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Patients with permanent hypoparathyroidism require lifelong replacement therapy to avoid life-threatening complications, The benefits of conventional treatment are limited, however. Transplanting a functional parathyroid gland (PTG) would yield better results. Parathyroid gland cells generated from pluripotent stem cells in vitro to date cannot mimic the physiological responses to extracellular calcium that are essential for calcium homeostasis. We thus hypothesized that blastocyst complementation (BC) could be a better strategy for generating functional PTG cells and compensating loss of parathyroid function. We here describe generation of fully functional PTGs from mouse embryonic stem cells (mESCs) with single-step BC. Using CRISPR-Cas9 knockout of Glial cells missing2 (Gcm2), we efficiently produced aparathyroid embryos for BC. In these embryos, mESCs differentiated into endocrinologically mature PTGs that rescued Gcm2-/- mice from neonatal death. The mESC-derived PTGs responded to extracellular calcium, restoring calcium homeostasis on transplantation into mice surgically rendered hypoparathyroid. We also successfully generated functional interspecies PTGs in Gcm2-/- rat neonates, an accomplishment with potential for future human PTG therapy using xenogeneic animal BC. Our results demonstrate that BC can produce functional endocrine organs and constitute a concept in treatment of hypoparathyroidism.
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Hipoparatireoidismo , Glândulas Paratireoides , Humanos , Animais , Camundongos , Ratos , Cálcio , Hipoparatireoidismo/genética , Hipoparatireoidismo/terapia , Cálcio da Dieta , BlastocistoRESUMO
Plasma thymidine levels in rodents are higher than in other mammals including humans, possibly due to a different pattern and lower level of thymidine phosphorylase expression. Here, we generated a novel knock-in (KI) mouse line with high systemic expression of human thymidine phosphorylase to investigate this difference in nucleotide metabolism in rodents. The KI mice showed growth retardation around weaning and died by 4 weeks of age with a decrease in plasma thymidine level compared with the litter-control WT mice. These phenotypes were completely or partially rescued by administration of the thymidine phosphorylase inhibitor 5-chloro-6-(2-iminopyrrolidin-1-yl) methyl-2,4(1H,3H)-pyrimidinedione hydrochloride or thymidine, respectively. Interestingly, when thymidine phosphorylase inhibitor administration was discontinued in adult animals, KI mice showed deteriorated grip strength and locomotor activity, decreased bodyweight, and subsequent hind-limb paralysis. Upon histological analyses, we observed axonal degeneration in the spinal cord, muscular atrophy with morphologically abnormal mitochondria in quadriceps, retinal degeneration, and abnormality in the exocrine pancreas. Moreover, we detected mitochondrial DNA depletion in multiple tissues of KI mice. These results indicate that the KI mouse represents a new animal model for mitochondrial diseases and should be applicable for the study of differences in nucleotide metabolism between humans and mice.
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Encefalomiopatias Mitocondriais , Miopatias Mitocondriais , Animais , Humanos , Camundongos , DNA Mitocondrial/metabolismo , Transtornos do Crescimento/genética , Mamíferos/metabolismo , Encefalomiopatias Mitocondriais/genética , Encefalomiopatias Mitocondriais/patologia , Nucleotídeos , Timidina , Timidina Fosforilase/genética , Timidina Fosforilase/metabolismoRESUMO
BACKGROUND: Patients with appropriately selected low-risk pulmonary embolism (PE) can be treated at home, although it has been controversial whether applies to patients with cancer, who are considered not to be at low risk.MethodsâandâResults: The current predetermined companion report from the ONCO PE trial evaluated the 3-month clinical outcomes of patients with home treatment and those with in-hospital treatment. The ONCO PE trial was a multicenter, randomized clinical trial among 32 institutions in Japan investigating the optimal duration of rivaroxaban treatment in cancer-associated PE patients with a score of 1 using the simplified version of the Pulmonary Embolism Severity Index (sPESI). Among 178 study patients, there were 66 (37%) in the home treatment group and 112 (63%) in the in-hospital treatment group. The primary endpoint of a composite of PE-related death, recurrent venous thromboembolism (VTE) and major bleeding occurred in 3 patients (4.6% [0.0-9.6%]) in the home treatment group and in 2 patients (1.8% [0.0-4.3%]) in the in-hospital treatment group. In the home treatment group, there were no cases of PE-related death or recurrent VTE, but major bleeding occurred in 3 patients (4.6% [0.0-9.6%]), and 2 patients (3.0% [0.0-7.2%]) required hospitalization due to bleeding events. CONCLUSIONS: Active cancer patients with PE of sPESI score=1 could be potential candidates for home treatment.
