RESUMEN
OBJECTIVE: The purpose of this study was to determine the role of smooth muscle cell-derived hypoxia-inducible factor-1α (Hif-1α) in the pathogenesis of aortic aneurysms. APPROACH AND RESULTS: Control mice and smooth muscle cell-specific hypoxia-inducible factor-1α-deficient mice were infused with ß-aminopropionitrile for 2 weeks and angiotensin II for 6 weeks to induce aortic aneurysm formation. Mutant mice experienced increased levels of aneurysm formation of the thoracic or abdominal aorta with more severe elastin disruption, compared with control mice. Smooth muscle cell-specific hypoxia-inducible factor-1α deficiency did not affect matrix metalloproteinase-2 activity; however, the activity of lysyl oxidase and the levels of tropoelastin mRNA in the angiotensin II- and ß-aminopropionitrile-treated aortae, associated with elastin fiber formation, were suppressed. Furthermore, we observed reduced volumes of mature cross-linked elastin in the thoracoabdominal aorta after treatment with angiotensin II and ß-aminopropionitrile. CONCLUSIONS: Deficiency of smooth muscle cell-derived hypoxia-inducible factor-1α augments aortic aneurysms, accompanied by disruption of elastin fiber formation, but not changes of elastin fiber degradation.
Asunto(s)
Aneurisma de la Aorta Abdominal/prevención & control , Aneurisma de la Aorta Torácica/prevención & control , Subunidad alfa del Factor 1 Inducible por Hipoxia/metabolismo , Músculo Liso Vascular/metabolismo , Miocitos del Músculo Liso/metabolismo , Aminopropionitrilo , Angiotensina II , Animales , Aorta Abdominal/metabolismo , Aorta Abdominal/patología , Aorta Torácica/metabolismo , Aorta Torácica/patología , Aneurisma de la Aorta Abdominal/inducido químicamente , Aneurisma de la Aorta Abdominal/metabolismo , Aneurisma de la Aorta Abdominal/patología , Aneurisma de la Aorta Torácica/inducido químicamente , Aneurisma de la Aorta Torácica/metabolismo , Aneurisma de la Aorta Torácica/patología , Células Cultivadas , Dilatación Patológica , Modelos Animales de Enfermedad , Tejido Elástico/metabolismo , Tejido Elástico/patología , Predisposición Genética a la Enfermedad , Subunidad alfa del Factor 1 Inducible por Hipoxia/deficiencia , Subunidad alfa del Factor 1 Inducible por Hipoxia/genética , Masculino , Ratones Noqueados , Músculo Liso Vascular/patología , Miocitos del Músculo Liso/patología , Fenotipo , Proteína-Lisina 6-Oxidasa/metabolismo , Tropoelastina/genética , Tropoelastina/metabolismo , Remodelación VascularRESUMEN
Using rational membrane protein design, we were recently able to obtain a ß-barrel protein nanopore that was robust under an unusually broad range of experimental circumstances. This protein nanopore was based upon the native scaffold of the bacterial ferric hydroxamate uptake component A (FhuA) of Escherichia coli. In this work, we expanded the examinations of the open-state current of this engineered protein nanopore, also called FhuA ΔC/Δ4L, employing an array of lipid bilayer systems that contained charged and uncharged as well as conical and cylindrical lipids. Remarkably, systematical single-channel analysis of FhuA ΔC/Δ4L indicated that most of its biophysical features, such as the unitary conductance and the stability of the open-state current, were not altered under the conditions tested in this work. However, electrical recordings at high transmembrane potentials revealed that the presence of conical phospholipids within the bilayer catalyzes the first, stepwise current transition of the FhuA ΔC/Δ4L protein nanopore to a lower-conductance open state. This study reinforces the stability of the open-state current of the engineered FhuA ΔC/Δ4L protein nanopore under various experimental conditions, paving the way for further critical developments in biosensing and molecular biomedical diagnosis.
