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Infectious virus shedding from individuals infected with severe acute respiratory syndrome-coronavirus 2 (SARS-CoV-2) is used to estimate human-to-human transmission risk. Control of SARS-CoV-2 transmission requires identifying the immune correlates that protect infectious virus shedding. Mucosal immunity prevents infection by SARS-CoV-2, which replicates in the respiratory epithelium and spreads rapidly to other hosts. However, whether mucosal immunity prevents the shedding of the infectious virus in SARS-CoV-2-infected individuals is unknown. We examined the relationship between viral RNA shedding dynamics, duration of infectious virus shedding, and mucosal antibody responses during SARS-CoV-2 infection. Anti-spike secretory IgA antibodies (S-IgA) reduced viral RNA load and infectivity more than anti-spike IgG/IgA antibodies in infected nasopharyngeal samples. Compared with the IgG/IgA response, the anti-spike S-IgA post-infection responses affected the viral RNA shedding dynamics and predicted the duration of infectious virus shedding regardless of the immune history. These findings highlight the importance of anti-spike S-IgA responses in individuals infected with SARS-CoV-2 for preventing infectious virus shedding and SARS-CoV-2 transmission. Developing medical countermeasures to shorten S-IgA response time may help control human-to-human transmission of SARS-CoV-2 infection and prevent future respiratory virus pandemics.
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COVID-19 , Humanos , SARS-CoV-2 , Eliminação de Partículas Virais , Formação de Anticorpos , Tempo de Reação , Anticorpos Antivirais , RNA Viral , Imunoglobulina G , Imunoglobulina A , Imunoglobulina A SecretoraRESUMO
OBJECTIVES: Intramuscular benzathine penicillin G is not available in certain countries. In a previous report, 3 g/day amoxicillin with probenecid was shown to be effective in treating syphilis in patients with HIV; however, 7.3% of patients changed their therapy owing to adverse events. The objective of this study was to assess the clinical efficacy and tolerability of 1.5 g/day amoxicillin without probenecid for the treatment of syphilis. METHODS: The routine clinical records of patients diagnosed with syphilis and treated with 1.5 g/day amoxicillin at a tertiary care hospital between 2006 and 2018 were retrospectively analysed. Syphilis was diagnosed if serum rapid plasma reagin (RPR) titres were ≥8 RU and the Treponema pallidum latex-agglutination test was positive. Serological cure was defined as a ≥fourfold decrease in the RPR titre within 12 months in symptomatic early syphilis and within 24 months in latent syphilis. RESULTS: Overall, 138 patients (112 with HIV) were analysed. The percentages of primary, secondary, early latent, late latent and latent syphilis of unknown duration were 8.0%, 50.0%, 25.4%, 5.8% and 10.9%, respectively. The median treatment duration was 4.5 weeks (IQR 4-8 weeks), which was not related to the stage of syphilis. Two patients (1.5%) changed treatment due to skin rash. The rate of serological cure was 94.9% (131/138; 95% CI 89.8% to 97.9%) overall; 93.8% (105/112; 95% CI 87.5% to 97.5%) in patients with HIV and 100% (26/26; 95% CI 86.8% to 100%) in patients without HIV. Treatment duration was not related to the treatment efficacy. CONCLUSION: The regimen of 1.5 g/day amoxicillin without probenecid is highly effective with a low switch rate in patients with and without HIV.
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Infecções por HIV , Sífilis , Amoxicilina/uso terapêutico , Antibacterianos/uso terapêutico , Infecções por HIV/complicações , Infecções por HIV/tratamento farmacológico , Humanos , Probenecid/efeitos adversos , Estudos Retrospectivos , Sífilis/diagnóstico , Sorodiagnóstico da Sífilis , Resultado do Tratamento , Treponema pallidumRESUMO
INTRODUCTION: While Streptococcus gallolyticus subsp. gallolyticus has a well-known association with colorectal cancer, an epidemiological association between S. gallolyticus subsp. pasteurianus (SGSP) and hepatobiliary diseases has been suggested. Here we described a case of gallstone pancreatitis and SGSP bacteremia in which species-identification by Matrix-Assisted Laser Desorption/Ionization Time-Of-Flight Mass Spectrometry (MALDI-TOF MS) helped to diagnose the biliary etiology. CASE REPORT: A 61-year-old Japanese man without history of alcohol consumption was hospitalized for acute pancreatitis. His past medical history included endoscopically treated familial adenomatous polyposis. A blood culture grew gram-positive cocci, identified to be SGSP by MALDI-TOF MS. A contrast-enhanced computed tomography scan showed pancreatic enlargement and increased fatty tissue concentration around the perirenal and pararenal space. He was diagnosed with acute pancreatitis and subsequently recovered after appropriate antimicrobial therapy and supportive care. Subsequent magnetic resonance cholangiopancreatography showed gallstones in the gallbladder neck, suggesting the cause of the acute pancreatitis. Seven months after admission, cholecystectomy was performed for cholelithiasis. CONCLUSION: This case highlights that the identification of subspecies enabled by MALDI-TOF MS supports the diagnosis of the underlying etiology from the microbiological point of view.