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BACKGROUND: The decongestion strategy using loop diuretics is essential for improving signs and symptoms of heart failure (HF). However, chronic use of loop diuretics in HF has been linked to worsening renal function and adverse clinical outcomes in a dose-dependent manner. Goreisan, a traditional Japanese herbal medicine, has a long history of use in Japan for regulating body fluid homeostasis and has been recognized as causing less adverse outcomes such as dehydration in contrast to loop diuretics in clinical practice. Therefore, we designed the GOREISAN-HF trial to evaluate the long-term effects of a new decongestion strategy adding Goreisan to usual care in patients with HF and volume overload. METHODS: The GOREISAN-HF trial is an investigator-initiated, multicenter, pragmatic, randomized, comparative effectiveness trial in which we will enroll 2,192 patients hospitalized for HF at 68 hospitals in Japan. All study participants will be randomly assigned to either a decongestion strategy that adds Goreisan at a dose of 7.5 g daily on top of usual care or usual care alone. Investigators have the flexibility to change the existing diuretic regimen in both groups. The primary end point is the improvement rate of cardiac edema at 12-month follow-up, and the co-primary end point is a composite of all-cause death or hospitalization up to the end of the planned follow-up period. Secondary end points include longitudinal changes in patient-reported outcomes, loop diuretics dose, and renal function. CONCLUSIONS: The GOREISAN-HF is the first large-scale randomized pragmatic trial to assess the efficacy and safety of a new congestion control strategy adding Goreisan to usual care in patients with HF and volume overload. REGISTRATION NUMBER: NCT04691700.
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Insuficiência Cardíaca , Inibidores de Simportadores de Cloreto de Sódio e Potássio , Humanos , Resultado do Tratamento , Insuficiência Cardíaca/complicações , Diuréticos/uso terapêuticoRESUMO
Recently, we have been working on enhancing the effectiveness of treatment for acute heart failure (HF) through team-based care. This study was designed to assess the benefits of this initiative by quantifying the prognostic impact on HF patients receiving treatment at our hospital. We identified 1977 consecutive HF patients (mean age 78.3 ± 11.9 years) being discharged from our hospital between February 2015 and December 2018, divided them by admission year, and tracked changes over time, with 2015 as a reference. The postdischarge clinical outcome measures were defined as a composite of all-cause death or rehospitalization for HF, all-cause death, and rehospitalization for HF. The risk of a composite of all-cause death or rehospitalization for HF was lower in 2017 (adjusted hazard ratio, 0.72; 95% confidence interval: 0.57 to 0.91; p = 0.005) and 2018 (adjusted hazard ratio, 0.78; 95% confidence interval: 0.61 to 0.99; p = 0.045) than in 2015, and that of all-cause death was lower in 2017 (adjusted hazard ratio, 0.72; 95% confidence interval: 0.53 to 0.98; p = 0.04) and 2018 (adjusted hazard ratio, 0.60; 95% confidence interval: 0.43 to 0.85; p = 0.004) than in 2015, but that of rehospitalization for HF was not significantly different through the study period. The mortality rate decreased at the end of the study period, but the rate of rehospitalization for HF did not. The benefits of team-based care were difficult to evaluate by quantification.