Asunto(s)
Proteínas de la Membrana Bacteriana Externa/química , Proteínas de Escherichia coli/química , Lípidos/química , Nanoporos , Ingeniería de Proteínas/métodos , Proteínas de la Membrana Bacteriana Externa/metabolismo , Biofisica/métodos , Técnicas Biosensibles , Conductividad Eléctrica , Electrofisiología , Escherichia coli/metabolismo , Proteínas de Escherichia coli/metabolismo , Concentración de Iones de Hidrógeno , Membrana Dobles de Lípidos/química , Potenciales de la Membrana , Conformación Molecular , Nanopartículas/química , Nanotecnología/métodos , Estructura Secundaria de ProteínaRESUMEN
Increasing evidence indicates that inflammation contributes to the pathogenesis of atrial fibrillation (AF). Pentraxin 3 (PTX3) is produced abundantly in local inflammatory lesions while C-reactive protein (CRP) is produced mainly in the liver. In this study, we investigated whether a local level of PTX3 might be a sensitive marker for the local inflammation of AF. Blood from the periphery and left atrial appendage (LAA) was sampled from 23 patients with AF undergoing pulmonary vein isolation, and from 10 control subjects with Wolff-Parkinson-White syndrome. We measured peripheral and LAA plasma concentrations of CRP, interleukin-6 (IL-6), tumor necrosis factor-α (TNF-α), and PTX3. Plasma PTX3 concentrations in both locations were higher in patients with AF than in control subjects. PTX3 concentrations were significantly higher in the LAA than the periphery in patients with AF (3.7 ± 1.4 vs 3.3 ± 1.2 ng/ml, P < 0.01), but not in control subjects (2.4 ± 0.5 vs 2.4 ± 0.5 ng/ml, not significant). Patients and controls showed no significant differences in CRP, IL-6, or TNF-α concentrations between the periphery and LAA. Interestingly, there was a significant positive correlation between LAA plasma concentrations of PTX3 and left atrial volume (r = 0.55, P < 0.01). These data demonstrate that local PTX3 production in the left atrium might reflect the local inflammation of AF.
Asunto(s)
Apéndice Atrial/inmunología , Fibrilación Atrial/inmunología , Proteína C-Reactiva/análisis , Mediadores de Inflamación/análisis , Componente Amiloide P Sérico/análisis , Anciano , Fibrilación Atrial/sangre , Fibrilación Atrial/diagnóstico , Fibrilación Atrial/cirugía , Biomarcadores/análisis , Estudios de Casos y Controles , Ensayo de Inmunoadsorción Enzimática , Femenino , Humanos , Inmunohistoquímica , Mediadores de Inflamación/sangre , Masculino , Persona de Mediana Edad , Valor Predictivo de las Pruebas , Pronóstico , Regulación hacia ArribaRESUMEN
Staphylococcal γ-hemolysin is a bicomponent pore-forming toxin composed of LukF and Hlg2. These proteins are expressed as water-soluble monomers and then assemble into the oligomeric pore form on the target cell. Here, we report the crystal structure of the octameric pore form of γ-hemolysin at 2.5 Å resolution, which is the first high-resolution structure of a ß-barrel transmembrane protein composed of two proteins reported to date. The octameric assembly consists of four molecules of LukF and Hlg2 located alternately in a circular pattern, which explains the biochemical data accumulated over the past two decades. The structure, in combination with the monomeric forms, demonstrates the elaborate molecular machinery involved in pore formation by two different molecules, in which interprotomer electrostatic interactions using loops connecting ß2 and ß3 (loop A: Asp43-Lys48 of LukF and Lys37-Lys43 of Hlg2) play pivotal roles as the structural determinants for assembly through unwinding of the N-terminal ß-strands (amino-latch) of the adjacent protomer, releasing the transmembrane stem domain folded into a ß-sheet in the monomer (prestem), and interaction with the adjacent protomer.
Asunto(s)
Proteínas Bacterianas/química , Toxinas Bacterianas/química , Proteínas Hemolisinas/química , Cristalografía por Rayos X , Leucocidinas/química , Modelos Moleculares , Complejos Multiproteicos/química , Conformación Proteica , Dominios y Motivos de Interacción de Proteínas , Multimerización de Proteína , Estructura Cuaternaria de Proteína , Estructura Secundaria de Proteína , Subunidades de Proteína , Proteínas Recombinantes/química , Staphylococcus aureus/química , Staphylococcus aureus/patogenicidad , Electricidad EstáticaRESUMEN
BACKGROUND: Vaccination against mpox (formerly known as monkeypox), an infectious disease caused by the monkeypox virus (MPXV), is needed to prevent outbreaks and consequent public health concerns. The LC16m8 vaccine, a dried cell-cultured proliferative live attenuated vaccinia virusbased vaccine, was approved in Japan against smallpox and mpox. However, its immunogenicity and efficacy against MPXV have not been fully assessed. We assessed the safety and immunogenicity of LC16m8 against MPXV in healthy adults. METHODS: We conducted a single-arm study that included 50 participants who were followed up for 168 days postvaccination. The primary end point was the neutralizing antibody seroconversion rate against MPXVs, including the Zr599 and Liberia strains, on day 28. The secondary end points included the vaccine "take" (major cutaneous reaction) rate, neutralizing titer kinetics against MPXV and vaccinia virus (LC16m8) strains, and safety outcomes. RESULTS: Seroconversion rates on day 28 were 72% (36 of 50), 70% (35 of 50), and 88% (44 of 50) against the Zr599 strain, the Liberia strain, and LC16m8, respectively. On day 168, seroconversion rates decreased to 30% (15 of 50) against the Zr599 and Liberia strains and to 76% (38 of 50) against LC16m8. The vaccine "take" (broad definition) rate on day 14 was 94% (46 of 49). Adverse events (AEs), including common solicited cutaneous reactions, occurred in 98% (45 of 48) of participants; grade 3 severity AEs occurred in 16% (8 of 50). No deaths, serious AEs, or mpox onset incidences were observed up to day 168. CONCLUSIONS: The LC16m8 vaccine generated neutralizing antibody responses against MPXV in healthy adults. No serious safety concerns occurred with LC16m8 use. (Funded by the Ministry of Health, Labour and Welfare of Japan; Japan Registry of Clinical Trials number, jRCTs031220171.)