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Bacteriemia , Pancreatite , Infecções Estreptocócicas , Doença Aguda , Bacteriemia/complicações , Bacteriemia/microbiologia , Humanos , Masculino , Pessoa de Meia-Idade , Pancreatite/complicações , Espectrometria de Massas por Ionização e Dessorção a Laser Assistida por Matriz , Infecções Estreptocócicas/microbiologia , Streptococcus , Streptococcus gallolyticusRESUMO
Invasive mucormycosis is a refractory fungal infection. Central nervous system (CNS) mucormycosis is a rare complication caused by infiltration from the paranasal sinuses or hematogenous dissemination. Here, we present a case of a brain abscess, due to mucormycosis, diagnosed using burr craniotomy. A 25-year-old Japanese woman with relapsed-refractory acute lymphoblastic leukemia underwent cord blood transplantation (CBT). The patient experienced prolonged and profound neutropenia, and oral voriconazole was administered as primary antifungal prophylaxis. The patient received a conditioning regimen on day -11 and complained of aphasia and right hemiparesis on day -6. Magnetic resonance imaging (MRI) revealed a T2-weighted high-intensity area in the left frontal cortex. A brain abscess was suspected, and liposomal amphotericin B (L-AMB) administration was started. The patient underwent CBT as scheduled and underwent neutrophil engraftment on day 14. Although the patient achieved complete remission on day 28, her consciousness level gradually deteriorated. MRI revealed an enlarged brain lesion with a midline shift sign, suggesting brain herniation. Craniotomy was performed to relieve intracranial pressure and drain the abscess on day 38, and a diagnosis of cerebral mucormycosis was confirmed. The L-AMB dose was increased to 10 mg/kg on day 43. Although the patient's consciousness level improved, she died of hemorrhagic cystitis and aspiration pneumonia. Cerebral mucormycosis should be suspected if neurological symptoms are observed in stem cell transplant recipients. Prompt commencement of antifungal therapy and debridement are crucial because mucormycosis has a poor prognosis.
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Abscesso Encefálico , Neoplasias Hematológicas , Mucormicose , Adulto , Anfotericina B , Antifúngicos/uso terapêutico , Abscesso Encefálico/tratamento farmacológico , Sistema Nervoso Central , Feminino , Neoplasias Hematológicas/tratamento farmacológico , Humanos , Mucormicose/complicações , Mucormicose/diagnóstico , Mucormicose/tratamento farmacológico , Voriconazol/uso terapêuticoRESUMO
Chiral Lewis acid-catalyzed asymmetric alcohol addition reactions to cyclic carbonyl ylides generated from N-(α-diazocarbonyl)-2-oxazolidinones featuring a dual catalytic system are reported. Construction of a chiral quaternary heteroatom-substituted carbon center was accomplished in which the unique heterobicycles were obtained in good yields with high stereoselection. The alcohol adducts were successfully converted to optically active oxazolidine-2,4-diones by hydrolysis. Mechanistic studies by DFT calculations revealed that alcohols could be activated by Lewis acids, enabling enantioselective protonation of the carbonyl ylides.