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Assistência ao Convalescente , Insuficiência Cardíaca , Humanos , Idoso , Idoso de 80 Anos ou mais , Estudos Prospectivos , Alta do Paciente , Hospitalização , Insuficiência Cardíaca/terapia , Insuficiência Cardíaca/tratamento farmacológico , Prognóstico , Hospitais , Readmissão do PacienteRESUMO
Our previous study indicated that intravenously administered ivabradine (IVA) augmented the dynamic heart rate (HR) response to moderate-intensity vagal nerve stimulation (VNS). Considering an accentuated antagonism, the results were somewhat paradoxical; i.e., the accentuated antagonism indicates that an activation of hyperpolarization-activated cyclic nucleotide-gated (HCN) channels via the accumulation of intracellular cyclic adenosine monophosphate (cAMP) augments the HR response to VNS, whereas the inhibition of HCN channels by IVA also augmented the HR response to VNS. To remove the possible influence from the accentuated antagonism, we examined the effects of IVA on the dynamic vagal control of HR under ß-blockade. In anesthetized rats (n = 7), the right vagal nerve was stimulated for 10 min according to binary white noise signals between 0 and 10 Hz (V0-10), between 0 and 20 Hz (V0-20), and between 0 and 40 Hz (V0-40). The transfer function from VNS to HR was estimated. Under ß-blockade (propranolol, 2 mg/kg iv), IVA (2 mg/kg iv) did not augment the asymptotic low-frequency gain but increased the asymptotic high-frequency gain in V0-10 (0.53 ± 0.10 vs. 1.74 ± 0.40 beats/min/Hz, P < 0.01) and V0-20 (0.79 ± 0.14 vs. 2.06 ± 0.47 beats/min/Hz, P < 0.001). These changes, which were observed under a minimal influence from sympathetic background tone, may reflect an increased contribution of the acetylcholine-sensitive potassium channel (IK,ACh) pathway after IVA, because the HR control via the IK,ACh pathway is faster and acts in the frequency range higher than the cAMP-mediated pathway.NEW & NOTEWORTHY Since ivabradine (IVA) inhibits hyperpolarization-activated cyclic nucleotide-gated channels, interactions among the sympathetic effect, vagal effect, and IVA can occur in the control of heart rate (HR). To remove the sympathetic effect, we estimated the transfer function from vagal nerve stimulation to HR under ß-blockade in anesthetized rats. IVA augmented the high-frequency dynamic gain during low- and moderate-intensity vagal nerve stimulation. Untethering the hyperpolarizing effect of acetylcholine-sensitive potassium channels after IVA may be a possible underlying mechanism.
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Antagonistas Adrenérgicos beta/farmacologia , Fármacos Cardiovasculares/farmacologia , Estimulação Elétrica , Frequência Cardíaca/efeitos dos fármacos , Canais Disparados por Nucleotídeos Cíclicos Ativados por Hiperpolarização/efeitos dos fármacos , Ivabradina/farmacologia , Nervo Vago/fisiologia , Animais , Pressão Arterial/efeitos dos fármacos , Pressão Arterial/fisiologia , AMP Cíclico/metabolismo , Canais de Potássio Corretores do Fluxo de Internalização Acoplados a Proteínas G/metabolismo , Frequência Cardíaca/fisiologia , Canais Disparados por Nucleotídeos Cíclicos Ativados por Hiperpolarização/metabolismo , Masculino , Canais de Potássio/efeitos dos fármacos , Canais de Potássio/metabolismo , Propranolol/farmacologia , RatosRESUMO
To generate a mouse glioblastoma model by genome editing, we introduced Cas9 protein and guide RNAs specific for Nf1, Pten, and Trp53 into the neonatal mouse forebrain by electroporation. We found a high incidence (approximately 90%) of glial tumor development, including glioblastomas, 15 weeks later. The histological features of the tumors were similar to those of diffuse gliomas and, in some cases, similar to human glioblastomas, with microvascular proliferation (glomeruloid structure). In addition, unlike glial fibrillary acidic protein (GFAP)-positive glioblastomas generated using a similar method in a previous model, the majority of tumor cells were positive for oligodendrocyte lineage transcription factor 2, but negative for GFAP and neurofilaments. One base pair insertions identical to those seen in a previous model were found around the target sequences in Nf1, Pten, and Trp53, and additional deletions were found only in Pten. Considering that the histological characteristics were different from those seen in the previous model, our new model provides an additional research tool to investigate the early stages of glioblastoma development.