Asunto(s)
Mpox , Vacuna contra Viruela , Vacunas , Adulto , Humanos , Anticuerpos Neutralizantes , Antígenos ViralesRESUMEN
Vagal nerve stimulation has been postulated to confer an antifibrillatory effect. We studied whether ghrelin administration would exert an antiarrhythmic effect via modulation of autonomic nerve activity in rats after acute myocardial ischemia (MI). Male Sprague-Dawley rats were exposed to 30 min of ischemia following ligation of the left coronary artery. Animals were then randomized to receive either ghrelin (n = 26) or saline (n = 26) during the period of coronary ligation. Power spectral analysis of heart-rate variability revealed that the administration of ghrelin increased the high-frequency (HF) power and decreased the low-frequency (LF)/HF ratio. Ventricular tachyarrhythmias were less frequent in rats after MI who received ghrelin in comparison with rats that received saline. Immunoblotting and immunohistochemistry revealed that rats given saline alone during MI exhibited a marked reduction in phosphorylated connexin-43 within the left ventricle, whereas those that received ghrelin displayed only minor reductions in comparison with sham-operated rats. These effects of ghrelin were diminished by the coadministration of atropine or the blockade of vagal afferents. These data demonstrate that the beneficial effect of ghrelin might be mediated by modulation of cardiac autonomic nerve activity.
Asunto(s)
Antiarrítmicos/farmacología , Conexina 43/metabolismo , Ghrelina/farmacología , Frecuencia Cardíaca/efectos de los fármacos , Ventrículos Cardíacos/efectos de los fármacos , Isquemia Miocárdica/tratamiento farmacológico , Taquicardia Ventricular/prevención & control , Animales , Atropina/farmacología , Modelos Animales de Enfermedad , Ventrículos Cardíacos/inervación , Ventrículos Cardíacos/metabolismo , Masculino , Antagonistas Muscarínicos/farmacología , Isquemia Miocárdica/complicaciones , Isquemia Miocárdica/metabolismo , Isquemia Miocárdica/fisiopatología , Fosforilación , Ratas , Ratas Sprague-Dawley , Taquicardia Ventricular/etiología , Taquicardia Ventricular/metabolismo , Taquicardia Ventricular/fisiopatología , Factores de Tiempo , Vagotomía , Nervio Vago/efectos de los fármacos , Nervio Vago/fisiopatología , Nervio Vago/cirugíaRESUMEN
A 67-year-old woman with asthma visited our hospital with increasing dyspnea and new-onset paresthesia and purpura in her legs. Physical examination showed a wheeze, pretibial edema, and surrounding purpura. Chest X-rays showed cardiac decompensation and an electrocardiogram revealed a new ST-T change. Laboratory data showed leukocytosis, hypereosinophilia (10,450/µL), troponin T(+), elevated BNP, and markedly elevated eosinophil cationic protein (ECP) (> 150 ng/mL). Echocardiography revealed diffuse left ventricular hypokinesis (ejection fraction 30%) with increased wall thickness. Coronary angiography was normal. Cardiac magnetic resonance imaging implied diffuse myocardial edema and subendocardial late gadolinium enhancement. Skin biopsy of purpura showed superfi cial perivascular dermatitis with remarkable eosinophilic infiltrations. No evidence of drug allergies, parasitic infection, or myeloproliferative disorder was detected. Based on these findings, a diagnosis of eosinophilic myocarditis due to Churg-Strauss syndrome was considered. She was administered prednisolone at a dose of 1 mg/kg, cyclophosphamide, and diuretics. Several markers of eosinophilic myocarditis and heart failure gradually improved, including ECP. She was discharged 30 days later with no cardiac event. Eosinophilic myocarditis is characterized by predominantly eosinophilic infi ltration. Eosinophilic granule proteins, such as ECP and major basic protein, play important roles in the pathogenesis of eosinophilic myocarditis. We experienced a rare case of eosinophilic myocarditis due to Churg-Strauss syndrome. Markedly elevated ECP played an important role in the early diagnosis and subsequent reduction in ECP served as a marker of monitoring. In an asthmatic patient with dyspnea, hypereosinophilia, and vasculitis, Churg-Strauss syndrome with eosinophilic myocarditis should be considered.
