = 0.009), and "sleep satisfaction" (ß = 0.237, P = 0.017), were analyzed by stepwise multiple regression analysis. The multiple correlation coefficient adjusted for the degrees of freedom was 0.738 (P < 0.001). CONCLUSION: Our analysis revealed that the maintenance of activities of daily living, and the presence of a suitable environment that enhances physical function recovery and promotes activity and participation, are necessary to improve self-esteem in stroke survivors living at home.