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Ivabradine is a selective bradycardic agent that reduces the heart rate (HR) by inhibiting the hyperpolarization-activated cyclic nucleotide-gated channels. Although its cardiovascular effect is thought to be minimal except for inducing bradycardia, ivabradine could interact with cardiovascular regulation by the autonomic nervous system. We tested whether ivabradine modifies dynamic characteristics of peripheral vagal HR control. In anesthetized Wistar-Kyoto rats (n = 7), the right vagal nerve was sectioned and stimulated for 10 min according to a binary white noise sequence with a switching interval of 500 ms. The efferent vagal nerve stimulation (VNS) trials were performed using three different rates (10, 20, and 40 Hz), and were designated as V0-10, V0-20, and V0-40, respectively. The transfer function from the VNS to the HR was estimated before and after the intravenous administration of ivabradine (2 mg/kg). Ivabradine increased the asymptotic dynamic gain in V0-20 [from 3.88 (1.78-5.79) to 6.62 (3.12-8.31) beats·min-1·Hz-1, P < 0.01, median (range)] but not in V0-10 or V0-40. Ivabradine increased the corner frequency in V0-10 [from 0.032 (0.026-0.041) to 0.064 (0.029-0.090) Hz, P < 0.01] and V0-20 [from 0.040 (0.037-0.056) to 0.068 (0.051-0.100) Hz, P < 0.01] but not in V0-40. In conclusion, ivabradine augmented the dynamic HR response to moderate VNS. At high VNS, however, ivabradine did not significantly augment the dynamic HR response, possibly because ivabradine reduced the baseline HR and limited the range for the bradycardic response to high VNS.NEW & NOTEWORTHY Ivabradine is considered to be a pure bradycardic agent that has little effect on cardiovascular function except inducing bradycardia. The present study demonstrated that ivabradine interacts with the dynamic vagal heart rate control in a manner that augments the heart rate response to moderate-intensity efferent vagal nerve stimulation.
Assuntos
Antiarrítmicos/administração & dosagem , Frequência Cardíaca/efeitos dos fármacos , Coração/inervação , Ivabradina/administração & dosagem , Estimulação do Nervo Vago , Nervo Vago/fisiologia , Administração Intravenosa , Anestesia Geral , Animais , Masculino , Ratos Endogâmicos WKY , Fatores de TempoRESUMO
Although heart rate (HR) is governed by the sympathetic and parasympathetic nervous systems, a head-to-head comparison of the open-loop dynamic characteristics of the total arc from a baroreceptor pressure input to the HR response has yet to be performed. We estimated the transfer function from carotid sinus pressure input to the HR response (HCSPâHR) before and after bilateral vagotomy (n = 7) as well as before and after the administration of a ß-blocker propranolol (n = 8) in anesthetized male Wistar-Kyoto rats. The carotid sinus pressure was perturbed according to a Gaussian white noise signal so that the input power spectra were relatively flat between 0.01 and 1 Hz. The gain plot of HCSPâHR was V-shaped. Vagotomy reduced the dynamic gain at 1 Hz (0.0598 ± 0.0065 to 0.0025 ± 0.0004 beats·min-1·mmHg-1, P < 0.001) but not at 0.01 or 0.1 Hz. ß-Blockade reduced the dynamic gain at 0.01 Hz (0.247 ± 0.069 to 0.077 ± 0.017 beats·min-1·mmHg-1, P = 0.020) but not at 0.1 or 1 Hz. We also estimated the efferent limb transfer function from electrical vagal efferent stimulation to the HR response (HVNâHR) under ß-blockade conditions. We associated the model parameters of HVNâHR with the mean HR and the standard deviation of HR so that HVNâHR could be estimated based only on the HR data. We finally estimated the neural arc transfer function from a pressure input to efferent vagal nerve activity by dividing HCSPâHR by HVNâHR. The mathematically determined vagal neural arc showed derivative characteristics with its phase near zero radians at the lowest frequency.