Asunto(s)
Síndrome de Churg-Strauss/complicaciones , Ciclofosfamida/administración & dosificación , Diuréticos/administración & dosificación , Eosinofilia , Miocarditis , Prednisolona/administración & dosificación , Anciano , Asma/complicaciones , Biopsia , Ecocardiografía/métodos , Electrocardiografía/métodos , Proteínas en los Gránulos del Eosinófilo/sangre , Eosinofilia/diagnóstico , Eosinofilia/tratamiento farmacológico , Eosinofilia/etiología , Eosinofilia/fisiopatología , Femenino , Insuficiencia Cardíaca/fisiopatología , Pruebas de Función Cardíaca/métodos , Humanos , Inmunosupresores , Imagen por Resonancia Magnética/métodos , Miocarditis/sangre , Miocarditis/diagnóstico , Miocarditis/tratamiento farmacológico , Miocarditis/etiología , Miocarditis/fisiopatología , Púrpura/complicaciones , Púrpura/patologíaRESUMEN
Although vaccines for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) disease 2019 (COVID-19) induce effective immune responses, vaccination with booster doses is necessary because of waning immunity. We conducted an open-label, non-randomized, single-arm study in adults in Japan to assess the immunogenicity and safety of a single booster dose of the KD-414 purified whole-SARS-CoV-2-virion inactivated vaccine candidate after vaccination with a primary series of BNT162b2. The primary endpoint was serum neutralizing activity at 7 days after booster injection compared with the primary series of BNT162b2. The SARS-CoV-2-structural protein-binding antibody level and T cell response against SARS-CoV-2-Spike (S) peptides were also examined as secondary endpoints, and safety profile assessments were conducted. Twenty subjects who participated in a previous study declined an injection of KD-414 (non-KD-414 group) and received a booster dose of BNT162b2 instead. The non-KD-414 group was compared to the KD-414 group as a secondary outcome. A single dose of KD-414 induced lower serum neutralizing activity against the wild-type virus within 7 days compared to after the primary series of BNT162b2 but significantly induced anti-SARS-CoV-2-S1-receptor-binding domain-binding immunoglobulin G (IgG) antibodies and SARS-CoV-2-S peptide-specific CD4+ and CD8+ T cell responses. Local or systemic symptoms were significantly lower in the participants who received KD-414 than in those who received BNT162b2 as the third COVID-19 vaccine dose. The present data indicate that a single booster dose of KD-414 induces a substantial immune response in BNT162b2-primed individuals and has a good safety profile, thereby supporting further clinical trials to identify rational targets.
Asunto(s)
Vacunas contra la COVID-19 , COVID-19 , Adulto , Humanos , Vacunas contra la COVID-19/efectos adversos , Vacuna BNT162 , Japón , COVID-19/prevención & control , SARS-CoV-2 , Anticuerpos Antivirales , Inmunogenicidad Vacunal , Anticuerpos NeutralizantesRESUMEN
BACKGROUND: In May 2022, a case of monkeypox (currently known as "mpox") with no history of overseas travel was reported in the United Kingdom, followed by reports of infections reported in Europe, the United States, and other countries worldwide. Due to the significant overlap in immune responses among viruses of the genus Orthopoxvirus (including smallpox virus, mpox virus, and vaccinia virus), it is believed that cross-immunity can be achieved by administering the smallpox virus vaccine. In Japan, a smallpox vaccine (LC16m8 strain vaccine) has been approved; however, there was no regulatory approval for the mpox vaccine during the design of this study. Although it is believed that individuals exposed to the mpox virus may receive smallpox vaccination as mpox prophylaxis, the existing evidence is not clear. OBJECTIVE: The primary objective was to evaluate the efficacy of the LC16m8 strain vaccine, approved for smallpox in Japan, for postexposure prophylaxis against mpox when administered to close contacts of individuals with mpox. The secondary objective was to investigate the safety of the vaccine for postexposure prophylaxis against mpox. METHODS: The study aimed to enroll 100 vaccinated participants who had been identified as close contacts of individuals with mpox. Consent was obtained, and the participants are inoculated with the vaccine. Daily recordings of symptoms (body temperature, headache, rash, and side effects) were made until day 21 and then again on day 28. Furthermore, additional evaluations of adverse events were performed by the investigators on days 7, 14, 21, and 28. Considering that the maximum incubation period for mpox is 21 days, the primary end point is the presence or absence of the disease 21 days after close contact. The primary analysis focused on cases within 4 days of intense contact as it has been reported that vaccination within this timeframe can reduce the incidence of the disease. RESULTS: The first trial participant was enrolled on July 28, 2022, and the research period concluded in March 2023. The study results will be published in a peer-reviewed scientific journal. CONCLUSIONS: This study allowed us to investigate the efficacy and safety of the LC16m8 strain vaccine in postexposure prophylaxis against mpox. TRIAL REGISTRATION: Japan Registry of Clinical Trials jRCTs031220137; https://jrct.niph.go.jp/en-latest-detail/jRCTs031220137. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): DERR1-10.2196/46955.