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Álcoois , Ácidos de Lewis , Carbono , Catálise , EstereoisomerismoRESUMO
INTRODUCTION: One of the most prominent and concerning complications associated with coronavirus disease 2019 (COVID-19) is venous and arterial thromboembolisms. The aim of the present study was to delineate the prevalence of thromboembolic events and the current status of prophylactic anticoagulation therapy in patients with COVID-19 in Japan. METHODS: Between February 1 and August 31, 2020, we performed a dual-center, retrospective cohort study based on data obtained from the medical charts of COVID-19 patients admitted to healthcare facilities in Japan. The primary outcome was any thromboembolic event including pulmonary embolism (PE), deep vein thrombosis (DVT), myocardial infarction, ischemic stroke and other systemic thromboemboli. RESULTS: During the study period, we extracted 628 consecutive patients admitted for COVID-19. Prophylactic anticoagulant therapy was administered in 63 (10%) patients of whom 20 (31.7%) were admitted to the intensive care unit (ICU). Thromboembolic events occurred in 18 (2.9%) patients (14.3% of patients in ICU and 2.2% of patients in the general wards). DVT were detected in 13 (2.1%) patients, PE in 11 (1.8%), and both DVT and PE in 6 (0.96%) patients. An increasing prevalence in thromboembolic events was noted with progressive clinical severity. Overall in-hospital mortality was 4.8%. CONCLUSIONS: Prophylactic anticoagulation therapy was administered in only 10% of all hospitalized COVID-19 patients. The prevalence of any thromboembolic events was 2.9% in COVID-19 patients with most events occurring in severe and critical patients. Therefore, prophylactic anticoagulation therapy may be warranted in severe and critical patients but in asymptomatic to moderate patients the practice remains controversial.
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Anticoagulantes/uso terapêutico , COVID-19 , Embolia Pulmonar , Tromboembolia , Adulto , COVID-19/complicações , Feminino , Mortalidade Hospitalar , Humanos , Japão/epidemiologia , Masculino , Pessoa de Meia-Idade , Prevalência , Embolia Pulmonar/epidemiologia , Embolia Pulmonar/prevenção & controle , Estudos Retrospectivos , Tromboembolia/epidemiologia , Tromboembolia/prevenção & controleRESUMO
BACKGROUND: Although severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has caused an international outbreak of coronavirus disease 2019 (COVID-19), data on the clinical characteristics of COVID-19 patients with cancer are limited. This study aimed to evaluate the clinical characteristics and outcomes including mortality and viral shedding period in COVID-19 patients with cancer in Japan. METHODS: We retrospectively analyzed 32 patients with a history of cancer who were referred to our hospital between January 31, 2020 and May 25, 2020. We evaluated the association between clinical outcomes and potential prognostic factors using univariate analyses. RESULTS: The median age was 74.5 (range 24-90) years and 22 patients (69%) were men. A total of 11 patients (34%) died. Our analyses demonstrated that the mortality was significantly associated with lymphocyte count, albumin, lactate dehydrogenase, serum ferritin, and C-reactive protein on admission. The median period between illness onset and the first effective negative SARS-CoV-2 PCR result was 22 days (interquartile range 18-25) in survivors. Of four patients with hematological malignancy who developed COVID-19 within the rest period of chemotherapy, three died and the other patient, who received bendamustine plus rituximab therapy, had the longest duration of viral shedding (56 days). CONCLUSION: Our study suggested that the risk factors for mortality previously reported in general COVID-19 patients, including lymphocytopenia, were also effective in cancer patients. Patients who received cytotoxic chemotherapy recently or were treated with chemotherapy, which can lead to lymphocyte reduction, had poor prognosis and prolonged periods of viral shedding.
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COVID-19 , Neoplasias , Adulto , Idoso , Idoso de 80 Anos ou mais , China , Humanos , Japão/epidemiologia , Masculino , Pessoa de Meia-Idade , Neoplasias/tratamento farmacológico , Neoplasias/epidemiologia , Estudos Retrospectivos , Fatores de Risco , SARS-CoV-2 , Tóquio , Adulto JovemRESUMO
Peptide bond formation in living cells occurs at the peptidyl transferase center (PTC) of the large ribosomal subunit and involves the transfer of the peptidyl group from peptidyl-tRNA to aminoacyl-tRNA. Despite numerous kinetic and theoretical studies, many details of this reaction -such as whether it proceeds via a stepwise or concerted mechanism- remain unclear. In this study, we calculated the geometry and energy of the transition states and intermediates in peptide bond formation in the PTC environment using the ONIOM (our own n-layered integrated molecular orbital and molecular mechanics) method. The calculations indicated that the energy of the transition states of stepwise mechanisms are lower than those of concerted mechanisms and suggested that the reaction involves a neutral tetrahedral intermediate that is stabilized through the hydrogen-bonding network in the PTC environment. The results will lead to a better understanding of the mechanism of peptidyl transfer reaction, and resolve fundamental questions of the steps and molecular intermediates involved in peptide bond formation in the ribosome.