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Frequência Cardíaca/fisiologia , Sistema Nervoso Simpático/fisiologia , Nervo Vago/fisiologia , Animais , Barorreflexo , Pressão Sanguínea/fisiologia , Estimulação Elétrica , Masculino , Modelos Biológicos , Neurônios Eferentes , Propranolol , Ratos , Ratos Endogâmicos WKYRESUMO
Escherichia coli O157:H7 and Salmonella enterica subsp. enterica are the pathogens that frequently cause foodborne illness. Bacteriophage applications have been proposed as effective for preventing food contamination caused by these pathogenic bacteria. Escherichia phage KIT03 was isolated from the soil of a poultry farm in Kyoto, Japan. KIT03 can infect Escherichia coli O157:H7 and Salmonella enterica serotypes Choleraesuis and Enteritidis. One-step growth analysis revealed that KIT03 can propagate within its initial host (E. coli NBRC 3972), E. coli O157:H7 and S. Choleraesuis with an approximate burst size of 39, 51 and 37 phage particles per infected cell, respectively. The morphological type and genome annotation suggested that KIT03 belongs to the family Myoviridae, subfamily Tevenvirinae, genus Tequatrovirus. In vitro challenge tests demonstrated that KIT03 can lyse the tested bacteria and suppress their growth. Based on the susceptibility test and adsorption assay of KIT03 with E. coli K-12 BW25113 mutants, it was proposed that KIT03 may recognise and infect bacteria with a deficient outer core of lipopolysaccharides.
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Escherichia coli O157/virologia , Myoviridae/isolamento & purificação , Myoviridae/fisiologia , Salmonella enterica/virologia , Animais , Escherichia coli/genética , Escherichia coli/virologia , Microbiologia de Alimentos , Doenças Transmitidas por Alimentos/microbiologia , Genoma Viral/genética , Japão , Lipopolissacarídeos/genética , Myoviridae/classificação , Myoviridae/genética , Filogenia , Aves Domésticas/microbiologiaRESUMO
It is well-known that a strange flavor, known as off-flavor, might be found in various food products. Even though these substances do not affect our body directly, they can cause a significant change in food flavor and smell, thereby lowering the quality of food products. A well-known example of off-flavor is the transfer of smell from one food product to another. We have previously studied how the smell of limonene, a flavor component of orange juice in paper cartons, is transferred from unopened packages to milk stored in paper cartons, and have confirmed cases where the milk develops a smell completely different from that of limonene. This smell was also confirmed to not have originated from orange juice, and was found to be similar to that of a halogenated phenol. This study aimed to identify this odor component, and our findings indicate the off-flavor component to be 2-iodo-4-methylphenol.
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Contaminação de Alimentos/análise , Iodobenzenos/análise , Leite/química , Animais , Análise de Alimentos , Odorantes/análiseRESUMO
Although diabetes mellitus (DM) is a major risk factor for cardiovascular diseases, changes in open-loop static and dynamic characteristics of the arterial baroreflex in the early phase of DM remain to be clarified. We performed an open-loop systems analysis of the carotid sinus baroreflex in type 1 DM rats 4 to 5 wk after intraperitoneal streptozotocin injection ( n = 9) and we compared the results with control rats ( n = 9). The operating-point baroreflex gain was maintained in the DM rats compared with the control rats (2.07 ± 0.67 vs. 2.66 ± 0.22 mmHg/mmHg, P = 0.666). However, the range of arterial pressure (AP) control was narrower in the DM than in the control group (48.0 ± 5.0 vs. 77.1 ± 4.5 mmHg, P = 0.001), suggesting that the reserve for AP buffering is lost in DM. Although baroreflex dynamic characteristics were relatively preserved, coherences were lower in the DM than in the control group. The decreased coherence in the neural arc may be related to the narrowed quasi-linear range in the static relationship between carotid sinus pressure and sympathetic nerve activity in the DM group. Although the reason for the decreased coherences in the peripheral arc and the total reflex arc was inconclusive, the finding may indicate a loss of integrity of the baroreflex-mediated sympathetic AP control in the DM group. The derangement of the baroreflex dynamic characteristics is progressing occultly in this early stage of type 1 DM in a manner where dynamic gains are relatively preserved around the normal operating point.