RESUMEN
Mpox is an acute exanthematous disease caused by the monkeypox virus. Since May 2022, it has spread as a community-acquired infection, mainly in Europe and the United States, and urgent measures to prevent this infection were also required in Japan. In this study, we investigated the post-exposure prophylaxis of mpox and safety after inoculating the smallpox vaccine. Participants in close contact with patients with mpox were inoculated with "Freeze-dried cell culture Smallpox Vaccine LC16," within 14 days after close contact. Six cases were registered, and all the participants were inoculated. No mpox symptoms or related complications were observed in the participants for 21 days after the close contact. Adverse events due to inoculation, such as rash, fever, lymphadenopathy, and local reaction at the inoculation site (comprising erythema, swelling, induration, and pain) were observed in the participants; however, all inoculation-related events were non-severe and non-serious, and the participants recovered during the 28-day observation period. The findings of this study suggest that inoculation with LC16 is an effective post-exposure prophylaxis in individuals who had close contact with patients with mpox. Further large-scale studies are warranted to validate these findings.
Asunto(s)
Exantema , Mpox , Profilaxis Posexposición , Vacuna contra Viruela , Humanos , Antígenos Virales , Técnicas de Cultivo de Célula , Vacuna contra Viruela/efectos adversos , Mpox/prevención & controlRESUMEN
Monkeypox (mpox) is an acute exanthematous disease caused by the monkeypox virus (MPXV). Since May 2022, patients with mpox have been reported worldwide, mainly in Europe and the Americas. In Japan, LC16"KMB," which is a smallpox vaccine derived from a dried cell culture, against mpox, has been approved. Although inoculation with a smallpox vaccine has been recommended to prevent MPXV infection, the immunogenicity of the smallpox vaccine against the MPXV is unclear, and information regarding postvaccination safety is scarce. We present the protocol for a single-arm open-label study to investigate the immunogenicity and safety of LC16"KMB" against the MPXV in healthy Japanese adults. The primary endpoint is the seroconversion rate of neutralizing antibodies against the MPXV on postvaccination day 28. The secondary endpoints are the seroconversion rates against the MPXV on postvaccination days 14 and 168; the seroconversion rates against the vaccinia virus on postvaccination days 14, 28, and 168; the incidence of mpox until day 168; and adverse and serious adverse events until postvaccination days 28 and 168. These results will pave the way for larger comparative studies using other smallpox vaccines to evaluate the test vaccine's safety and efficacy in preventing mpox.
RESUMEN
BACKGROUND: Growing evidence suggests that epicardial adipose tissue (EAT) may contribute to the development of coronary artery disease (CAD). In this study, we explored gender disparities in EAT volume (EATV) and its impact on coronary atherosclerosis. METHODS: The study population consisted of 90 consecutive subjects (age: 63 ± 12 years; men: 47, women: 43) who underwent 256-slice multi-detector computed tomography (MDCT) coronary angiography. EATV was measured as the sum of cross-sectional epicardial fat area on CT images, from the lower surface of the left pulmonary artery origin to the apex. Subjects were segregated into the CAD group (coronary luminal narrowing > 50%) and non-CAD group. RESULTS: EATV/body surface area (BSA) was higher among men in the CAD group than in the non-CAD group (62 ± 13 vs. 33 ± 10 cm3/m2, p < 0.0001), but did not differ significantly among women in the 2 groups (49 ± 18 vs. 42 ± 9 cm3/m2, not significant). Multivariate logistic analysis showed that EATV/BSA was the single predictor for >50% coronary luminal narrowing in men (p < 0.0001). Predictors excluded were age, body mass index, hypertension, diabetes mellitus, and hyperlipidemia. CONCLUSIONS: Increased EATV is strongly associated with coronary atherosclerosis in men.