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Teoria da Densidade Funcional , Peptídeos/química , Ribossomos/química , Estrutura Molecular , TermodinâmicaRESUMO
The detection of exercise-induced hypoxemia is important for evaluating disease status in patients with chronic respiratory diseases. The 6-min walk test (6MWT) is useful for detecting exercise-induced hypoxemia. This pilot study aimed to validate the breath-holding test (BHT) as a screening for exercise-induced hypoxemia and compare its utility with that of the 6MWT in patients with chronic respiratory diseases. Fifty-nine patients with chronic respiratory diseases underwent BHTs lasting 10, 15, and 20 s. Percutaneous oxygen saturation (SpO2), pulse rate, and severity of dyspnoea were measured. The participants also underwent a 6MWT, a pulmonary function test, and analysis of arterial blood gas at rest. Multivariate linear regression analysis was performed to identify significant predictors of desaturation in the 6MWT. The minimum SpO2 during the BHT (all durations) and 6MWT were significantly correlated. Receiver operating characteristic analysis revealed the optimal cut-off for predicting SpO2 < 90% during the 6MWT as a minimum SpO2 ≤ 94% during the 15-s BHT. Perceived dyspnoea and maximum pulse rate were significantly lower during the 15-s BHT than during the 6MWT. In the multivariate linear regression analysis, the minimum SpO2 during the 15-s BHT (ß, 0.565, p < 0.001) and %DLco (ß, 0.255, p < 0.028) were independent predictors of desaturation in the 6MWT. The minimum SpO2 during the 15-s BHT may be a useful measure for screening for exercise-induced hypoxemia in patients with chronic respiratory diseases. The BHT is easier to perform, more readily available, and better tolerated than the 6MWT.
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Teste de Esforço , Doença Pulmonar Obstrutiva Crônica , Dispneia/diagnóstico , Dispneia/etiologia , Humanos , Hipóxia/diagnóstico , Hipóxia/etiologia , Oxigênio , Projetos Piloto , Teste de CaminhadaRESUMO
The development of carbon dioxide fixation under mild conditions is a central theme in organic synthesis. Despite the tremendous progress in the field of organocatalysis in the past two decades, the coupling reactions of epoxides with carbon dioxide that proceed at atmospheric pressure at temperatures of less than 100 °C have remained challenging. In our aspirational studies of tetraarylphosphonium salts (TAPS) catalysis, we report here the bifunctional TAPS-catalyzed synthesis of five-membered cyclic carbonates by chemical fixation using 1 atm of carbon dioxide at 60 °C. Intriguing substituent effects of TAPS were observed, in which electron-donating groups enhanced their reactivity. In addition, the mechanism was thoroughly investigated by undertaking both experimental and theoretical studies, suggesting that the electronic properties of TAPS affect carbon dioxide insertion into halohydrin intermediates. The results provided fruitful information to understand the origin of the TAPS behavior, which would contribute to the design of novel catalysts for carbon dioxide capture.
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BACKGROUND: Herpes simplex virus (HSV) has various presentations, depending on the patient's immune status, age, and the route of transmission. In adults, HSV type 1 is found predominantly in the oral area, and HSV type 2 (HSV-2) is commonly found in the genital area. HSV-2 infection without genital lesions is uncommon. Herein we report a unique case of pharyngotonsillitis as an initial manifestation of disseminated HSV-2 infection without genital involvement. CASE PRESENTATION: A 46-year-old male was admitted to our hospital with a 1-week history of fever and sore throat. His past medical history included hypereosinophilic syndrome diagnosed at age 45 years. Physical examination revealed throat congestion, bilaterally enlarged tonsils with exudates, tender cervical lymphadenopathy in the left posterior triangle, and mild epigastric tenderness. The laboratory data demonstrated bicytopenia, elevated liver enzyme levels, and hyperferritinemia. A bone marrow smear showed hypocellular marrow with histiocytes and hemophagocytosis. The diagnosis of HLH was confirmed, and the patient was treated with methylprednisolone pulse therapy on days 1-3. On day 5, despite initial improvement of the fever and sore throat, multiple, new, small bullae developed on the patient's face, trunk, and extremities. Additional testing showed that he was positive for HSV-specific immunoglobulin M and immunoglobulin G. Disseminated HSV infection was suspected, and intravenous acyclovir (10 mg/kg every 8 h) was begun. A subsequent direct antigen test of a bulla sample was positive for HSV-2. Moreover, tonsillar and esophageal biopsies revealed viral inclusion bodies. Immunohistochemical staining and a quantitative real-time polymerase chain reaction (PCR) assay confirmed the presence of HSV-2. Disseminated HSV-2 infection with multiple bullae, tonsillitis, esophagitis, and suspected hepatic involvement was diagnosed. After a 2-week course of intravenous acyclovir, his hematological status and liver function normalized, and his cutaneous skin lesions resolved. He was discharged on day 22 in good general health and continued taking oral valacyclovir for viral suppression due to his immunosuppressed status. CONCLUSION: Disseminated HSV-2 infection should be considered as one of the differential diagnoses in patients with pharyngotonsillitis and impaired liver function of unknown etiology even if there are no genital lesions.