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Pressão Arterial , Barorreflexo , Seio Carotídeo/inervação , Diabetes Mellitus Experimental/fisiopatologia , Diabetes Mellitus Tipo 1/fisiopatologia , Neuropatias Diabéticas/fisiopatologia , Estreptozocina , Sistema Nervoso Simpático/fisiopatologia , Animais , Diabetes Mellitus Experimental/induzido quimicamente , Diabetes Mellitus Tipo 1/induzido quimicamente , Neuropatias Diabéticas/induzido quimicamente , Masculino , Modelos Neurológicos , Ratos Endogâmicos WKY , Fatores de TempoRESUMO
Low blood flow velocity in the left atrial appendage (LAA) indicates a high risk of thromboembolism. Although transesophageal echocardiography (TEE) has been the standard method with which to evaluate the LAA blood flow velocity, a clinically noninvasive method is desired. We hypothesized that the ratio of the Hounsfield unit (HU) density at two distinct points within the LAA represents the blood flow velocity in the LAA. We retrospectively investigated 60 consecutive patients with atrial fibrillation (paroxysmal type, n = 29) who underwent enhanced computed tomography (CT) and TEE. The peak emptying flow velocity in the LAA (LAAPV) was evaluated using TEE. HU density was measured at proximal and distal sites of the LAA (LAAp and LAAd) on CT images. The LAAd/LAAp ratio was correlated with the LAAPV (P < 0.01, r = 0.69). Among several indices, the HU ratio was the most significant parameter associated with the LAAPV (ß = 0.469, CI 28.602-68.286, P < 0.001). Receiver-operating characteristic analysis (area under the curve, 0.91) demonstrated that an HU density ratio cutoff of 0.32 discriminated a low LAAPV (<25 cm/s) with sensitivity of 90% and specificity of 84%. Flow velocity of the LAA can be estimated by the HU density ratio at distal and proximal sites within the LAA. Our method might be a feasible substitution for TEE to discriminate patients with a reduced LAAPV.
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Apêndice Atrial/fisiopatologia , Fibrilação Atrial/diagnóstico por imagem , Fibrilação Atrial/fisiopatologia , Velocidade do Fluxo Sanguíneo , Idoso , Ecocardiografia Transesofagiana , Feminino , Humanos , Japão , Modelos Lineares , Modelos Logísticos , Masculino , Pessoa de Meia-Idade , Curva ROC , Estudos Retrospectivos , Sensibilidade e Especificidade , Tomografia Computadorizada por Raios XRESUMO
PURPOSE: Acupuncture stimulation is known to act on the autonomic nervous system and elicits depressor and bradycardic effects. However, previous studies on humans did not conduct quantitative analyses on optimal acupuncture conditions such as the stimulation frequency and duration to achieve maximum depressor and bradycardic effects. The aim of the present study was to investigate the effects of varying stimulation frequencies of electroacupuncture on time-dependent changes in blood pressure and heart rate in humans. METHODS: Twelve healthy volunteers participated in the study. An acupuncture needle was inserted at the Ximen acupoint (PC4 according to WHO nomenclature), located at the anterior aspect of the forearm. An electrical stimulation was delivered through the acupuncture needle at an intensity of 1 V, pulse width of 5 ms, and stimulation frequencies of 0.5, 1, 5, and 10 Hz in a random order. The duration of electroacupuncture was 6 min, during which blood pressure and heart rate responses were monitored. RESULTS: Group-averaged data indicated that 1-Hz electroacupuncture decreased blood pressure and heart rate. Blood pressure was significantly decreased from the prestimulation baseline value of 86.6 ± 2.9 to 81.4 ± 2.3 mmHg during 4-6 min of 1-Hz electroacupuncture (mean ± SE, P < 0.01). Heart rate was also significantly decreased (from 66.2 ± 2.0 to 62.7 ± 1.7 beats/min, P < 0.01). CONCLUSIONS: These results provide fundamental evidence that bradycardiac and depressor responses are effectively produced by electrical acupuncture in humans.