Asunto(s)
Tejido Adiposo/diagnóstico por imagen , Pueblo Asiatico , Angiografía Coronaria/métodos , Enfermedad de la Arteria Coronaria/diagnóstico por imagen , Estenosis Coronaria/diagnóstico por imagen , Disparidades en el Estado de Salud , Tomografía Computarizada Multidetector , Pericardio/diagnóstico por imagen , Factores de Edad , Anciano , Superficie Corporal , Distribución de Chi-Cuadrado , Enfermedad de la Arteria Coronaria/etnología , Estenosis Coronaria/etnología , Femenino , Humanos , Japón/epidemiología , Modelos Logísticos , Masculino , Persona de Mediana Edad , Análisis Multivariante , Valor Predictivo de las Pruebas , Medición de Riesgo , Factores de Riesgo , Índice de Severidad de la Enfermedad , Factores SexualesRESUMEN
BACKGROUND: The coronavirus disease 2019 (COVID-19) pandemic is currently ongoing, and there have been significant efforts in the development of COVID-19 vaccines. However, the neutralizing antibody titers in vaccinated individuals are reported to progressively decrease over time. Japanese pharmaceutical companies have published the results of Phase I and II studies on the safety and efficacy of different vaccines. Final clinical trials will be conducted with the aim of practical application by March 2023. To effectively utilize vaccines developed by Japanese companies, the efficacy and safety of a booster dose (i.e., third vaccination) must be evaluated among individuals who have received three doses of different vaccines. METHODS: This protocol describes a study that aims to examine the effect of a booster dose of "KD-414", a novel Japanese inactivated vaccine, on antibody titers among participants involved in a previous study. Volunteers in this protocol will be recruited from participants in the previous study and immunized with KD-414 after obtaining consent. The antibody titers, before and after immunization with KD-414, among participants who previously received two doses of the BNT162b2 mRNA vaccine, will be comparatively analyzed. DISCUSSION: The reactogenicity and immunogenicity of seven different COVID-19 vaccines including an inactivated vaccine as a third dose after two doses of ChAdOx1 nCov-19 or BNT162b2, has been tested previously, and found to be superior to control (quadrivalent meningococcal conjugate vaccine) regardless of which vaccine had been received during the initial course. This suggests that many types of third booster doses are efficacious. It is anticipated that this study will provide evidence of the safety and immunogenicity of KD-414 as a booster vaccine, which will have profound public health implications.
RESUMEN
BACKGROUND: Coronavirus disease 2019 is a global public health concern. As of December 2020, the therapeutic agents approved for coronavirus disease 2019 in Japan were limited to two drugs: remdesivir, an antiviral drug, granted a Special Approval for Emergency on 7 May 2020, and dexamethasone, which has an anti-inflammatory effect. The aim of this study is to evaluate the efficacy of convalescent plasma collected from donors who recovered from coronavirus disease 2019. METHODS: This is an open-label, randomized controlled trial comprising two groups: a convalescent plasma and a standard-of-care group. Plasma administered to patients with coronavirus disease 2019 randomized in the convalescent plasma group of this trial will be plasma that has been collected and stored in an associated study. Patients with a diagnosis of mild coronavirus disease 2019 will be included in this trial. The efficacy of convalescent plasma transfusion will be evaluated by comparing the convalescent plasma group to the standard-of-care group (without convalescent plasma transfusion) with respect to changes in the viral load and other measures. The primary endpoint will be time-weighted average changes in the SARS-CoV-2 virus load in nasopharyngeal swabs from day 0 to days 3 and 5. It is hypothesized that the intervention should result in a decrease in the viral load in the convalescent plasma group until day 5. This endpoint has been used as a change in viral load has and been used as an index of therapeutic effect in several previous studies. DISCUSSION: The proposed trial has the potential to prevent patients with mild COVID-19 from developing a more severe illness. Several RCTs of convalescent plasma therapy have already been conducted in countries outside of Japan, but no conclusion has been reached with respect to the efficacy of convalescent plasma therapy, which is likely in part because of the heterogeneity of the types of target patients, interventions, and endpoints among trials. Actually, previous clinical trials on plasma therapy have shown inconsistent efficacy and are sometimes ineffective in COVID-19 patients with severe disease, which is due to unmeasured neutralizing antibody titer in the COVID-19 convalescent plasma. To improve this issue, in this study, we measure neutralizing activity of convalescent plasma before administration and provide the plasma with high neutralizing activity to the subjects. It is hoped that this study will further evidence to support the role of convalescent plasma therapy in COVID-19.