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Esofagite/diagnóstico , Herpes Simples/diagnóstico , Herpesvirus Humano 2/isolamento & purificação , Linfo-Histiocitose Hemofagocítica/diagnóstico , Tonsilite/diagnóstico , Aciclovir/uso terapêutico , Esofagite/complicações , Esofagite/tratamento farmacológico , Esofagite/virologia , Herpes Simples/complicações , Herpes Simples/tratamento farmacológico , Herpes Simples/virologia , Humanos , Hospedeiro Imunocomprometido , Linfo-Histiocitose Hemofagocítica/complicações , Linfo-Histiocitose Hemofagocítica/tratamento farmacológico , Linfo-Histiocitose Hemofagocítica/virologia , Masculino , Pessoa de Meia-Idade , Faringite/diagnóstico , Faringite/tratamento farmacológico , Faringite/virologia , Tonsilite/complicações , Tonsilite/tratamento farmacológico , Tonsilite/virologia , Sistema Urogenital/virologiaRESUMO
Rat-bite fever (RBF) is a disease that usually presents with fever, arthralgia and skin rash. Streptobacillus moniliformis was considered the main cause of RBF among the genus Streptobacillus. Although with similar clinical presentation, RBF due to Streptobacillus notomytis is unusual in humans. To the best of our knowledge, we present a case involving the first isolate of S. notomytis in humans. A 63-year-old woman was admitted to our hospital with fever, rash and polyarthritis. She recalled being bitten by a rat on her finger 5 days before presentation. Clinical manifestations were compatible with rat-bite fever (RBF) and the diagnosis was confirmed by the detection of Streptobacillus species from both blood and pustule samples. Initial polymerase chain reaction tests revealed that the organism was S. moniliformis. However, thorough genetic analysis revealed the organism to be S. notomytis. The condition was successfully treated with ampicillin.
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Vesícula/microbiologia , Febre por Mordedura de Rato/diagnóstico , Febre por Mordedura de Rato/microbiologia , Streptobacillus/isolamento & purificação , Administração Intravenosa , Ampicilina/uso terapêutico , Animais , Antibacterianos/uso terapêutico , Feminino , Humanos , Pessoa de Meia-Idade , RNA Ribossômico 16S/genética , Febre por Mordedura de Rato/sangue , Febre por Mordedura de Rato/tratamento farmacológico , Ratos , Streptobacillus/genéticaRESUMO
The first example of asymmetric 1,3-dipolar cycloadditions between nitrile oxides and o-hydroxystyrenes, mediated by cinchona-alkaloid-based amine-ureas is reported. The method is based on a dual activation involving both LUMO and HOMO activations. In addition to the stoichiometric asymmetric induction, a catalytic amount of amine-urea enables the cycloadditions to proceed in an enantioselective manner. Computational studies strongly support the HOMO activation of o-hydroxystyrenes and LUMO activation of nitrile oxides by hydrogen-bonding interactions with the Brønsted acid/base bifunctional catalyst.
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We present 3 cases of ocular syphilis in patients who had been newly diagnosed as having HIV. All the patients had only complained of ophthalmologic symptoms at the time of their initial visit. Treatment with penicillin was successful, resulting in no significant sequelae. Ocular syphilis may lead to reduced visual acuity or even blindness if left untreated. However, the diagnosis may be challenging, since patients may lack symptoms that are commonly observed in cases with primary and secondary syphilis. Considering the recent increase in the number of syphilis patients, clinicians should be aware of ocular syphilis and should have a high index of suspicion for syphilis in any patient at risk so as to ensure a prompt diagnosis.