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Pressão Sanguínea/fisiologia , Eletroacupuntura/métodos , Frequência Cardíaca/fisiologia , Sistema Nervoso Autônomo/fisiologia , Bradicardia/fisiopatologia , Feminino , Humanos , Masculino , Adulto JovemRESUMO
PURPOSE: To provide an initial retrospective evaluation of early postoperative outcomes after wavefront-guided myopic LASIK using a new-generation Hartmann-Shack wavefront sensor. METHODS: A noncomparative, retrospective study of 243 eyes of 126 patients that underwent primary wavefront-guided LASIK, using wavefront data obtained with a new Hartmann-Shack aberrometer (iDesign Advanced WaveScan aberrometer; Abbott Medical Optics, Inc., Santa Ana, CA). Visual acuity, refraction, and patient satisfaction were evaluated 1 month after surgery. RESULTS: The manifest spherical equivalent was reduced from -3.28 ± 1.79 diopters (D) (range: -9.88 to -0.38 D) before surgery to -0.03 ± 0.29 D (range: -1.00 to +1.25 D) 1 month after surgery. The manifest spherical equivalent was within 0.50 and 1.00 D of target in 93.0% and 99.6% of eyes, respectively. Manifest astigmatism preoperatively (-0.72 ± 0.67 [range: 0.0 to -5.00 D]) was reduced to -0.14 ± 0.20 (range: 0.0 to -1.00 D) at 1 month and the vector-derived correction ratio (surgically induced refractive change/intended refractive correction) was 1.02 ± 0.30. Uncorrected distance visual acuity of 20/16, 20/20, and 20/25 or better was achieved in 79.0%, 93.4%, and 96.7% of eyes, respectively. No eyes lost two or more lines of corrected distance visual acuity, whereas a gain of one or more lines was observed in 14.0%. Most patients (98.5%) reported that they were satisfied with the outcome of their procedure. CONCLUSIONS: Wavefront-guided LASIK using the new aberrometer in this retrospective evaluation was effective, safe, and predictable in the early postoperative time period for the correction of myopia with high patient satisfaction.
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Aberrometria , Córnea/fisiopatologia , Ceratomileuse Assistida por Excimer Laser In Situ/métodos , Lasers de Excimer/uso terapêutico , Miopia/cirurgia , Cirurgia Assistida por Computador , Adolescente , Adulto , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Miopia/fisiopatologia , Satisfação do Paciente , Refração Ocular/fisiologia , Estudos Retrospectivos , Inquéritos e Questionários , Resultado do Tratamento , Acuidade Visual/fisiologia , Adulto JovemRESUMO
BACKGROUND: To identify a pharmacological agent that can selectively activate cardiac vagus nerve for potential use in vagal activation therapy against heart failure, the effects of medetomidine on autonomic nerve activities in both the heart and stomach were examined. METHODS AND RESULTS: In anesthetized rabbits, microdialysis probes were implanted into both the right atrial and gastric walls. Dialysate acetylcholine (ACh) and norepinephrine (NE) concentrations were measured by high-performance liquid chromatography. First, the effects of 100µg/kg of intravenous medetomidine on vagal ACh and sympathetic NE releases were examined. Medetomidine significantly increased cardiac ACh release (4.7±1.1 to 7.8±0.9nmol/L, P<0.05), but suppressed gastric ACh release (8.0±2.6 to 3.5±1.5nmol/L, P<0.01). In contrast, medetomidine suppressed both cardiac and gastric NE releases. Second, the effects of medetomidine on ACh releases induced by electrical vagus nerve stimulation (VNS; 10Hz) were examined. Electrical VNS significantly increased both cardiac (6.7±1.2 to 14.8±1.8nmol/L, P<0.01) and gastric (3.8±0.8 to 181.3±65.6nmol/L, P<0.01) ACh releases. Medetomidine did not alter the VNS-induced increases in ACh release. CONCLUSIONS: Medetomidine suppresses both cardiac and gastric sympathetic nerve activities. In contrast, medetomidine activates cardiac vagus nerve but inhibits gastric vagal activity. Medetomidine might be one of the potential pharmacological agents for vagal activation therapy against heart failure without the risk of gastric adverse effects.
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Agonistas de Receptores Adrenérgicos alfa 2/farmacologia , Coração/inervação , Medetomidina/farmacologia , Estômago/inervação , Sistema Nervoso Simpático/fisiopatologia , Nervo Vago/fisiopatologia , Acetilcolina/metabolismo , Animais , Mucosa Gástrica/metabolismo , Coração/fisiopatologia , Norepinefrina/metabolismo , Coelhos , Estômago/fisiopatologia , Sistema Nervoso Simpático/metabolismo , Nervo Vago/metabolismoRESUMO
Aligning spawning timing with seasonal environmental changes is critical for both terrestrial and aquatic organisms. However, mechanisms to regulate reproductive activity in response to environmental factors are not well understood, partly owing to the technical difficulty in maintaining detailed long-term observational data of the reproductive activities in the same population across years. In this study, we present an application of the aquarium system to examine the long-term spawning properties of corals. Spawning records over a 15-year period at the Okinawa Churaumi Aquarium revealed that the spawning timing of Acropora corals in aquarium tanks aligned well with that of wild corals from a neighbouring reef. Using the aquarium population as a model, we investigated the relationship between key environmental factors and the timing of the first and peak spawning dates of Acropora corals during a 15-year period. The results suggest that the spawning window of each spawning season is largely influenced by the water temperature and that the timing of peak spawning can be fine-tuned in response to environmental fluctuations. This behavioural feature can prevent synchronous spawning events during unfavourable environmental conditions and increase long-term reproductive reliability.