RESUMEN
BACKGROUND: Automated function imaging (AFI) is a recently developed method of calculating the longitudinal peak systolic strains (LS) of the regional left ventricular (LV) wall using speckle tracking echocardiography and displaying them on a single bull's-eye map. The feasibility of AFI in patients with regional LV wall motion abnormalities caused by myocardial infarction (MI) was evaluated by comparison with visual assessment and myocardial perfusion single-photon emission computed tomography (SPECT). METHODS AND RESULTS: Segmental LS was measured by AFI in 60 patients with MI (67 ± 11 years) and 58 controls (71 ± 9 years). Wall thickening (WT) was measured by SPECT in 20 patients with MI. There was a strong positive linear relationship between the wall motion score index by expert visual assessment and global LS. The receiver-operating characteristic analysis revealed the best cutoff value of 11% < LS to identify hypokinetic segments. The overall accuracy of wall motion scoring by LS in the 2,006 segments was 96.8% (κ = 0.90) compared with visual assessment. The correlation coefficient between LS and WT was R² = 0.65 in the 340 segments. CONCLUSIONS: Assessment of LV regional asynergy by AFI showed good agreement with visual and SPECT assessments. AFI is clinically useful for quantitative assessment of LV regional wall motion abnormalities.
Asunto(s)
Ecocardiografía Doppler , Contracción Miocárdica , Infarto del Miocardio/complicaciones , Imagen de Perfusión Miocárdica/métodos , Tomografía Computarizada de Emisión de Fotón Único , Disfunción Ventricular Izquierda/diagnóstico por imagen , Función Ventricular Izquierda , Anciano , Anciano de 80 o más Años , Algoritmos , Estudios de Casos y Controles , Estudios de Factibilidad , Humanos , Interpretación de Imagen Asistida por Computador , Japón , Persona de Mediana Edad , Infarto del Miocardio/fisiopatología , Variaciones Dependientes del Observador , Valor Predictivo de las Pruebas , Reproducibilidad de los Resultados , Disfunción Ventricular Izquierda/etiología , Disfunción Ventricular Izquierda/fisiopatologíaRESUMEN
A 76-year-old male diagnosed with interstitial pneumonia in December 2002 was treated with a steroid in a nearby hospital. Exacerbation of infectious pneumonitis and interstitial pneumonia required complementary inpatient treatment in August 2007. Although polymerase chain reaction examination of expectorated sputa revealed the absence of Mycobacterium tuberculosis, M. avium, and M. intracellulare on admission, nontuberculous M. abscessus was detected in the routine blood cultures. Taken together with clinical findings, M. abscessus was most likely the primary causative organism. Diagnosis of mycobaterium-induced septicemia generally involves the use of mycobacterium-designated bottles, MGIT method, and Ogawa medium; however, we used microbe cultures with routine blood-culture bottles in the present case. Of the 24 mycobacterium-induced septicemia cases reported in the past 10 years, only eight cases were detected from routine blood-culture bottles; they were all rapidly growing bacteria. Mycobacteria other than the rapidly growing mycobacteria display delayed culture proliferation, therefore it is possible that non-detected microbes were probably present in the patients despite the fact that they were suffering from septicemia. In cases suspected to have severe infections, particularly those with a depressed immunodefense system, blood-culture testing for mycobacteria would be highly helpful for diagnosis.
Asunto(s)
Sangre/microbiología , Huésped Inmunocomprometido , Enfermedades Pulmonares Intersticiales/terapia , Infecciones por Mycobacterium/microbiología , Mycobacterium/aislamiento & purificación , Neumonía Bacteriana/microbiología , Sepsis/microbiología , Anciano , Antibacterianos/uso terapéutico , Técnicas de Cultivo , Quimioterapia Combinada , Resultado Fatal , Humanos , Masculino , Infecciones por Mycobacterium/tratamiento farmacológico , Terapia por Inhalación de Oxígeno , Neumonía Bacteriana/tratamiento farmacológico , Reacción en Cadena de la Polimerasa , Prednisolona/uso terapéutico , Sepsis/tratamiento farmacológicoRESUMEN
The active involvement of hospital laboratory in surveillance is crucial to the success of nosocomial infection control. The recent dramatic increase of antimicrobial-resistant organisms and their spread into the community suggest that the infection control strategy of independent medical institutions is insufficient. To share the clinical data and surveillance in our local medical region, we developed a microbiology data warehouse for networking hospital laboratories in Akita prefecture. This system, named Akita-ReNICS, is an easy-to-use information management system designed to compare, track, and report the occurrence of antimicrobial-resistant organisms. Participating laboratories routinely transfer their coded and formatted microbiology data to ReNICS server located at Akita University Hospital from their health care system's clinical computer applications over the internet. We established the system to automate the statistical processes, so that the participants can access the server to monitor graphical data in the manner they prefer, using their own computer's browser. Furthermore, our system also provides the documents server, microbiology and antimicrobiotic database, and space for long-term storage of microbiological samples. Akita-ReNICS could be a next generation network for quality improvement of infection control.