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Antibacterianos/uso terapêutico , Infecções Oculares Bacterianas/tratamento farmacológico , Infecções por HIV/tratamento farmacológico , Penicilinas/uso terapêutico , Sífilis/tratamento farmacológico , Adulto , Infecções Oculares Bacterianas/diagnóstico , Infecções Oculares Bacterianas/patologia , Infecções por HIV/complicações , Infecções por HIV/diagnóstico , Humanos , Masculino , Sífilis/complicações , Sífilis/diagnóstico , Sífilis/patologia , Resultado do TratamentoRESUMO
Soft X-ray angle-resolved photoemission has been performed for metallic V2O3. By combining a microfocus beam (40â µm × 65â µm) and micro-positioning techniques with a long-working-distance microscope, it has been possible to observe band dispersions from tiny cleavage surfaces with a typical size of several tens of µm. The photoemission spectra show a clear position dependence, reflecting the morphology of the cleaved sample surface. By selecting high-quality flat regions on the sample surface, it has been possible to perform band mapping using both photon-energy and polar-angle dependences, opening the door to three-dimensional angle-resolved photoemission spectroscopy for typical three-dimensional correlated materials where large cleavage planes are rarely obtained.
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Klippel-Feil syndrome (KFS) is a rare disease characterized by a classic triad comprising a short neck, a low posterior hairline, and restricted motion of the neck due to fused cervical vertebrae. We report repeated anesthetic management for orthognathic surgeries for a KFS patient with micrognathia. Because KFS can be associated with a number of other anomalies, we therefore performed a careful preoperative evaluation to exclude them. The patient had an extremely small mandible, significant retrognathia, and severe limitation of cervical mobility due to cervical vertebral fusion. As difficult intubation was predicted, awake nasal endotracheal intubation with a fiberoptic bronchoscope was our first choice for gaining control of the patient's airway. Moreover, the possibility of respiratory distress due to postoperative laryngeal edema was considered because of the surgeries on the mandible. In the operating room, tracheotomy equipment was always kept ready if a perioperative surgical airway control was required. Three orthognathic surgeries and their associated anesthetics were completed without a fatal outcome, although once the patient was transferred to the intensive care unit for precautionary postoperative airway management and observation. Careful preoperative examination and preparation for difficult airway management are important for KFS patients with micrognathia.
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Anestesia Dentária , Anestesia Geral , Síndrome de Klippel-Feil/cirurgia , Procedimentos Cirúrgicos Ortognáticos/métodos , Adulto , Manuseio das Vias Aéreas/métodos , Broncoscópios , Vértebras Cervicais/anormalidades , Feminino , Humanos , Intubação Intratraqueal/métodos , Laringoscopia/métodos , Mandíbula/anormalidades , Mandíbula/cirurgia , Micrognatismo/cirurgia , Fibras Ópticas , Osteogênese por Distração/métodos , Técnica de Expansão Palatina , Retrognatismo/cirurgia , Traqueotomia/instrumentaçãoRESUMO
An 80-year-old man presented in December with the main complaint of jaundice. Blood tests revealed hemolytic anemia and renal dysfunction. Positive syphilis serology results led to a diagnosis of untreated latent syphilis. A positive direct Coombs test led to a diagnosis of autoimmune hemolytic anemia (AIHA). Antibiotics were started for the syphilis, with improvement in the anemia and renal dysfunction observed. However, paroxysmal intravascular hemolysis occurred after his discharge. Based on a positive Donath-Landsteiner (D-L) test, paroxysmal cold hemoglobinuria (PCH) diagnosis was made. The hemolytic anemia improved after further treatment for syphilis, and further avoiding exposure to cold.