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Autologous skin grafting is a standard treatment for skin defects such as burns. No artificial skin substitutes are functionally equivalent to autologous skin grafts. The cultured epidermis lacks the dermis and does not engraft deep wounds. Although reconstituted skin, which consists of cultured epidermal cells on a synthetic dermal substitute, can engraft deep wounds, it requires the wound bed to be well-vascularized and lacks skin appendages. In this study, we successfully generate complete skin grafts with pluripotent stem cell-derived epidermis with appendages on p63 knockout embryos' dermis. Donor pluripotent stem cell-derived keratinocytes encroach the embryos' dermis by eliminating p63 knockout keratinocytes based on cell-extracellular matrix adhesion mediated cell competition. Although the chimeric skin contains allogenic dermis, it is engraftable as long as autologous grafts. Furthermore, we could generate semi-humanized skin segments by human keratinocytes injection into the amnionic cavity of p63 knockout mice embryos. Niche encroachment opens the possibility of human skin graft production in livestock animals.
Assuntos
Derme , Queratinócitos , Camundongos Knockout , Transplante de Pele , Animais , Transplante de Pele/métodos , Queratinócitos/citologia , Queratinócitos/transplante , Humanos , Derme/citologia , Derme/transplante , Camundongos , Epiderme/metabolismo , Células-Tronco Pluripotentes/citologia , Células-Tronco Pluripotentes/transplante , Pele Artificial , Células Epidérmicas/transplante , Células Epidérmicas/citologia , Matriz Extracelular/metabolismo , Pele/citologiaRESUMO
Although suppression of sympathetic activity is suggested as one of the underlying mechanisms for the cardioprotective effects afforded by sodium-glucose cotransporter 2 (SGLT2) inhibitors, whether the modulation of glucose handling acutely affects sympathetic regulation of arterial pressure remains to be elucidated. In Goto-Kakizaki diabetic rats, we estimated the open-loop static characteristics of the carotid sinus baroreflex together with urine glucose excretion using repeated 11-min step input sequences. After the completion of the 2nd sequence, an SGLT2 inhibitor empagliflozin (10 mg kg-1) or vehicle solution was administered intravenously (n = 7 rats each). Empagliflozin did not significantly affect the baroreflex neural or peripheral arc, despite significantly increasing urine glucose excretion (from 0.365 ± 0.216 to 8.514 ± 0.864 mg·min-1·kg-1, P < 0.001) in the 7th and 8th sequences. The possible sympathoinhibitory effect of empagliflozin may be an indirect effect associated with chronic improvements in renal energy status and general disease conditions.
Assuntos
Barorreflexo , Diabetes Mellitus Experimental , Ratos , Animais , Barorreflexo/fisiologia , Diabetes Mellitus Experimental/tratamento farmacológico , Pressão Arterial , Glucose , Pressão Sanguínea/fisiologiaRESUMO
In contrast to a second dose of the SARS-CoV-2 mRNA vaccine, a third dose elicits potent neutralizing activity against the Omicron variant. To address the underlying mechanism for this differential antibody response, we examined spike receptor-binding domain (RBD)-specific memory B cells in vaccinated individuals. Frequency of Omicron-reactive memory B cells increased â¼9 mo after the second vaccine dose. These memory B cells show an altered distribution of epitopes from pre-second memory B cells, presumably due to an antibody feedback mechanism. This hypothesis was tested using mouse models, showing that an addition or a depletion of RBD-induced serum antibodies results in a concomitant increase or decrease, respectively, of Omicron-reactive germinal center (GC) and memory B cells. Our data suggest that pre-generated antibodies modulate the selection of GC and subsequent memory B cells after the second vaccine dose, accumulating more Omicron-reactive memory B cells over time, which contributes to the generation of Omicron-neutralizing antibodies elicited by the third vaccine dose.