Asunto(s)
Redes Comunitarias , Bases de Datos Factuales , Hospitales , Control de Infecciones/métodos , Gestión de la Información/métodos , Microbiología , Técnicas Bacteriológicas , Infección Hospitalaria/microbiología , Infección Hospitalaria/prevención & control , Farmacorresistencia Bacteriana , Humanos , JapónRESUMEN
Sonoporation is achieved by ultrasound-mediated destruction of ultrasound contrast agents (UCA) microbubbles. For this, UCAs must be tissue specific and have good echogenicity and also function as drug carriers. Previous studies have developed acoustic liposomes (ALs), liposomes that encapsulate phosphate buffer solution and perfluoropropane (C(3)F(8)) gas and function as both UCAs and drug carriers. Few studies have examined the co-existence of gas and liquid in ALs. This study aims to elucidate AL structure using TEM. The size, zeta potential and structure of ALs were compared with those of two other UCAs, human albumin shell bubbles (ABs; Optison) and lipid bubbles (LBs). ABs and LBs encapsulate the C(3)F(8) gas. Particle size was measured by dynamic light scattering. The zeta potential was determined by the Smoluchowski equation. UCA structure was investigated by TEM. ALs were approximately 200 nm in size, smaller than LBs and ABs. ALs and LBs had almost neutral zeta potentials whereas AB values were strongly negative. The negative or double staining TEM images revealed that approximately 20% of ALs contained both liquid and gas, while approximately 80% contained liquid alone (i.e. nonacoustic). Negative staining AB images indicated electron beam scattering near the shell surface, and albumin was detected in filament form. These findings suggest that AL is capable of carrying drugs and high-molecular-weight, low-solubility gases.
Asunto(s)
Liposomas/ultraestructura , Microscopía Electrónica de Transmisión/métodos , Ultrasonido , Albúminas , Medios de Contraste/química , Sistemas de Liberación de Medicamentos , Humanos , Aumento de la Imagen , Lípidos , MicroburbujasRESUMEN
OBJECTIVE: Infection control is essential for health care facilities. Aiming at improving the activity for infection control, increasing number of health care facilities has settled infection control team (ICT) in this decade. However, the quality of infection control activity has not been evaluated. METHOD: The quality of infection control was investigated in 49 hospitals and 55 welfare institutions for the aged in Akita prefecture using a questionnaire. RESULT: All the hospitals with more than 400 beds or more had ICT; however, less than 50% of the hospitals with 399 beds or less had ICT. The coverage of full-time specialist for infection control remained at a low level. Collection and analysis of information such as the prevalence of multi-drug resistant microorganisms and the consumption of antibiotics remained at a low level. More than 88% of the facilities hoped for a regional infection control network system to improve infection control activities. Reciprocal help in case of outbreak, education, lectures, sharing rules on infection control, making guidelines and teaching materials for infection control, analysis of infection control-related epidemiological data and getting suggestions and recommendations from authorized infection control specialists were included in the strongly required functions of the network.
Asunto(s)
Instituciones de Salud , Control de Infecciones , Calidad de la Atención de Salud , Antibacterianos , Infecciones Bacterianas/epidemiología , Infecciones Bacterianas/microbiología , Infecciones Bacterianas/prevención & control , Redes Comunitarias/estadística & datos numéricos , Resistencia a Múltiples Medicamentos , Utilización de Medicamentos/estadística & datos numéricos , Humanos , Control de Infecciones/organización & administración , Control de Infecciones/estadística & datos numéricos , Japón/epidemiología , Encuestas y CuestionariosRESUMEN
Recently, our group has contrasted an endothelial cell-smooth muscle cell (EC-SMC) co-culture model with 3D-cultured SMCs and found that SMCs could respond to high shear stress (SS), which has not been explored before. SMCs were not directly exposed to the flow but were under an EC monolayer; therefore, it is necessary to explore the influence of EC on SMC behaviors under high SS for understanding the mechanism of SMC response to various magnitudes of SS. In the present study, TGF-ß1 expression in ECs in an EC-SMC co-culture model was suppressed by an siRNA transfection method. Next, phenotypic changes were observed and MMP-2 and -9 productions were measured in SMCs in the co-culture model after 72-h flow exposure to different SS levels. We confirmed that TGF-ß1 expression in ECs could influence SMC phenotypic change under SS conditions and that TGF-ß1 expression in ECs could also change MMP-2 production but not MMP-9 production in SMCs under SS conditions in the co-culture model. These results could be useful for understanding the mechanisms of SMC response to SS, particularly for understanding signal transduction emanating from ECs.