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Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease with an unknown pathogenesis. It has been reported that mutations in the gene for Cu/Zn superoxide dismutase (SOD1) cause familial ALS. Mutant SOD1 undergoes aggregation and forms amyloid more easily, and SOD1-immunopositive inclusions have been observed in the spinal cords of ALS patients. Because of this, SOD1 aggregation is thought to be related to the pathogenesis of ALS. Some core regions of amyloid have been identified, but the issue of whether these regions form aggregates in living cells remains unclear, and the mechanism responsible for intracellular SOD1 aggregation also remains unclear. The findings reported in this study indicate that the aggregation of the ALS-linked mutant SOD1-EGFP was significantly enhanced when the BioID2 gene was fused to the N-terminus of the mutant SOD1-EGFP plasmid for cellular expression. Expression of a series of BioID2-(C-terminal deletion peptides of SOD1)-EGFP permitted us to identify 1-35 as a minimal N-terminal sequence and Ile35 as an essential amino acid residue that contributes to the intracellular aggregation of SOD1. The findings also showed that an additional substitution of Ile35 with Ser into the ALS mutant SOD1 resulted in the significant suppression of aggregate formation. The fact that no Ile35 mutations have been reported to date in ALS patients indicates that all ALS mutant SOD1s contain Ile35. Taken together, we propose that Ile35 plays a pivotal role in the aggregation of the ALS-linked SOD1 and that this study will contribute to our understanding of the mechanism responsible for SOD1 aggregation.
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The neuropeptide Y (NPY) system is known as one of the major neural signaling pathways. NPY, produced by peripheral tissues including osteoblasts, is known to bind to the Y1 receptor. Recently, osteoblast-specific Y1 receptor knockout mice were developed and were found to have a high bone mass phenotype, indicating a role for the NPY-Y1 receptor axis as a regulator of bone homeostasis. However, regulation of Y1 receptor expression during osteoblastic differentiation remains unexplored. In the present study, we examined the role of bone morphogenetic protein (BMP) 2 signaling in regulating Y1 receptor expression. In C2C12 cells, expression of Y1 receptor mRNA was induced by BMP2. This induction was also observed after co-transfection with Smad1 and Smad4, the intracellular signaling molecules of the BMP2 signaling pathway. In a transfection assay, Smad1/4 up-regulated transcriptional activity through interaction with the Y1 receptor gene promoter. Following transfection of MC3T3-E1 cells with siRNA for the Y1 receptor, the expression of alkaline phosphatase, osteocalcin, Runx2 and osterix were increased. These results show that BMP2 signaling regulates Y1 receptor gene expression, and raises the possibility that NPY acts in osteoblasts via an autocrine mechanism.
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Proteína Morfogenética Óssea 2/genética , Mioblastos/metabolismo , Receptores de Neuropeptídeo Y/genética , Animais , Proteína Morfogenética Óssea 2/metabolismo , Linhagem Celular , Camundongos , Osteoblastos/metabolismo , RNA Mensageiro/metabolismo , Receptores de Neuropeptídeo Y/metabolismo , Transdução de Sinais , Proteína Smad1/genética , Proteína Smad1/metabolismo , Proteína Smad4/genética , Proteína Smad4/metabolismoRESUMO
INTRODUCTION: Although the rapid plasma reagin (RPR) test is used to determine treatment efficacy for syphilis, animal studies show that it decreases gradually after an initial increase even without treatment. Pre-treatment changes in RPR titer in humans and its relationship with post-treatment changes in RPR titer are not well known. METHODS: We retrospectively analyzed the clinical records of syphilitic patients who underwent automated RPR (Mediace) testing twice before treatment (i.e., at diagnosis and treatment initiation) within 1-3 months at an HIV/AIDS referral hospital in Japan between 2006 and 2018. The RPR values were expressed as the ratio to the value at treatment initiation. The mean monthly relative change in the RPR after treatment was calculated on the log2 scale for each patient and analyzed by multivariable linear regression. RESULTS: Sixty-eight patients were identified. The median age was 45 (interquartile range [IQR], 38-50), 98.5% (67/68) were men, and 97.1% (66/68) had HIV. The median RPR titer ratio at treatment initiation/diagnosis was 0.87 (IQR, 0.48-1.30). The RPR titer decreased more than twofold in 26.5% (18/68) and more than fourfold in 10.3% (7/68) before treatment. In the multivariable analysis, higher age (predicted monthly RPR relative change on the log2 scale 0.23/10 years [95% confidence interval [CI], 0.090-0.37]), history of syphilis (0.36 [95% CI, 0.07-0.65]), and a lower ratio of RPR at treatment initiation/diagnosis (-0.52/every 10-fold increase [95% CI, -0.81 to -0.22]) were associated with a slower RPR decrease after treatment. CONCLUSIONS: In a mostly HIV patient population, RPR titer can show more than four-fold spontaneous increase or decrease within 1-3 months. Pre-treatment spontaneous decrease of RPR titer was associated with a slower decrease in post-treatment RPR titer.